Hematologic diseases

To the Editor: The recent "New Drugs, Old Drugs" review of low molecular weight heparins (LMWH) and heparinoids1 provides a timely reminder of the limitations of studies that support the use of these agents in preventing venous thromboembolism (VTE), particularly in orthopaedic surgery. A new class of anticoagulants has recently been released in Australia and is being promoted as being more effective than LMWH in preventing VTE. However, while several randomised controlled trials suggest that fondaparinux reduces the risk of asymptomatic deep vein thrombosis (DVT) in patients undergoing hip and knee replacement surgery,2,3 there is currently no evidence to suggest that it reduces the risk of symptomatic VTE. Fondaparinux is a synthetic penta-saccharide that selectively binds to antithrombin III, enhancing the neutralisation of factor Xa and inhibiting generation of thrombin and subsequent clot formation.2 Unlike LMWH, fondaparinux does not appear to affect platelet function, thus potentially reducing bleeding tendencies and avoiding the risk of immune-mediated thrombocytopenia. The main problem facing researchers who study VTE prophylaxis in patients undergoing orthopaedic surgery is that, while asymptomatic DVT is common, symptomatic VTE is rare. The rate of fatal pulmonary embolism in patients undergoing hip replacement surgery is 0.1%–0.2% in those who receive no prophylaxis.4 Trials to demonstrate a reduction in symptomatic VTE are not performed because huge sample sizes are required to show a statistically significant difference in outcome (50 000 patients would need to be enrolled in a trial to show a reduction in the rate of fatal pulmonary embolism from 0.2% to 0.1% with 80% power). If such a difference could be shown, it would probably be clinically irrelevant to an orthopaedic surgeon performing 50 joint replacements a year. Although asymptomatic DVT is used as a surrogate endpoint for trials that support VTE prophylaxis, the natural history of asymptomatic DVT is poorly documented. There is some evidence to suggest that asymptomatic DVT is not associated with an increased risk of subsequent chronic venous insufficiency,5 and the association between asymptomatic DVT and subsequent clot propagation and embolisation is not well established. Further information on the natural history of asymptomatic DVT must be obtained before the clinical relevance of results from current studies of VTE prophylaxis can be determined. Until then, the clinical relevance of studies comparing the use of "new drugs" with "old drugs" in preventing VTE in orthopaedic surgery cannot be assessed.

Owen D Williamson · Alison M. Street

In reply: Walters and Graham question the role of low-molecular-weight heparin (LMWH) as a replacement for unfractionated heparin during pregnancy, and cite the lack of randomised comparisons to support their view that the standard initial treatment for pulmonary embolism during pregnancy remains intravenous unfractionated heparin. We do not deny the lack of clinical trials of LMWH in pregnancy; we were simply referring to the increased use of LMWH.1,2 However, the lack of evidence of effectiveness does not equate with evidence of lack of effectiveness of LMWH in pregnancy. Clinical trials are needed to determine optimal anticoagulant strategies during pregnancy, particularly in patients with prosthetic heart valves. While awaiting the results of these trials, we believe that the major pharmaco-kinetic and safety advantages of LMWH over unfractionated heparin, coupled with an extensive body of evidence demonstrating their efficacy and safety in non-pregnant patients, should not be ignored in our pursuit of optimal anticoagulation therapies. Williamson and Street question the validity of asymptomatic deep vein thrombosis as a surrogate for symptomatic venous thromboembolism in patients undergoing major orthopaedic surgery. Further, they cite a 0.1%–0.2% incidence of pulmonary embolism in patients undergoing hip replacement surgery without prophylaxis3 to support the conclusion that any effect of thromboprophylaxis on reducing symptomatic events is likely to be irrelevant for individual orthopaedic surgeons. We believe that their argument is seriously flawed. Firstly, the "meta-analysis" they cite3 had major methodological limitations, as elegantly highlighted by "Sherlock Holmes" in his critical appraisal of systematic reviews of surgical thromboprophylaxis.4 Secondly, rigorously conducted randomised trials and meta-analyses of randomised trials have demonstrated the efficacy of antithrombotic therapy for the prevention of both symptomatic and fatal venous thromboembolism in high-risk surgical patients, including lower-limb orthopaedic surgery.5,6 Thirdly, the clear correlation between reduction in asymptomatic and symptomatic venous thromboembolism in patients undergoing elective joint replacement surgery7 suggests that asymptomatic thrombosis detected by screening venography is a valid surrogate for symptomatic events. Fourthly, we agree that an individual orthopaedic surgeon performing 50 joint replacements per year may remain unaware of a small reduction in fatal pulmonary emboli in his or her own practice (eg, a 0.1% absolute risk reduction would be equivalent to preventing one death in 20 years of practice). Yet, on a population basis, even a 0.1% absolute reduction (which is likely to be an underestimate — the PEP study showed a 0.3% absolute reduction in fatal pulmonary embolism with aspirin5) equates to 50 preventable deaths per year in Australia alone8 and many thousands worldwide. There is now overwhelming evidence of the efficacy of thromboprophylaxis for preventing venous thromboembolism, including symptomatic and fatal pulmonary embolism, in high-risk surgical patients. With the rapid ageing of the Australian population and the expected increase in joint replacement surgery in coming years,9 the failure to use effective thromboprophylaxis in orthopaedic patients will likely result in a growing burden of preventable morbidity and mortality from venous thromboembolism.

John W Eikelboom · Graeme J Hankey

Objectives: To estimate the appropriateness of transfusions of platelets, fresh frozen plasma (FFP) and cryoprecipitate using National Health and Medical Research Council and Australasian Society for Blood Transfusion guidelines (NHMRC/ASBT 2002).Design and setting: Three separate retrospective surveys of medical records from 1 January to 31 August 2000 (1147 transfused patients) from 14 hospitals selected randomly from all public hospitals that use these blood products in New South Wales: five tertiary referral, five major metropolitan, and four major rural (base) hospitals.Main outcome measures: Proportion of potentially inappropriate transfusions.Results: 33% (136/414) of platelet, 37% (248/669) of FFP and 62% (37/60) of cryoprecipitate transfusions were assessed as inappropriate. By hospital type, 29% (75/259) of platelet transfusions were inappropriate at tertiary referral hospitals, 51% (40/78) at major urban hospitals, and 27% (21/79) at major rural hospitals. For FFP, 36% (112/313), 37% (80/216) and 39% (55/140) were inappropriate for referral, urban and rural hospitals, respectively. Cryoprecipitate was used almost exclusively at tertiary referral hospitals.Conclusions: In terms of the NHMRC/ASBT guidelines on use of blood products, there is considerable inappropriate transfusion of platelets, FFP and cryoprecipitate in NSW public hospitals.

William N Schofield MA, DipEdPsych · George L Rubin FAFPHM, FACR · Mark G Dean FRACP, FRCPA

Objective: To determine the incidence and appropriateness of use of allogenic packed red blood cell (RBC) transfusion in Australian and New Zealand intensive care practice.Setting: Intensive care units of 18 Australian and New Zealand hospitals: March 2001.Design: Prospective, observational, multicentre study.Methods: All admissions to participating intensive care units were screened and all patients who received a transfusion of RBC were enrolled. The indications for transfusion were recorded and compared with Australian National Health and Medical Research Council guidelines. Transfusions conforming to these guidelines were deemed appropriate.Main outcome measures: RBC transfusion in intensive care and transfusion appropriateness.Results: 1808 admissions to intensive care units were screened: 357 (19.8%) admissions (350 patients) received an RBC transfusion while in intensive care. Overall, 1464 RBC units were administered in intensive care on 576 transfusion days. The most common indications for transfusion were acute bleeding (60.1%; 880/1464) and diminished physiological reserve (28.9%; 423/1464). The rate of inappropriate transfusion was 3.0% (44/1464). Diminished physiological reserve with haemogloblin level ≥ 100 g/L was the indication in 50% (22/44) of inappropriate transfusions; no indication was provided for 31% (15/44).Conclusion: The rate of inappropriate transfusion in Australian and New Zealand intensive care units in 2001 was remarkably low.

and the ANZICS Clinical Trials Group*

Rheumatoid arthritis is a common disorder. Its various articular and extra-articular manifestations are well described, but less well known is the association between rheumatoid arthritis and malignancy. There is an intrinsic risk of lymphoma, particularly non-Hodgkin's lymphoma, in rheumatoid arthritis. In determining causality, it is difficult to separate the effects of treatment from those of the disease itself — most patients with rheumatoid arthritis are treated with more than one immunosuppressive agent during the course of their disease. Cyclosporin has been implicated in the development of lymphoma, predominantly in association with transplantation.1,2 In addition, there are an increasing number of reports of B-cell lymphomas in rheumatoid arthritis patients that would seem to implicate methotrexate.3-10 Clinical recordA 63-year-old white man with seropositive rheumatoid arthritis presented to our outpatient clinic with a 4-week history of right hip and buttock discomfort. He described a deep ache, with no radiation. The pain was worse on weight-bearing and during the night. He had had mild fevers, and had lost 7 kg in weight over the previous 2 months. His rheumatoid arthritis had been difficult to control in the 10 years since the initial diagnosis, and at the time of presentation his medications were methotrexate 20 mg weekly, cyclosporin 125 mg twice daily, sulfasalazine 1 g three times daily, and hydroxychloroquine 200 mg daily. He does not have Sjögren's syndrome. Intercurrent medical conditions included bronchiectasis since childhood and interstitial lung disease secondary to rheumatoid arthritis. Examination revealed painful restriction of movement of the right hip and swelling of the right buttock. Mild synovitis was present in the hands, shoulders, neck and knees. He also had clubbing, bilateral basal crepitations and splenomegaly (all longstanding). There was no lymphadenopathy. The erythrocyte sedimentation rate and C-reactive protein level were elevated at 84 mm/h (normal range, 0–14 mm/h) and 100 mg/L (normal range, < 10 mg/L), respectively. He had normocytic anaemia, with a haemoglobin level of 103 g/L (normal range, 130–180 g/L). His white cell count and platelet count were normal, as were liver function test results and electrolyte levels. His creatinine level had risen from 110 mol/L to 180 mol/L (normal range, 50–90 mol/L) over 3 months. Cyclosporin was stopped because of his worsening renal function. Radiography of his hips, pelvis and lumbosacral spine revealed mild degenerative changes only. A bone scan showed increased uptake in the region of the right buttock, right sacroiliac joint and the superior aspect of the right acetabulum. Computed tomography (CT) scan revealed diffuse swelling involving the right gluteus medius and piriformis muscles (Box, Figure 1). Magnetic resonance imaging (Box, Figure 2) confirmed these findings, but also showed swelling of the obturator internus and part of the gluteus maximus muscles, as well as some increased signal in the right iliac bone seen on T1-weighted images. Tissue from the right gluteus medius muscle was obtained by open biopsy. Histological examination revealed diffuse infiltration of malignant lymphoid cells (Box, Figure 3), with positive immunoperoxidase staining for the leukocyte common antigens CD20 and CD79. A diagnosis of diffuse large B-cell, non-Hodgkin's lymphoma was made. Staging (CT of the chest, abdomen and pelvis; bone marrow biopsy; and gallium scanning) revealed no other sites of lymphoma. Serological tests for HIV gave negative results. The malignant cells were negative for Epstein–Barr virus DNA by polymerase chain reaction. When the diagnosis was established, methotrexate was also stopped. The patient presented for CHOP-based chemotherapy (cyclophosphamide, adriamycin, vincristine, prednisolone) 19 days later (2 months after he stopped taking cyclosporin). The palpable swelling of the right buttock had disappeared, and a repeat CT scan confirmed resolution of the previously diffuse muscle swelling (Box, Figure 4). Chemotherapy was withheld. Fifteen months later, there has been no recurrence. His rheumatoid arthritis flared when he was taking sulfasalazine and hydroxychloroquine, and is being managed with combination corticosteroids and non-steroidal anti-inflammatory medication. DiscussionPatients with rheumatoid arthritis have been reported to have a two- to threefold increased risk of lymphatic cancer (eg, non-Hodgkin's and Hodgkin's lymphoma).3,4 The suggestion that disease-modifying drugs further increase this risk is controversial, as it is difficult to match patients for disease severity. Disease activity may, in itself, be a risk factor for development of lymphoma,5 and, because more potent immunosuppressive agents are used in more severe disease, there may not be a true relationship between treatments and lymphoma. However, lymphoma in patients taking cyclosporin in association with transplantation is well described, with a 28-times-higher prevalence.1 There is a predominance of non-Hodgkin's lymphoma, and suggestive evidence that Epstein–Barr virus plays a role in the aetiology of some of these lymphomas, with documented remission on reduction or cessation of the immunosuppressive therapy.2 There are an increasing number of reports of lymphoma in patients treated with methotrexate for rheumatoid arthritis.6-8 Extranodal involvement is common, occurring in 69% of cases, although, in contrast to findings in AIDS patients and patients having transplantation, high frequencies of brain involvement have not been found.6 The predominant lymphoma type is large B-cell, non-Hodgkin's lymphoma. Epstein–Barr virus has been found in the lymphoma cells in 41% of cases.6 The strongest causal link is spontaneous lymphoma remission after stopping methotrexate. This has been documented in at least 15 patients with rheumatoid arthritis,6-8 with remission occurring within 4 weeks of stopping the drug. Therefore, a period of observation without immunosuppressive treatment is mandatory. Given the widespread use of methotrexate in rheumatoid arthritis, the number of reported cases is small. The increased risk of lymphoma in rheumatoid arthritis patients treated with methotrexate is probably real, but it is a low risk. It has been suggested that this effect of methotrexate and of cyclosporin occurs only in the subgroup of rheumatoid arthritis patients who already have severely disturbed immunity.7,9,10 Immunosuppressive treatment may lead to even poorer oncogenic surveillance and the survival of a malignant clone. As combination therapy, such as methotrexate and cyclosporin, becomes more widespread, physicians will have to be more aware of the potential for lymphoma. Competing interestsNone identified. Imaging and histological examination of the right gluteal region of a man with rheumatoid arthritis 1: CT scan, showing diffuse swelling of the right gluteus medius and piriformis muscles. 2: MRI (T1-weighted), showing diffuse swelling of the right gluteus medius, piriformis and gluteus maximus muscles (also increased signal in the right iliac bone). 3: Histological examination of tissue from gluteus medius, showing cords of intermediate to large malignant lymphoid cells infiltrating skeletal muscle and fat. 4: CT scan 3 weeks after stopping immunosuppressive therapy, showing spontaneous resolution of the previous swelling of the right gluteus medius muscle.

Irwin G S Lim MB BS · James V Bertouch MB BS, MD, FRACP

Several low molecular weight (LMW) heparin preparations, including dalteparin, enoxaparin and nadroparin, as well as the heparinoid danaparoid sodium, are approved for use in Australia. LMW heparins are replacing unfractionated heparin for the prevention and treatment of venous thromboembolism and the treatment of non-ST-segment-elevation acute coronary syndromes. The advantages of LMW heparins over unfractionated heparin include a longer half-life (allowing once-daily or twice-daily subcutaneous dosing), high bioavailability and predictable anticoagulant response (avoiding the need for dose adjustment or laboratory monitoring in most patients), and a low risk of heparin-induced thrombocytopenia and osteoporosis. Laboratory monitoring of LMW heparin therapy should be considered in newborns and children, patients with renal impairment, those who are pregnant, and those at the extremes of bodyweight (eg, < 40 kg or > 100 kg). LMW heparins should: ■ be avoided or used with caution in patients undergoing neuraxial anaesthesia, owing to the potential for epidural haematoma formation; ■ not be used (ie, are contraindicated) in patients with immune heparin-induced thrombocytopenia, as they may cross-react with anti-heparin antibodies. Conventional unfractionated heparin retains a role in the management of patients at high risk of bleeding, undergoing invasive procedures, and patients with renal failure owing to its shorter half-life, reversibility with protamine sulfate, and extrarenal metabolism. The heparinoid danaparoid sodium is effective for the treatment of heparin-induced thrombocytopenia.

John W Eikelboom MB BS, MSc, FRACP, FRCPA · Graeme J Hankey MB BS, MD, FRCP, FRCP(Edin), FRACP

To the Editor: The Australian Red Cross Blood Service (ARCBS) introduced a national policy for therapeutic venesection in December 1999 which allows the collection of blood from people with haemochromatosis. There is no charge for this service. The policy outlines the principles under which ARCBS provides a therapeutic venesection service, conditions of management of the donors and the acceptability of the donations for clinical use.1 These conditions are: The patient's condition benefits from regular venesection and the patient does not have a transfusion-transmissible disease. The blood donation will be used in clinical or derivative products only if the donors fully meet the donor selection guidelines for clinical use. Responsibility for patient management remains with the referring physician. ARCBS is responsible for the collection and for ensuring donor safety during the procedure. We will liaise with referring physicians about the venesection protocol if necessary, and reserve the right to refuse to venesect if there is a concern for donor safety. A diagnosis of hereditary haemochromatosis (evidence of iron overload together with appropriate genetic studies2) is required before patients are accepted into the therapeutic venesection program. Contact your local ARCBS for copies of the therapeutic request form. Completion of this will facilitate the entry of people to the ARCBS therapeutic program. The full policy can be obtained from our website <www.arcbs.redcross.org.au>.

Margaret L Buring

To the Editor: I wish to report a case of quinine-induced disseminated intravascular coagulation (DIC) and haemolytic–uraemic syndrome (HUS). A 78-year-old woman presented with nausea, vomiting, diarrhoea, fever and confusion three hours after taking 150 mg of quinine for leg cramps. Five months earlier she had been admitted overnight for similar symptoms after quinine ingestion, her symptoms resolving over 12 hours without sequelae. Before this she had ingested quinine infrequently for the preceding five years without complication. Her past history included hypertension, hypercholesterolaemia and glaucoma; medications were simvastatin, lisinopril and latanoprost eye drops. On presentation her temperature was 40ºC, blood pressure was 150/90 mmHg; physical examination was otherwise unremarkable. Initial investigations showed serum creatinine concentration, 0.11 mmol/L (reference range, 0.05–0.10 mmol/L); platelet count, 124 × 109/L (reference range, 150–400 × 109/L); prothrombin time, 21.2 seconds (reference range, 11s–16s); activated partial thromboplastin time, 66.3 seconds (reference range, 25s–42s); fibrinogen concentration, 2.1 g/L (reference range, 1.5–4.0 g/L); and D-dimer level, > 4.0 mg/L (reference range, < 0.35 mg/L). No haemolysis was present on the initial blood film. The patient rapidly developed oliguric renal failure, progressive coagulopathy and thrombocytopenia. There was no focus of infection, and blood, urine and faecal cultures were negative. Urine microscopy showed 3 × 106 leukocytes per litre (reference range, < 10 × 106/L), 270 × 106 erythrocytes per litre (reference range, < 10 × 106/L) and granular casts. Her urine output improved following infusions of saline, dopamine and high dose frusemide, but renal function continued to deteriorate. The coagulopathy had resolved by 48 hours after taking the quinine, but thrombocytopenia and renal function continued to worsen, with a platelet count of 18 × 109/L and a serum creatinine concentration of 0.58 mmol/L, evidence of haemolysis with fragmentation of red blood cells, elevated concentrations of lactate dehydrogenase (2450 U/L; reference range, 110–250 U/L) and bilirubin (32 µmol/L; reference range, < 20 µmol/L), and low haptoglobin concentration (< 0.06 g/L; reference range, 0.3–2.15 g/L), consistent with haemolytic–uraemic syndrome. The patient was treated with four cycles of plasma exchange with 3 L volumes, corticosteroids and two cycles of haemodialysis over 11 days. Renal function gradually improved, although the serum creatinine concentration remained elevated at 0.17 mmol/L two months later. The most common adverse reaction to quinine is thrombocytopenia. Six cases of DIC and 10 cases of HUS following quinine ingestion have been previously reported.1-5 This is the first report of both DIC and HUS occurring together after exposure to quinine. Many of the case reports describe multiple presentations before quinine was identified as the precipitant. It is important that prescribers are aware of this rare but serious reaction which may occur following exposure to quinine, and that a history of ingestion is sought in anyone presenting with otherwise unexplained DIC or HUS.

Andrew P Morton MB BS, FRACP

Clinical use of blood in medicine, obstetrics, paediatrics, surgery and anaesthesia, trauma and burns. Geneva: World Health Organization, 2001 (337 pp). ISBN 92 4 154538 0. This World Health Organization (WHO) publication is a result of collaboration between numerous experts from around the world. As the title suggests, the book is aimed at clinicians using blood products, and is not a specialised transfusion textbook. A pocket summary is also available (Clinical use of blood handbook. Geneva: World Health Organization, 2001; 219 pp. ISBN 92 4 15439 9), which contains the essential guidelines for transfusion practice. Being a WHO publication, the authors have had to ensure that the principles espoused are practical and can be implemented in a variety of settings depending on available resources. The book is well written, clearly set out and has excellent illustrations and summary boxes. It is easy to find specific subjects and “get to the meat” of an issue. The text is addressed to medical, nursing and scientific professionals and should be easily readable and understandable to all. This is a practical, procedure-oriented, “how to do” book, with introductory chapters on the principles of transfusion medicine and the basic physiology of blood. Each chapter has learning outcomes and exercises that direct the application of the theory and practice to individual circumstances. There are chapters dealing with replacement fluids, and the full range of blood products and their composition. The section covering the clinical procedures involved in getting the right product to the right patient at the right time, and potential adverse effects of transfusion, should be mandatory reading for all clinicians. The second half addresses each of the medical disciplines named in the title. All common indications for blood component therapy are addressed in theoretical and practical detail. Despite the enormous amount of material covered in its 337 pages (and the pocket summary) it does not suffer from the problems which bedevil some multiauthored works. It displays a uniformity of style, shows no repetition, and is relatively lightweight and readable. This is definitely not a book that should sit in the library collecting dust — it is a day-to-day manual for any professional involved in the provision and/or administration of blood and blood products. It is affordable, and readily accessible copies should be available in all clinical and laboratory settings. James IsbisterDepartment of Haematology Royal North Shore Hospital, St Leonards, NSW

James Isbister

We document the first case of the sickle-cell gene — Hb-S gene importation leading to Hb-S/β-thalassaemia double heterozygosity — in the apparently previously Hb-S gene-free setting of Papua New Guinea.

