Hematologic diseases

Warfarin and heparin are the traditional mainstay anticoagulant therapies for treating thromboembolic disease. These drugs, with a documented history of utility, also have inherent difficulties in usage; in particular, the complicated monitoring and numerous drug–drug interactions of warfarin, and the need for parenteral administration of heparins. New agents have recently emerged that target specific elements of the clotting pathway. Rivaroxaban, which inhibits activated factor X (Xa), is currently in clinical trials and is the most advanced factor Xa inhibitor. The drug offers once-daily oral dosing, with no need for injections, dose titration, or frequent blood tests to monitor the international normalised ratio. It has a rapid onset of action and, although there is no specific antidote, it has a short plasma elimination half-life (about 5–9 hours). Evidence from recently published large-scale phase III clinical trials shows rivaroxaban to be superior to enoxaparin for prophylaxis of venous thromboembolism after major orthopaedic surgery. Studies have shown rivaroxaban to have a sound safety profile, with an incidence of bleeding similar to enoxaparin in phase III clinical trials. Few side effects and drug–drug interactions between rivaroxaban and common medications have been found thus far, although some interactions with potent cytochrome P450 3A4 inhibitors have been observed. It is hoped that rivaroxaban may be used as a first-line anticoagulant for prophylaxis of venous thromboembolic disease in postsurgical patients.

Abhishek K Verma BSc(Med), MB BS · Timothy A Brighton MD, FRACP, FRCPA

To the Editor: In the 3 November 2008 issue of the Journal, Millar recommends against routine thromboprophylaxis in medical patients.1 The evidence base for clinical decision making regarding thromboprophylaxis in medical patients remains limited. Although its overall benefit may be low, the absolute benefit to the community is significant. As up to 40% of cases of venous thromboembolism (VTE) occur in patients recently hospitalised for medical illness,2-3 there is a significant burden of disease that justifies prophylaxis in patients at high risk of VTE. The challenge is to identify medical patients at greatest risk of VTE, and to provide appropriate pharmacological prophylaxis, but to avoid using prophylaxis in patients at lower risk of VTE. Millar states that aspirin is as effective as heparin, with reference to the Pulmonary Embolism Prevention (PEP) trial.4 However, the PEP trial compared aspirin with placebo, and many participants also received heparin — it did not compare aspirin with heparin. Participants were undergoing surgery for hip fracture, and none were medical patients. A reduction in the endpoint of fatal pulmonary embolus (PE) is difficult to demonstrate in trials where imaging is used to detect disease at an early stage. This prompts treatment of asymptomatic deep vein thrombosis and modifies the natural history, leading to low reported PE rates. Rather than recommend for or against routine thromboprophylaxis in medical patients, we advise that patients should have a VTE risk assessment and that appropriate prophylaxis should be given according to evidence-based guidelines such as those of the American College of Chest Physicians5 and the International Consensus Statement6 (which we have attempted to summarise and condense into a practical, pocket-sized booklet7).

John P Fletcher · Donald MacLellan · Harry Gibbs · Geoff Matthews

Objective: To document haemopoietic stem cell transplantation (HSCT) activity and trends among paediatric patients in Australia and New Zealand.Design, setting and participants: A retrospective analysis of data reported to the Australasian Bone Marrow Transplant Recipient Registry by the seven paediatric HSCT institutions in Australia and New Zealand over the 9-year period 1998–2006, with particular focus on the most recent years (2002–2006).Main outcome measures: Types of HSCT performed; transplant-related mortality (TRM); stem cell sources; indications for HSCT; causes of death after HSCT.Results: Over the period 1998–2006, 522 autologous HSCT procedures (41%) and 737 allogeneic procedures (59%) were performed. About 60% of allogeneic transplants involved alternative donors (donors other than a human leukocyte antigen-matched sibling). The use of umbilical cord blood as a source of haemopoietic stem cells has doubled since 1998, with 34% of allogeneic transplants in 2006 using cord blood. Over the period 2002–2006, the median age of patients receiving transplants was 7 years (range, 0–19 years). The most common indications for allogeneic HSCT were acute lymphoblastic leukaemia (33%) and acute myeloid leukaemia (24%). The most common indications for autologous HSCT were neuroblastoma (23%), medulloblastoma (21%) and Ewing sarcoma (10%). TRM at 1 year after transplant was 22% for alternative donor transplants, 7% for matched-sibling transplants and 5% for autologous transplants. Relapse or persistence of a child’s underlying condition accounted for 54% of all deaths within 1 year after transplant.Conclusions: HSCT is an important procedure for children with a range of life-threatening illnesses. Local trends in the indications for HSCT, donor selection and TRM reflect contemporary international practice.

Andrew S Moore MB BS · Peter J Shaw MB BS, MRCP, FRACP · Andrew R Hallahan BSc(Med), MB BS(Hons), FRACP · Tina L Carter MB BS, FRACP, PhD · Tatjana Kilo MD · Ian Nivison-Smith BSc, MAppStat · Tracey A O’Brien MB ChB, FRACP, MHL · Heather Tapp MB BS, FRACP, FRCPA · Lochie Teague MB ChB, FRACP, FRCPA · Shaun R Wilson MB ChB, DCH, MRPCH · Karin Tiedemann OAM, MB BS, FRACP

To the Editor: Samuel and colleagues’ article on the ethics of umbilical cord blood (UCB) banking1 reflects much of the misinformation and bias that bedevil this debate. They argue against storage of autologous stem cells from UCB for a variety of contradictory, paternalistic or ideologically driven reasons. The indication for autologous UCB storage is in anticipation of developments in regenerative medicine, an exciting field that holds great promise; it is not in anticipation of transplantation for malignancy, which is unlikely to occur. Samuel et al acknowledge these points, yet base their criticism of autologous storage on the latter indication. Next, they state that autologous stem cells can be easily harvested at any time in life. Perhaps, for use in transplantation; but cells obtained later in life are likely to be of little use in regenerative medicine. Capacity for in-vitro manipulation declines with age. Third, they argue that the two alternatives of public and private UCB storage are mutually incompatible — “public good or private benefit” (my emphasis). Australia’s three public banks are close to achieving the desired number of cords (about 20 000) needed for transplantation medicine in the non-Indigenous population.2 There is no shortage, and certainly no shortage of potential donors. Why argue against autologous storage as if there is? Fourth, the authors disapprove of the for-profit motive in private-sector medicine. That may be their ideological position, but it is paternalistic to impose that view on the rest of us. Can parents not make up their own minds on the value of autologous storage? At $2000 upfront and $150 a year, storage is not so expensive that “only a small proportion of the population are able to afford [it]”. I remind readers of media reports that the Australian Government’s Baby Bonus (now $5000) was often used to purchase luxury items such as flat-screen televisions rather than being spent on the baby’s needs.3 The authors are correct in one respect: some (but not all) private UCB banks have been deliberately deceptive and misleading in their marketing, and, in so doing, have been predatory and exploitative. However, it does not then follow that parents cannot access sound and sober health advice in the marketplace. The public versus private UCB storage debate does have an ethical dimension, but not this one. This debate is really just a turf war.

David E Roberts

In reply: Roberts asserts that we are biased, paternalistic and driven by an ideological objection to private umbilical cord blood (UCB) storage. While this is impressive rhetoric, it bears little resemblance to the points made in our article.1 Contrary to Roberts’ assertion, we do not object to private UCB storage. Our primary concern is that marketing campaigns make misleading or grandiose claims about the possible application of privately stored UCB in cancer care and regenerative medicine. For, although stem cell research does have great promise, it remains clinically unproven in the management of degenerative conditions. Offering hope of cure or amelioration of illness based on scientific speculation is enormously problematic, especially when directed at vulnerable parents concerned about their unborn child. While some private UCB banks take great care to avoid deliberate deception, many do not.2,3 We agree that parents should be able to decide for themselves how and if to store their child’s UCB, but they need accurate information to do so. Finally, Roberts asserts that there is no shortage of public UCB units or donors. In reality, there is a vast shortage of UCB units available to ethnic minority and Indigenous patients.4 North Caucasian donation also needs to be maintained, particularly as the impact of double-cord transplantation becomes apparent.4

Gabrielle N Samuel · Ian H Kerridge · Tracey A O’Brien

Routine thromboprophylaxis in hospitalised medical patients is based on trials that predominantly use asymptomatic deep vein thrombosis (DVT) as the endpoint. As asymptomatic DVT is 10–30-fold more common than symptomatic DVT, this exaggerates estimates of benefit and cost-effectiveness. Based on symptomatic disease, the number needed to treat per venous thromboembolism (VTE) prevented is high (150–1600), and the true cost-effectiveness of thromboprophylaxis for symptomatic event reduction is uncertain. The incidence of major bleeding among patients receiving prophylaxis is at least equal to the reduction in clinical VTE. Routine thromboprophylaxis in hospitalised medical patients is not warranted, and better patient selection is needed.

J Alasdair Millar PhD, FRACP, FRCP

To the Editor: Venous thromboembolism (VTE) is frequently described among air travellers but data on VTE related to train travel are limited.1-3 We report a case of VTE in a patient after a prolonged train journey. A 35-year-old man presented with sudden onset of breathlessness, perspiration and syncope after a 14-hour train journey, during which he had limited mobility. He had no history of similar episodes, no significant comorbidities or previous periods of prolonged immobility and no family history of thromboembolic disorders, and he was vegetarian. Physical examination revealed tachycardia, tachypnoea, blood pressure of 90/60 mmHg, raised jugular venous pressure and a right ventricular third heart sound. Blood-gas analysis showed hypoxaemia with respiratory alkalosis: Pao2, 49 mmHg (reference range [RR], 95 ± 5 mmHg), pH 7.49 (RR, 7.40 ± 0.02), Paco2, 22 mmHg (RR, 40 ± 2 mmHg). A plasma D-dimer test result was positive. Electrocardiography revealed right axis deviation with an S1Q3T3 pattern. Echocardiography revealed right ventricular dilatation, a thrombus in the main pulmonary artery, and pulmonary arterial hypertension (pulmonary artery systolic pressure, 65 mmHg) (Box, A). Computed tomographic angiography of the pulmonary artery confirmed the presence of a large saddle embolus at the bifurcation of the main pulmonary artery (Box, B) and a wedge-shaped infarct in the middle lobe of the right lung. Venous Doppler imaging showed a thrombus in the left popliteal vein. The patient had fasting hyperhomocysteinaemia (plasma homocysteine level, 36.6 μmol/L; RR, 4.4–10.8 μmol/L] secondary to nutritional vitamin B12 deficiency (serum vitamin B12 level, 42 pmol/L; RR, 206–735 pmol/L]. Tests for antithrombin III, protein C, protein S, factor V Leiden mutation and antiphospholipid antibodies returned normal results. The patient was successfully treated with intravenous streptokinase followed by standard anticoagulation therapy and vitamin B12 supplementation. He was well on follow-up. The association between thrombosis and prolonged travel was first described in 1954.1 Symptoms usually develop within 1–8 weeks of travel. Any journey of more than 4 hours poses a risk of VTE. Factors involved are low humidity, hypoxia, immobilisation and cramped conditions.2,3 Individuals with underlying hypercoagulation states such as factor V Leiden mutation, prothrombin gene G20210A mutation, and protein C and protein S deficiency have increased risk of VTE.4 Recently, hyperhomocysteinaemia has also been identified as an important risk factor for VTE.5 Acquired risk factors include obesity, oral contraceptive use, pregnancy, recent trauma or surgery, malignancy and history of VTE. This case highlights the association between train travel and VTE, and the importance of considering all types of prolonged travel as potential risk factors for VTE. Echocardiogram and angiogram of a patient with venous thromboembolism after prolonged train travel A: Echocardiogram (parasternal long axis view) showing dilatation of the right ventricle (arrow) as a result of acute pulmonary arterial hypertension. B: Computed tomographic angiogram of pulmonary artery showing a saddle embolus (arrows) at the bifurcation of the main pulmonary artery (MPA).