Evelyn K Lavu FRCPA · John D Vince MD, FRCP(UK) · Gilchrist Oswyn MMed(Child Health)

With our increased understanding of the molecular mechanisms of haematological disorders, it has become possible to target therapy precisely to the underlying defect. Targeted therapy can increase safety and potency, while causing fewer side effects than standard treatment. "Smart" drugs and gene therapy have recently shown great promise in a wide range of malignant haematological and coagulation disorders. Figure: Cytogenetic analysis showing ABL probe (red) on chromosome 9, BCR probe (green) on chromosome 22, and both probes on the Philadelphia chromosome, indicating the abnormal hybrid BCR-ABL gene. Chronic myeloid leukaemia.1 Since the Philadelphia chromosome was recognised over 40 years ago, the genetic changes that lead to chronic myeloid leukaemia (CML) have been progressively unravelled. A reciprocal translocation between chromosomes 9 and 22 creates a unique hybrid gene, BCR-ABL, which encodes a protein with tyrosine kinase activity. The abnormal gene is found in almost all patients with CML and can be detected routinely on cytogenetic analysis using fluorescent markers (Figure). The BCR-ABL protein confers on its host cell extended life span, disregard for marrow inhibitory signals and inevitable progression to a more malignant phenotype, clinically recognised as blast crisis. Imatinib is a specifically designed, highly targeted drug that blocks BCR-ABL tyrosine kinase action. At well tolerated oral doses, it eliminates the abnormal Philadelphia clone and dramatically normalises blood counts in almost all chronic-phase patients, as well as in most of those with advanced disease (accelerated phase and blast crisis). Remissions appear durable, although long term data are unavailable. While imatinib is not yet believed to cure CML, it could become initial therapy for all patients, including those who would otherwise have proceeded immediately to allogeneic stem-cell transplantation. Gene therapy in haemophilia.2 Much is already known about the genetic abnormalities, laboratory measurement and clinical course of haemophilia. This condition is an excellent model to demonstrate the feasibility of human gene transfer, as large clinical benefits can follow even small improvements in the level of clotting factors (eg, from less than 1% to 5% of factor VIII or IX). Factor VIII or IX genes have been successfully transferred in at least 29 people with haemophilia, using either skin, blood, muscle or liver cells transformed by various carrier vectors. All studies have demonstrated some clinical efficacy, with sustained improvement in factor level over a period, and reductions in bleeding symptoms and use of clotting-factor concentrate. However, concerns remain about the potential of the technique to alter the individual's genetic code, leading to cancer and transmission of changed genes to the next generation. "Magic bullet" therapy in non-Hodgkin's lymphoma.3 The CD20 antigen is a specific protein expressed in virtually all malignant B-cell lymphomas, but not non-lymphoid cells, normal early B lymphocytes or plasma cells. This antigen is the target for the monoclonal antibody rituximab, which has shown great clinical benefit in patients with non-Hodgkin's lymphoma. Around half of patients with relapsed or refractory low-grade, non-Hodgkin's lymphoma have a response to rituximab, which can last for over a year (median, 12 months). Because of its specificity, rituximab has side effects that are milder than and differ from those of other forms of chemotherapy. The main, but uncommon, problem is infusion-related fever, chills or wheeze. When rituximab is used in conjunction with standard chemotherapy as initial treatment for lymphoma, it improves response with virtually no added toxicity. Further benefit is seen in patients with refractory lymphoma, when radioactively tagged anti-CD20 antibody can be used to deliver targeted local radiation treatment. New anticoagulants.4,5 Anticoagulants have been designed that are more specific than standard and low molecular weight heparin. Most focus has been on factor X and thrombin, but there are new anticoagulants for almost every coagulant factor. Three direct thrombin inhibitors (hirudin, bivalirudin, and argatroban) are approved for clinical use in the United States. Four other anticoagulants (activated protein C, tissue factor pathway inhibitor, synthetic pentasaccharide, and the oral thrombin inhibitor H376/95) are undergoing or have completed phase III evaluation studies. Each drug must show a positive benefit-to-risk profile, and particularly cost effectiveness, in the face of the marginal therapeutic advantage over established agents. The new drugs are likely to avoid the serious non-anticoagulant side effects of heparin, such as thrombocytopenia, and perhaps osteoporosis. With the trend for reduced hospital stay and evidence suggesting that the risk of venous thrombosis remains high for several months after orthopaedic surgery, oral agents are likely candidates for improving care. The oral thrombin inhibitor H376/95 is arousing most interest, as it produces predictable anticoagulant response without laboratory monitoring. It is currently being evaluated in phase III trials as a possible substitute for warfarin in venous disease and atrial fibrillation. The early completion of the Human Genome Project and advances in biotechnology will inevitably increase the number of new therapies specifically designed for the individual patient and disease.

Ross I Baker FRACP, FRCPA · Alison M Street FRACP, FRCPA · Kerry M Taylor FRACP, FRCPA

Letter Economy class syndrome: a forgotten lesson MJA 2001; 175: 669-670 To the Editor: The editorial by Gallus and Baker,1 and subsequent correspondence which speculated about prolonged calf pressure contributing to causing deep vein thrombosis,2 reminded me of an undergraduate lecture in 1948 about pulmonary embolism in people who slept in deck chairs in London air raid shelters during World War II. This lecture was given by Simpson, then a lecturer in forensic medicine (and later a respected authority in this specialty), who reported a significant increase in deaths from pulmonary embolism (to 24) in September and October 1940, soon after serious night air-attacks on London began.3 This compared with only four in September and October 1939. Twenty-one of these 24 deaths occurred in, or soon after leaving, air raid shelters. The pople who died were mostly elderly, obese and often had varicosities of the leg veins. A typical case was that of an overweight, 60-year-old woman who complained of numb legs and swollen ankles after sitting for 10 hours in a deck chair — she dropped dead in the street while walking home, eight minutes after leaving the shelter. Autopsy showed multiple small pulmonary embolisms and small tags of very fresh antemortem clot in the tibial veins. Simpson concluded that the process was mainly mechanical (calf compression causing obstruction, stasis, oedema and thrombosis), as sleeping in deck chairs causes compression of calf veins against the front edge of the chair for many hours. He proposed that people in air raid shelters should therefore be given provision for lying down. Indeed, by the time his letter was published, in December 1940, he noted that the number of cases of fatal pulmonary embolism were already decreasing, coinciding with the provision of bunks in the shelters. Stasis remains the precipitating factor in Virchow's triad of thrombus formation (abnormal blood flow [stasis], endothelial injury and hypercoagulability). Venous flow rate while lying down slows to half on standing and a third on sitting,4 even before calf compression is added. In 1940, civil authorities acknowledged the cause of an excess of cases of fatal pulmonary embolism and preventive measures were implemented, with documented success within two months. In 1954, Homans reported venous thromboembolism "probably due to sitting travel" by air and car.5 In 1988, calf pressure in cramped seating was blamed by the originators of the popular but restrictive term "economy class syndrome".6 In the 1990s, and in relation to the 2000 Olympic Games, a host of cases of flight-related pulmonary embolism were reported.1 But, in 2001, it seems the evidence for a causative effect must still be considered "circumstantial".1 Lloyd K Morgan Retired General Practitioner, PO Box 150, Lorne, VIC 3232 Gallus AS, Baker RI. Economy class syndrome [editorial]. Med J Aust 2001; 174: 264-265. Slonim L. Economy class syndrome Med J Aust 2001; 175: 176 Simpson K. Shelter deaths from pulmonary embolism. Lancet 1940; 2: 744. Ferrari E, Chevallier T, Chapelier A, Baudouy M. Travel as a risk factor for thromboembolic disease: a case-control study. Chest 1999; 115: 440-444. Homans J. Thrombosis of the deep leg veins due to prolonged sitting. N Engl J Med 1954; 250: 148-149. Cruickshank JM, Gorlin R, Jannett B. Economy class syndrome. Lancet 1988; 2: 497-498. Make a comment

Lloyd K Morgan

Editorial Holistic care in hospital patients Patients who require long-term, frequent specialty care may have their primary healthcare needs ignored MJA 2001; 175: 292-293 In this issue of the Journal, Jang and colleagues highlight an apparent neglect of women's health issues in a cohort of women undergoing regular haemodialysis in Victoria.1Their cross-sectional survey of 48 women undergoing haemodialysis in hospitals or satellite dialysis centres contributes to the scarce literature on reproductive health issues in women with end-stage renal disease (ESRD). It also clearly illustrates the potential for holistic care to be neglected when patients are managed in a highly specialised environment. The most startling finding of the study is the poor adherence to accepted guidelines for cervical cancer screening and mammography: 55% of patients had not had cervical screening within the previous two years, while 38% of those aged 50 years or over had not had mammography within the same period. These findings are echoed in a recent report on women undergoing haemodialysis in the United States.2 The figures compare with contemporary Australian screening adherence rates of 64% for cervical screening (women aged 20-69 years)3 and 54% for mammography (women aged 50-69 years).4 Thus, despite intense contact of dialysis patients with the healthcare system, adherence to screening is lower than in the general population. Results from the survey also indicate the need to improve sexual counselling, contraceptive advice, menopausal management and fracture prevention among these women. . . . why are nephrologists, or indeed other hospital-based specialists, not currently dealing with patients' global health issues? . . . Consideration of hormone replacement therapy (HRT) and osteoporosis treatment is difficult in women with ESRD. As the authors outline, HRT carries a potential risk of vascular access thrombosis, and there are currently no evidence-based data on the risk-benefit ratio in this group.5 Treating or preventing bone disease in ESRD is complex, and currently limited by lack of efficacy and side effects of the common therapeutic agents and lack of data on agents such as bisphosphonates. Nevertheless, it is surprising that few of the 11 postmenopausal patients with fractures could recall HRT being discussed with them, and only one was taking this therapy. An important question raised by this survey is "Who should be responsible for general healthcare issues in these patients?". The report does not say how many respondents claimed to have a general practitioner (GP) and, if so, maintained regular contact with this GP. However, a reason usually given by dialysis patients for not attending a GP is that they already spend many hours at the hospital or dialysis centre (usually about four hours, three times a week) and, not unreasonably, expect all their health issues to be dealt with during that contact. Jang and colleagues conclude from their survey that hospital-based dialysis services should include a service that deals with women's health issues to ensure that this aspect of their routine health management is not neglected. So, why are nephrologists, or indeed other hospital-based specialists, not currently dealing with patients' global health issues? Clearly, specialists are generally aware of guidelines for women's health screening. However, it is not a major daily focus of the already complicated care of their patients and is more likely to be overlooked by a physician focusing on time-consuming, dialysis-related problems. The burgeoning number of dialysis patients combines with limited funding to compound this problem. In view of these real-life pressures, I suggest an alternative approach that involves patients' GPs, whose daily practice already encompasses women's health screening. Since 1995, the Renal Unit at the Princess Alexandra Hospital, Brisbane, has implemented a "Renal Care and Support Program" to consolidate links between GPs and dialysis and transplant centres. Interaction is via a booklet which contains a summary of the patient's active and past problems, status of their health screening checks (such as those raised by Jang and colleagues), list of medications, information pages and key guidelines for care of the ESRD patient. Advances in information technology continue to enhance these lines of communication. Many studies have shown that integrated management involving GPs achieves outcomes similar to, and in some instances better than, hospital care.6 Our program aims to address the global health issues of patients.7In comparison, the model proposed by Jang seems limited. It would underutilise the skills of primary care physicians in healthcare screening, duplicate services available in general practice, and move these aspects of patient care to a system and staff not resourced to deal with them. However, if GPs are to be significantly involved in the care of patients with ESRD, we must consider the suitability of applying general principles of care to these patients. This, I believe, can be achieved by providing guidelines in specific areas where approaches differ. For example, it is reasonable to exercise caution in administering HRT to a patient with recurrent vascular-access thrombosis, and some women with ESRD have such a poor prognosis that applying general population guidelines is not appropriate. This issue has not been addressed by Jang and colleagues. The findings of Jang's study illuminate an increasing problem in our contemporary healthcare system: patients who have frequent contact with subspecialty care may have primary healthcare issues ignored. One way of addressing this issue is a hospital-based service to deal with women's health issues, as proposed by Jang and colleagues, while an alternative is shared care between the specialist service and GPs. Clearly, further consideration and research is required. The issues raised are also likely to translate to subspecialty services other than nephrology. Carmel M Hawley Director of Nephrology Princess Alexandra Hospital, Brisbane, QLD carmel_hawleyAThealth.qld.gov.au Jang C, Bell RJ, White VS, et al. Women's health issues in haemodialysis patients. Med J Aust 2001; 175: 298-301. Rush H, Neugarten J, Coco M. Women's health issues in a dialysis population. Clin Nephrol 2000; 54: 455-462. Cervical screening in Australia 1997-1998. Canberra: Australian Institute of Health and Welfare, 2000. (AIHW Cat. No. CAN 9.) BreastScreen Australia achievement report 1997 and 1998. Canberra: Australian Institute of Health and Welfare, 2000. (AIHW Cat. No. CAN 8.) Weisinger JR. Role of hormone replacement in the management of osteoporosis in haemodialysis women: perspectives for the future. Nephrol Dial Transplant 2000; 15 Suppl 5: 36-37. Hampson J, Roberts R, Morgan D. Shared care: a review of the literature. Fam Pract 1996; 13: 264-279. Smith R, de Looze F, Kelly B, Rigby R. "Shared care". An integrated model of service delivery for renal and renal transplant patients [abstract]. Abstracts of the 35th Annual Scientific Meeting of the Australian and New Zealand Society of Nephrology; 3-5 Mar, 1999; Brisbane (QLD). Make a comment

Carmel M Hawley

Editorial Tumour banks: providing human tissue for cancer research Providing there are safeguards to protect the rights of patients, the supply of human tissue for research can benefit the community as a whole MJA 2001; 175: 293-294 Unprecedented insights into the biology of cancer cells are coming from research using recently developed methods such as global gene expression analysis.1 In clinical oncology, the benefits of these advances are likely to be significant in the diagnostic classification of tumours and informed design of novel anticancer agents. However, for this potential to be realised, the molecular analysis of large numbers of tumours is required, which in turn is dependent on the availability of collections of well-preserved and well-characterised tumour tissue for research. Coincident with increased need for human tissue specimens in cancer research is the increased complexity of the attending ethical issues. Ironically, it is the power of modern genetic analysis that creates the most difficult ethical dilemmas. The potential for discovering inherited genetic lesions that confer an increased risk of developing cancer (eg, a mutation in the breast cancer susceptibility gene BRCA1) has led to concern that "genetic research" may uncover information that is unwanted by the patient, has implications for family members and could potentially lead to discrimination.2 Serious ethical questions are also raised by the involvement of commercial interests in human-tissue-based research, in particular relating to potential conflicts of interest and the distribution of financial benefits.2,3 Moreover, these ethical issues must be negotiated in the current climate of public concern following recent media reporting on the retention of human organs following autopsy.4,5 Cancer remains a leading cause of morbidity and mortality in our community and the continued need for research into its nature and treatment is undisputed. It is also clear that society's view on involvement of individuals in all aspects of their healthcare has changed, resulting in the expectation of a more stringent regulatory environment for the conduct of research. This is reflected in a number of initiatives relevant to the collection and use of human tissue. In 1999, the National Health and Medical Research Council (NHMRC) issued updated guidelines for the conduct of ethical research involving humans.6 The guidelines incorporate the internationally accepted principles of integrity, respect for persons, beneficence and justice in the conduct of research, and reaffirm the crucial role of independent human research ethics committees (HRECs) to review and regulate research in specific institutions. Recently, the necessity for legislation on these issues has been considered, with a proposed review of the Human Tissue Act 1983 (NSW)7 and a joint inquiry into protection of human genetic information by the Australian Law Reform Commission and the Australian Health Ethics Committee of the NHMRC.8 The supply of human tissue for cancer research requires an integrated system of safeguards to protect the rights of patients, allow research that may benefit the wider community to continue, and offer a workable framework for hospitals, and, in particular, pathology departments, to support the process. Increasingly, tumour banks are emerging as an appropriate response to the concerns of involved parties. A tumour bank is an independent facility that collects samples of surgical specimens removed in the course of usual treatment from cancer patients who have given informed consent for their removal and use in research. The tissue taken is in excess of requirements for histopathological assessment and may include both cancer and normal tissue. The tumour bank also includes a database of relevant demographic, clinical and follow-up information.9 Researchers may apply to the tumour bank for samples to use in projects that have appropriate HREC approval. The decision to supply samples is generally made by a committee, comprised of clinicians and scientists, on the basis of scientific merit, available resources and the extent of collaboration with groups involved in collection of tumour bank specimens. The key safeguard in the conduct of ethical research is the involvement of an HREC, and the most important issues for the HREC to oversee in relation to a tumour bank pertain to donor consent and privacy protection.6 The informed consent process relating to tumour banks does not involve supply of the specific details of research projects, as these may not be known at the time of sample collection. The non-specific nature of this consent needs to be taken into account by the HREC when researchers proposing to use tumour bank specimens submit projects for review.6 The extent to which research participants are identifiable is an important factor. Tumour banks maintain links between donor identity and tissue samples, but supply samples to researchers without identifying information.9 The benefits of this system are that the privacy of donors is protected while maintaining the capacity to collect valuable follow-up information and to recontact donors if necessary. In the event that research studies uncovered information that might be relevant to the wellbeing of a donor, the HREC would play a pivotal role in consideration of the issues. Establishment and management of a tumour bank is a long-term commitment requiring substantial resources and secure funding. However, these costs must be met to ensure that progress in cancer research continues, ethical challenges posed by new investigative technology are met and public confidence in the conduct of research is maintained. Rosemary L Balleine Staff Specialist Karen E Humphrey Senior Tumour Bank Officer Christine L Clarke NHMRC Senior Research Fellow, and Department Head Department of Translational Oncology, Westmead and Nepean Hospitals Westmead, NSW rosemary_balleineATwmi.usyd.edu.au Marx J. DNA arrays reveal cancer in its many forms. Science 2000; 289: 1670-1672. Reilly PR, Boshar MF, Holtzman SH. Ethical issues in genetic research: disclosure and informed consent. Nat Genet 1997; 15: 16-20. Magnusson RS. The use of human tissue samples in medical research: legal issues for human research ethics committees. J Law Med 2000; 7: 390-403. Jacobsen G. Morgue chief removed over "sickening" tests. Sydney Morning Herald 2001; 19 March; 3. Retention of organs after necropsy. Lancet 2001; 357: 157. National Health and Medical Research Council. National statement on ethical conduct in research involving humans. Commonwealth of Australia, 1999. Available at: <http://www.nhmrc.gov.au/publications/pdf/e35.pdf>. Accessed 14 August 2001. Review of the Human Tissue Act 1983 (NSW). Discussion paper. Organ and tissue donation and use and post mortem examination. October 1999. Available at <http://www.health.nsw.gov.au/csd/llsb/organ/issuespaper.pdf>. Accessed 7 August 2001. Protection of human genetic information. A joint inquiry of the Australian Law Reform Commission and Australian Health Ethics Committee of the National Health and Medical Research Council. Commonwealth of Australia, February 2001. Available at: <http//:www.alrc.gov.au/current/genetic/overview.htm>. Accessed 14 August 2001. Grizzle WE, Aamodt R, Clausen K, et al. Providing human tissues for research: how to establish a program. Arch Pathol Lab Med 1998; 122: 1065-1076. Make a comment

Rosemary L Balleine · Karen E Humphrey · Christine L Clarke

Editorial "Should we treat leuchæmia in children?" Fifty years ago the first controlled clinical trial of cancer chemotherapy was published MJA 2000; 173: 568-569

Peter J Smith

Recommendations from the Australasian Society of Thrombosis and Haemostasis Abstract The anticoagulant effect of warfarin should be kept at an international normalised ratio (INR) of about 2.5 (desirable range, 2.0-3.0), although a higher level may be better in a few clinical conditions. The risk of bleeding increases exponentially with INR and becomes clinically unacceptable once the INR exceeds 5.0. Warfarin therapy should be continued for around six weeks for symptomatic calf vein thrombosis, and for 3-6 months after proximal deep vein thrombosis (DVT) that occurs after surgery or limited medical illness. Therapy for six months or longer could be considered for DVT occurring without an obvious precipitating factor, proven recurrent venous thromboembolism (VTE), or if there are continuing risk factors. Oral anticoagulants prevent ischaemic stroke in atrial fibrillation (AF). Maximum efficacy requires an INR > 2.0, but some benefit remains at an INR of 1.5-1.9. Patients aged over 75 years are at greatest risk of intracranial bleeding during warfarin therapy for AF, and the target INR may be reduced to 2.0-2.5, or perhaps as low as 1.5-2.0, in such patients. Warfarin should be withheld if it is more likely to cause major bleeding than to protect from stroke (eg, in young people with isolated AF where the annual baseline risk of stroke is < 1%). In patients with AF, aspirin is less effective than warfarin (much less effective after such patients have had a stroke or transient cerebral ischaemia). In people with prosthetic heart valves, an INR of 2.5-3.5 is probably sufficient for bileaflet or tilting disc valves, but a higher target INR is necessary for caged ball or caged disc valves. The addition of aspirin (100 mg/day) further decreases the risk of embolism but increases the risk of gastrointestinal bleeding. Warfarin is used for preventing and treating venous or arterial thrombosis and embolism. It is a potentially hazardous drug, causing major bleeding in 1%-2% of people treated, and intracranial bleeding in about 0.1%-0.5% during each year of therapy. These risks are well recognised, but strong recent evidence that many otherwise healthy people with atrial fibrillation (AF) or venous thromboembolism (VTE) can benefit from long term warfarin therapy has led to a major increase in its use. These consensus guidelines offer advice on the selection of patients for warfarin therapy and management of such patients. The recommendations draw on proceedings of the Fifth American College of Chest Physicians Consensus Conference on Antithrombotic Therapy,1 and are consistent with the most recent Guidelines on oral anticoagulation developed for the British Society for Haematology.2 Warfarin therapy and management of complications The INR The INR (international normalised ratio) is a good indicator of effectiveness and risk of bleeding during warfarin therapy and is best kept at about 2.5, with a target range of 2.0-3.0, for most clinical indications, although higher levels may be better for certain patients (Box 1). The lower limit of this target range recognises a threshold level for effectiveness, while the upper limit is set to minimise bleeding. Starting and maintaining warfarin therapy The daily maintenance dose of warfarin differs greatly between individuals, commonly between 0.5 mg/day and 15 mg/day, and often fluctuates over time. The average maintenance dose is about 4.5 mg/day, although this is lower in the elderly. The drug is rapidly and completely absorbed and immediately blocks further hepatic synthesis of the functional vitamin K-dependent haemostasis factors (II, VII, IX, X, protein C, protein S). However, its impact on the INR is delayed until preformed coagulation factors are removed, so dose adjustment must allow for these delayed effects. The plasma half-life of warfarin is about 36 hours.3 In the past, it was customary to use a loading dose of 10 mg. However, for most situations, a reduced starting dose of 5 mg per day will achieve an INR of 2.0 in four to five days.4 INR is measured daily or every second day during the first week of treatment, with the dose of warfarin (taken in the evening) titrated against the morning's INR. It is then measured at increasing intervals depending on response. Many patients, once the dose is stable, can be well controlled with 4-6-weekly testing and dose adjustment, but others need more frequent assessment. An empirical approach to warfarin dosing can be smooth and effective but published dose-adjustment tables can help.2 Old age, reduced body weight, and impaired cardiac or liver function all predict a smaller than average dose requirement. Multiple comorbidities and a need for many drugs increase the risk of an unstable anticoagulant response. The effect of warfarin is subject to multiple interactions. These include the dietary content or extent of absorption of vitamin K, the absorption of warfarin and its effect on the liver (which are increased or decreased by many other drugs), and the clearance of blood-clotting factors.1,3 Intercurrent illness, starting or stopping therapy with other drugs (especially antibiotics and amiodarone) and changes in diet or bowel function can all influence the INR. Rechecking the INR within a few days of any change in medication or clinical condition is prudent. Bleeding is minimised by regular monitoring to avoid an excessive INR and by educating patients about how warfarin works, why their dose requirement may change, and the likely settings and symptoms of bleeding complications. Successful warfarin therapy requires a partnership with patients, who should be encouraged to have their INR checked soon after any change in their normal routine. Clinics should periodically audit their results with warfarin therapy and review exceptional cases. Between 50% and 75% of INRs are likely to fall into their designated therapeutic range.5 Two recent Australian case reports are reminders that bioequivalence has not been formally demonstrated for Coumadin and Marevan (both from Boots Healthcare Australia, Sydney, NSW), the two locally available formulations of warfarin.6 Warfarin and bleeding Major bleeding has been reported in 1.1%-8.1% of patients during each year of long-term warfarin therapy (1.1%-2.7% by anticoagulant clinics managing patients with prosthetic heart valves,7-9 1.3% in atrial fibrillation trials, and 2.8%-8.1% after a stroke or transient ischaemic attack10-12). Risk factors include old age, serious illness (cerebral, cardiac, kidney or liver disease), cerebrovascular or peripheral vascular disease, and an unstable anticoagulant effect. Forgetfulness, non-steroidal anti-inflammatory drugs and alcohol abuse may also contribute.7,9,13-15 Warfarin appears to be especially hazardous after a transient ischaemic attack or minor stroke; in one trial, 14 months of warfarin therapy with a relatively high target INR of 3.0-4.5 increased major bleeding from 0.9% to 8.1%, intracranial bleeding from 0.5% to 4.1%, and fatal intracranial bleeding from 0.2% to 2.6% (relative to low dose aspirin therapy).12 Bleeding is most likely during the first three months of treatment, and often follows trauma or unmasks a previously unsuspected comorbidity.8,13-15Age alone is not a contraindication to warfarin therapy. Although one report showed that each decade above the age of 40 raised the risk of major bleeding by almost 50%, with a maximum effect above 70 years,7 others have found that age below 70 years has no influence.8,15 The INR is the dominant determinant, whether bleeding is expressed as the absolute risk per annum (Box 2) or as relative risk. In a 1996 study, the bleeding rate was doubled as the INR increased from 2.0-2.9 to 3.0-4.4, quadrupled between 4.5-6.0, and was multiplied by five when the INR was above 7.0.15 There is a consistent increase in major bleeding (including intracranial bleeding16) when the INR exceeds 4.0-5.5.7,11,14 A 1997 trial found that each increase in INR by 0.5 multiplied the risk of major bleeding (mostly intracranial) by 1.43.12 Managing an excessively prolonged INR or bleeding caused by warfarin therapy An INR above 5.0 requires close monitoring and often needs intervention, as determined by the level of the INR and the presence or absence of bleeding (Box 3). The INR often remains elevated for some days, even if warfarin is withheld, but small amounts of vitamin K1 quickly correct the INR to safer levels. In most patients, 1-2.5 mg of oral vitamin K1 reduces the INR from 5.0-9.0 to 2.0-5.0 within 24-48 hours; this intervention is usually sufficient in the absence of bleeding.17,18 These small doses are obtained by withdrawing the desired amount from a 10 mg vial of injectable vitamin K1 and giving this orally or parenterally. When the INR is > 9.0, then 5 mg vitamin K1 may be more appropriate and can be given orally, subcutaneously or intravenously (very rarely, the last may cause a serious anaphylactoid reaction). In people with a massive accidental or self-inflicted warfarin overdose, the long half-life of warfarin means that the INR may rebound over several days as the effects of vitamin K1 wear off. In any case, the response to vitamin K1 needs to be monitored. Bleeding caused by a warfarin overdose is controlled with clotting factor replacement (Box 3), and this may also be indicated in the absence of bleeding when the risk is very high.19 Bleeding or an unstable dose-response should trigger a review of the need for warfarin. Continued treatment will require closer monitoring of the INR, both to detect the transient warfarin resistance caused by too much vitamin K1, and to avoid further overanticoagulation. Heparin treatment may be required to cover a prolonged period of warfarin resistance. Interrupting warfarin therapy for surgery When there is a need for surgery, the risk of perioperative bleeding under continued warfarin therapy must be balanced against the risk of thromboembolism if warfarin therapy is stopped.20Most surgery, including hip or knee replacement and many thoracic or abdominal operations, can proceed under continued warfarin cover without undue bleeding (provided the INR during and soon after surgery is about 1.5-2.0). Warfarin therapy is a contraindication for regional anaesthesia (eg, spinal, epidural, brachial blocks) and is unacceptable where even minor bleeding might cause critical damage (as in neurosurgery and some plastic surgery). It is also unpopular with most surgeons. However, the absolute daily risk of a serious thromboembolic event is small in most people with AF, previous systemic embolism or a prosthetic heart valve (the hazard is greatest from mitral and older-model prosthetic valves, and in patients with more than one prosthetic valve). Thus, it is safe to stop warfarin therapy for several days before and after surgery in such patients. High-dose heparin cover for these indications is rarely indicated as the risk of bleeding is usually prohibitive.20 The risk of recurrence is greatest during the first four weeks after VTE, so warfarin therapy should not be interrupted during this time if at all possible. If anticoagulants must be stopped for surgery soon after VTE, a vena cava filter can be placed to minimise the risk of life-threatening pulmonary embolism. Specific indications for warfarin therapy Deep vein thrombosis and pulmonary embolism Prevention: Heparins are now usually the preferred drugs for the prevention of perioperative VTE, but warfarin retains a limited role when the risk of thrombosis is very high. Its main role is in long-term therapy. Warfarin is no less effective than low molecular weight heparins after hip or knee replacement, and the risk of bleeding is similar or lower when therapy is started at about the time of surgery and continued at least until patients are fully mobile.21 Treatment: Anticoagulants prevent early thrombus extension and embolism and minimise late recurrence. Heparin treatment can be stopped after a minimum of five days when warfarin therapy is also being given, provided that the two drugs are overlapped for at least four days and the INR has exceeded 2.0 for two or more days.22 Increasingly, deep vein thrombosis (DVT) is now managed at home -- an approach preferred by many patients and made possible by trials which found that initial treatment with low molecular weight heparins given in a fixed dose by subcutaneous injection is no less effective or safe after DVT than standard heparin therapy. Home heparin therapy requires close monitoring to ensure compliance and a safe and effective start for warfarin therapy.23,24 Although warfarin is now usually given for 3-6 months after VTE, there is growing evidence that the optimal duration of treatment is determined by the patient's clinical presentation. Six to 12 weeks of warfarin therapy is probably enough when DVT follows surgery or transient immobilisation ("secondary" DVT), as recurrence is minimised by six weeks of treatment after symptomatic calf vein DVT,7 and by three months of treatment after proximal DVT.25,26 However, warfarin therapy for longer than six months may be required after "idiopathic" DVT, recurrent VTE, or when there is a continuing cause like cancer or an inherited or acquired "hypercoagulable" state.27-30 Whether, in these circumstances, warfarin should be given for 12 months, two years, or longer, remains under active investigation. For individuals, the choice will also be influenced greatly by risk of bleeding. Controversies in the management of DVT and VTE Calf vein thrombosis: Although calf vein DVT poses little immediate threat and is commonly believed to be clinically unimportant, it has the potential to extend and embolise. In a randomised comparison where 51 patients with symptomatic calf DVT were treated for five days with heparin only or with heparin followed by ongoing warfarin therapy, there was a recurrence during the next three months in eight of 28 patients from the first group (23%: seven clinically suspected and confirmed; five with proximal extension and one with embolism), but none in the second.31 Therefore, patients with calf vein thrombosis should be treated with warfarin unless there are contraindications. Accuracy of diagnostic tests for DVT: Venous ultrasonography has now replaced venography as the first-line diagnostic test for clinically suspected DVT. Despite its limited sensitivity to small calf vein DVTs, a negative ultrasound result almost excludes thrombosis when there is a low pretest clinical probability for DVT (a DVT score of zero on a checklist of clinical features obtained before ultrasonography, such as active cancer, immobilisation, major surgery, entire leg swelling, localised tenderness, calf swelling, pitting oedema and collateral superficial veins).32 However, for patients in whom the pretest clinical probability is moderate (DVT score of 1-2) or high (score, > 3), a negative ultrasound result does not exclude a small DVT, and they should have either early venography or further ultrasonography once or twice within the next seven days in case there is proximal extension of an undetected calf thrombus. This approach is validated by extensive clinical follow-up.33 Recurrent or idiopathic DVT or VTE: In a randomised trial of patients presenting with recurrent DVT, oral anticoagulant therapy for six months was followed by a recurrence in 21% during four years of follow-up, compared with 3% when treatment was continued. However, ongoing warfarin therapy increased the rate of major bleeding during the four years from 2.7% to 8.6%, while mortality remained unchanged.27 Similarly, in a separate trial of management after a first "idiopathic" VTE, warfarin therapy for three months was followed by recurrence in 16 of 77 patients during 10 months of follow-up, compared with only one of 76 patients in whom warfarin therapy was continued.30 However, the use of warfarin increased the annual risk of major bleeding from zero to 4%.30 These high rates of bleeding reinforce the need for careful risk assessment when considering patients for long term anticoagulant therapy after VTE. The results of these trials suggest that warfarin therapy should be continued for one year after an "idiopathic" or recurrent VTE if the risk of bleeding is acceptable, and that treatment should be extended to two years if warfarin control is straightforward and the bleeding risk remains low. Atrial fibrillation Warfarin is now widely used to prevent systemic embolism in otherwise healthy patients with atrial fibrillation (AF). In clinical trials, warfarin consistently reduced the annual risk of a first ischaemic stroke (including stroke with a residual functional deficit) by almost 70% (from 7% to 3% per annum) and mortality by 33%, at the cost of a small increase in serious bleeding (from 1.0% to 1.3% per annum).10,34,35 The prevalence of AF rises from about 3% at 65 years to more than 10% by 85 years, and AF accounts for about 1.5% of all strokes in people aged 50-59 years, and almost 25% of strokes in people aged 80-89 years. Age is therefore an important determinant of ischaemic stroke in AF (the relative risk [RR] of stroke in AF rises by 1.4 with each decade).35 Previous stroke or transient ischaemic attack (RR, 2.5), diabetes (RR, 1.7), and treated hypertension (RR, 1.6) also contribute, as do heart failure, ischaemic heart disease, a large left atrium, and left ventricular dysfunction.10 Stroke is unlikely in isolated AF but becomes more likely as additional risk factors accumulate (Box 4). This makes warfarin therapy inappropriate for young people with AF alone and no other cardiac risk factor (isolated AF), as their annual risk of stroke (< 1%) is low enough to ensure that risk of bleeding always equals or exceeds any likelihood of gain. Because of the risk of bleeding, these reports raise important questions about the best target level of INR, and about which patients with AF should be offered long-term warfarin therapy. The incidence of stroke is minimised by an INR > 2.0 and increases exponentially below this level, but some benefit remains while the INR is 1.5-1.9. When considering warfarin therapy for AF, each candidate requires a formal estimate of the relative risks of stroke (Box 4) and bleeding (Box 2). Controversies about the use of warfarin or aspirin to prevent stroke in atrial fibrillation Stroke and the INR: The risk of stroke during warfarin therapy for AF is dictated by the INR. Below 2.0, the relative risk doubles at 1.7, triples at 1.5, sextuples at 1.3, and reaches 18 times once the INR is normal, but nothing is gained by increasing the INR beyond its therapeutic threshold of 2.0.36 Results were similar when warfarin was given for secondary stroke prevention in patients with AF who had already developed a stroke or transient cerebral ischaemia.11 Again, in a randomised trial in which patients with AF plus at least one other risk factor for stroke were given either warfarin in a dose to prolong their INR (INR, 2.0-3.0; median, 2.4) or aspirin combined with a low dose of warfarin (0.5-3.0 mg/day; INR, 1.2-1.5; median, 1.3), the dose aiming for the higher INR was clearly superior.37 Aspirin or warfarin for AF? The 30% risk reduction in stroke from aspirin treatment is well below the 70% achieved with warfarin therapy.10 In a blinded analysis of clinical outcomes when the two drugs were compared, warfarin was better at preventing cardioembolic strokes and strokes of uncertain cause.38 This is consistent with the small effect observed with aspirin for secondary stroke prevention in patients with AF and who have had a stroke or TIA -- warfarin reduced the risk of recurrence by 62%, compared with only 16% for aspirin.39 It may be a useful compromise to reserve aspirin for patients with uncomplicated AF whose baseline risk of embolism is low. Warfarin, INR and aspirin in elderly patients with AF: Age above 75 years and a high INR both increase the hazard from intracranial and other major bleeding during warfarin therapy. Because there is some residual benefit at an INR of 1.5-1.9, this reduced target range may offer an acceptable exchange of safety for benefit in some elderly patients. Where the risk of bleeding is high, aspirin is less effective, but safer than warfarin. Cardioembolic stroke prevention in conditions other than AF There is evidence that cardioversion to correct a recent cardiac arrhythmia should be delayed until after three weeks of anticoagulant cover to prevent systemic embolism.35 Warfarin prevents embolic stroke and other arterial embolism, as well as VTE, after myocardial infarction (MI), and is often given for 3-6 months when MI is followed by intraventricular thrombus formation (risk factors include transmural anterior infarction and ventricular dysfunction).40 A good case also exists for long term warfarin therapy in some patients with ongoing left ventricular dysfunction.41,42Prosthetic heart valves Improved design has greatly reduced the thrombogenicity of mechanical prosthetic heart valves, but the need for effective, lifelong warfarin therapy remains because systemic embolism is still the main source of late mortality and morbidity. The risk is determined by the type of valve and its position (higher for mitral than aortic valves, greatest when both are replaced). Tissue valves, by contrast, are almost free of thromboembolic complications, except during the first three months.43The American College of Chest Physicians recommends an INR of 2.0-3.0 for recent-model bileaflet or tilting disc valves, and 2.5-3.5 for older and more thrombogenic valves that have a caged ball or disc; patients with a newly placed bioprosthetic (tissue) valve require three months of warfarin and an INR of 2.0-3.0.43 However, in our view, because the evidence is incomplete, it remains prudent to retain a target range of 2.5-3.5 for most ("low-risk") prosthetic valves while aiming higher (3.0-4.5) for older and more thrombogenic models, provided there is no contraindication (Box 1). This view is consistent with recent recommendations from the British Society for Haematology.2 Antiplatelet drugs alone are ineffective, but combining dipyridamole or aspirin (100 mg/day) with warfarin reduces the risk of systemic embolism. Meta-analysis suggests that the penalty for adding aspirin is a 2.5-times increase in major gastrointestinal bleeding,44 so the combination is perhaps best avoided, except in patients considered to be at unusually high risk of systemic thromboembolism (more than one mechanical valve, previous embolism, associated AF).43 Special circumstances for anticoagulation Antiphospholipid antibody syndrome and factor V Leiden: Two retrospective surveys of clinical outcomes in patients with antiphospholipid antibody syndrome and venous and/or arterial thrombosis suggest that warfarin therapy fails to prevent recurrent thromboses unless the INR is prolonged above 3.0.45,46 This contrasts with a more recent report of few recurrences while the INR was 2.0-3.5.47 Without better information, and until randomised trials are complete, it is not possible to make a firm recommendation about the optimal target range for this condition. The effect of aspirin alone in preventing thrombosis in the antiphospholipid antibody syndrome is unclear.45-47 There is no current evidence to suggest that patients with factor V Leiden-heterozygous abnormality should require more intense anticoagulation. It is still uncertain whether the duration of therapy should be increased in these patients, as evidence from reports about the risk of recurrent VTE is conflicting.28,29,48 Oral anticoagulants in pregnancy: Oral anticoagulants cross the placenta and should be avoided throughout pregnancy, especially during the first and third trimesters.49 Treatment at 6-12 weeks' gestation causes calcified epiphyses (chondrodysplasia punctata) and a characteristic nasal hypoplasia in offspring,50 while later exposure is associated with central nervous system abnormalities, including microcephaly.51 In one report, almost 30% of children (10 of 35) born to mothers with a prosthetic heart valve were malformed if acenocoumarol was taken through 6-12 weeks' gestation, but none of 19 developed a malformation when this drug was replaced with heparin before the sixth week.52 Continuing warfarin therapy until term also exposes infants to the risk of intracranial and other major bleeding during birth. Heparins do not cross the placenta and do not cause these problems.53-55 It is safe to breastfeed during warfarin therapy as there is minimal excretion into breast milk.56 References Hirsh J, Dalen JE, Anderson D, et al. Oral Anticoagulants. Mechanism of action, clinical effectiveness and optimal therapeutic range. Chest 1998; 114 Suppl: 445S-469S. Walker ID, Machin S, Baglin TP, et al. Guidelines on oral anticoagulation. 3rd ed. Br J Haematol 1998; 101: 374-387. Holbrook AM, Wells PS, Crowther NR. Pharmacokinetics and drug interactions with warfarin. In: Poller L, Hirsh J, editors. Oral anticoagulants. Sydney: Arnold, 1996: 30-48. Crowther MA, Ginsberg JB, Kearon C, et al. A randomized trial comparing 5 mg and 10 mg warfarin loading doses. Arch Intern Med 1999; 159: 46-48. Rose P. Audit of anticoagulant therapy. J Clin Pathol 1996; 49: 5-9. Coumadin and Marevan are not interchangeable. Aust Adverse Drug React (ADRAC) Bull 1999; 18: 6. van der Meer FJM, Rosendaal FR, Vandenbroucke JP, Briet E. Bleeding complications in oral anticoagulant therapy: an analysis of risk factors. Arch Intern Med 1993; 153: 1557-1562. Cannegieter SC, Rosendaal FR, Wintzen AR, et al. Optimal oral anticoagulant therapy in patients with mechanical heart valves. N Engl J Med 1995; 333: 11-17. Levine M, Raskob GE, Landefeld S, Kearon C. Hemorrhagic complications of anticoagulant treatment. Chest 1998; 114 Suppl: 511S-523S. Laupacis A, Boysen G, Connolly S, et al. Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Analysis of pooled data from five randomized controlled trials. Arch Intern Med 1994; 154: 1449-1457. The European Atrial Fibrillation Trial Study Group. Optimal oral anticoagulant therapy in patients with nonrheumatic atrial fibrillation and recent cerebral ischemia. N Engl J Med 1995; 333: 5-10. The Stroke Prevention in Reversible Ischemia Trial (SPIRIT) Study Group. A randomized trial of anticoagulants versus aspirin after cerebral ischemia of presumed arterial origin. Ann Neurol 1997; 42: 857-865. Landefeld S, Beyth RJ. Anticoagulant-related bleeding: clinical epidemiology, prediction and prevention. Am J Med 1993; 95: 315-328. Fihn SD, McDonnell M, Martin D, et al. Risk factors for complications of chronic anticoagulation. A multicenter study. Ann Intern Med 1993; 118: 511-520. Palareti G, Leali N, Coccheri S, et al. Bleeding complications of oral anticoagulant treatment: an inception-cohort, prospective collaborative study (ISCOAT). Lancet 1996; 348: 423-428. Hylek EM, Singer D. Risk factors for intracranial hemorrhage in outpatients taking warfarin. Ann Intern Med 1994; 120: 897-902. Weibert RT, Le DT, Kayser SR, Rapaport SI. Correction of excessive anticoagulation with low-dose oral vitamin K1. Ann Intern Med 1997; 125: 959-962. Crowther M, Donovan D, Harrison L, et al. Low-dose oral vitamin K reliably reverses over-anticoagulation due to warfarin. Thromb Haemost 1998; 79: 1116-1118. Makris M, Greaves M, Philips W, et al. Emergency oral anticoagulant reversal: the relative efficacy of infusions of fresh frozen plasma and clotting factor concentrate on correction of the coagulopathy. Thromb Haemost 1996; 77: 477-480. Kearon C, Hirsh J. Management of anticoagulation before and after elective surgery. N Engl J Med 1997; 336: 1506-1511. Clagett GP, Anderson FA, Geerts WH, et al. Prevention of venous thromboembolism. Chest 1998; 114 Suppl: 531S-560S. Hyers TM, Agnelli G, Hull RD, et al. Antithrombotic therapy for venous thromboembolic disease. Chest 1998; 114 Suppl: 561S-578S. Koopman MMW, Prandoni P, Piovella F, et al. Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous low-molecular-weight heparin administered at home. N Engl J Med 1996; 334: 682-687. Levine M, Gent M, Hirsh J, et al. A comparison of low-molecular-weight heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep-vein thrombosis. N Engl J Med 1996; 334: 677-681. Schulman S, Rhedin A-S, Lindmarker P, et al. Comparison of six weeks with six months of oral anticoagulant therapy after a first episode of venous thromboembolism. N Engl J Med 1995; 332: 1661-1665. Levine MN, Hirsh J, Gent M, et al. Optimal duration of oral anticoagulant therapy: a randomized trial comparing four weeks with three months of warfarin in patients with proximal DVT. Thromb Haemost 1995; 74: 606-611. Schulman S, Granqvist S, Holmstrom M, et al. The duration of oral anticoagulant therapy after a second episode of venous thromboembolism. N Engl J Med 1997; 336: 393-398. van den Belt AGM, Sanson B-J, Simioni P, et al. Recurrence of venous thromboembolism in patients with familial thrombophilia. Arch Intern Med 1997; 157: 2227-2232. Simioni P, Prandoni P, Lensing AWA, et al. The risk of recurrent venous thromboembolism in patients with an Arg506 to Gln mutation in the gene for factor V (Factor V Leiden). N Engl J Med 1997; 336: 399-403. Kearon C, Gent M, Hirsh J, et al. A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism. N Engl J Med 1999; 340: 901-907. Lagerstedt CI, Olsson C-G, Fagher BO, et al. Need for long-term anticoagulant treatment in symptomatic calf-vein thrombosis. Lancet 1985; 2: 515-518. Wells PS, Anderson DR, Bormanis J, et al. Value of assessment of pretest probability of deep-vein thrombosis in clinical management. Lancet 1997; 350: 1795-1798. Heijboer H, Buller HR, Lensing AW, et al. A comparison of real-time compression ultrasonography with impedance plethysmography for the diagnosis of deep-vein thrombosis in symptomatic outpatients. N Engl J Med 1993; 329: 1365-1369. Singer DE. Overview of the randomized trials to prevent stroke in atrial fibrillation. Ann Epidemiol 1993; 3: 563-567. Laupacis A, Albers GW, Dalen JE, et al. Antithrombotic therapy in atrial fibrillation. Chest 1998; 114 Suppl: 579S-589S. Hylek EM, Skates SJ, Sheehan MA, Singer DE. An analysis of the lowest effective intensity of prophylactic anticoagulation for patients with nonrheumatic atrial fibrillation. N Engl J Med 1996; 335: 540-546. Stroke Prevention in Atrial Fibrillation Investigators. Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: Stroke Prevention in Atrial Fibrillation III randomised clinical trial. Lancet 1996; 348: 633-638. Miller VT, Pearce LA, Feinberg WM, et al. Differential effect of aspirin versus warfarin on clinical stroke types in patients with atrial fibrillation. Neurology 1996; 46: 238-240. European Atrial Fibrillation Trial Study Group. Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke. Lancet 1993; 342: 1255-1262. Cairns JA, Theroux P, Lewis HD Jr, et al. Antithrombotic agents in coronary artery disease. Chest 1998; 114 Suppl: 611S-633S. Fuster V, Gersh BJ, Giuliani ER, et al. The natural history of idiopathic dilated cardiomyopathy. Am J Cardiol 1981; 47: 525-531. Al-Khadra AS, Salem DN, Rabd WR, et al. Warfarin anticoagulation and survival: a cohort analysis from the studies of left ventricular dysfunction. J Am Coll Cardiol 1998; 31: 749-753. Stein PD, Alpert JS, Dalen JE, et al. Antithrombotic therapy in patients with mechanical and biological prosthetic heart valves. Chest 1998; 114 Suppl: 602S-610S. Cappelleri JC, Fiore LD, Brophy MT, et al. Efficacy and safety of combined anticoagulant and antiplatelet therapy versus anticoagulant monotherapy after mechanical heart-valve replacement: a metaanalysis. Am Heart J 1995; 130: 547-552. Rosove MH, Brewer PM. Antiphospholipid thrombosis: clinical course after the first thrombotic event in 70 patients. Ann Intern Med 1992; 117: 303-308. Khamashta MA, Cuadrado MJ, Mujic F, et al. The management of thrombosis in the antiphospholipid-antibody syndrome. N Engl J Med 1995; 332: 993-997. Krnic-Barrie S, O'Connor CR, Looney SW, et al. A retrospective review of 61 patients with antiphospholipid syndrome: analysis of factors influencing recurrent thrombosis. Arch Intern Med 1997; 157: 2101-2108. Eichinger S, Pabinger I, Stumpflen, et al. The risk of recurrent venous thromboembolism in patients with and without Factor V Leiden. Thromb Haemost 1997; 77: 624-628. Ginsberg J, Barron W. Pregnancy and prosthetic heart valves. Lancet 1994; 344: 1170-1172. Koren G, Pastuszak A, Ito S. Drugs in pregnancy. N Engl J Med 1998; 338: 1128-1137. Hall JG, Pauli RM, Wilson KM. Maternal and fetal sequelae of anticoagulation during pregnancy. Am J Med 1980; 68: 122-140. Iturbe-Alessio I, del Carmen Fonseca M, Mutchinik O, et al. Risks of anticoagulant therapy in pregnant women with artificial heart valves. N Engl J Med 1986; 315: 1390-1393. Ginsberg JS, Kowalchuk G, Hirsh J, et al. Heparin therapy during pregnancy. Risks to the fetus and mother. Arch Intern Med 1989; 149: 2233-2236. Fejgin MD, Lourwood DL. Low molecular weight heparins and their use in obstetrics and gynecology. Obstet Gynecol Surv 1994; 49: 424-431. Sanson B-J, Lensing AWA, Prins MH, et al. Safety of low-molecular-weight heparin in pregnancy: a systematic review. Thromb Haemost 1999; 81: 668-672. Orme ML, Lewis PJ, de Swiet M, et al. May mothers given warfarin breast-feed their infants? BMJ 1977; 1: 1564-1565. Background and evidence basis of recommendations The Australasian Society of Thrombosis and Haemostasis Consensus Guidelines for Warfarin Therapy were written on behalf of the Australasian Society of Thrombosis and Haemostasis (ASTH). The writing committee was commissioned by council and consisted of Associate Professor A S Gallus (Chairman), Dr R I Baker, Professor B H Chong, Dr P A Ockelford and Associate Professor A M Street. The guidelines were developed after extensive consultation with the membership of the ASTH, including several workshops and teleconferences. The draft recommendations were open for comment and discussion at the 1998 annual scientific meeting of the ASTH in Sydney. They draw upon review of all available evidence from published studies and from clinical experience. The aim is to provide an Australian perspective on the evidence to guide all practitioners in the safe and effective use of oral anticoagulants in hospital and the community. We are grateful for the help of Dr K McGrath, Dr M Herzberg (Quality Assurance Program in Haematology, Royal College of Pathologists of Australasia), Dr P Montanaro (Royal Australian College of General Practitioners), Dr P Steele (Australia and New Zealand Cardiac Society) and Professor J Fletcher (International Union of Angiology). Authors' details Australasian Society of Thrombosis and Haemostasis, Perth, WA. Alex S Gallus, FRACP, FRCPA, Chairman; Ross I Baker, FRACP, FRCPA; Beng H Chong, FRACP, FRCPA; Paul A Ockelford, FRACP, FRCPA; Alison M Street, FRACP, FRCPA. Reprints will not be available from the authors. Correspondence: Professor A S Gallus, Director, SouthPath, C/- Flinders Medical Centre, Bedford Park, SA 5042. 1: Range of international normalised ratio (INR) recommended for specific applications of warfarin therapy* Condition INR range Preventing DVT (high risk patients, like those who have had hip replacement) 2.0-3.0 Therapy after DVT or pulmonary embolism 2.0-3.0 Preventing systemic embolism Atrial fibrillation Valvular heart disease After myocardial infarction Tissue heart valves (first 3 months) 2.0-3.0 2.0-3.0 2.0-3.0 2.0-3.0 Bileaflet mechanical heart valve (aortic) 2.5-3.5 Mechanical prosthetic heart valve (high risk) 3.0-4.5 Preventing recurrence of myocardial infarction 3.0-4.5 Thrombosis in antiphospholipid antibody syndrome 3.0-4.5 DVT=deep vein thrombosis . *Based largely on the 5th American College of Chest Physicians Consensus Conference1 and consistent with current recommendations of the British Society for Haematology.2 2: Risk of major bleeding (% per annum) and international normalised ratio (INR) - findings of two studies23,30 INR Study 130 Study 223 < 2.0 2.0-2.9 3.0-3.9 4.0-4.9 5.0-5.9 ≥ 6 3% 2%-3% 2%-3% 4% 5% 5%-13% 0 1% 3% 4% 50% 3: Managing overdose and bleeding during warfarin therapy* Clinical setting Action INR >5.0 but < 9.0 (no bleeding) Stop warfarin, give 1-2.5mg vitamin K1, measure INR in 6-12 hours, restart warfarin at reduced dose once INR is < 5 INR ≥9.0 (no bleeding) Stop warfarin, give 5mg vitamin K1, measure INR in 6-12 hours, restart warfarin at reduced dose once INR is < 5, clotting factor replacement? if high risk of bleeding Major bleeding (any level of INR) Stop warfarin, give 5mg vitamin K1, clotting factor replacement, measure INR as required, assess need to restart warfarin INR=international normalised ratio. *Based on Makris et al, 1996.19 ?Blood products available in Australia for clotting factor replacement after warfarin overdose include fresh frozen plasma and Prothrombinex-HT (CSL Limited), a factor II, IX and X concentrate. 4: Risk of ischaemic stroke in patients with atrial fibrillation (AF), grouped by age and other risk factors* (derived from Laupacis et al10) Risk categories Patients affected per annum Lone atrial fibrillation† Age < 60 years Age 60-69 years Age 70-79 years Age ≥80 years 0 1.6% 2.1% 3.0% Age < 65 years No risk factors One or more risk factors 1.0% 4.9% Age 65-75 years No risk factors One or more risk factors 4.3% 5.7% Age >75 years No risk factors One or more risk factors 3.5% 8.1% *Hypertension, diabetes, previous stroke or transient ischaemic attack. †Atrial fibrillation without transient ischaemic attack or stroke, myocardial infarction, hypertension or heart failure.