Jeet Ram Kashyap · Sanjay D’Cruz · Sandeep Chauhan · Suman Kochhar

Tumour necrosis factor inhibitors have revolutionised the management of Crohn’s disease, but reports of a possible association between concomitant infliximab and immunomodulator therapy and hepatosplenic T-cell lymphoma (a rare form of aggressive non-Hodgkin’s lymphoma) have emerged. We describe the first case in Australia of hepatosplenic T-cell lymphoma in a patient who had been treated with infliximab and immunomodulators for Crohn’s disease. Clinical recordIn January 2006, a 39-year-old man of European background presented with severe sepsis of unidentified source. This was complicated by hypotension and multiorgan failure, including renal impairment, abnormal liver function and myocardial injury, and he required intensive care. He had a 13-year history of active perianal and ileal Crohn’s disease, which had been treated with prednisolone (varying doses) continuously from 1993, and with azathioprine (2–2.5 mg/kg) from 1993 to 1994 and then continuously from August 1999 (after drainage of a perianal abscess). He had also received three doses of infliximab (5 mg/kg) between November 1999 and January 2000, which achieved a partial response. Azathioprine and prednisolone therapy were continued after infliximab therapy, with relatively good control of symptoms. Results of full blood examinations during azathioprine therapy were within normal ranges. On admission, azathioprine therapy was discontinued, but corticosteroids were continued. Blood cultures grew methicillin-sensitive Staphylococcus aureus. Full blood examination revealed mild anaemia (haemoglobin level, 91 g/L; reference range [RR], 130–170 g/L) and mild lymphocytopenia (white blood cell count, 0.6 × 109/L; RR, 4.0–11.0 × 109/L), but other parameters were initially normal. Biochemical analysis revealed acute renal failure (potassium, 6.5 mmol/L [RR, 3.5–5.0 mmol/L]; bicarbonate, 21 mmol/L [RR, 22–31 mmol/L]; creatinine, 580 μmol/L [RR, 60–110 μmol/L]; and urea, 19.9 mmol/L [RR, 2.5–8.3 mmol/L]). Liver function tests revealed transaminitis (alanine aminotransferase, 432 U/L [RR, < 55 U/L]; aspartate aminotransferase, 2246 U/L [RR, < 50 U/L]; and bilirubin, 53 μmol/L [RR, < 19 μmol/L]). There was also evidence of coagulopathy (international normalised ratio [INR], 2.8 [RR, 0.8–1.3]), grossly abnormal levels of inflammatory markers (C-reactive protein, 218 mg/L [RR, < 8 mg/L]; erythrocyte sedimentation rate, 140 mm/h [RR, 2–14 mm/h]), and elevated troponin I levels (5.24 μg/L; RR, < 0.10 μg/L). Nine days after admission, the patient developed pancytopenia (haemoglobin level, 78 g/L; white blood cell count, 0.9 × 109/L; and neutrophil count, 0.3 × 109/L [RR, 2.0–8.0 × 109/L]). This was attributed to drug-induced suppression of bone marrow, and granulocyte-colony stimulating factor (G-CSF) was administered. On discharge, leukocyte and neutrophil levels were normal, G-CSF therapy was discontinued, and follow-up was arranged. Ten days after the patient was discharged, he re-presented with a 2-day history of fever, malaise and non-specific abdominal pain. Physical examination revealed a temperature of 38.5°C, tachycardia (heart rate, 110 beats/min), and hypotension (blood pressure, 100/60 mmHg); cardiovascular and respiratory systems were otherwise unremarkable. Abdominal examination revealed new hepatosplenomegaly, with no stigmata of chronic liver disease. There was no clinical evidence of lymphadenopathy. Repeat haematological testing revealed pancytopenia: haemoglobin level, 100 g/L; white blood cell count, 0.7 × 109/L; platelet count, 48 × 109/L (RR, 140–400 × 109/L); neutrophil count, 0.0 × 109/L; and lymphocyte count, 0.5 × 109/L (RR, 1.2–4.0 × 109/L). A blood film showed atypical lymphocytes and blast cells. Serum lactate dehydrogenase level was grossly elevated at 5351 U/L (RR, 210–420 U/L), and liver function tests showed abnormal results. Abdominal computed tomography confirmed gross splenomegaly, with the spleen being 24 cm long on its major axis, but no lymphadenopathy. Microscopic examination of a liver core biopsy specimen revealed an atypical lymphoid infiltrate in the sinusoids, especially around central veins (Box), with immunophenotype bcl-2+, CD3+, CD43+, Ki67+, ALK1 −, bcl-6 − , CD5 −, CD10 −, CD20 −, CD30 −, CD79 − and cyclin D1 − . Subsequent genetic studies of a bone marrow biopsy specimen revealed rearrangement of the T-cell receptor γ-chain gene, consistent with hepatosplenic T-cell lymphoma (HSTCL). The lymphoma was treated with one cycle of cyclophosphamide, mesna, dexamethasone, doxorubicin and vincristine, which achieved a partial response, but subsequent salvage chemotherapy with ifosfamide, carboplatin and etoposide did not arrest disease progression. In June 2006, the patient received a sibling allogeneic bone marrow transplant, after conditioning with etoposide and total body irradiation.1 The patient remained largely free of disease after transplantation, with monitoring on an outpatient basis and adjustment of immunosuppression as clinically indicated. However, in April 2007, he was hospitalised for investigation of diarrhoea and worsening liver function. He underwent colonoscopy and biopsy of a caecal polypoid mass; results of histological examination were consistent with recrudescence of HSTCL. Positron emission tomography showed multiple sites of relapse. A palliative approach was adopted, and the patient died in June 2007. DiscussionWe describe the first case, to our knowledge, in Australia of HSTCL in a patient with Crohn’s disease who had been treated with infliximab and immunomodulators. Inhibitors of tumour necrosis factor (TNF) such as infliximab have shown great efficacy in the treatment of luminal and fistulising Crohn’s disease, as well as ulcerative colitis.2 Infliximab is a chimeric (human/murine) monoclonal antibody that binds to human TNF-α. It was approved by the United States Food and Drug Administration (FDA) in 1998 for the treatment of moderate-to-severe Crohn’s disease when response to immunomodulator therapy is inadequate. More recently, the FDA has expanded the indication to include ulcerative colitis refractory to conventional treatment. In Australia, the Pharmaceutical Benefits Advisory Committee recently approved TNF inhibitors for the treatment of Crohn’s disease. However, the safety of such biological therapy is a concern: a recent meta-analysis reported a threefold increase in the risk of malignancy (solid and haematological) with the use of anti-TNF therapy in rheumatoid arthritis patients.3 This increase may be partly due to severity of disease or to other aspects of disease management. Interestingly, to date there have been no reports of HSTCL in rheumatoid arthritis patients. The TREAT (Crohn’s Therapy Resource, Evaluation and Assessment Tool) registry, which monitors over 3000 patients with Crohn’s disease who have been treated with infliximab, has not reported an increased incidence of lymphoma.4 However, it is estimated that a substantially larger number of patients would need to be monitored to detect a significant increase in a rare adverse event, such as lymphoma.5 Between 2000 and 2006, the Adverse Drug Reactions Advisory Committee received 319 reports involving anti-TNF therapy, including five cases of lymphoma.6 HSTCL is a rare form of aggressive non-Hodgkin’s lymphoma that comprises 5% of peripheral T-cell lymphomas. Reports of approximately 120 cases have been published worldwide. Eight cases of HSTCL have been identified from the post-marketing infliximab safety database run by the FDA, which seems more than expected, all in young men with a history of Crohn’s disease and concomitant use of azathioprine or mercaptopurine.7 In addition, there have been 15 reports of ‘‘T-cell lymphoma’’ in patients treated with infliximab, but data from the Adverse Event Reporting System were limited.7 Furthermore, there have been no reports of HSTCL associated with other anti-TNF therapies (eg, etanercept and adalimumab) used for any indication.7 Of note, there have been four reports of HSTCL in patients who received azathioprine or mercaptopurine alone for 4–6 years.8 The case we describe differs substantially from previously reported cases of HSTCL associated with concomitant infliximab and immunomodulator treatment in Crohn’s disease. To our knowledge, it involves the oldest patient and longest lead time (72 months) reported to date. Patients in most other cases have been younger than 22 years, with a lead time of less than 58 months7 (unpublished data, Centocor, Horsham, Pa, USA). Recent data suggest an association between lymphoma — especially HSTCL — and concomitant use of infliximab and immunomodulators in Crohn’s disease. However, the mechanism of this possible association remains unclear. The use of biological therapy as a “bridge” to stabilise the disease, while waiting for immunomodulators to become clinically effective, may need to be considered with increased caution. Immunomodulators might need to be avoided after infliximab therapy, and alternative treatments considered. These may include maintenance with ongoing biological therapy alone, use of newer anti-TNF therapy, or earlier surgery (especially in young men). Until further evidence emerges, long-term surveillance of patients who have used biological therapy is warranted. In particular, biological therapy should be used cautiously in the management of refractory inflammatory bowel disease. The decision to use infliximab should be tempered by observations of an association with HSTCL, and strategies for long-term maintenance therapy need to be developed. Liver core biopsy specimen of a patient with Crohn’s disease, following infliximab and immunomodulator therapy Low magnification (A: haematoxylin and eosin stain; original magnification, × 10) and high magnification (B: CD3 stain; original magnification, × 40) views of a liver core biopsy specimen, showing prominent atypical lymphoid infiltrate in the sinusoids and around central veins, and occasional red cell extravasation. The high magnification shows strong CD3 staining (arrows), findings consistent with hepatosplenic T-cell lymphoma.