Alex S Gallus · Ross I Baker · Beng H Chong · Paul A Ockelford

Research Investigation of a cluster of leukaemia in the Illawarra region of New South Wales, 1989-1996 Victoria J Westley-Wise, Bernard W Stewart, Irene Kreis, Paolo F Ricci, Anthony Hogan, Chris Darling, Steve Corbett, John Kaldor, Neill H Stacey, and Pauline Warburton MJA 1999; 171: 178-183 For editorial comment, see Cartwright Abstract - Introduction - Methods - Results - Discussion - Conclusions - Follow-up - Acknowledgements - References - Authors' details - - More articles on Haematology Abstract Objectives: To investigate a cluster of leukaemia among young people and assess the plausibility of a disease-exposure relationship. Design: Descriptive analysis of population-based leukaemia incidence data, review of evidence related to the causation of leukaemia, assessment of environmental exposures to known leukaemogens, and resulting risks of leukaemia. Setting: Illawarra region of New South Wales, Australia, focusing on suburbs between the Port Kembla industrial complex and Lake Illawarra (the Warrawong area). Main outcome measures: Standardised incidence ratios (SIRs) for leukaemia; current measured and past estimated ambient air benzene concentrations; and expected leukaemia cases attributable to estimates of ambient air benzene concentrations. Results: In 1989-1996, 12 leukaemia cases among Warrawong residents aged less than 50 years were observed, more than the 3.49 cases expected from the rate in the rest of the Illawarra region (SIR, 343.8; 99% CI, 141.6-691.7). These people lived in suburbs immediately to the south-southwest of a coke byproducts plant (a major industrial source of benzene, one of the few known leukaemogens). The greatest excess was among 15-24-year-olds (SIR, 1085.6; 99% CI, 234.1-3072.4). In 1996, ambient air concentrations of benzene averaged less than 1 part per billion (ppb). Since 1970, ambient air concentrations of benzene were estimated to have averaged up to 3 ppb, about one-thousandth of the level at which leukaemia risk has been identified in occupational epidemiological studies. Using the risk assessment model developed by the US Environmental Protection Agency, we estimate that past benzene levels in the Warrawong area could have resulted in 0.4 additional cases of leukaemia in 1989-1996. Conclusions: The excess occurrence of leukaemia in the Warrawong area in 1989-1996 is highly unusual. Current environmental benzene exposure and the reconstructed past environmental benzene exposure level are too low to explain the large excess of leukaemia. The cause of the cluster is uncertain. Introduction In July 1996 the Illawarra Public Health Unit (located in the Wollongong/Port Kembla region, New South Wales) was notified that four former students of a local high school had been diagnosed with leukaemia since 1989. Preliminary investigations established that a cluster of at least 11 people aged less than 40 years who had lived in suburbs near the school had been diagnosed with leukaemia since 1989. On the basis of New South Wales cancer registration data, only about 2 to 3 cases would have been expected. Established causes of leukaemia include occupational benzene exposure, ionising radiation, chemotherapeutic agents, and some inherited and congenital conditions.1-5 Coke byproduct plants are a recognised source of occupational, and potentially of environmental, benzene exposures.1,6,7 The people in the cluster lived in suburbs adjacent to the Port Kembla industrial complex, which includes coke ovens and an associated byproducts plant. We report the investigation of the Illawarra region leukaemia cluster and discuss the plausibility of a disease-exposure relationship. Methods Our investigation followed published guidelines for cancer cluster investigations.8-10 The main components were evaluations of: the pattern of leukaemia incidence in the Illawarra region, with specific attention to residential areas near the Port Kembla industrial complex; environmental exposure to known and putative leukaemogens; and the plausibility of a disease-exposure relationship (whether past environmental exposures to known leukaemogens could explain the excess leukaemia occurrence). The NSW Cancer Council Ethics Committee approved the study. Case finding and investigation Active and passive case-finding methods were used to identify all people resident in the Illawarra region (Wollongong, Shellharbour and Kiama Local Government Areas) aged less than 50 years who had been diagnosed with leukaemia in 1989-1996. The cut-off at age 50 years was chosen as the index cases were young and the age interval 40-50 years represents a natural change in leukaemia occurrence, when the leukaemia risk begins to rise steeply. We actively identified cases from bone marrow aspirate reports, hospital discharge and day-only admission data, and discussions with clinicians in Sydney and Wollongong, community members and organisations. The population-based New South Wales Central Cancer Registry provided the passive case-finding data. For each leukaemia case, we sought to review the medical record and interview the patient and/or a relative to obtain or confirm information about dates of birth and diagnosis, leukaemia cell-type, genetic and medical risk factors, residential and school histories, and personal and/or parental occupational histories. Occurrence evaluation Leukaemia incidence was analysed in eight areas within the Illawarra region with a similar population size (about 20 000-30 000 in 1986), including the area close to the Port Kembla industrial complex (Area 1) (Figure 1). Leukaemia incidence rates in the whole Illawarra region, and each of the eight areas within it, were compared with rates in a reference population by calculating standardised incidence ratios (SIRs) as a means of indirect age standardisation.11 The reference population used was "Urban NSW" (Sydney, Wentworth, Central Coast, Hunter and Illawarra administrative health areas). The calculation of rates was based on place of residence at diagnosis. Using Central Cancer Registry data, we calculated leukaemia SIRs for males and females and for people aged less than 50 years for four five-year periods which had Census years as their mid-points: 1974-1978, 1979-1983, 1984-1988 and 1989-1993. The SIR is the ratio of the number of cancer cases in a study population to the number of cases expected according to the age-specific rate in the reference population (multiplied by 100). For the Illawarra region, leukaemia rates could be calculated to 1996. Thus, for 1989-1996, leukaemia SIRs were calculated for each of the Illawarra areas. In Area 1, they were also classified by age group and cell-type (according to ICD-9),12 using the rest of the Illawarra region as the reference population. Australian Bureau of Statistics (ABS) census data for 30 June 1976, 1981, 1986 and 1991 were used for urban NSW reference populations.13 For the Illawarra region, the ABS provided population data by postcode. Exact Poisson confidence intervals (CI) around the SIRs were estimated.14 CIs were set at 99%, rather than 95%, to reduce the possibility of identifying a chance excess of cancer as statistically significant. SIRs and CIs were calculated with SAS for Windows version 6.11. NSW Central Cancer Registry data and urban NSW population data were accessed from NSW Health's Health Outcomes Information and Statistical Toolbox, a repository of health-related databases for New South Wales. Environmental monitoring and historical exposure reconstruction We undertook an extensive review of the literature on risk factors for and causes of leukaemia, and on carcinogenic effects of occupational and environmental exposures. The environmental assessment focused on exposure to known leukaemogens from the 1970s to 1996. It involved interviewing representatives from industry, government agencies, local residents and workers; inspecting relevant sites; reviewing government, industry and press reports; and collecting and reviewing information on environmental and occupational exposure for residents and workers. The NSW Environment Protection Authority (EPA) and BHP Steel began daily ambient air benzene monitoring in September 1996 in the residential areas nearest the plant (Figure 2). Monitoring was also conducted at three control sites. The EPA used the standard protocol developed by the US Environmental Protection Agency (US EPA) for assessing toxic organic compounds in ambient air.15 BHP used personal samplers, adapted to a stationary role, which collected organic vapours onto an active adsorbent medium by drawing air through the sampler. Both the EPA and BHP analysed the samples with gas chromatography at laboratories registered with the National Association of Testing Authorities. We estimated environmental benzene exposure from the main local sources before September 1996. Using methods developed by the US EPA,16 we estimated levels of emissions from the coke production facilities for each year since 1970 (based on levels in 1996, adjusted for changes in plant equipment and processes and changes in coke and benzene production). Information related to benzene emissions from motor vehicles and other petroleum sources, including Roads and Traffic Authority data on local traffic volumes, was used to provide an upper estimate of the extent to which emissions from these other major local sources may have differed in previous years relative to 1996. Risk estimation The US EPA's benzene risk assessment model of dose-response17 was used to estimate the number of excess leukaemia cases expected in Area 1 between 1989-1996. It was assumed that the Area 1 population had breathed ambient air (70 kg person breathing 20 m3 of air daily) with benzene concentrations equivalent to the estimated maximum annual average concentration since 1970 for the maximally exposed site, continuously over a lifetime (24 hours per day for 70 years). Results Case finding and investigation The same cases were identified by both active and passive case-finding methods. We identified 44 Illawarra residents aged less than 50 years who were diagnosed with leukaemia in 1989-1996. These included 12 people resident in Area 1 at diagnosis, and a 13th person who had moved out of Area 1 a few months before diagnosis (Table 1). None of these 13 people from Area 1 were found to have genetic or medical risk factors for leukaemia. Nor had they ever worked in the production of coke or its byproducts. Six were diagnosed with acute lymphoblastic leukaemia (ALL), four with chronic myeloid leukaemia (CML), and three with acute myeloid leukaemia (AML). Immunophenotypic features and leukaemic classifications revealed no unusual patterns. Six people have died. Of the nine people from Area 1 aged 20 years or less, seven had lived there all their lives, and two for about 11 years. Four attended the same high school in the late 1980s, with three being in the same school year; these three people had leukaemia of different cell-types. Occurrence evaluation For the four five-year periods between 1974-1993, leukaemia incidence in the Illawarra region, and each of its areas, was not significantly different to that throughout urban New South Wales.18 The incidence of total cancers and other specific cancers (including lymphoma and multiple myeloma) was also not significantly higher in Area 1.18However, leukaemia incidence among Area 1 residents aged less than 50 years in 1989-1996 was more than three times higher than in the rest of the Illawarra region (12 cases observed, versus 3.49 expected; SIR, 344; P = 0.0003) (Table 2). The SIR was more than 200 for all leukaemia cell-types, and was significantly increased for ALL (Table 3). The greatest excess of leukaemia was among teenagers and young adults. Among 15-24-year-olds, five cases were observed, versus 0.46 expected (SIR, 1086; 99% CI, 234.1-3072; P = 0.0001). Environmental monitoring and reconstruction of historical exposure The Port Kembla industrial complex contains heavy industries such as copper smelting, sulphuric acid and superphosphate manufacture, petroleum depots, and Australia's largest steelworks, which includes coke ovens and their byproducts plant. In spring and summer, the predominant wind direction is from the northeast; hence, the residential area where the people with leukaemia lived received the greatest exposure from industrial emissions in the region. Benzene was the only known leukaemogen for which local environmental exposures may have been relevant. While ionising radiation is also an established leukaemogen, and there is evidence that exposure to occupational ethylene oxide or 1,3-butadiene can cause leukaemia,3-5 no specific local environmental sources of these agents were identified. At the byproducts plant, coke oven gases are distilled into a benzene- toluene-xylene commercial product (which is 80% benzene), while past practices (until 1977) separated them. The closest residences are more than 1 km from the plant, with all but two Area 1 cases residing 1-3 km from the plant. The other major benzene sources in Area 1 are motor vehicles and petroleum storage tanks. Both EPA and BHP monitoring found that ambient air benzene concentrations in Area 1 averaged less than one part per billion (ppb) in 1996 (Table 4), typical of urban sites in Sydney.19 Analysis of benzene, toluene and xylene ratios in the EPA's samples indicated that about 50% of the benzene was from petroleum. Annual average ambient air benzene concentrations at the most exposed site within Area 1, since 1970, are estimated to have been up to about 3 ppb. Roads and Traffic Authority data showed that traffic volumes in Area 1 have not changed appreciably since the 1970s.20 Local petroleum storage tanks had a greater storage capacity in previous years, which may have been associated with higher emissions.20 Risk estimation The estimated maximum annual average ambient air benzene concentration in Area 1 of 3 ppb is only about one-thousandth of concentrations at which leukaemia risk has been detected in occupational studies.1 The World Health Organization (WHO) has concluded that occupational exposure to an average of 1 part per million (1 ppm, ie 1000 ppb) over a working lifetime has been associated with no statistical increase in leukaemia deaths.1Using the US EPA benzene risk assessment model,17 if a population of 17 500 people (the number of people in Area 1 aged less than 50 years in 1991) had all breathed air with an average benzene concentration of 3 ppb over a lifetime, at the most 0.2 excess leukaemia deaths (or 0.4 cases) would have been expected in 1989-1996. Discussion This investigation into the reported cluster found a highly significant excess leukaemia occurrence in the Warrawong area, particularly among teenagers, in 1989-1996. Estimated past environmental benzene levels are too low to explain this excess. Cluster studies Cancer cluster studies have rarely provided insights into aetiology.3,8-10,21,22 Studies of very rare diseases with well-defined, high exposures are the most likely to yield conclusive results.22 However, these circumstances, in the context of geographic (spatial or spatiotemporal) clusters, are uncommon.10,22 Disease clusters occur continually in any population, and as such represent "expectedly unexpected" events.9,22Drawing boundaries tightly around people observed in clusters inadvertently identifies and overestimates disease excesses.21,22 However, in this study, the geographic, age and time criteria setting the boundaries were not defined or varied to influence the magnitude of the observed excess. Area 1 was a natural geographic grouping of postcodes bounded by industrial zones, Lake Illawarra and the Pacific Ocean. It included suburbs and a postcode area in which no cases were resident. The age range 0-49 years was broad given that the reported cluster was among teenagers. On the other hand, the most recent period analysed (1989-1996) was preceded by a period in which few leukaemia cases were diagnosed.18 Possible leukaemogens Several known leukaemia causes and risk factors were excluded as explanations for the cluster: ionising radiation, ethylene oxide, 1,3-butadiene, and genetic and medical risk factors. For other agents considered, such as dioxins, pesticides, and heavy metals, evidence is lacking of a causal relationship between these agents and leukaemia, despite numerous studies conducted worldwide.5 Although benzene is structurally related to carcinogenic polycyclic hydrocarbons, these agents are generally associated with lung and some other cancers, but not leukaemia.23 Similarly, the influence of genetic polymorphisms, specifically within the cytochrome P450 family, has been associated with lung cancer rather than leukaemia.24Viruses have been causally associated with the rare hairy cell leukaemia and adult T-cell leukaemia.4,5 They have also been suspected to cause leukaemia in childhood and adolescence, but there is still little convincing evidence that they play an important role.4,5,25 Several studies have associated parental smoking with childhood leukaemia.3,26 While many other parental occupational and/or personal exposures (including pesticides, benzene, solvents, petroleum products, and spray paints) have also been implicated in childhood leukaemia, most relevant studies have used poor exposure measures, with inconsistent results.2,3 To our knowledge no leukaemia "clusters" have been reported and investigated in close proximity to industrial facilities similar to those in the Warrawong area. Occupational exposure during steel and coke production has been causally associated with an increased risk of lung and certain other cancers, but not leukaemia.23,27-29 Benzene Benzene was the only known human leukaemogen to which people in Area 1 had potentially significant environmental exposures. Despite the inevitable focus on the steelworks and coke byproducts plant as a benzene source, petrol exhaust and tobacco smoke (the primary source of benzene for smokers, and relevant to non-smokers through passive smoking) are the most significant sources in urbanised populations.1 Food and water are not major sources of benzene exposure,30 and the possibility of contamination of the water supply in Area 1 with benzene from local sources was examined and excluded.20While other haematological malignancies have been associated with occupational benzene exposure,31-36 the evidence has been considered strongest for AML,1 which affected only three people in this cluster. However, a recent review concluded that the few available studies of leukaemia cell-types do not indicate larger or more consistent elevations in risk for AML than for other cell-types.36 Study strengths and limitations Studies of geographic cancer clusters must typically deal with poor information about environmental exposures.22 In this study we had to rely on estimates of past environmental benzene exposure, but several factors suggest that the emission estimates for the coke production facilities are accurate. An independent audit of the emissions estimates concluded that the underlying assumptions were robust and that the emissions inventory was calculated as accurately as possible without an onsite testing program.37 The estimated past annual average ambient air benzene concentration in the maximally exposed part of the Warrawong area, 3 ppb, was similar to concentrations measured38-40 and modelled41 at similar distances from byproducts plants overseas. Measured occupational benzene exposures for Port Kembla byproducts plant workers between 1979 and 199642 were similar to occupational monitoring results for byproducts plant workers from the United States43 and Britain in the 1980s.29,44Using the US EPA benzene risk assessment model,17 even if we assume that average ambient air benzene concentration in Area 1 was 30 ppb (rather than the estimated 3 ppb), this level of exposure would still only explain up to four excess leukaemia cases. Given that the observed leukaemia excess was primarily among young people, the default assumption of 70 kg adults used in our risk estimate is also likely to have slightly overestimated the risk, and hence the number of expected cases. Consistent with public health principles, the US EPA benzene risk assessment model, which uses data from studies of US rubber and chemical workers,36,45,46 is itself based on assumptions that would exaggerate rather than minimise risk, including a linear relationship between exposure to genotoxic carcinogens and leukaemia risk. However, results from some animal studies suggest that a non-linear response may be more biologically plausible.47,48 If this applies to benzene-induced human leukaemia, application of the US EPA model may considerably overestimate risks in the low exposure range. More plausible are biologically based multistage stochastic models for chemical carcinogenesis, which account for cellular birth, death, initiation, promotion and other biological processes, each stage being linked by a stochastic transition probability that accounts for exposure (or dose).47,48 Such models are likely to produce lower estimates of leukaemia risk for low levels of environmental exposure. However, large uncertainties are inherent in any conversion of risk estimates from animal studies or occupational studies to risk estimates for benzene exposure in the general community. Many people -- children, people of reproductive age, those with other risk factors -- may have susceptibilities to leukaemia quite different from those of the male workers studied in occupational studies. Animal and human studies have begun to clarify the potential risk associated with relatively high transient and/or intermittent benzene exposure49 versus cumulative exposure, but the relationship is still poorly understood for low dose extrapolations. In addition, people in the community are exposed to a variety of agents, which may have as yet unidentified additive and possibly synergistic effects. Conclusions On current knowledge, the recent ambient air benzene concentrations in the Warrawong area represent a negligible leukaemia risk, and the estimated past benzene concentrations are too low to explain the large excess of leukaemia cases that occurred in 1989-1996. However, factors such as variation in susceptibilities of individuals and population groups such as children, the possible effects of intermittent and high transient benzene exposures, and interactions between different agents, mean that we cannot exclude a causal association between leukaemia occurrence among young people in the Warrawong area and chemical exposures. Follow-up A feasibility study is being undertaken to examine the potential for relating disease to chemical exposures through a case-control study. Broadly, chemical exposures of interest are personal exposures (environmental and individual, to benzene and industrial emissions in general) and parental exposures (focusing on those with prior evidence of an association with leukaemia). In addition, routine surveillance of leukaemia and lymphoma is continuing, as is ambient air monitoring for benzene and other hazardous pollutants in the Warrawong area. Acknowledgements We gratefully acknowledge the assistance given by the individuals with leukaemia and their relatives, and other community members who participated in the investigation's Community Reference Group. We give special thanks to members of the Illawarra Leukaemia Investigation Steering Committee for their commitment and contributions: Giovanna Crocco and David Gilmour (Community Reference Group), Richard Willison and Trevor Dunn (Illawarra Public Health Unit), Joe Woodward and Craig Lamberton (NSW Environmental Protection Authority), Ron Hales (Wollongong City Council), and Christine Ewan (University of Wollongong). Many individuals and organisations assisted in and supported the study, but we would particularly like to thank the following organisations: NSW Health; Illawarra Area Health Service; New South Wales Cancer Council; BHP Port Kembla; NSW Environmental Protection Authority; and the University of Wollongong. We also thank John Marthick (University of Wollongong) and Paddy Ranasinghe (Illawarra Public Health Unit) for preparing the maps. References World Health Organization. Benzene (Environmental Health Criteria No. 150). Geneva: International Programme on Chemical Safety, 1993. Ross JA, Davies SM, Potter JD, Robison LL. Epidemiology of childhood leukaemia, with a focus on infants. Epidemiol Rev 1994; 16: 243-272. Cartwright RA, Staines A. Acute leukaemias. Clin Haematol 1992; 5: 1-26. Finch SC, Linet MS. Chronic leukaemias. Clin Haematol 1992; 5: 27-56. Tomatis L, editor. Cancer: causes, occurrence and control (IARC Scientific Publications No. 100). Lyon: International Agency for Research on Cancer, 1990. Fishbein L, O'Neill IK, editors. Benzene and alkylated benzenes. Environmental carcinogens: methods of analysis and exposure measurement, vol. 10 (IARC Scientific Publications No. 85). Lyon: International Agency for Research on Cancer, 1988. United States Environmental Protection Agency. National emission standards for hazardous air pollutants; regulation of benzene; response to public comments. US Federal Register 1984, 40 CFR Part 61, AD-FRL-2523-7. Centers for Disease Control. Guidelines for investigating clusters of health events. MMWR Morb Mortal Wkly Rep 1990, 39 (R-11): 1-23. Bender AP, Williams AN, Johnson RA, Jagger HG. Appropriate public health responses to clusters: the art of being responsibly responsive. Am J Epidemiol 1990; 132 Suppl 1: S48-S52. Fiore BJ, Hanrahan LP, Anderson HA. State health department response to disease cluster reports: a protocol for investigation. Am J Epidemiol 1990; 132 Suppl 1: S14-S22. Breslow NE, Day NE. Statistical methods in cancer research. Vol II. Lyon: International Agency for Research on Cancer, 1987. World Health Organization. Manual of the International Statistical Classification of Diseases, Injuries and Causes of Death. 9th Revision. Geneva: WHO, 1977. Australian Bureau of Statistics. Estimated resident populations by age and sex in statistical local areas, New South Wales (Catalogue. No. 3209.1, 30 June 1976, 1981, 1986, 1991). Canberra: ABS, 1978, 1983, 1988, 1993. Daly L. Simple SAS macros for the calculation of exact binomial and Poisson confidence limits. Comput Biol Med 1992; 22: 351-361. United States Environmental Protection Agency. Compendium of methods for the determination of toxic organic compounds in ambient air. 2nd edition. Compendium method TO-14A. Determination of volatile organic compounds (VOCs) in ambient air using specially prepared canisters with subsequent analysis by gas chromatography (EPA/625/R-96/010b). Cincinnati, OH: Center for Environmental Research Information, 1999. <http://www.epa.gov/ttn/amtic/files/ambient/airtox/to-14ar.pdf> Accessed 5 July 1999. United States Environmental Protection Agency. AP-42, 5th ed., vol. I. Chapter 12: metallurgical industry. 12.2 Coke production [draft]. Research Triangle Park, NC: Emission Factor And Inventory Group, US EPA, 1995. <http://www.epa.gov/ttn/chief/ap42pdf/c12s02.pdf>. Accessed 5 July 1999. [No longer available, but see final version at <http://www.epa.gov/ttn/chief/ap42/ch12/final/c12s02.pdf> Accessed 10 May 2001. United States Environmental Protection Agency. Integrated risk information system (IRIS). Benzene (CASRN 71-43-2). 16 October 1998. Cincinnati, OH: Environmental Criteria and Assessment Office, Office of Health and Environmental Assessment, Office of Research and Development, Cincinnati, 1996. <http://www.epa.gov/ngispgm3/iris/subst/0276.htm> Accessed 5 July 1999. Westley-Wise V, Hogan A. Report on the occurrence of leukaemia (1974-96) and other cancers (1974-93) in the Illawarra. Illawarra Area Health Service. Wollongong 1997. Wadge A, Salisbury J. Benzene. National Environmental Health Forum Monographs, Air Series 2. National Environmental Health Forum, South Australian Health Commission, Adelaide,1997. Kreis I, Willison R. Environmental assessment related to a leukaemia cluster. University of Wollongong. Wollongong 1997. Olsen SF, Martuzzi M, Elliott P. Cluster analysis and disease mapping -- why, when and how? A step by step guide. BMJ 1996; 313: 863-866. Rothman KJ. A sobering start for the cluster busters' conference. Am J Epidemiol 1990; 132 Suppl 1: S6-S13. International Agency for Research on Cancer. Polynuclear aromatic compounds. Part 3, Industrial exposures in aluminium production, coal gasification, coke production, and iron and steel founding. IARC Monographs on the evaluation of the carcinogenic risk of chemicals to humans, vol. 34. Lyon: IARC, 1984. Wormhoudt LW, Commandeur JNM, Vermeulen NPE. Genetic polymorphisms of human N-acetyltransferase, cytochrome P450, glutathione-S-transferase, and epoxide hydrolase enzymes: relevance to xenobiotic metabolism and toxicity. Crit Rev Toxicol 1999; 29: 59-124. Alexander FE. Viruses, clusters and clustering in childhood leukaemia: a new perspective? Eur J Cancer 1993; 29A: 1424-1443. Sorahan T, Lancashire RJ, Hulten MA, Stewart AM. Childhood cancer and parental use of tobacco: Deaths from 1953 to 1955. Br J Cancer 1997; 75: 134-138. Redmond CKA, Strobino BR, Cypress RH. Cancer experience among coke byproduct workers. Ann N Y Acad Sci 1976; 217: 102-115. Swaen GM, Slanged JAM, Volovics A, et al. Mortality of coke plant workers in the Netherlands. Br J Indust Med 1991; 48: 130-135. Hurley JF, Cherrie JW, Maclaren W. Exposure to benzene and mortality from leukaemia: results from coke oven and other coal product workers. Br J Indust Med 1991; 48: 502-504. Wallace L. Environmental exposure to benzene: an update. Environ Health Perspect 1997; 104: 1129-1136. Yin SN, Hayes RB, Linet MS, Li GL, et al. A cohort study of cancer among benzene-exposed workers in China: overall results. Am J Indust Med 1996; 29: 227-235. Hayes RB, Yin S-N, Dosemeci M, Li G-L, et al. Benzene and the dose-related incidence of hematologic neoplasms in China. J Natl Cancer Inst 1997; 89: 1065-1071. Rinsky RA, Alexander B, Smith MD, Hornung R, et al. Benzene and leukaemia: an epidemiological risk assessment. N Engl J Med 1987; 136: 1044-1050. Christie D, Robinson K, Gordon I, Bisby J. A prospective study in the Australian petroleum industry. I. Mortality. Br J Indust Med 1991; 48: 507-510. Wong O. An industry wide mortality study of chemical workers occupationally exposed to benzene. II. Dose response analyses. Br J Indust Med 1987; 44: 382-395. Savitz DA, Andrews KW. Review of epidemiologic evidence on benzene and lymphatic and hematopoietic cancers. Am J Indust Med 1997; 31: 287-295. Holmes Air Sciences 1997. Air quality report: review of BHP report to the Illawarra Area Health Service Leukaemia Task Force. Report prepared for the NSW Environment Protection Authority. Sydney: Holmes Air Sciences, 1997. Harkov R, Olsakovsky AC, Fillo JP. Determining the ambient impacts of coke and coke by-products manufacturing on selected pollutant levels in neighboring communities: I -- results from a six-month ambient air benzene monitoring study. Air toxics and volatile organic compounds: papers from the 84th Annual Meeting and Exhibition of the Air and Waste Management Association, Vancouver, 1991. Vol 6. Pittsburgh: Air and Waste Management Association, 1991. GDCh (Society of German Chemists) Advisory Committee on Existing Chemicals of Environmental Relevance. Benzene. Weinhmam, VCH Verlagsgesellschaft, 1988. In: World Health Organization. Benzene (Environmental Health Criteria No. 150). Geneva: WHO, 1993: 36. Fentiman AF, Neher MB, Kinzer GW, et al. Environmental monitoring benzene (PB-295 641). Prepared for US EPA. Springfield, VA: Battelle Columbus Laboratories, National Technical Information Service, 1979. In: IARC. Some industrial chemicals and dyestuffs (IARC monographs on the evaluation of the carcinogenic risk of chemicals to humans, vol. 29). Lyon: IARC, 1982. United States Environment Protection Agency. Benzene emissions from coke byproduct recovery plants -- background information for proposed standards (EPA-450/3-83-016a). Research Triangle Park, NC: Office of Air Quality Planning and Standards, 1984. BHP Flat Products Division. Report to the Illawarra Area Health Service. Port Kembla: BHP Flat Products Division, 1997. Runion HE, Scott LM. Benzene exposure in the United States, 1978-1983: an overview. Am J Indust Med 1985; 7: 385-393. Drummond L, Luck R, Afacan AS, Wilson HK. Biological monitoring of workers exposed to benzene in the coke oven industry. Br J Indust Med 1988; 45: 256-261. Rinsky RA, Young RJ, Smith AB. Leukemia in benzene workers. Am J Indust Med 1981; 2: 217-245. Ott MG, Townsend DT, Fishbeck WA, Langner RA. Mortality among workers occupationally exposed to benzene. Arch Environ Health 1978; 33: 3-10. Cox LA Jr, Ricci PF. Reassessing benzene cancer risks using internal doses. Risk Analysis 1992; 12: 401-409. Cox LA Jr, Ricci PF. Dose-response non-linearities for benzene revisited: A reply to C Crump. Risk Analysis 1993; 14: 485-486. (Received 2 July 1998, accepted 18 May 1999) Authors' details Illawarra Public Health Unit, Illawarra Area Health Service, Wollongong, NSW. Victoria J Westley-Wise, MPH, FAFPHM, Director; Anthony Hogan, MSc(Hons), PhD, Public Health Officer. Children's Cancer Research Institute, Sydney Children's Hospital, Sydney, NSW. Bernard W Stewart, PhD, FRACI, Research Director; now Head of Cancer Control Program, South Eastern Sydney Area Health Service. University of Wollongong, Wollongong, NSW. Irene Kreis, PhD, FAFPHM, Senior Lecturer; Paolo F Ricci, MSc, PhD, Professorial Fellow. BHP Steel Flat Products Division, Wollongong, NSW. Chris Darling, MSc(Occup Med), FAFOM, Occupational Health Advisor. NSW Health Department, Sydney, NSW. Steve Corbett, MPH, FAFPHM, Manager. National Centre for HIV Epidemiology and Clinical Research, University of New South Wales, Sydney, NSW. John Kaldor, PhD, Deputy Director, and Professor of Epidemiology. University of Sydney, Sydney, NSW. Neill H Stacey, BSc(Hons), PhD, Associate Professor. Illawarra Regional Hospital, Illawarra Area Health Service, Wollongong, NSW. Pauline Warburton, MB BS, FRACP, Director. Reprints: Dr V J Westley-Wise, Illawarra Public Health Unit, PO Box 66, Keiraville, NSW 2500. Email: vwestATdoh.health.nsw.gov.au Figure 1 (above): Map of the Illawarra region, showing areas used for comparing leukamia incidence. Back to textFigure 2 (below): Map of the Warrawong area (central portion of area 1), showing the location of the four ambient air monitoring stations. Back to textBack to textBack to textBack to textBack to text

Victoria J Westley-Wise · Bernard W Stewart · Irene Kreis · Paolo F Ricci · Anthony Hogan · Chris Darling · Steve Corbett · John Kaldor · Neill H Stacey · Pauline Warburton

How can we best achieve optimal transfusion practice? Before optimal practice can be promoted, it must be defined MJA 1997; 167: 462-463 Readers may print a single copy for personal use. No further reproduction or distribution of the articles should proceed without the permission of the publisher. For permission, contact the Australasian Medical Publishing Company Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au/>". - - ©MJA1997 Most therapeutic agents are prescribed within a framework of licensed indications agreed between the manufacturer and a regulatory authority. However, single donor blood components are not subject to this form of licensing, and rarely is rigorous evidence of their efficacy available from large scale randomised studies, as there is for other therapeutic agents, such as drugs. In an era when medical practice is increasingly governed by the threat of litigation, the proper use of blood products is particularly sensitive and closely scrutinised. Prescription of blood products based solely on presumed benefit, without balancing the risks of infection and other complications, is no longer acceptable. Yet, achieving the correct balance requires sound evidence of efficacy, accurate risk assessment and effective methods of ensuring universal good transfusion practice. How close are we to achieving this? Recent evidence suggests that a common understanding of the efficacy of blood components is a long way off. The Royal College of Physicians of Edinburgh consensus statement on red cell transfusion concluded: "...there is no general agreement at which point transfusion should be given, or on the optimal target concentration to be achieved. There is no single haemoglobin or haematocrit value applicable to all patients."1 For platelet transfusion, the "transfusion trigger" is more clearly defined. Even so, it was revised from 20x109/L to 15x109/L, or even 10x109/L in 1991.2 Further, a review of surgical transfusion practice in 43 hospitals in 10 countries of the European Union (the SANGUIS study) found that use of blood components in five common surgical procedures (hemicolectomy, coronary artery bypass grafts, abdominal aortic aneurysmectomy, transurethral resection of the prostate, total hip replacement) ranged from 0 to 80% of procedures for whole blood, 0 to 50% for fresh frozen plasma and 0 to 15% for platelets.3 Consequently, the cost in blood products varied by a factor of four for coronary artery bypass grafts, and a factor of 16 for transurethral resection of the prostate. limiting use of blood components to occasions when they are strictly necessary would benefit patients, prescribers, suppliers and society If efficacy is difficult to define, are we better at assessing transfusion risk? Transfusion-transmitted infections are the focus of concern for prescribers and the public alike, and studies on this topic are welcome.4 However, national requirements for reporting and collating major transfusion hazards vary. The United States5 and France have mandatory reporting, and the United Kingdom recently launched voluntary reporting.6 Australia also has voluntary reporting systems in all States, but these are believed to be underutilised (Dr Gordon Whyte, Director, Victorian Red Cross Blood Bank, Melbourne, VIC, personal communication). However, although such data-gathering is critical for monitoring risk, there is no evidence as yet that it is effective in moderating transfusion prescribing. Even if best transfusion practice could be formulated, how could it be promoted? In this issue of the Journal, Tuckfield et al. assess one strategy -- prospective monitoring of blood product request forms.7 They found that, assessed on hospital guidelines, this approach markedly reduced the rate of inappropriate transfusions. This systematic review of blood product prescriptions may be more educational and have longer lasting effects than would a paper audit. However, it has the disadvantages of being labour intensive and possibly delaying treatment, and is probably not applicable on a regular basis. A range of other strategies have been used, including issuing of national guidelines, consensus conferences and devolution of budgets to prescribers. All have their drawbacks. For example, guidelines produced at the national level have the potential to reflect local practice as well as scientifically validated assessments. The guidelines used by Tuckfield et al. could be challenged on the same basis. The SANGUIS study suggests that basing guidelines on current practice would lead to dramatically different criteria in different European countries, against which, in case of litigation, physicians might be judged. In addition, results of strategies are not always as expected. After publication of national guidelines for use of fresh frozen plasma (FFP) in the UK,8 FFP issues from our blood centre actually increased, as subtherapeutic doses had often been used previously. In contrast, FFP use in Belgium decreased dramatically after a safer but more expensive product (virally inactivated FFP) was introduced without an overall budget increase. Ultimately, limiting use of blood components to occasions when they are strictly necessary would benefit patients, prescribers, suppliers and society. Patients would receive optimal treatment with the lowest risk of side effects and, in some countries, minimum out-of-pocket cost. Prescribers providing treatment according to guidelines would offer state-of-the-art care and be protected from legal action in the rare case of a nosocomial event. Suppliers would be able to supply products more easily because of decreased demand. In addition, by fulfilling their duty to ensure maximum precautions are taken to provide safe blood components according to, and sometimes beyond, national recommendations or regulations, and to inform providers of potential risks, suppliers would protect themselves from potential litigation. (For example, in the United Kingdom some blood centres introduced systematic screening for hepatitis C antibodies before it became mandatory.) At the end of this process, society would benefit, with optimal use of limited resources in the context of growing health expenditure. However, before rushing headlong into further expensive manoeuvres to improve transfusion practice, we should remember that the relative cost-effectiveness of guidelines, consensus conferences and other strategies, such as prospective monitoring, in changing transfusion practice has not been assessed. Failure to change practice is often blamed on the prescribers rather than on the limitations of the methods used. But who will audit the auditors? Jean-Pierre Allain Professor of Transfusion Medicine, Department of Haematology, University of Cambridge, Cambridge, United Kingdom. Lorna M Williamson Consultant and Lecturer, National Blood Service, East Anglia Centre, Cambridge, United Kingdom. Consensus statement on red cell transfusion. Transfus Med 1994; 4: 177-178. Gmur J, Burger J, Schanz U, et al. Safety of stringent prophylactic platelet transfusion policy for patients with acute leukaemia. Lancet 1991; 338: 1223-1226. Sirchia G, Giovanetti AM, McClelland B, Fracchia GN, editors. Safe and good use of blood in surgery (SANGUIS). European Commission Publisher, 1994. Schreiber GB, Busch MP, Kleinman SH, Korelitz JJ. The risk of transfusion-transmitted viral infections. N Engl J Med 1996; 334: 1685-1690. Linden JV, Tourault MA, Scribner CL. Decrease in frequency of transfusion fatalities. Transfusion 1997; 37: 243-244. Williamson LM, Heptonstall J, Soldan K. A SHOT in the arm for safer blood transfusion. BMJ 1996; 313: 1221-1222. Tuckfield A, Haeusler M, Grigg A, Metz J. Reduction of inappropriate use of blood products by prospective monitoring of transfusion request forms. Med J Aust 1997; 167: 473-476. British Committee for Standards in Haematology. Guidelines for the use of fresh frozen plasma. Transfus Med 1992; 2: 57-63. ©MJA 1997 <URL: http://www.mja.com.au/> © 1997 Medical Journal of Australia.