Musa Drini MB BS · Peter J Prichard MD, FRACP · Gregor J E Brown PhD, FRACP · Finlay A Macrae MD, FRACP, FRCP

Objective: To determine whether Helicobacter pylori eradication is an effective treatment for Australian patients with chronic immune thrombocytopenic purpura (ITP).Design, setting and patients: Retrospective analysis of clinical records of a consecutive series of ITP patients referred to a gastrointestinal surgeon in a tertiary referral hospital for laparoscopic splenectomy between August 2005 and November 2007.Main outcome measures: Platelet response (measured at least 3-monthly) following successful H. pylori eradication therapy (confirmed by urea breath test 4 weeks later).Results: Of 16 patients, seven were H. pylori-negative and underwent laparoscopic splenectomy. Nine were H. pylori-positive and successfully underwent H. pylori eradication therapy; five of the nine had an initial platelet response. Four patients had platelet counts > 100 × 109/L (reference range, 140–450 × 109/L) and were off all immunosuppression at 9 months; three had a sustained response beyond 12 months. One patient had an initial response at 3 months (15 × 109/L to 208 × 109/L), but relapsed 4 months after H. pylori eradication and underwent splenectomy with platelet count recovery. The remaining four patients showed no platelet response and subsequently underwent splenectomy.Conclusion: Larger prospective studies are needed to fully ascertain the role of H. pylori in Australian patients with ITP. However, H. pylori eradication is simple and safe. H. pylori screening and eradication should be considered before immunosuppression or splenectomy.

Vanaja Sivapathasingam BSc(Med), MB BS(Hons) · Michael P Harvey PhD, FRACP, FRCPA · Robert B Wilson BSc, MB BS(Hons), FRACS

Now that we can predict risk accurately, we need to reconsider screening strategies The recent completion of the Human Genome Project offered great promise that medical genetics would have a population-based impact on the prevention and treatment of inherited conditions. A common inherited condition, hereditary haemochromatosis, was initially touted as a “poster child” for population genetic screening. Most cases are due to homozygosity for a single mutation of the HFE gene, leading to iron overload. Hereditary haemochromatosis is considered an ideal candidate for population genetic screening as genetic susceptibility is common, testing is inexpensive, and iron studies can detect early stages of the disease.1 Most importantly, venesection is a simple and effective way to both prevent and manage the potential sequelae of iron overload,2 which include severe fatigue, arthritis, impotence, cirrhosis, diabetes, and cardiomyopathy.3 However, even for an inherited condition as apparently straightforward as haemochromatosis, justifying population genetic screening has proven more complicated than initially expected.4 After the gene linked with hereditary haemochromatosis was identified in 1996,5 a flurry of publications called for the consideration of population genetic screening, as it was thought that most people who were homozygous for the C282Y mutation would eventually develop the disease. Although more than 90% of cases are due to C282Y homozygosity,3 there is now good evidence that not all those who are homozygous will progress through all stages of the disease. These stages comprise genetic predisposition without abnormality; iron overload (raised serum ferritin in the presence of a raised fasting transferrin saturation) without symptoms; iron overload with haemochromatosis-associated symptoms, such as arthritis and fatigue; and iron overload with organ damage, particularly cirrhosis.6 Although most of those who are homozygous appear to develop raised serum ferritin and raised transferrin saturation by the fifth decade of life,7 until now there have been few reliable data on the number of homozygous individuals who develop disease as a result of iron overload. Population estimates of the prevalence of non-specific signs and symptoms of haemochromatosis (eg, arthritis and fatigue) and disease due to documented iron overload (eg, cirrhosis) in C282Y homozygous individuals have been hindered by either the failure to clinically assess individuals before knowledge of their genetic status or an inability to account for the long lead time of preclinical iron-overload status. A cross-sectional population study of participants aged 20–80 years suggested that disease attributable to haemochromatosis occurs in fewer than 1% of those who are homozygous, regardless of sex.8 However, this study did not conduct clinical examinations or liver biopsies, and a quarter of the homozygous patients were excluded on the basis that they had been previously diagnosed. This exclusion would be expected to reduce the estimate of clinical penetrance of C282Y homozygosity. Furthermore, the study included homozygous patients of ages at which disease would not be expected to have developed. Until recently, there had been only two longitudinal studies of hereditary haemochromatosis designed to accurately estimate the proportion of homozygous patients who will develop disease secondary to iron overload.9,10 However, with a combined total of 23 patients, they were substantially underpowered to assess disease prevalence. In the largest longitudinal prospective study to date, my colleagues and I assessed 203 homozygous individuals among a healthy population of 31 192, followed up over 12 years.11 Data were collected by physicians who were blinded to genotype, and liver biopsies were performed as clinically indicated (serum ferritin > 1000 μg/L, unexplained hepatomegaly or raised serum aminotransferase levels).12 We found that homozygous individuals with a serum ferritin level higher than 1000 μg/L were at increased risk of haemochromatosis-associated signs and symptoms, when compared with either those who were homozygous with a serum ferritin level of 1000 μg/L or less, or individuals with other HFE genotypes. In particular, homozygous men with a serum ferritin level higher than 1000 μg/L reported greater fatigue, use of arthritis medication and history of liver disease than men without the C282Y mutation. We also assessed the proportion of homozygous individuals with disease that was directly attributable to iron overload using the combined definition of documented iron overload13 and one or more of the following: cirrhosis, liver fibrosis, hepatocellular carcinoma, raised aminotransferase concentration, physician-diagnosed symptomatic hereditary haemochromatosis, and arthropathy of the second and third metacarpophalangeal joints. Iron overload-related disease developed in 28% of homozygous men, but only 1% of homozygous women.11 Our study is important because it enables us, for the first time, to make accurate predictions about the proportion of those at genetic risk of haemochromatosis who will develop symptoms that could otherwise be prevented. Furthermore, we confirmed that homozygous individuals with a serum ferritin level higher than 1000 μg/L were not only at increased risk of cirrhosis, but also of non-specific signs and symptoms of haemochromatosis. This has implications for a cost-effectiveness analysis of population genetic screening for hereditary haemochromatosis. Other criticisms of such screening,14 including concerns over insurance implications and creating a cohort of “worried well” among those at genetic risk of haemochromatosis, have proved unfounded.15,16 It appears that cost is the last barrier to screening. The questions that remain regarding population screening include: Would it be more cost-effective to simply offer screening to men? What is the most cost-effective age to screen at? What is the most pragmatic way to access a population before an age at which disease is likely to develop? Hereditary haemochromotosis may yet offer a prototype for population genetic screening programs, but the journey of justification has offered unexpected challenges.