Reduction of inappropriate use of blood products by prospective monitoring of transfusion request forms Annabel Tuckfield, Michael N Haeusler, Andrew P Grigg and Jack Metz For editorial comment, see Allain & Williamson Readers may print a single copy for personal use. No further reproduction or distribution of the articles should proceed without the permission of the publisher. For permission, contact the Australasian Medical Publishing Company Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au/>". Abstract - Introduction - Methods - Results - Discussion - References - Authors' details - - ©MJA1997 Abstract Objective: To determine the effect of prospective monitoring on appropriateness of transfusions of red cells, platelets and fresh frozen plasma (FFP). Design: Prospective interventional study. Setting: Royal Melbourne Hospital (a tertiary teaching hospital), Melbourne, Victoria, March-May 1996. Intervention: The blood product request form was modified to incorporate indications for transfusion and clinical and laboratory data. Requests were monitored by blood bank laboratory staff for conformation with hospital transfusion guidelines; non-conforming requests were discussed with the requesting medical practitioner by the Haematology Registrar before blood products were issued. In cases of disagreement, blood products were always issued. Subjects: 200 consecutive transfusion episodes for each product (red cells, platelets and FFP). Outcome measures: Appropriateness of transfusion, assessed by a Consultant Haematologist according to hospital guidelines. Rates of inappropriate transfusion episodes after intervention were compared with rates in a previous study. Results: After intervention, rates of inappropriate transfusion episodes fell significantly (red cells, 16% to 3% [P=0.004]; platelets, 13% to 2.5% [P=0.02]; and FFP, 31% to 15% [P=0.02]). Almost all inappropriate FFP transfusion episodes post-intervention were due to failure to demonstrate prolongation of prothrombin or activated partial thromboplastin times more than 1.5 times the control value. Conclusion: Prospective monitoring of request forms can reduce rates of inappropriate transfusions. High rates of inapproriate FFP transfusions possibly reflect uncertainty about appropriate laboratory criteria for FFP transfusion. While results of large prospective randomised controlled clinical trials of FFP transfusions are awaited, current laboratory criteria can be retained, but should be applied with flexibility. MJA 1997; 167: 473-476 Introduction In 1995, we reported results of an audit of blood product use at a tertiary teaching hospital (Royal Melbourne Hospital, Victoria).1 Indications for transfusion were analysed, mainly by retrospective review of medical records. We found that blood product use was inappropriate for 16% of red cell, 13% of platelet and 31% of fresh frozen plasma (FFP) transfusion episodes. In a significant number of episodes, the specific indication for transfusion was not documented in the medical record. Blood products must be used appropriately to minimise patient exposure to potential hazards, to conserve a limited resource and to contain costs. Measures to reduce inappropriate use of blood products have had varying results. While retrospective audit and education do not produce consistent and continuing improvements,2-8 prospective monitoring (monitoring of requests for blood products before issue) has usually been more successful.9-15 Consequently, in March 1996, the Royal Melbourne Hospital introduced prospective monitoring of transfusion requests with the aim of reducing inappropriate use of blood products. We present the results of the first three months of this intervention. Methods Intervention Blood products request form: The blood products request form was redesigned to incorporate the indication for transfusion and relevant clinical and laboratory data. These included: For red cells: haemoglobin level and clinical parameters (pulse rate and blood pressure); For platelets: platelet count and presence or absence of bleeding; For FFP: results of coagulation tests (prothrombin time [PT] or international normalised ratio [INR] and activated partial thromboplastin time [APTT]); and For all blood products: reasons for transfusion and operation (if applicable). In addition, the redesigned request form stipulates that the indication for transfusion must conform with the hospital's transfusion guidelines, which are printed on the reverse of the form (Box 1). Criteria for appropriate transfusions: The criteria were the same as those used in the audit.1 For FFP use, the requirement for coagulation times to be prolonged by more than 50% translated to PT >20 seconds or APTT >40 seconds. For massive blood transfusion (10 or more units of red cells in less than 24 hours), blood products were issued before laboratory results were available, and these transfusions were accepted as appropriate. In view of the potentially devastating effects of minor haemorrhage associated with neurosurgical procedures, these were exempted from the criteria for FFP use.1 Monitoring: On receiving a completed blood product request form, the senior medical laboratory scientist determined that the necessary information had been provided, and telephoned the requesting doctor to obtain any missing information. The scientist then checked that the indications conformed with transfusion guidelines, and if so, blood products were issued. If clinical or laboratory indications did not conform, the request was referred to the Haematology Registrar who consulted the requesting doctor. There were three possible outcomes: they agreed (i) either that the transfusion was not indicated and the blood products were not issued or (ii) that it was indicated and the products were issued or (iii) they disagreed and the products were issued. The consultation was never confrontational, and the blood product was always issued when there was disagreement. However, for the study these cases were subsequently referred to the Consultant Haematologist who reviewed the haematological data, transfusion request and medical record to decide if the transfusion was indeed inappropriate. Analysis of outcomes For each type of blood product (red cells, platelets and FFP), we analysed 200 consecutive transfusion episodes between March and May 1996. As in the initial audit, we excluded FFP transfusions for patients with thrombotic thrombocytopenic purpura, because of the different rationales for FFP use in this condition and in coagulation factor depletion. Rates of inappropriate blood product use after introduction of prospective monitoring were compared with those found during the previous audit (pre-intervention) with two-sided Fisher's exact tests. Results Indications for transfusion of red cells, platelets and FFP after introduction of prospective monitoring are shown in Box 2 (below). They were the same as in the pre-intervention audit.1 Numbers of transfusions referred to the Consultant Haematologist for review were: red cells, eight; platelets, 12; and FFP, 41. Final numbers of transfusion episodes deemed inappropriate were: red cells, six (3%); platelets, five (2.5%); and FFP, 30 (15%). Compared with the pre-intervention audit, rates of inappropriate transfusion episodes were significantly reduced, from 16% to 3% for red cells (P= 0.004), 13% to 2.5% for platelets (P=0.02) and 31% to 15% for FFP (P= 0.02). Of the six patients in whom red cell use was deemed inappropriate, five had a pretransfusion haemoglobin concentration greater than 100 g/L, the threshold for appropriate transfusion (range in these patients, 104-114 g/L). The sixth patient had a haemoglobin concentration of 98 g/L, but no clinical indications to warrant transfusion. In four of the five inappropriate platelet transfusion episodes, the platelet count was greater than 63x109/L (range, 63x109-159x109/L), a level at which platelets are not indicated except in the case of excessive bleeding with cardiac bypass surgery. Although three of these four transfusions were given in association with cardiac bypass surgery, there was no evidence of excessive bleeding. In 30 patients, FFP transfusion was deemed inappropriate as coagulation test results did not meet the criterion of a 50% prolongation of coagulation times. In one of these 30, this was because no coagulation tests had been performed. Discussion We found that the rate of inappropriate transfusion episodes fell significantly after introduction of prospective monitoring, from 16% to 3% for red cells, from 13% to 2.5% for platelets and from 31% to 15% for FFP. The success of prospective monitoring in reducing rates of inappropriate transfusions for red cells and platelets was not matched for FFP. This agrees with results of three previous studies, which have found persistently high rates of FFP transfusions despite monitoring (>40%,8 33%13 and 27%,15 respectively). As in these studies, we found the reason for deeming FFP use inappropriate was almost invariably failure to show sufficient abnormality in coagulation test results. The need to document abnormal coagulation with a PT or APTT greater than 1.5 x the control value, before FFP transfusion is deemed appropriate, rests on the assumptions that abnormal bleeding is unlikely if coagulation times are shorter than this but likely if they are longer, and that, when coagulation times are greater than 1.5 x the control value, FFP transfusion is likely to prevent or control bleeding. Detailed analysis of published data suggests that these assumptions are questionable.16-23 It is of interest that we found that lowering the cut-off for appropriate FFP transfusions from PT >20 seconds (1.5 times the control value) to PT >17 seconds would have lowered the rate of inappropriate transfusions from 15% to 3%, comparable to the rate found for red cell and platelet transfusions. A PT of 17 seconds is still 3.5 seconds longer than the median control value. Further investigation is needed to establish the clinical guidelines for FFP transfusion. Two publications24,25 have pointed to the need for a large multicentre prospective randomised controlled clinical trial to provide a definitive answer for the role of FFP in patients with acquired multiple coagulation defects. In the interim, it would seem reasonable to require docu mentation of abnormal coagulation as a criterion for appropriate FFP use, but the available evidence does not warrant rigid application of a cut-off level, such as 50% prolongation of PT or APTT. Other issues that must be addressed before a system of prospective monitoring can be introduced include exemption criteria. Some protocols exempt operating room patients,6 "desperate situations"14 and haematology and oncology patients.13 Emergency situations are also usually exempted from the requirement for laboratory data if the laboratory cannot provide urgent results at all times. If the criteria are to be applied to emergency situations, laboratory facilit ies must be available to provide the data quickly. In some programs of prospective monitoring, blood products are never withheld, but apparently inappropriate transfusions are later reviewed.11,14 Refusal to issue blood products leads to an adversarial relationship between clinicians and laboratory staff, which may compromise patient care. Refusal might also have medicolegal implications if subsequent patient morbidity or death could be attributed to withholding of the transfusion. For sustained improvement in practice, prospective monitoring must be continued indefinitely.11 This is both time consuming and demanding of staff. The demand might be lessened by computerised audit of transfusion requests; clinical and laboratory data could be entered into a program which flags non-compliant requests for review by blood bank staff.26 In conclusion, prospective monitoring was successful in reducing inappropriate use of red cells and platelets, but only partly successful for FFP. This probably reflects uncertainty about the appropriate clinical guidelines for FFP use, and although current laboratory criteria for FFP use should probably be retained, they should be applied with flexibility. References Metz J, McGrath KM, Copperchini ML, et al. Appropriateness of transfusions of red celIs, platelets and fresh frozen plasma. An audit in a tertiary care teaching hospital. Med J Aust 1995; 162: 572-577. Lam HTC, Schweitzer SO, Petz L, et al. Are retrospective peer-review transfusion monitoring systems effective in reducing red blood cell utilization? Arch Pathol Lab Med 1996; 120: 810-816. Toy PTCY. Audit and education in transfusion medicine. Vox Sang 1996; 70: 1-5. Bamerte RE, Fish DJ, Eisenstaedt RS. Modification of fresh frozen plasma transfusion practices through educational intervention. Transfusion 1990; 30: 253-257. Soumerai SB, Salem-Schatz S, Avorn J, et al. A controlled trial of educational outreach to improve blood transfusion practice. JAMA 1993; 270: 961-966. Solomon RR, Clifford JS, Gutman SI. The use of laboratory intervention to stem the flow of fresh frozen plasma. Am J Clin Pathol 1988; 89: 518-521. Brien WF, Buttier RJ, Inwood MJ. An audit of blood component therapy in a Canadian general teaching hospital. Can Med Assoc J 1989; 140: 812-815. Shanberge JN, Quattrochiocchi-Longe T. Analysis of fresh frozen plasma administration with suggestions for ways to reduce usage. Transfus Med 1992; 2: 189-194. Simpson MB. Prospective concurrent audits and medical consultation for platelet transfusions. Transfusion 1987; 27: 192-195. McCullough J, Steeper TA, Connelly DP, et al. Platelet utilization in a university hospital. JAMA 1988; 259: 2414-2418. Silver H, Tahhan HR, Anderson J, et al. A non- computer dependent prospective review of blood and blood component utilization. Transfusion 1992; 32: 260-265. Brandis K, Richards B, Ghent A, et al. A strategy to reduce inappropriate red blood cell transfusion. Med J Aust 1994; 160: 721-722. Hawkins TE, Carter JM, Hunter PM. Can mandatory pretransfusion approval programmes be improved? Transfus Med 1994; 4: 45-50 Cheng G, Wong HF, Chan A, et al. The effects of a self-educating blood component request form and enforcements of transfusion guidelines on FFP and platelet usage. Clin Lab Haem 1996; 18: 83-87. Marconi M, Almini D, Pizzi MN, et al. Quality assurance of clinical transfusion practice by implementation of the privilege of blood prescription and computerized prospective audit of blood requests. Transfus Med 1996; 6: 11-19. Counts RB, Haisch C, Simon TL, et al. Hemostasis in massively transfused trauma patients. Ann Surgery 1979; 190: 91-99. Braunstein AH, Oberman HA. Transfusion of plasma components. Transfusion 1984; 24: 281-286. Ciavarella D, Reed RL, Counts RB, et al. Clotting factor levels and the risk of diffuse microvascular bleeding in the massively transfused patient. Br J Haematol 1987; 67: 365-368. Harvey MP, Greenfield TP, Sugrue ME, et al. Massive blood transfusion in a tertiary referral hospital. Clinical outcomes and haemostatic complications. Med J Aust 1995; 163: 356-359. Houry S, Georgeac C, Hay J, et al. A prospective multicentre evaluation of preoperative hemostatic screening tests. Am J Surg 1995; 170: 19-23. Gelb AB, Roth RI, Levid J, et al. Changes in blood coagulation during and following cardiopulmonary bypass. Lack of correlation with clinical bleeding. Am J Clin Pathol 1996; 106: 87-99. Murray DJ, Olson JD, Strauss AR, et al. Coagulation changes during packed red cell replacement of major blood loss. Anesthesiology 1988; 69: 839-845. Murray DJ, Pennell BJ, Weinstein SL, et al. Packed red cells in acute blood loss: dilutional coagulopathy as a cause of surgical bleeding. Anesth Analg 1995; 80: 336-342. McVay PA, Toy PTCY. Lack of increased bleeding after liver biopsy in patients with mild hemostatic abnormalities. Am J Clin Pathol 1990; 94: 747-753. Cohen H. Avoiding the misuse of fresh frozen plasma. BMJ 1992; 307: 395-396. Gardner RM, Golubjatnikov OK, Laub RM, et al. Computer critiqued blood ordering using the HELP system. Comput Biomed Res 1990; 23: 514-528. (Received 20 Mar, accepted 1 Jul 1997) Authors' details Department of Diagnostic Haematology, Royal Melbourne Hospital, Melbourne, VIC. Annabel Tuckfield, FRACP, FRCPA, Registrar; Michael N Haeusler, FAIMS, Senior Scientist, Blood Bank; Andrew P Grigg, FRACP, FRCPA, Haematologist; Jack Metz, MD, FRCPA, Head. Reprints will not be available from the authors. Correspondence: Dr A Tuckfield, Diagnostic Haematology, Post Office, Royal Melbourne Hospital, Parkville, VIC 3050. E-mail: depATmis.medrmh.unimelb.edu.au ©MJA 1997 <URL: http://www.mja.com.au/> © 1997 Medical Journal of Australia.

The risk of transmitting HCV, HBV or HIV by blood transfusion in Victoria Gordon S Whyte and Helen F Savoia Readers may print a single copy for personal use. No further reproduction or distribution of the articles should proceed without the permission of the publisher. For permission, contact the Australasian Medical Publishing Company Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au/>". Abstract - Introduction - Methods - Incident rates - Risk estimation - Results - Hepatitis B virus - Hepatitis C virus - HIV - Discussion - Acknowledgements - References - Authors' details - ©MJA1997 Abstract Objective: To report the incidence rate of hepatitis B virus (HBV), hepatitis C virus (HCV) and HIV in Victorian repeat blood donors and to derive the residual risk of transmission of the viruses by screened blood transfusion. Design: The interval from the previous whole blood donation was extracted retrospectively from Victorian Red Cross Blood Bank records for each of the 358 332 repeat donations given between March 1994 and December 1995. Records of repeat donors found positive for the viruses in this period were traced to the previous seronegative donation and accepted if screened by the same test. For each virus, the number of previous donations screened by the same test was calculated and the sum of all donation intervals used to derive the incidence of infection in the repeat donor population. Published intervals after infection (when a donation can be infective although seronegative) were used to calculate the risk of release of a seronegative unit which would be infective. Participants and setting: Homologous blood donors at the Red Cross Blood Bank of Victoria. Main outcome measures: Incidence rate of HBV, HCV and HIV in regular blood donors and risk of infective donations being seronegative. Results: The incidence of infection in repeat donors was: HBV: 1.67 per 100 000 person-years; HCV: 1.89 per 100 000 person-years; and HIV: 1.31 per 100 000 person-years. The risk of a seronegative repeat donation being infective was: HBV: 2.71 per million donations (adjusted to 6.45 to account for viraemias which remain seronegative); HCV: 4.27 per million donations; and HIV: 0.79 per million donations. Conclusion: The risk of transmitting HCV, HBV or HIV by repeat blood donors is low and compares favourably with overseas data. Repeat donors have an incidence rate of HIV and HBV comparable to that of the general population, but the incidence rate of HCV is lower for repeat donors than in the general population. MJA 1997; 166: 584-586 Introduction There are no current Australian estimates of the risks of transmission by blood of hepatitis B virus (HBV) or hepatitis C virus (HCV), although the theoretical risk of HIV transmission has been estimated to be less than 1 in 903 000.1 Accurate estimates of the risk of transfusion-transmitted viral infections are important data for the risk-benefit analysis of homologous blood transfusions and in assessing the cost-effectiveness of new screening tests or methods of donor assessment. Schreiber et al. recently reported estimates of the risk of transfusing blood collected during the infectious "window period" (the time between a non- reactive blood donation and a repeat blood donation confirmed positive by the same test) at five United States blood centres.2 We used a method similar to that of Schreiber et al. to estimate the incidence of HBV, HCV and HIV in repeat Victorian blood donors and the risk of collecting blood infective for the viruses but seronegative by screening tests. Window-period collections are responsible for most transmissions of these three viruses. Methods A glossary of terms is shown in the Box. The donation interval was extracted from Victorian Red Cross Blood Bank records for all repeat whole blood donations given in Victoria in the 22-month period 1 March 1994 to 31 December 1995. This period was chosen because an algorithm was finalised in March 1994 to decide whether a donor reactive to a second generation HCV screening test was truly positive, liable to transmit HCV and liable to the sequelae of infection.3 Patients attending for autologous, directed or therapeutic donations were excluded, as were donors returning for repeat testing or counselling only. Plasma donors were not analysed because they are selected from repeat donors, there are no seroconversions and plasma undergoes virucidal procedures in fractionation. In the study by Schreiber et al., seroconversion intervals all lay within a three-year period.2 In contrast, in our study, seroconversion intervals were not required to commence in the same period, but were taken back to the year of the introduction of the screening test for each virus that was used in 1994-1995 in order to increase the number of seroconversions available for study. Therefore, the study period was different for different tests, but required that the reactive donation was given between March 1994 and December 1995. HBV: Seroconverting donors were identified whose seroconversion interval lay between the introduction of the current HBV surface antigen test (Auszyme Monoclonal, Abbott Laboratories, Illinois, USA) in January 1994 and the end of the study in December 1995. HCV: Seroconverting donors were identified whose initial (negative) donation was given after the introduction of the current second generation screening test (Abbott HCV EIA 2nd generation, Abbott Laboratories, Wiesbaden, Germany) in December 1991 and whose second (reactive) donation was given between March 1994 and December 1995. HIV: Seroconverting donors were identified whose initial (negative) donation was given after the current screening test for HIV antibody (Genelavia MIXT. Screening kit for the detection of antibodies to HIV-1 and HIV-2 in serum/plasma by enzyme immunoassay. Sanofi Pasteur, Marne la Coquette, France) was introduced in July 1992 and whose second (reactive) donation was given between March 1994 and December 1995. The repeat donor population screened by the same test was calculated to match the seroconversion study period for each disease by assuming that all repeat donors in the study period gave blood on 31 January 1995 (midpoint of the study period). For HBV, the number of donors was found whose previous donation was less than 53 weeks before (January 1994); for HCV, the interval was 165 weeks (December 1991); and, for HIV, the interval was 134 weeks (July 1992). Incident rates The incident rate was calculated as the number of incident cases (i.e., the number of seroconversions) divided by the sum of the interdonational intervals, in person-years, as described by Busch et al.,3 of all the donors in the study period. Risk estimation To derive the residual risk of transmission of each virus, the number of seroconversions were multiplied by the reported window periods before seroconversion, expressed in fractions of a year. The product is the probability that a seroconverting donor gave an infectious unit of blood during the window period that was not detected as seropositive by the screening tests currently in use and could therefore have been given in a blood transfusion.2 Results Repeat whole blood donors gave 358 332 donations in which the interdonational interval lay between March 1994 and December 1995. Half of the interdonational intervals were 12-15 weeks, with none less than 12 weeks. Ninety per cent of interdonational intervals were less than 54 weeks. Hepatitis B virus There were two seroconversions in the interval covered by the same screening test. There were 325 534 interdonational intervals after January 1994, calculated as 53 weeks before the end of January 1995, representing 6 221 761 person-weeks. The incidence rate of HBV was therefore 2 in 6 221 761 person-weeks, or 1.67 per 100 000 person-years. Interdonational intervals for the two seroconvertors were 77 and 178 days. The HBV window period is thought to be 59 days (range, 37-87),5 so the previous donation of each of the two seroconvertors could have been falsely negative for a total window period of 118 days (range, 74-174) in 6.22 million person-weeks, or 2.71 per million donations. The risk of giving blood infective for HBV (i.e., in the window period) was therefore 2.71 per million donations (range, 1.70-4.00). Hepatitis C virus There were three seroconverting whole blood repeat donors whose seronegative donation was after December 1991 and whose second (reactive) donation was between March 1994 and December 1995. Interdonational intervals for the three seroconvertors were 96, 651 and 1369 days, respectively. Of the 358 332 repeat donations in the 22 months from March 1994, the first donation of 349 226 interdonational intervals was given after December 1991, calculated as 165 weeks before the end of January 1995. The intervals represent 8 221 189 person-weeks, giving an incidence rate of HCV of 1.89 per 100 000 person-years. The HCV window period for second generation antibody tests is considered to be 82 days (range, 54-192).3,6 The risk of donating blood infective for HCV but seronegative was therefore 246 days (range, 162-576) in 8 221 189 person-weeks, or 4.27 per million donations (range, 2.82-10.01). HIV There were two seroconverting whole blood repeat donors whose seronegative donation was after July 1992 and whose reactive donation was between March 1994 and December 1995. Interdonational intervals for the two seroconvertors were 279 and 223 days. There were 347 076 interdonational intervals after July 1992, calculated as 134 weeks before January 1995. The donations represent 7 951 347 person-weeks, or 152 911 person-years, giving an incidence rate of HIV of 1.31 per 100 000 person-years. The HIV window period for second generation tests is considered to be 22 days (range, 6-38).7 The risk of donating blood infective for HIV but seronegative was therefore 44 days (range, 12-76) in 7 951 341 person-weeks, or 0.79 per million donations (range, 0.22-1.37). Discussion The effect of modifying the model used by Schreiber et al.3 depends on the length of the interdonational intervals of the study population compared with the intervals for seroconvertors. If long interdonational intervals are characteristic of seroconvertors, there will be a progressive overestimation of incidence in our model compared with that of Schreiber et al. This is because the total population of intervals is skewed strongly towards 12-15 weeks, and long intervals are under-represented in this study. HBV: Schreiber et al. argued that the true risk of a seronegative donation which is nevertheless infective is higher than that identified by HBV surface antigen because only 42% of HBV incident infections persist to be detected by the HBV surface antigen assay.2 Application of this adjustment to the risk in Victoria yields a window-period risk of 6.45 per million donations (range, 4.05-9.52). The comparable figure in the United States is 15.83 per million (range, 6.82-31.97)2 and, in France, 8.45 per million (range, 2.8-25.2).8 In our study, the unadjusted incidence of HBV in Victorian repeat volunteer donors was 1.67 per 100 000 person-years, comparable to the unadjusted incidence in the Australian general population of 2.4 per 100 000 person-years.9 The similarity of the two figures suggests that the critical factors for community transmission of HBV have not been identified well enough to assist in donor selection. During the study period, each time they donated blood donors signed a form stating that they had not engaged in male-to-male sex or used intravenous drugs. HCV: A current estimate of the incidence of HCV in Australia is 7.6 per 100 000 person-years.10 The estimate has been considered unreliable because of the unlikeliness that mild cases would be detected, although most of the individuals tested were more likely to be at high risk. Locarnini et al. hypothesised that if the number of incident cases were underestimated by a factor of three, and that 75% were intravenous drug users, then the true rate could be extrapolated to 22.2 per 100 000 per year.11 In our study, the 10-times-lower incident rate of HCV in repeat donors of 1.89 per 100 000 person-years is evidence of the low-risk behaviour of repeat volunteer blood donors. The risk of transmission of HCV by blood transfusion in Victoria in the window period was 246 days in 8 221 189 person-weeks, or 1 in 234 000 donations (range, 100 000-355 000). The comparable United States figure is 1 in 103 0002 and, in France, 1 in 223 000.8 HIV: The incidence of HIV in Australia is thought to be 480 per year from 1993, or 2.7 per 100 000 person-years.12 Our study shows that repeat Victorian blood donors have an incidence of HIV of 1.31 per 100 000 person-years. The limited reduction in the incidence of HIV in repeat volunteer donors is evidence of an increasing proportion of seroconversions caused by activity not identified as high risk. The risk of collecting a seronegative but HIV-infected donation in the window period is 1 in 1.27 million, similar to the calculation by Dax et al.1 The comparable United States figure is 1 in 493 0002 and, in France, 1 in 571 000.8 The incidence rate of HBV and HIV in regular blood donors is comparable to that of the general population. This suggests that donor assessment is ineffective in repeat donors, presumably because those who contract HBV or HIV do not regard themselves as at risk by the criteria applied by the blood bank. The incidence rate of HCV is lower for regular blood donors than the general population. The relative effectiveness of HCV discrimination presumably reflects the lack of experimentation by regular donors with intravenous drugs. The risk of window-period transmission of HBV, HCV and HIV in Victoria is low and compares favourably with overseas figures. The risk is probably overestimated for HIV because of the long seroconversion intervals. Care should be exercised when generalising from these figures because of the small number of seroconversions. However, the medical community and the general public should be reassured by this evidence that the blood supply is very safe. Acknowledgements We wish to thank John Butler, Christine Carroll, Phil Keily and Tony Chan at the Red Cross Blood Bank Victoria for data collation and processing, and John McNeil of Monash University for critical review of the manuscript. References Dax EM, Healey DS, Crofts N. Low risk of HIV-1 infection from blood donation: a test-based estimate. Med J Aust 1992; 157: 69. Schreiber GB, Busch MP, Kleinman SH, Korelitz JJ. The risk of transfusion-transmitted viral infections. N Engl J Med 1996; 334: 1685-1690. Busch MP, Korelitz JJ, Kleinman SH, et al. Declining value of alanine aminotransferase in screening of blood donors to prevent posttransfusion hepatitis B and C virus infections. Transfusion 1995; 35: 903-910. Strasser SI, Smith BC, Watson KJR, et al. Evaluation of blood donors with equivocal hepatitis C serological results. Med J Aust 1995; 162: 459-461. Mimms LT, Mosely JW, Hollinger FB, et al. Effects of concurrent acute infection with hepatitis C on hepatitis B virus infection. BMJ 1993; 307: 1095-1097. Lelie PN, Cuypers HT, Reesink HW, et al. Patterns of serological markers in transfusion transmitted hepatitis C infection using second generation HCV assays. J Med Virol 1992; 37: 203-209. Busch MP, Lee LL, Satten GA, et al. Time course of detection of viral and serological markers preceding human immunodeficiency virus type 1 seroconversion: implications for screening blood and tissue donors. Transfusion 1995; 35: 91-97. Courouce A-M, Pillonel J. Transfusion transmitted viral infections. N Engl J Med 1996; 335: 1609-1610. Kaldor JM, Plant AJ, Thompson SC, et al. The incidence of hepatitis B infection in Australia: an epidemiological review. Med J Aust 1996; 165: 322-326. Andrews R, Curran M. Enhanced surveillance for incident cases of hepatitis C in Australia, 1995. Communicable Diseases Intelligence 1996; 20: 384-388. Locarnini S, McAnulty. Hepatitis C surveillance [editorial]. Communicable Diseases Intelligence 1996; 20: 388-389. Feachem RGA. Valuing the past -- investing in the future: evaluation of the National HIV/AIDS Strategy 1993-94 to 1995-96. Canberra: Commonwealth Department of Human Services and Health, 1995: 29-40. (Received 5 Dec 1996, accepted 16 April 1997) Authors' details Red Cross Blood Bank, Southbank, VIC. Gordon S Whyte, FRACP, FRCPA, Director; Helen F Savoia, MB BS, Registrar. No reprints will be available from the author. Correspondence: Dr G S Whyte, PO Box 354, South Melbourne, VIC 3205. E-mail: gwhyte @ rcbbv.org.au ©MJA 1997 <URL: http://www.mja.com.au/> © 1997 Medical Journal of Australia.

Gordan S Whyte · Helen F Savoia

HTLV-I and blood safety: let the community decide Discussion on screening of blood for rare viruses must go beyond the blood transfusion services MJA 1997; 166: 454Subsequently cited in Moaven L. Should we be screening blood donors for hepatitis G virus? The case for screening. MJA 1998; 169: 373-374 Readers may print a single copy for personal use. No further reproduction or distribution of the articles should proceed without the permission of the publisher. For permission, contact the Australasian Medical Publishing Company Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au/>". - ©MJA1997 Despite the steady reduction over time in the risks associated with blood transfusion, there has been a parallel increase in the community's expectations of the safety standards that must be met by blood and blood products. In the past, the acute complications of transfusion were perhaps viewed by the community as acceptable risks. The contamination of blood products by HIV changed all that; here was a bloodborne infection that produced life-threatening complications years after transfusion. Virtually all patients who received HIV-contaminated blood or blood products became chronically infected and progressed to AIDS and a premature death. Furthermore, in the community, HIV was widely perceived as being associated with society's stigmatised or marginalised groups. Human T-cell lymphotropic virus type I (HTLV-I) was discovered before HIV, but screening of blood for HTLV-I was not implemented with the same degree of urgency as for HIV. In most developed countries, HTLV-I was considered to be an exotic infection which posed a minimal threat to the blood supply. Even in countries endemic for HTLV-I, less than 5% of people with the infection develop serious disease.1,2 There is so little HTLV-I-related morbidity in Australia that single cases still merit case reports.3 Nevertheless, by the mid 1980s HTLV-I screening tests were ready for mass use, and Japan, the only industrialised country with a substantial prevalence of HTLV-I infections, began screening blood for the virus. With litigation arising from HIV infection with transfusion of blood or blood products in full swing in the industrialised world, the American Red Cross in 1988 decided to screen all donations for HTLV-I.4 Can a decision be made to reduce the safety of the blood supply, even if only to a very small degree? In Australia, a response was required. The national peak blood transfusion advisory body, the Red Cross National Blood Transfusion Committee, recommended universal screening of blood donors in 1989 and again in 1991, but the National Health and Medical Research Council did not concur because, it was argued, the costs of universal screening far outweighed any public health benefit.5 Despite these differences in professional judgements, by early 1993 all Australian Red Cross blood banks had introduced HTLV-I screening. In this issue of the Journal, Whyte outlines for the first time in Australia the results of this screening and shows that Australian blood donors have among the lowest HTLV-I prevalence rates ever recorded. He then goes on to implicitly ask whether it is time to review the screening policy. The answer to this question depends very much on the perspective being taken. For blood transfusion services wishing to reduce the risk to the recipients of their products, not to mention their medicolegal vulnerability, the decision to screen all donations for HTLV-I can seem very logical, even if the prevalence of infection is very low. In the United Kingdom, where HTLV-I prevalence in blood donors is some five times higher than in Australia,6 universal screening has not been adopted, but there have been recent calls to review this policy.7 From the point of view of governments and tax-payers, facing ever-increasing demands on health care and escalating health budgets, perhaps health expenditure in other areas may have had a greater impact in value-for-money terms. Screening blood donations for HTLV-I in Australia has an annual cost of two to three million dollars per year in test kits alone, and laboratory staff and handling costs probably account for seven million dollars (E Dax, Director, National Serological Reference Centre, personal communication). The contrasting recommendations of the Australian Red Cross and the National Health and Medical Research Council on HTLV-I screening highlight a deficiency in the decision-making processes on aspects of blood transfusion in Australia. While governments fund State and Territory blood transfusion services and strongly influence their functioning, the Australian Red Cross is the legal entity liable for the blood products. The decisions by the blood transfusion services may inevitably be based on a narrower view of the issues involved than that shared by the community. Is it possible to reconsider the decision to screen blood donations for HTLV-I? Put in another way, can a decision be made to reduce the safety of the blood supply, even if only to a very small degree? If the answer is yes, the process of re-evaluation should take place in a broader context than has been adopted in the past. A framework must be established so that the decision is made by the community as a whole, not just by the blood transfusion services. The recent establishment by the Australian Health Ministers Advisory Council of a Blood and Blood Products Committee, and the national restructuring of the State and Territory Red Cross blood transfusion services into a single corporate entity (see page 453 of this issue of the journal), are valuable steps towards integrated decision-making, but these changes do not go far enough. These two entities need to be brought closer together and utilise expertise in public health, health economics and other areas, as required. A review of HTLV-I screening would ideally be carried out in the context of other infectious agents that can be transmitted by blood. It may be more cost-effective to screen for agents such as parvovirus B19 (which causes pure red cell aplasia), although susceptibility is limited to a very small proportion of the population. Hepatitis G virus and human herpesvirus type 8 (associated with Kaposi's sarcoma and B-cell body cavity lymphoma) are newly discovered viruses that may also require consideration for routine screening once tests become available.8 If deliberations about blood screening are to take place in a broader context, thought must also be given to legal changes that shift the burden of sole liability from the blood transfusion services. The New Zealand "no-fault" compensation model has long been discussed as one possible solution. Another approach may be legislated protection of the blood transfusion services against litigation, provided bloodscreening policies were determined and implemented according to specified guidelines. Although HTLV-I-related disease has been rare in Australia, HTLV-I infection is present at relatively high levels in some populations of indigenous people, and probably also in some migrant groups. If it is decided to reconsider HTLV-I screening of donations, its abandonment is not the only alternative to the status quo. A policy of screening only new donors would have detected all 21 HTLV-I-positive individuals in the time period of Whyte's study and reduced the extent of testing required by over 80%. Therefore, it may be sufficient to screen blood donors only once and thereafter assume that their HTLV-I status remains unchanged, or carry out testing again after five or 10 years. Another approach could be to use the donor interview to identify people who may be at higher risk of HTLV-I. Screening on the basis of country of birth, for example, would have detected a third of the individuals confirmed positive for HTLV-I in Whyte's study. Blood transfusion will never be risk-free. With the risk-benefit balance now many times more favourable than it has ever been, perhaps the time is right to engage the community in a discussion that brings both public health and economic issues into decision-making about blood safety. John M Kaldor Deputy Director and Professor of Epidemiology National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Sydney, NSW. Morris JDH, Eddleston ALWF, Crook T. Viral infection and cancer. Lancet 1995; 346: 754-758. Kondo T, Kono H, Miyamoto N, et al. Age- and sex-specific cumulative rate and risk of ATLL for HTLV-I carriers. Int J Cancer 1989; 43: 1061-1064. Kirkland MA, Frasca J, Bastian I. Adult T-cell leukaemia lymphoma in an Aborigine. Aust N Z J Med 1991; 21: 739-741. Centers for Disease Control. Licensure of screening tests for antibody to human T-lymphotropic virus type I. MMWR Morb Mortal Wkly Rep 1988; 37: 736-740, 745-747. National Health and Medical Research Council, Communicable Diseases Standing Committee. HTLV-I screening: outcome of consideration by the Executive. Canberra: NHMRC, 4 December 1992. Brennan M, Runganga J, Barbara JAJ, et al. Prevalence of antibodies to human T cell leukaemia/lymphoma virus in blood donors in north London. BMJ 1993; 307: 1235-1239. Pagliuca A, Pawson R, Mufti GJ. HTLV-I screening in Britain. BMJ 1995; 311: 1313-1314. Allain J-P. Screening blood donors for markers of new viruses. Lancet 1997; 349: 584-585. World Health Organization, International Agency for Research on Cancer. Human Immunodeficiency viruses and human T-cell lytmphotropic viruses. Monographs from the meeting of an IARC Working Group on the Evaluation of Carcinogenic Risks to Humans; 1996 June 11-18; Lyon. Geneva: WHO, 1996. ©MJA 1997 <URL: http://www.mja.com.au/> © 1997 Medical Journal of Australia.

John M Kaldor

Is screening of Australian blood donors for HTLV-I necessary? Gordon S Whyte MJA 1997; 166: 478 For editorial comment see Kaldor Subsequently cited in Wong et al. Should we be screening blood donors for hepatitis G virus? The case against screening. MJA 1998; 169: 375-377 Readers may print a single copy for personal use. No further reproduction or distribution of the articles should proceed without the permission of the publisher. For permission, contact the Australasian Medical Publishing Company Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au/>". Abstract - Introduction - The decision to screen blood for HTLV-I - Blood donor data collection - Extrapolation of State data to national data - New and repeat Australian donors - Screening of donors - Prevalence and incidence of HTLV-I - Risk of HTLV-I transmission - Discussion - Acknowledgement - References - Authors' details - ©MJA1997 Abstract Objective: To re-examine the 1992 decision by Australian Red Cross for its blood banks to screen blood donors for antibody to human T-cell lymphotropic virus type I (HTLV-I) by determining the risk of its transmission by blood transfusion. Methods: Data on patterns of return behaviour by repeat blood donors in Victoria were modelled to deduce the number of donors giving repeat donations in Australia from March 1993 to December 1995. Data on annual donor and issued cellular blood products from 1992 to 1995 were obtained from national Red Cross statistics. From the numbers of donations given by repeat donors, together with the number of new donors, the number tested for HTLV-I was deduced. The number and characteristics of donors screened positive for HTLV-I antibody were collated. The crude prevalence of HTLV-I was calculated by dividing the number of donors with HTLV-I by the total number of donors (repeat donors and new donors). The incidence of HTLV-I was calculated by dividing the number of seroconversions in repeat donors by the cumulative period of donor exposure. Results: Sixteen homologous and five autologous donors were found to be positive for HTLV-I; none seroconverted and no clear risk factors for HTLV-I were identified. The prevalence of HTLV-I in Australian donors is 1 in 100 000 and the incidence less than 1 in 1 million person-years. In the absence of HTLV-I screening, the calculated risk of a transfused patient developing HTLV-I infection is 1 in 370 000, with a risk of developing HTLV-I disease of 1 in 9 to 15 million. Conclusion: Three possible future courses of action for screening for HTLV-I are to screen every donation, to screen only new donors or to discontinue screening altogether. Using the information in this study, public discussion should be encouraged to assist stakeholders to agree on an acceptable level of risk and an appropriate level of screening for HTLV-I in Australia. MJA 1997; 166: 478-481 Introduction Human T-cell lymphotropic virus type I (HTLV-I) is endemic in all continents including Australia,1,2 where in some Aboriginal communities it is present in up to 14% of individuals.3-6 HTLV-I was first described in cases of aggressive T-cell leukaemia in southern Japan7 and in a T-cell lymphoma in a Jamaican patient.8 In areas endemic for the virus, 2% to 4% of those infected rapidly develop fatal leukaemia, with a peak incidence in the sixth decade of life.9 Progressive spastic myelopathy (or tropical spastic paraparesis), first reported in association with HTLV-I infection in Caribbean patients,9 occurs infrequently (0.25%).9 Transmission of HTLV-I is primarily by sexual contact and by infected cellular blood products (packed red cells, platelet-rich plasma and whole blood); breast milk is a major route of HTLV-I transmission in communities where the virus is endemic.10 In predominantly white communities, occasional cases of HTLV-I infection, in the absence of any risk factors, may represent transmission across several generations in a family.11 In a survey of 11 121 Northern Territory blood donors in 1991-1992, only one donor (with no evident risk factors) was confirmed as HTLV-I seropositive.6 Since March 1993, all Australian blood donors have been screened for antibody to HTLV-I. The decision to implement screening was made by the National Executive of the Australian Red Cross in February 1992, despite a lack of agreement among some government advisory bodies. The decision to screen for a rare transfusion-transmitted disease can be re-examined in the light of the results of HTLV-I screening of Australian blood donors from 1993 to 1995. The decision to screen blood for HTLV-I in Australia In October 1986, the American Red Cross proposed that, when a test became available, blood donors should be screened for HTLV-I as this retrovirus could be spread by blood transfusion and had been detected in blood donors.12 In November 1988, the United States Food and Drug Administration recommended testing of whole blood and cellular blood products for antibodies to HTLV-I,13 which was followed by a public review of the issues involved.14 Universal screening was also introduced in Canada, France, the Netherlands and Sweden. In Australia, after recommendations by the Red Cross National Blood Transfusion Committee (in September 1989 and later in March 1991) for HTLV-I screening to be funded, the then Federal Minister for Health sought advice from the National Health and Medical Research Council (NHMRC) in January 1992. In July 1991, the Communicable Diseases Standing Committee of the NHMRC had decided that the costs of screening Australian blood supplies (for HTLV-I) outweighed any public health benefits. This position was endorsed in 1992 by the Public Health Committee of the NHMRC15 and published by the Executive of the NHMRC in December 1992.16 However, the NHMRC also stated ". . . decisions on screening may have to be made on other than public health grounds".16 In February 1992, in the absence of a decision from NHMRC and acting on legal advice, the National Blood Transfusion Committee of the Australian Red Cross recommended that cellular blood products be screened from May 1992.17 By March 1993, although some State governments refused to fund HTLV-I screening, all Red Cross Blood Banks had commenced routine testing for HTLV-I under instruction from the Red Cross National Executive. A report by the Australian Health Ethics Committee, which was endorsed by the NHMRC in November 1993, stated that the cost of screening for HTLV-I was considerable and the risk to the community was low, and that "the spectre of large damages (litigation) . . . probably had a significant influence on the reasoning leading to implementation".17 It considered that the risk of transfusing HTLV-I-infected blood, although real, was rare. The report concluded that a decision not to screen all blood in Australia for HTLV-I would not be unethical.17 Blood donor data collection Data on the number of individuals who donated whole blood in Victoria between March 1994 and December 1995 and the interval from the date of the previous donation were extracted from Victorian Red Cross Blood Bank records. Patients attending for autologous, directed or therapeutic donations were excluded, as were donors returning for repeat testing or counselling only. Plasma donors were excluded because HTLV-I is not transmitted by plasma. The 1994-1995 attendance pattern was comparable with attendance patterns of repeat donors attending in June and July between 1993 and 1996 and was therefore applicable. Data on the number of whole blood collections in Australia and the number of new donors each year were obtained from the annual statistics of the Australian Red Cross Society. Data on the number of blood donations and the number of issues of cellular blood products in Australia for the financial years 1992-95 were obtained from national Red Cross statistics. Extrapolation of State (Victorian) data to national data Donor attendance patterns Repeat donors give many donations, so it is necessary to deduce the number of donors tested for HTLV-I from the total number of donations. The total number of repeat donations is used to calculate the number of repeat donors giving the donations by using a hypothetical model, together with the number of donations given by new donors. Using this information, the prevalence of HTLV-I in donors can then be estimated. Iterative model: The pattern of return after previous donations by Victorian repeat donors was applied to a hypothetical model in which 1000 donations were given each month over 34 months. Using an iterative spreadsheet model, the number of donors giving 1000 repeat donations each month from March 1993 to December 1995 was calculated (Figure, below). It was assumed that all repeat donors in Australia had a similar pattern of repeat donation. By analogy, the proportion of repeat donors contributing the 34 000 donations from repeat donors in the model was applied to the total number of donations from repeat donors in Australia over the 34-month period. To apply the model, it was assumed that the same number of repeat donations was given each month and that the discounting effect of donor rejection was constant over time. The number of Victorian donors and the intervals between donations were extrapolated to all repeat donations in Australia between March 1993 and December 1995 to derive a figure for donor exposure in person-years. "Donor exposure" is the sum of the time between one donation and the next for all donation intervals during the period. The sex and age distribution of Victorian donors was extrapolated to all Australian donors. Prevalence, incidence and risks of HTLV-I The number and characteristics of donors confirmed positive for HTLV-I were provided by Red Cross blood banks in each State and Territory. Donors were confirmed positive if their plasma reacted in triplicate with one of seven HTLV-1 enzyme-linked immunosorbent assay screening tests (Genetic Systems; Abbott; Cambridge recombinant/Ortho; Serodia particle-agglutination; Murex; Sanofi Platelia new; Organon Teknica), as approved by the National Reference Laboratory, and showed a diagnostic pattern on a western blot. The crude prevalence of HTLV-I was calculated by dividing the number of donors with HTLV-I by the total number of donors tested (repeat donors and new donors). The incidence of HTLV-I was calculated by dividing the number of seroconversions in repeat donors by the cumulative period of donor exposure. The risk of disease transmission was calculated from the infectivity rate for HTLV-I and the long-term risk of HTLV-I disease in patients. New and repeat Australian donors The return patterns for repeat donors over the period remained much the same. No donors returned within 12 weeks of donating blood. Of the donors who returned after making a previous donation, 0.29, 0.74, 0.84, 0.89, 0.92 and 0.94 had returned after successive quarters and 0.06 had returned after 18 months. Across Australia, first-time donors gave 335 183 whole blood donations and repeat donors gave 2 038 927 whole blood donations between March 1993 and December 1995. The proportion of first-time donations over the four fiscal years from July 1992 was 0.14, 0.14, 0.14, and 0.13, respectively. Screening of donors for HTLV-I By applying the pattern of return for repeat donors in Victoria to a hypothetical figure of 1000 donations a month over 34 months from repeat donors, it was concluded that the 34 000 donations would have been given by 19 197 donors in Victoria who had returned within 18 months. Furthermore, 6% (2040) would have been given by repeat donors whose previous donation was more than 18 months previously. By applying the Victorian model to the national statistics, it was concluded that over the 34 months 2 038 927 donations were given by 1 273 550 repeat donors. In addition, there were 335 183 new donors and donations. Therefore, a total of 1 608 733 individuals had been screened for HTLV-I. Some States had begun testing for HTLV-I before March 1993, but the high proportion of repeat donors in Australia, the small number of infected donors and the absence of serconversion permit the assumption that they would have been identified if screening had been delayed to March 1993. Prevalence and incidence of HTLV-I in blood donors To December 1995, 21 donors had been confirmed positive for HTLV-I in Australia, each on the first occasion the donor was tested. Five of the blood collections were for autologous transfusion. There were no seroconversions (a change in serological status from negative to positive) during the study period. Two donors were identified before June 1992, with 5, 8 and 6 in each subsequent 12 months. More men and more first-time donors were positive than expected, but the age distribution matched that of the general donor population (Box, below). There were no clear patterns of disease acquisition, although four of the five donors born in endemic areas were aged less than 40. Therefore, the crude prevalence of HTLV-I in Australian blood donors was 16 in 1 608 733, or 1 in 100 546. In Victoria, repeat whole blood donors gave 358 332 donations between March 1994 and December 1995, with intervals from the previous donation of up to 23.5 years. The repeat donors represent 11 851 014 person-weeks of exposure, or 227 904 person-years. By extrapolation, 2 038 927 repeat donations in Australia represent 1 296 785 person-years of exposure. There were no seroconversions. Therefore, the crude incidence of HTLV-I in Australian blood donors was less than 1 in 1 000 000 person-years. Risk of HTLV-I transmission via blood transfusion The risk of transmitting HTLV-I in Australia by blood transfusion over the study period was calculated from the number of donations given by 16 donors in 2 374 110 donations. The spreadsheet calculations showed that 1.6 million donors gave 2.4 million donations, so 16 donors would have given 24.6 donations. Therefore, the risk of receiving blood infected with HTLV-I before testing was about 1 in 100 000. The infectivity rate has been recently reported as 0.27,18 so only 1 in 370 000 transfusion recipients would become infected. Relatively few (2.5%-4%) people with HTLV-I infection not acquired by blood transfusion risk developing disease after 10 to 30 years.19 Therefore, the risk of developing HTLV-I disease from blood transfusion in Australia without testing would have been 1 in 9 to 15 million. Transfusion recipients, particularly those who are immunocompromised, may have a shorter incubation period,20 and infants of infected mothers have a 25% chance of becoming infected.21 If universal screening were discontinued, then the risk of transfusing infected blood would progressively return to the pretesting situation because of the recruitment of new donors from a population with the same characteristics as at present, as well as the retirement of repeat donors who have already been screened. In the absence of seroconversion, if only previously untested donors are screened for HTLV-I then there will be a zero risk of transmitting HTLV-I by blood transfusion. However, seroconversion has been reported in Dutch, French and American studies.22-24 If only the 14% of donations by new donors are screened, then the costs to Red Cross and the community would be significantly reduced. Discussion Our results have shown that the prevalence of HTLV-I in Australian donors is 1 in 100 000. By comparison, the prevalence of hepatitis C virus in new Victorian donors is 1 in 560; of hepatitis B virus, 1 in 650; and of HIV, 1 in 27 000. However, the introduction of universal blood screening for these diseases has reduced the risk to the transfused population for hepatitis C virus to 1 in 150 000, for hepatitis B virus to 1 in 150 000 and for HIV to 1 in 1.3 million.25 The risk of transfusing HTLV-I-infected blood would have been 1 in 100 000 without screening. In the United Kingdom, HTLV-I has been found in 1 in 20 000 donors; in the United States, in 1 in 6000; and in Sweden and the Netherlands, in 1 in 50 000.19 The decision by the Australian Red Cross to commence testing of all blood donations for HTLV-1 was contentious. Red Cross had shown that HTLV-I was present in the Australian blood supply,9 and believed that testing should be undertaken to ensure the safety of the blood supply as well as its own credibility.26 Our findings have shown that in the three years since screening began 16 Australian blood donors were found with HTLV-I. Without screening, the risk of viral transmission by blood transfusion would have been 1 in 100 000. On the other hand, the NHMRC and some State governments believed that universal screening was not justified on public health grounds. The findings in this study show that the risk of a blood transfusion recipient developing HTLV-I-related disease as a result of transfusion is about 1 in 10 million; these data were not available when Red Cross made their decision for universal screening. From the perspective of Red Cross and transfusion recipients, screening affords the certain benefit27 of the removal of the threat of HTLV-I infection from transfusion whatever the future risk of developing leukaemia. From a public health perspective, the certain benefit is the prevention of the very low risk of leukaemia or spastic paraparesis. Stakeholders (Australian Red Cross Blood Service, State and Federal governments and the community) would be assisted by public discussion of an acceptable level of risk and appropriate level of screening for rare transfusion-transmitted diseases; HTLV-I provides a suitable test case. It may be appropriate to screen only new donors for HTLV-I (at a lower cost) now that the donor base has been repeatedly screened. However, it is likely that Red Cross would need a form of statutory defence, such as that provided in Victoria for HIV and hepatitis C virus,28 if it were to apply less-than-universal screening for HTLV-I and other conditions of low risk to public health. Acknowledgement I thank the Directors of each State Blood Transfusion Service for providing the figures for HTLV-I and for constructive and critical comment. References Doherty RR. HTLV-I in Australia and Oceania: long term resident or recent immigrant? Med J Aust 1996; 164: 84-86. Gallo RC. A surprising advance in the treatment of viral leukemia. N Engl J Med 1995; 332: 1783-1784. Ascher D, Goudsmit J, Poeroy K, et al. Antibodies to HTLV-I in populations of the south western Pacific. J Med Virol 1988; 26: 339-351. Bastian I, Hinuma Y, Doherty RR. HTLV-I among Northern Territory Aborigines. Med J Aust 1993; 159: 12-16. Bastian I, Gardner J, Webb D, Gardner I. Isolation of a human T-lymphotropic virus type I strain from Australian Aboriginals. J Virol 1993; 67: 843-851. Bastian I, Dent J, McFarlane R, et al. HTLV-I among Northern Territory blood donors. Med J Aust 1993; 159: 7-12. Hinuma Y. Natural history of the retrovirus associated with a human leukemia. Bio essays 1985; 3: 205-209. Poeisz B, Ruscetti F, Gazdar A, et al. Detection and isolation of type C retrovirus particle from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma. Proc Natl Acad Sci U S A 1980; 77: 7415-7419. Hollsberg P, Hafler DA. Pathogenesis of diseases induced by human lymphtropic virus type 1 infection. N Engl J Med 1993; 328: 1173-1182. Nakano S, Ando Y, Saito K, et al. Primary infection of Japanese infants with adult T-cell leukemia associated retrovirus (ATLV): evidence for viral transmission from mothers to children. J Infect 1986; 12: 205-212. May JT, Stent G, Schnagl RD. Antibody to human T-cell lymphotropic virus type I in Australian Aborigines [letter]. Med J Aust 1988; 149: 104. Barnes D. HTLV-I: to test or not to test. Science 1988; 242: 372-373. Parkman PD. HTLV-I antibody testing; instruction of all registered blood establishments. Bethesda: Food and Drug Administration, 1988. Public Health Service Working Group. Licensure of screening tests for antibody to human lympotropic virus type I. MMWR Morb Mortal Wkly Rep 1988; 37: 736-747. Anon. Blood tests would drain funds: medics. Courier Mail 1992 June 5: 15. National Health and Medical Research Council, Communicable Diseases Standing Committee. HTLV-I screening: outcome of consideration by the Executive. Canberra: NHMRC, 4 December 1992. National Health and Medical Research Council. Case study of screening blood donations for human T-cell lymphotropic virus type I: Report of the Australian Health Ethics Committee. Canberra: NHMRC, November 1993. Donegan E, Lee H, Operskalski GM, et al. Transfusion transmission of retroviruses: human T-lymphotropic virus type I and II compared with human immunodeficiency virus type I. Transfusion 1994; 34: 478-483. Pagliuca A, Pawson R, Mufti GJ. HTLV-I screening in Britain. BMJ 1995; 311: 1313-1314. Kaplan JE, Litchfield B, Roualt C, et al. HTLV-I associated myelopathy associated with blood transfusion in the United States. Neurology 1991; 41: 192-197. Sugiyama H, Doi H, Yamaguchi K, et al. Significance of post-natal mother-to-child transmission of human T-lymphotropic virus type-1 on the development of adult T-cell leukemia/lymphoma. J Med Virol 1986; 20: 253-260. Vrielink H, van der Poel CL, Reesink HW. Efficacy of selected versus random blood donor screening for anti HTLV-I antibodies [letter]. Vox Sang 1995; 68: 251-252. Courouce AM, Pillonel J. Transfusion-transmitted viral infections. N Engl J Med 1996; 335: 1609-1610. Schreiber GB, Busch MP, Kleiman SH, Korelitz JJ. The risk of transfusion-transmitted viral infections. N Engl J Med 1996; 334: 1685-1690. Whyte G S, Savoia H F. The effectiveness of donor selection for reducing the risk of HCV, HBV and HIV in new blood donors in Victoria. Med J Aust . In press. Wylie B. HTLV-I: is donor screening really necessary? [editorial] Med J Aust 1993; 159: 4-5. McGuire A, Henderson J, Mooney G. The economics of health care. London: Routledge, 1994: 112. Health Act 1958 (Vic.), s. 139. Melbourne: The Law Printer, 1995.(Received 5 Aug 1996, accepted 18 Feb 1997) Authors' details Australian Red Cross, Blood Bank of Victoria, Southbank, VIC. Gordon S Whyte, FRACP, FRCPA, Director. Reprints will not be available. Correspondence: Dr G S Whyte, PO Box 354, Southbank, VIC 3205. E-mail: rcbb AT peg.apc.org ©MJA 1997 <URL: http://www.mja.com.au/> © 1997 Medical Journal of Australia.