Katrina J Allen BMedSc, FRACP, PhD

Chronic myeloid leukaemia (CML) was the first human cancer linked to an acquired chromosomal abnormality, subsequently shown to be a reciprocal translocation between chromosomes 9 and 22. The resulting fusion gene product, BCR-ABL, was shown to be the causative agent of the disease. CML has an incidence of around 1–2 cases per 100 000; in Australia, there are probably more than 200 new cases per year and more than 1300 prevalent cases. Treatment of CML with imatinib has been a powerful vindication of the concept of rational, gene-targeted drug design. Five-year published experience with imatinib at 400 mg orally daily demonstrates 89% overall survival and an estimated 93% freedom from disease progression. Adverse effects are mostly mild and transient. Higher doses of imatinib may be more efficacious and will be studied in upcoming clinical trials in Australia; however, imatinib is almost certainly not curative. Up to 28% of patients may have to stop imatinib because of intolerance or disease resistance, mostly due to point mutations of BCR-ABL. In this situation, many patients will respond to second- and third-generation tyrosine kinase inhibitors. Management of CML patients should involve close monitoring, especially in the first 2 years, with regular cytogenetics and quantitative polymerase chain reaction to optimise response and identify suboptimal responders as early as possible. Bone marrow transplantation remains the only known cure, but is reserved for patients whose kinase inhibitor therapy has failed, or who have advanced disease (accelerated phase or blastic transformation).

David J L Joske MB BS, FRACP, FRCPA

VTE prophylaxis is effective and safe, but grossly underused in Australian hospitals In this issue of the Journal, Ho and colleagues report their findings from a Perth community-based study of venous thromboembolism (VTE).1 They found an incidence of VTE, which includes deep vein thrombosis and pulmonary embolism, of 0.83 (95% CI, 0.69–0.97) per 1000 population per year. This figure is consistent with hospital discharge data from the Australian Institute of Health and Welfare, which predict an estimated 14 716 VTE cases in 20082 or an incidence of 0.74 per 1000. This incidence comes with high costs to Australian society in terms of deaths, morbidity and health care expenditure. VTE is a major cause of hospital deaths — Australian Institute of Health and Welfare data indicate that 7% of all deaths in Australian hospitals are due to VTE,2 and autopsy studies suggest the percentage may be as high as 10%.3 Thus, VTE causes more deaths than any common cancer (breast, lung, prostate or bowel) and is 40 times more deadly than HIV/AIDS in Australia. VTE also causes significant long-term morbidity from post-thrombotic syndrome (chronic leg swelling, pain and skin ulcers) and pulmonary hypertension. A report by Access Economics estimated that the cost to Australia of treating VTE is currently $1.72 billion annually (0.15% of gross domestic product).2 This estimate includes costs attributable to direct health system expenditure ($148 million), productivity loss ($1.38 billion) and efficiency loss ($162 million). If costs relating to premature mortality are included, then VTE represents the most costly disease burden among the 16 diseases (including cancer, dementia, osteoporosis, cardiovascular disease and schizophrenia) that have been studied and ranked by Access Economics in recent years. The key to saving lives, improving patient outcomes and reducing the huge financial cost to individuals and the nation lies in prevention of this disease. Evidence-based findings from well designed studies have clearly shown that prevention is possible.4,5 With a modest outlay, VTE incidence can be significantly reduced, effectively and safely, using anticoagulants such as unfractionated or low-molecular-weight heparins, or, particularly if a risk of bleeding exists, by mechanical means (compression stockings and intermittent calf compression). However, current data suggest that VTE prophylaxis is grossly underused in hospitals in Australia and overseas.6 The ENDORSE study (which enrolled over 68 000 medical and surgical patients in 32 countries, including Australia) showed that 51.8% of hospital inpatients were at risk of VTE, but only 58.5% of at-risk surgical patients and 39.5% of at-risk medical patients received VTE prophylaxis.6 This is consistent with the findings of a prospective audit carried out by the National Health and Medical Research Council (NHMRC) National Institute of Clinical Studies in Australian hospitals in 2005–2006 (Dr Sue Phillips, Director, Research Implementation Program, National Institute of Clinical Studies, NHMRC, Melbourne, personal communication). These studies show that many at-risk hospital patients in Australia and overseas, especially medical inpatients, are left unprotected against VTE. Adoption of clinical guidelines by hospitals can lead to increased levels of appropriate prescribing of VTE prophylaxis.7 However, the risk of thromboembolic events continues after hospital discharge, and far less research has been conducted into the use of VTE prophylaxis in the community. There is an increasing trend for at-risk medical patients (eg, patients with chronic lung disease or cardiac failure) to be managed in the community, especially through hospital-in-the-home and early discharge programs.8 With increasingly short hospital stays for both surgical and medical patients, it is important that community-based doctors are aware of the importance of VTE risk assessment and the continuation or commencement of VTE prophylaxis for their patients. The Australia & New Zealand Working Party on the Management and Prevention of Venous Thromboembolism has been convened to formulate a national strategy to promote the optimal use of VTE prophylaxis. Initiatives of the Working Party will include: Developing simple, user-friendly VTE prevention guidelines that will assist doctors to identify and treat at-risk patients. The fourth edition of the Working Party’s VTE prevention guidelines — based on the recommendations of the American College of Chest Physicians4 and the International Union of Angiology,5 but adapted to local conditions (see http://stgcs.med.unsw.edu.au/stgcsweb.nsf/page/TBD) — has recently been published.9 Promoting hospital and community education programs to create awareness of the VTE prevention guidelines and enhance understanding of VTE risk assessment. Researching and developing recommendations for reminder systems, including computer alerts10 or interventions by a VTE nurse or pharmacist, with the intention of reminding doctors to prescribe appropriate VTE prophylaxis. Establishing VTE centres of excellence that will act to promote optimal VTE patient care. Lobbying federal and state governments to initiate health policies that will lead to increased use of VTE prophylaxis in Australian hospitals, including designating VTE prophylaxis rate as a hospital performance indicator. This is particularly relevant now, while the federal government is working with state governments to reduce surgical waiting lists. If patients undergoing surgery do not receive appropriate VTE prophylaxis, this could lead to increases in adverse outcomes of VTE and fatal pulmonary embolism. Hosting a national VTE summit to generate new ideas for improving VTE prevention. VTE is a significant health issue internationally and in Australia. It is a common cause of hospital deaths and a considerable financial burden on governments and individuals. Doctors, nurses, health administrators and governments should work together to ensure all surgical and medically ill patients in hospital have their VTE and bleeding risk assessed, and to maximise appropriate use of VTE prophylaxis. Achieving this will improve patient outcomes, save lives and reduce health costs.

Beng H Chong MB BS, FRACP, PhD · Jeffrey Braithwaite MBA, PhD, FCHSE · Mark F Harris MB BS, FRACGP · John P Fletcher MD, MS, FRACS

Haematopoietic stem cell transplantation (HSCT) is an accepted curative therapy for many malignant and non-malignant conditions affecting children and adults. Where possible, stem cells for HSCT are provided by human leukocyte antigen (HLA)-matched, related donors. Only 30% of patients have a suitable matched donor; for other patients, donors are sought from bone marrow registries or public umbilical cord blood (UCB) banks. While public UCB banks have been established to support transplant programs in Australia and internationally, parents also have the option of storing their child’s UCB in a private commercial UCB bank for personal or family use. In contrast with public UCB banks, there is little social or medical justification for private UCB banking, as it provides no benefit to the community and little benefit to parents (other than reassurance and amelioration of regret), due to the very low likelihood of requiring autologous UCB later in life. Should UCB prove to be beneficial for tissue repair or replacement in the management of degenerative disorders, such as diabetes and Parkinson’s disease, then a stronger case may be made in support of commercial banking of UCB for personal use. This may have a major impact on public UCB programs.

Gabrielle N Samuel PhD · Ian H Kerridge MPhil, FRACP, FRCPA · Tracey A O’Brien FRACP, BMed, MHL

To the Editor: The assertion of Davis and Batmanian and their colleagues that thrombolytic treatment for ischaemic stroke is reasonably safe and highly effective1,2 is not supported by the primary randomised trials of its use.3 Is tissue plasminogen activator (tPA) safe? It remains undisputed that none of the trials for thrombolysis in stroke have shown any mortality benefit.4 All of the trials have shown increases in symptomatic intracranial haemorrhage; in the NINDS trial, the increase was from 0.6% in the placebo arms to 6.4% in the treatment arms — a 1000% relative increase — and 45% of those with symptomatic bleeds died.5 Presumably, any mortality benefit from opening blocked arteries is lost because of the increased mortality from intracranial bleeding. Therefore, the drug is not safe. Is tPA effective? Thrombolysis for acute myocardial infarction was assessed in tens of thousands of patients in many independent studies, with virtually all showing clear mortality benefit. By comparison, the stroke thrombolysis literature is full of negative studies, with only one positive result. The NINDS trial4 stands alone as the only randomised controlled trial (RCT) providing positive evidence for thrombolysis for stroke. Ignoring criticisms of its interpretations and methodology, of which there are many, it had fewer than 600 patients and its results have not been reproduced independently. Breaches of protocol continue to be published. Batmanian and colleagues gave patients tPA after 180 minutes despite all the evidence saying this has no benefit, justifying it by saying the decision had been made at 170 minutes.2 Davis and colleagues1 based their claims of safety and efficacy on registries, subgroup analyses, meta-analyses, and expert panels all based on the same single RCT — the NINDS trial.4 This is low-grade evidence for a potentially lethal therapy. It is time a major RCT was done to repeat the NINDS trial and finally determine whether its result was a statistical anomaly or a real effect. There is no shortage of stroke patients — Batmanian et al found that 14% of patients were eligible for this therapy.2 The paucity of evidence for thrombolysis for stroke does not justify rushing patients to stroke centres, bypassing perfectly good hospitals in the hope of finding some of the 3% of patients eligible for treatment, of whom one in eight (0.38% of all stroke patients) would theoretically have a better neurological symptom score if given thrombolysis.6,7 I feel that it is a waste of time and effort, and a danger to patients, to focus all resources on supplying a potentially lethal therapy that is often incorrectly used and provides a marginal benefit.

Gino J Toncich

A 14-year-old boy was admitted with a 2-week history of increasing breathlessness and fatigue. He had a pulse rate of 130 beats/min and blood pressure of 100/66 mmHg with 16 mm paradox. Jugular venous pressure was raised 10 cm above the sternal angle, and heart sounds were faint. He had been diagnosed with refractory iron-deficiency anaemia in early childhood, for which he had been receiving blood transfusions. He denied any history of epistaxis, haemoptysis, malaena, haematuria or overt bleeding from any other site. On examination, the patient had multiple, blue-black, papular and nodular, compressible, non-pulsatile, vascular skin lesions, ranging in size from a few millimetres to 1–2 cm, distributed over the trunk and limbs, including the soles of the feet, perineal region (Figure A) and lips. A chest x-ray showed an enlarged cardiac silhouette suggestive of pericardial effusion (Figure B). This was confirmed by transthoracic echocardiography. Therapeutic pericardiocentesis showed haemopericardium. Blue rubber bleb naevus syndrome (Bean syndrome) is diagnosed in the presence of distinctive venous malformations on the skin, in the gastrointestinal tract and, less often, in other organs, leading to occult or overt gastrointestinal bleeding and chronic anaemia.1-3

Pankaj Malhotra · Madhav C Menon · Subramaniyan S Anand · Arshjyot Narula · Subhash Varma

A 59-year-old man presented with persistent abdominal discomfort 12 months after splenectomy for thrombocytopenia to ameliorate progressive myelofibrosis. Physical examination revealed bilateral loin masses. Computed tomography of the abdomen identified perinephric cuffing by soft tissue nodular masses in the perinephric fat (Figure A). Core needle biopsy of the right perinephric fat revealed haematopoietic cells (Figure B). Extramedullary haematopoiesis is not uncommon when intramedullary haematopoiesis is impaired.1-3 Common sites include the liver and spleen. It is unusual for extramedullary haematopoiesis to involve the perinephric fat. The role of splenectomy in accelerating the development of extramedullary haematopoiesis in uncommon sites has become increasingly apparent.1