Gordon S Whyte

Prevalence of hepatitis G virus in Queensland blood donors Len D Moaven, Catherine A Hyland, Ian F Young, D Scott Bowden, Rhonda McCaw, Leigh Mison and Stephen A Locarnini MJA 1996; 165: 369 Subsequently cited in Moaven L. Should we be screening blood donors for hepatitis G virus? The case for screening. MJA 1998; 169: 373-374 and Wong et al. Should we be screening blood donors for hepatitis G virus? The case against screening. MJA 1998; 169: 375-377 Readers may print a single copy for personal use. No further reproduction or distribution of the articles in whole or in part should proceed without the permission of the publisher. For copyright permission, contact the Australasian Medical Publishing Company Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au/>". Abstract - Introduction - Methods - Blood donors - Serological and biochemical testing - Reverse transcription PCR testing - Results - Discussion - Box - References - Authors' details - - ©MJA1996 Abstract Objective: To determine the prevalence of hepatitis G virus (HGV) carriage in Queensland blood donors. Design: Cross-sectional survey with retrospective longitudinal study of HGV-positive donors. Setting: Brisbane Red Cross Blood Bank, 1995. Subjects: 100 consecutive blood donors attending the Blood Bank on two days in October 1995 and 20 blood donors with a raised plasma alanine aminotransferase (ALT) level on their last donation. Outcome measures: Presence of HGV RNA by reverse transcription polymerase chain reaction (RT-PCR) in currently donated blood and in blood samples archived for up to 34 months. RT-PCR used two different reverse transcription methods and three different specific sets of primers and probes. Results: Five of the 120 blood donors were positive for HGV RNA by all RT-PCR methods (four of the 100 with normal ALT levels [4%] and one of the 20 with raised ALT levels [5%]). Retrospective testing of archived samples showed that four of these five had been persistently HGV RNA-positive for at least two years, while the fifth had been HGV RNA-negative on two donations before becoming HGV RNA-positive. No risk factors were identified for this donor. Conclusions: A relatively large number of Queensland blood donors (4%) are persistently HGV RNA-positive. MJA 1996; 165: 369-371 Introduction S ince the introduction of improved diagnostic assays for hepatitis C virus 1 and increased screening of blood donors, 2 the incidence of post-transfusion hepatitis has been reduced to low levels. However, there are still cases of post-transfusion hepatitis where an aetiological agent is not identified. 3 While searching for novel agents that may be associated with post-transfusion hepatitis, two independent groups recently discovered an RNA virus that causes acute and chronic infection in man. 4,5 The two isolates, designated hepatitis G virus (HGV) and GB virus C, respectively, belong to the same species, 6 and findings for one seem applicable to the other. Currently, the only reliable method for determining the prevalence of infection with these viruses is specific reverse transcription polymerase chain reaction (RT-PCR) assay to detect viral RNA. A serological assay to detect carriers of HGV is unlikely to be available in the immediate future, and much of the epidemiology of HGV will rely on RT-PCR-based assays. From the available RT-PCR data, it appears that HGV is transmitted parenterally, with increased prevalence in injecting drug users and patients who have received multiple transfusions. 4,7,8 HGV has a high prevalence in developed countries, with about 1.5% of volunteer blood donors from the United States and Europe being positive for HGV RNA. 4,8 It is not known whether these positive donors are transiently infected or chronic carriers of HGV. We examined the prevalence of HGV in Queensland blood donors. As most donors had plasma stored from previous donations, we were also able to collect unique longitudinal data. Methods Blood donors Consecutive blood donors at the Brisbane Red Cross Blood Bank over two days in October 1995 were asked to participate. The first 100 to sign a consent form agreeing to be tested for HGV were studied (compliance was 100%). These donors all had normal plasma alanine aminotransferase (ALT) levels. Blood was also collected over a three-month period from 20 donors with a raised ALT level on their most recent donation. Six of the 20 had raised ALT levels on two or more previous donations. All donors had signed the donor declaration form indicating they did not fall into an "at risk" group. All testing was performed with the approval of the Queensland Red Cross Blood Transfusion Service Ethics Committee. Serological and biochemical testing All donors were tested for antibodies to hepatitis C virus (HCV), HIV 1, HIV 2 and human T-cell lymphotropic virus (HTLV) and for hepatitis B surface antigen (HBsAg) (Abbott Diagnostics, Chicago, Illinois, USA). They were also screened with a syphilis antibody assay, Sysmic RPR (Diagast, Lille, France). Plasma ALT levels were measured by a microtitre tray assay. 9 Samples positive for HGV RNA were also tested for hepatitis B core specific antibody (Abbott Diagnostics). Reverse transcription PCR testing For RT-PCR testing, the recommendations of Kwok and Higuchi 10 were followed to prevent sample contamination. Blood samples were collected in acid-citrate-dextrose and plasma was stored at 2 70 o C within two hours of collection. RNA was subsequently extracted from these plasma samples with a guanidine thiocyanate and phenol-chloroform extraction procedure. 11 RT-PCR was performed with random hexamers and two sets of PCR primers from the 5 9 untranslated region and the region encoding the non-structural protein 5a of the HGV genome. These primers are part of an HGV primer and capture probe set commercially available from Boehringer Mannheim (Germany). In addition, RT-PCR was performed with primers from the region encoding the protein 5b, as described previously. 12 If a plasma sample was positive for HGV RNA, a separate aliquot of plasma was retrieved from frozen storage and RNA was extracted and tested with all three primer sets. Samples positive for HGV RNA were also tested for HCV RNA (Amplicor, Roche Diagnostic Systems, Branchberg, New Jersey, USA). Donors positive for HGV RNA were tested retrospectively by recovering archived frozen plasma samples from previous donations. These samples had been frozen within two hours of collection and stored at 2 30 o C. As controls, archived plasma samples were also recovered from donors negative for HGV RNA. Archived samples were coded and tested blind. In addition, four of the five donors found to be positive for HGV RNA returned subsequently to donate blood and were retested for HGV RNA. These retrospective and prospective samples were tested with the NS5b primers alone. Results Five of the 120 blood donors were HGV-positive by RT-PCR with all three of the primer sets. These positive donors comprised four of the 100 with normal ALT levels (4%; 95% confidence interval [CI], 1%-10%) and one of the 20 with raised ALT levels (5%; 95% CI, 0.1%-25%). This donor had not had raised ALT levels previously. The remaining 115 donors were negative by all three primer sets. Repeat PCR testing of a separate aliquot of each HGV-positive sample revealed complete concordance of results. The five HGV-positive donors were negative for hepatitis B core-specific antibody and HCV RNA. All donors were negative for antibodies to HCV, HIV 1, HIV 2 and HTLV, for HBsAg and for syphilis RPR antibody. Plasma samples from 22 previous donations given by the five HGV-positive donors were also tested for HGV RNA (see Box). Four donors were HGV-positive for all previous donations ( n = 18), made up to 22-34 months previously. The fifth, a 38-year-old man, was HGV-positive from August 1994, but two previous donations (May 1994 and November 1993) were HGV-negative. His ALT level was normal on each occasion and no risk factor or illness could be identified for this donor despite specific questioning about the period May 1994 to August 1994. Potential risk factors were noted for three of the other HGV carriers (see Box). All HGV-positive donors were well. Four returned for further testing, including the donor who appeared to acquire HGV infection in 1994; they remained HGV-positive on all occasions (up to six months after initial tests). The control archived plasma samples were tested blindly and found to be HGV-negative. Discussion This is the first study to describe the prevalence of HGV in an Australian blood donor population and to provide longitudinal data on a cohort of HGV-infected donors. Five of 120 blood donors (4.2%) were HGV-positive, a higher prevalence than seen in other developed countries. 4,8 All five appeared to be chronic carriers of HGV (assuming infection does not resolve after HGV carriage for longer than a year). It has yet to be determined why this infection is so prevalent in a group normally assumed to be at low risk for exposure to blood-borne viruses. Mother-to-baby (and early horizontal) transmission may account for the pattern of distribution (analogously to HBV in developing countries). 12 One donor had grown up in a developing country and another had potential risk factors (e.g., tattooing). Even so, one of the donors appeared to acquire HGV infection recently, without evident risk factors. This suggests that there are multiple modes of transmission. We found that only one of the HGV-positive donors had a raised ALT level, and on only one occasion. Although HGV infection is associated with an early and mild rise in results of liver function tests in some recipients of HGV-infected blood, 4 this is not unusual in acute viral infections. There is currently little evidence that HGV commonly causes chronic liver disease, but this does not preclude association with another disease. Indeed, we would argue that it is unlikely that a positive-strand RNA virus could cause chronic infection and not be associated with a disease syndrome. It is worth noting that with such a high prevalence of HGV in the general population the demonstration of a disease association will have to be particularly rigorous. The strategy we developed for HGV testing is time consuming and expensive, but, without a reliable serological or alternative virological marker, nucleic acid amplification by PCR remains the method of choice. An alternative to our PCR strategy could be use of a single reliable primer set, with automation of RNA extraction and RT-PCR. Blood donations may have to be tested for HGV RNA when suitable assays become available for mass screening, especially if evidence emerges that it causes significant disease. A National Health and Medical Research Council working party on novel viral hepatides has been set up in collaboration with the Red Cross Blood Transfusion Service to determine the significance of HGV in blood donations. In the meantime, it is important that recipients of donated blood continue to be advised of the potential complications of heterologous blood transfusion and, specifically, that they may acquire HGV infection. 2 However, currently the clinical significance of HGV infection is unclear and further clinical and epidemiological studies are needed on this new and emerging virus. References Aach RD, Stevens CE, Hollinger B, et al. Hepatitis C virus infection in post-transfusion hepatitis: an analysis with first and second generation assays. N Engl J Med 1991; 325: 1325-1329. Sloand EM, Pitt E, Klein HG. Safety of the blood supply. JAMA 1995; 274: 1368-1373. Alter HJ. Transfusion transmitted hepatitis C and non-A, non-B, non-C. Vox Sang 1994; 67: 19-24. Linnen J, Wages J, Zhen-Yong ZK, et al. Molecular cloning and disease association of hepatitis G virus: a transfusion-transmissible agent. Science 1996; 271: 505-508. Simons JN, Leary TP, Dawson JG, et al. Isolation of novel virus-like sequences associated with human hepatitis. Nat Med 1995; 1: 564-569. Zuckerman AJ. Alphabet of hepatitis viruses [editorial]. Lancet 1996; 347: 558-559. Bowden DS, Moaven LD, Locarnini SA. New hepatitis viruses: are there enough letters in the alphabet? Med J Aust 1996; 164: 87-89. Dawson GJ, Schlauder GG, Coleman P, et al. Prevalence and clinical significance of GBV-C [abstract]. Proceedings of the Ninth Triennial International Symposium on Viral Hepatitis and Liver Disease; 1996 April 21-25; Rome (Italy). Rome: CpA (Viale delle Medaglie d'Oro, 342100136), 33: 116. Hyland CA, Douglas R, Mazzocchi R, Young IF. Surrogate testing for non-A, non-B hepatitis in Queensland, Australia, an ALT microtitre tray method for screening blood donors. Pathology 1988; 20: 271-274. Kwok S, Higuchi R. Avoiding false positives with PCR. Nature 1989; 339: 237-238. Chemczynski P, Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate phenol-chloroform extraction. Anal Biochem 1987; 167: 156-159. Moaven LD, Tennakoon PS, Bowden DS, Locarnini SA. Mother-to-baby transmission of hepatitis G virus. Med J Aust 1996; 165: 84-85. (Received 15 May, accepted 9 Aug 1996) Authors details Victorian Infectious Diseases Reference Laboratory, Fairfield Hospital, Melbourne, VIC. Len D Moaven, FRCPA, Senior Registrar in Virology; D Scott Bowden, PhD, Senior Scientist (Molecular Virology); Rhonda McCaw, BSc, Scientist (Molecular Virology); Stephen A Locarnini, PhD, MRC(Path), Director. Red Cross Blood Transfusion Service, Brisbane, QLD. Catherine A Hyland, PhD, Scientist-in-Charge (Viral Serology); Ian F Young, FRCPA, Director; Leigh Mison, BSc, Scientist. Reprints: Dr S A Locarnini, Victorian Infectious Diseases Reference Laboratory, Fairfield Hospital, PO Box 65, Fairfield, VIC 3078. E-mail: stephenL AT hna.ffh.vic.gov.au <URL: http://www.mja.com.au/> © 1997 Medical Journal of Australia. We appreciate your comments.

Len D Moaven · Catherine A Hyland · Ian F Young · Rhonda McCaw · Leigh Mison · Stephen A Locarnini

Haemophilia -- darkest hours before the dawn We have the technology to make plentiful and relatively safe supplies of coagulation factors, and a cure may be within our grasp MJA 1996; 164: 453 Readers may print a single copy for personal use. No further reproduction or distribution of the articles should proceed without the permission of the publisher. For permission, contact the Australasian Medical Publishing Company Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au/>". Introduction - Reducing viral transmission - Replacement therapy - Immune complications - References - - ©MJA1997 Introduction Haemophilia is often considered to be our community's most expensive disease because of the life-long need for frequent replacement of coagulation factors VIII (haemophilia A) and IX (haemophilia B). The incidence of haemophilia in Australia is one in 7000 males -- the same in all ethnic groups. Its prevalence is much reduced because of premature death from bleeding in pre-replacement- therapy days and past transmission of infections such as HIV and hepatitis B and C through unsterilised pooled plasma concentrates. History's most famous person with haemophilia, the Tsarevitch Alexei, had almost reached his likely lifespan of 20 years when he was murdered in 1917. His frequent crippling haemarthroses and muscle bleeds are obvious from photographs. Today, because of major technical advances in coagulation factor production, most boys born in Australia with haemophilia can expect a normal lifespan and lifestyle, with neither plasma-derived viral infection nor disabling progressive arthropathy. Reducing viral transmission In Australasia, concentrates are prepared from plasma collected and screened for viral markers by State Red Cross Blood Banks, fractionated by CSL Ltd and sterilised by terminal dry heating at 80ûC for 72 hours. No case of HIV transmission from concentrates has been identified in the haemophilia population since 1985. Between 1981 and 1984, 245 people with haemophilia contracted HIV, at least 98 of whom have died (figures courtesy of the Mark Fitzpatrick Trust), and patients in all Australian States and Territories have received recompense payments for HIV infection. Because of the high prevalence of hepatitis C virus in pooled plasma before appropriate screening and increased heat technologies became available, most patients who received concentrates before 1989 were also infected with this virus, leading to serious comorbidity with HIV infection, chronic liver disease and hepatocellular carcinoma. Despite many improvements and sequential application of multiple virucidal technologies, some human viruses, such as parvovirus B19, may remain in plasma concentrates. Novel techniques, such as viral nanofiltration and partitioning during fractionation, are being developed, but a threat known as the TNV (the next virus!) to the safety of human-derived products always remains. The genes for factor VIII and IX, which occur on the tip of the long arm of the X chromosome, were sequenced in 1984 and 1985.1 By 1988 recombinant human factor VIII expressed in rodent cell lines was available for human trial.2 This product is now licensed and has been used in Australia since January 1995, so with political goodwill and financial support the supply of factor VIII may finally match demand. The possibility of human virus transmission is not completely abolished as, presently, recombinant factor VIII is resuspended in human serum albumin (although this product has not yet been reported to transmit such infec tions). Recombinant factor IX concentrates are now in clinical trial overseas. Replacement therapy In the past, the approach to haemophilia treatment was to arrest bleeding after it had occurred. This is called "on-demand" therapy. Unfortunately, this strategy is like shutting the gate after the horse has bolted, as it fails to prevent the significant joint damage caused by the reaction of the synovial membrane to blood. It is possible, however, to shut the gate somewhat earlier with "prophylactic therapy". In patients whose factor VIII level is greater than 1%, there is seldom spontaneous bleeding into joints. Hence, prophylactic therapy aims to maintain factor VIII levels at more than 1% at all times. As the factor VIII half-life is approximately 12 hours, this can be achieved by giving factor VIII concentrates in a dose of 25-40 IU/kg body weight three times a week. Reports from Sweden3 and the United States4 have demonstrated the effectiveness of such a regimen, and virtually all eligible children in Australia can now potentially receive prophylaxis, although Victoria is the only State to have matched Commonwealth Government funding for this therapy to date. A recent review of the results of prophylactic treatment at the Royal Children's Hospital, Melbourne, has confirmed a dramatic reduction in the incidence of joint bleeding and the number of hospital visits and, consequently, a reduction in morbidity from haemophilia (H E, unpublished results). The cost to the community of treating haemophilia patients prophylactically, in current costs for recombinant factor VIII, is no less than $100 000 per year (for an average of 100 000 units per patient). There are, however, significant cost savings from a reduced need for medical and allied health professional treatment, and the prospects that, without joint damage, young men will be able to pursue active and productive lives without the need for pension support. Immune complications Despite the advances in treatment, there are patients with severe haemophilia who develop allo-antibodies to infused factor VIII, and then do not respond to human factor VIII. In some instances, these patients face forms of treatment which are barely superior to those which were practised in the days of Rasputin, and suffer high morbidity and mortality compared with patients who do not develop these antibodies or inhibitors. While 20% of individuals with severe haemophilia (factor VIII activity < 1%) develop such antibodies, only half of those have high enough levels of antibodies to inactivate the infused factor VIII. Thus, one in 10 patients with severe disease are at risk of having no effective factor VIII replacement therapy. At present, Australians with this problem are more disadvantaged than similar patients in countries such as the United States, Canada or Western Europe. The only product available for treating their life-threatening or organ-threatening bleeds is porcine factor VIII. Its use has to be approved by the Therapeutic Goods Administration (TGA), and its usefulness is often offset by the development of antiporcine factor VIII antibodies, which restricts its use to bleeds that threaten life, limb or an organ and, even then, for a short time only. The only other products presently available are activated prothrombin complex concentrates, which are of unpredictable efficacy and can only be obtained with TGA approval. Because these products are costly and infrequently used, they are not always available in Australia. A new and recombinant product, activated factor VIIa (Novo Seven), has been shown to be the most effective in the treatment of inhibitors, including cover for surgery -- this product is not currently registered by the TGA5 and is no longer available for compassionate use. This is a serious situation for patients who are otherwise "untreatable". Treating bleeding in patients with activated prothrombin complex concentrates or recombinant VIIa is a form of on-demand therapy. European workers have shown conclusively that, in most patients newly diagnosed as having factor VIII inhibitors, giving factor VIII in a daily dose of 100-200 IU/kg body weight can often suppress the inhibitor to non-detectable levels, with normal factor VIII recovery in the plasma. 6 This is known as "tolerising therapy" and is a form of prophylaxis. Unfortunately, there is insufficient factor VIII in Australia to use it for this indication, even though tolerising is the most logical way to prevent the morbidity associated with poorly controlled bleeding, and it is cost-effective in comparison with on-demand therapies. It is to be hoped that the working parties currently convened by Australian Health Ministers to investigate optimum therapies for patients with haemophilia and factor VIII inhibitors will recommend funding for tolerising therapy in all newly diagnosed patients with inhibitors. These patients are usually children, thus small, requiring much less product than adults with established inhibitors. Genetic technology can be used to detect female relatives who are at risk of being carriers, and to detect haemophilia antenatally. In the long term the tantalising prospects of "cure" of this molecular disease by gene therapy is stimulating much research into mechanisms of vector biology which allow efficacious, safe and continuous expression of factors VIII and IX. Fortunately, the days when patients with haemophilia could be treated only by Rasputin are over. Comprehensive care centres in each State coordinate surgical, medical and dental management while providing counselling and diagnostic services. With the potential for plentiful and safe factor supplies for prophylactic, surgical and inhibitor- suppressing programs, and hope of a cure by gene therapy, the future for our children with haemophilia is bright. Alison M Street Head, Haematology Unit, Alfred Healthcare Group, Melbourne, VIC Henry Ekert Senior Consultant, Department of Haematology/Oncology, Royal Children's Hospital, Melbourne, VIC References Mandel JL, Willard HF, Nussbaum RL, et al. Report of the committee on the genetic constitution of the X chromosome. Cytogenet Cell Genet 1988; 49: 107-128. White GC, McMillan CW, Kingston HS, Shoemaker CB. Use of recombinant antihemohilic factor in the treatment of two patients with classic hemophilia. New Engl J Med 1989; 320: 166-170. Nilsson IM, Berntrop E, Lofqvist T, Pettersson H. Twenty-five years experience of prophylactic treatment in severe haemophilia A and B. J Intern Med 1992; 232: 23-32. Aledort LM. Experience with prophylactic treatment in the USA. Clinical benefits; a multi-center view. Round Table Series 1991; 25: 26-32. McPherson J, Teague L, Lloyd JV, et al. Experience with recombinant factor VIIa in Australia and New Zealand. Haemostasis 1996; 26 (Suppl 1): 109-117. Brackman HH. Induced immune tolerance in factor VIII inhibitor patients. Prog Clin Biol Res 1983; 150: 181-195. ©MJA 1997 <URL: http://www.mja.com.au/> © 1997 Medical Journal of Australia.

Alison M Street · Henry Ekert