Philip Y-I Choi

Five cases of methaemoglobinaemia after ingestion of sodium nitrite occurred in two clusters in Sydney in 2006. All cases were unintentional poisonings following use in cooking of an imported compound sold as a food additive. In all cases, methaemoglobinaemia was recognised early and treated promptly, with all patients making a full recovery. These cases highlight the importance of accurate food labelling and surveillance of imported goods. Clinical recordIn 2006, at Liverpool Hospital in Sydney, two separate clusters of patients presented to the emergency department with cyanosis after consuming home-prepared food to which sodium nitrite had been added. In the first cluster, a husband and wife of Vietnamese–Chinese origin developed cyanosis and dyspnoea after consuming homemade rice cakes containing “Nutre Powder” and “Borax Powder”, which were commonly available from local Asian food stores in the area. Both patients arrived by ambulance and, despite oxygen therapy, remained cyanotic. Their blood samples had a distinctive chocolate brown appearance, and laboratory testing confirmed methaemoglobinaemia. The husband, who was the more unwell, had a measured methaemoglobin level of 57%. After treatment with intravenous methylene blue, his condition rapidly improved. The wife, who had a methaemoglobin level of 21%, was treated supportively with oxygen and monitored closely. Both patients were admitted to the intensive care unit for a brief period of observation before being transferred to the haematology unit. Their subsequent progress was uneventful, and both patients were discharged from hospital 2 days later. On request from medical staff, the couple brought into the hospital the two packets used, both containing whitish powder. The first was labelled “Goldfish” brand “Borax” and the second, “Goldfish” brand “Nutre Powder” (Box). No further information about the contents was printed on the packaging. The packets were imported through a specialty Asian food distributor based in Melbourne, and the wife claimed they were commonly available food additives. She had used both ingredients in the meal she prepared that evening from a recipe given to her by her mother. She also claimed her mother had previously used the products in China without incident. Neither patient knew the composition of the products, and questioning of the product’s importer by the medical team yielded no further information. Two weeks later, a second cluster of three new cases, involving a Vietnamese family unrelated to the index cases, presented to Liverpool Hospital emergency department with identical symptoms after eating a pork dish prepared using an unidentified white powder. Laboratory testing again confirmed methaemoglobinaemia, with levels ranging from 39% to 51%. Intravenous methylene blue was administered, leading to rapid clinical improvement. All three patients made uneventful recoveries after being observed in the emergency department overnight and were released from hospital the next day. In both clusters, the onset of initial symptoms, such as vomiting, shortness of breath and dizziness, was dramatic, within minutes of consuming the contaminated food preparations. In the second cluster, two family members who had eaten the contaminated pork dish noticed the symptoms just after leaving home. They called back to warn the others that the food might be contaminated, but the others had already consumed the dish as well. A fourth person in that cluster also became ill, but had much less severe symptoms, having eaten only a small amount. She was seen by paramedics but not transported to hospital with the others. On review by her local doctor the next day, she had made a full recovery. Investigation by the New South Wales Food Authority and staff of the Public Health Unit of Sydney South West Area Health Service found that identical Goldfish brand Nutre Powder had been used in food consumed by the patients in the second cluster, reportedly as a flavour enhancer. The packages were purchased from separate local retailers. Importantly, this group was found not to have been exposed to any other known causes of methaemoglobinaemia. Residual Nutre Powder from both clusters and Borax Powder from the first cluster were submitted to the Division of Analytical Laboratories in Lidcombe, Sydney, for testing. Those labelled Nutre Powder contained 100% sodium nitrite, while the packet labelled Borax contained 100% sodium tetraborate. On the day that laboratory results on the additives used by the first cluster patients became available, NSW Health alerted hospital emergency departments and the public to the risk of methaemoglobinaemia associated with ingestion of Nutre Powder. As Goldfish brand Nutre Powder was imported via Victoria, the Victorian Department of Human Services initiated a national recall after the discovery of nutritional information on some packets of the products, implying that they were intended for human consumption. The Borax packets and two other packets labelled “Natural Powder” and “Natural Baking Powder”, which were also found to contain sodium nitrite, were recalled as well. Nevertheless, packets labelled Nutre Powder were found for sale in Asian grocery stores in NSW several months after the national recall, and the proprietors denied any knowledge about the product being potentially harmful or illegal for sale as a food additive. They were directed to the NSW Food Authority and have since stopped selling these products. DiscussionMethaemoglobinaemia is a potentially fatal condition in which native haemoglobin loses its ability to carry oxygen due to oxidation of the ferrous iron component of the haem molecule to the ferric state. Ferric forms of the haem molecule are unable to bind oxygen, and the oxygen affinity of accompanying ferrous haems in the haemoglobin tetramer is increased. As a result, the oxygen dissociation curve is “left shifted”, and oxygen delivery to the tissues is impaired.1 Ferric forms of the haem molecule are generated physiologically by deoxygenation, but are kept at low levels by endogenous haemoglobin reduction mechanisms, so that blood concentrations of methaemoglobin do not normally exceed 1%–2%.2 Hereditary causes of methaemoglobinaemia are well described but rare.3 Most reported cases arise from exposure to an oxidising agent, including those containing nitrites. Symptoms include nausea, vomiting, lethargy, shortness of breath, obtundation and coma. Patients typically present with profound cyanosis and have a deeply greyish-blue appearance. Blood samples from affected individuals often have a characteristic chocolate brown colour. The degree of oxygen desaturation varies with the degree of methaemoglobinaemia, but may not correlate well clinically and therefore is not necessarily a reliable predictor of outcome. Pulse oximetry readings of oxygen saturation are generally inaccurate, and arterial blood gas measurements frequently show normal dissolved oxygen and carbon dioxide tensions with falsely elevated oxygen saturations.4 The observed cyanosis is refractory to standard oxygen therapy. Despite this, management of methaemoglobinaemia comprises both supportive measures, such as oxygen therapy, and intravenous methylene blue administration in moderate to severe cases. Methylene blue is reduced by the action of a normally minor enzyme pathway involving reduced nicotinamide adenine dinucleotide phosphate (NADPH) — methaemoglobin reductase. The reduced form of methylene blue, leukomethylene blue, can then go on to reduce methaemoglobin to haemoglobin.5,6 Methylene blue (2 mg/kg bodyweight as a 1% solution) is administered to patients with methaemoglobin levels exceeding 25%–30% and to patients with underlying anaemia or cardiac or respiratory disease, in whom tissue oxygen delivery might already be impaired. While methylene blue is generally well tolerated, it must be administered with caution to people with severe renal impairment and is relatively contraindicated in those with glucose-6-phosphate dehydrogenase (G6PD) deficiency, as it may lead to profound oxidative haemolysis in these individuals without lowering methaemoglobin levels, and, indeed, has been reported to cause methaemoglobinaemia itself.7 Of interest, follow-up of one of the patients who was given methylene blue demonstrated G6PD deficiency, although no adverse effects were seen clinically. G6PD deficiency is more common in South-East Asian populations, where it is believed to offer some protection against malaria.8 Thus, although an effective antidote for nitrite-induced methaemoglobinaemia exists, it is not without risk, which can present a management dilemma in an emergency setting where rapid assessment for G6PD deficiency is not available. Rapid administration of methylene blue has also been associated with local pain and tissue necrosis.9 While sodium tetraborate is used as a food additive in some countries — particularly in noodles, where it is believed to improve colour, texture and flavour — this use is prohibited in Australia. Though potentially fatal in large doses, it is not known to cause methaemoglobinaemia.10,11 Nitrites, on the other hand, are a well known cause of methaemoglobinaemia, although the mechanism underlying this process has recently been disputed.12 Numerous cases have been reported worldwide, most commonly associated with drinking contaminated water6,13 or ingestion of meat products in which nitrite compounds have been used as a preservative.14,15 Both sodium and potassium nitrite are permitted for use in Australia in the preparation of processed meat, poultry and game products, where they are used both as a preservative and to improve appearance. However, their sale is prohibited for use in home cooking.16 Fortunately, in the cases reported here, all patients promptly sought medical attention, and there were no deaths or persistent adverse outcomes. The cases we report here highlight the need for accurate labelling of all potential food products and surveillance of these products to ensure that imported goods meet local standards. Overall, the recall delivered an effective and rapid response, with national media coverage (including community media in local spoken languages) and the alerting of hospital emergency departments. However, the cases also highlight potential problems in putting these measures into practice. Unlabelled or inappropriately labelled goods are able to slip into Australia undetected if they are not specifically imported as food additives. The Australian Quarantine and Inspection Service works with Food Standards Australia New Zealand on a national level, and the responsibility for products released into the marketplace passes to state and territory authorities. If improperly labelled goods have entered the country undetected and been locally distributed, coordination of their recall is complex, requiring cooperation of numerous parties across levels of government as well as bridging communication and cultural barriers. A packet of “Goldfish” brand “Nutre Powder”

Peter Maric MB BS(Hons) · Sayed S Ali MD · Leon G Heron FRCPA, FAFPHM · David Rosenfeld FRACP, FRCPA · Matthew Greenwood FRACP, FRCPA

Cryoglobulins are plasma immunoglobulins or immunoglobulin-containing complexes that precipitate on exposure to cold and redissolve on warming. They should be distinguished from red cell agglutinins and from the blood-component cryoprecipitates manufactured from donor plasma. The typical clinical triad of cryoglobulinaemia comprises purpura, arthralgia and weakness, with possible multisystemic organ involvement, notably glomerulonephritis and neuropathy. In blood smears prepared at room temperature, cryoglobulins can be detected by their peculiar morphology, which can assume globular, rhomboid or cylindrical amorphous precipitates (Figure, A–C, arrows; Wright–Giemsa stain, original magnification, × 200). Occasionally, these may be mistaken for blood cells, leading to spuriously high blood cell counts. Cryoglobulins are associated with infections (eg, hepatitis C), lymphoproliferative diseases and autoimmune diseases. Plasmapheresis is a useful adjunctive treatment for severe active disease, but the replacement fluid must be warmed to prevent precipitation of circulating cryoglobulins.

Herman H Lee · Chi-hung Hui

With three iron chelating agents now available, management options have substantially increased Outcomes in patients with thalassaemia major have been revolutionised over the past 50 years. Without transfusions, death usually occurred in the first decade of life. In the 1950s, transfusions were given to manage the symptoms of anaemia, which resulted in increased survival but significant morbidity. In the 1960s, regular blood transfusions were introduced to maintain relatively high mean haemoglobin levels in order to suppress the production of abnormal red cells in the bone marrow. This permitted good quality of life in childhood, but led to cardiac death from transfusional iron overload at a mean age of 18 years.1 Fortunately, the parenteral iron chelating agent desferrioxamine was also introduced in the 1960s, and its use to control iron load led to improved survival2 and reduced morbidity.3 Nevertheless, the difficult treatment regimen (subcutaneous infusion for 8–12 hours per night, 3–7 nights per week) resulted in poor compliance. Cardiomyopathy remains the most common cause of premature death in patients with thalassaemia,3 even in well chelated patients.4 The recent development of new magnetic resonance imaging (MRI) techniques (T2*) has allowed the assessment of tissue iron levels (albeit indirectly), including myocardial iron levels, and has increased our understanding of iron overload. The use of this methodology has demonstrated that practically all thalassaemia major patients with cardiomyopathy have excess cardiac iron. It has also shown that the conventional surrogate markers — liver iron concentration and/or ferritin levels — are not predictive of cardiac iron levels.5,6 Cardiac iron overload has also been observed in patients who were previously thought to be well chelated.5,6 The licensing, in 1999, of the oral chelating agent deferiprone as a second-line iron chelator was initially embraced as a relief for patients who could not tolerate desferrioxamine or had adverse reactions to it. Recent data demonstrate that deferiprone is more effective than desferrioxamine in removing excess cardiac iron7 and suggest that it may even be more protective of endocrine glands (eg, the pancreas, thyroid and gonads).8 The beneficial effect may be related to the characteristics of deferiprone, which has a low molecular weight, an uncharged molecule and favourable lipophilicity and is largely unbound to plasma proteins, enabling easy entry into all tissues. The use of deferiprone and desferrioxamine in combination has even been demonstrated to reverse established cardiomyopathy.9 The bottom line is survival. For ethical reasons, prospective studies of survival are not feasible, and in any case it would take many years to acquire meaningful results. Data from observational and retrospective studies must therefore be given due consideration. An Italian epidemiological, natural history study of 516 patients demonstrated a higher incidence of cardiac disease and cardiac-related deaths in a group of patients who continued on desferrioxamine (359 patients) than in a group who were switched to deferiprone (157 patients).10 The latter group experienced no de-novo cardiac disease or iron-related deaths. Reports from other centres are also indicating reduction in cardiac deaths over the past few years, which may be attributable to the use of deferiprone.11 Both chelators are needed because the value of desferrioxamine is limited by poor compliance with treatment, and, although deferiprone is well accepted, its use is limited by concerns about potential adverse effects, particularly agranulocytosis. Although the incidence of this complication is low, its potential occurrence necessitates weekly blood counts. Some patients also complain of the relatively large number of tablets that need to be taken in three divided doses daily. The article by Kidson-Gerber and colleagues in this issue of the Journal12 comes from a unit in which patients are offered optimal management with appropriate monitoring and treatment, including prescription of desferrioxamine and deferiprone (→ Management and clinical outcomes of transfusion-dependent thalassaemia major in an Australian tertiary referral clinic). The authors quantified compliance by comparing prescriptions written with the actual amount of drug collected from the hospital pharmacy. This confirmed that, on average, patients took only 50% of the desferrioxamine prescribed, and only 10% took it exactly as prescribed. Their report firstly confirms the relationship between acceptance of chelation therapy and morbidity, making it clear that acceptance and use of chelation therapy is crucial for satisfactory outcomes, and secondly demonstrates increased compliance with oral chelation therapy. Seventeen patients (mainly non-compliant with desferrioxamine therapy) were additionally prescribed deferiprone. Relatively few took the prescribed quantity of desferrioxamine, but most took the deferiprone, sometimes even more than prescribed, indicating “creep” on the part of the patients towards the more acceptable oral therapy. The therapeutic armamentarium has been further expanded by the recent licensing of the oral chelator deferasirox in Australia and a number of other countries. Deferasirox is a soluble tablet that needs to be taken only once daily and therefore has high patient acceptance. At adequate doses, deferasirox is equivalent to desferrioxamine in its ability to reduce liver iron concentration.13 It has produced some adverse effects, particularly a rise in creatinine levels, but overall its safety profile is acceptable. Prospective studies of its ability to remove cardiac iron are in progress. We need to ensure that all patients with thalassaemia major have access to MRI (to assess their myocardial iron load) and the full portfolio of iron chelation options. In developing countries, the treatments available will be strongly influenced by cost. If the newer oral agents can be shown to be at least as effective as desferrioxamine in preventing iron-induced morbidity, the higher cost of deferasirox may be offset by the reduced cost of managing complications secondary to poor tolerance of desferrioxamine treatment. With three chelating agents now available, the options for chelation management are significantly increased. Chelation therapy can now be tailored to individual patients based on the severity and tissue distribution of the patient’s iron load. Intensive chelation regimens, combining deferiprone and desferrioxamine, are now possible, and data on the various potential combinations of the three chelators are expected to be available in the near future. In summary, the management of thalassaemia major has improved significantly with the ability to monitor not only iron load but also the sites of iron loading, and because clinicians now have the choice of three iron chelators. It can be anticipated that mortality and morbidity will be further reduced and that life expectancy will approach the norm — especially for younger patients. However, as shown by Kidson-Gerber and colleagues,12 prognosis will be largely dependent on compliance with iron chelation therapy.

Vasili Berdoukas OAM, MB BS, FRACP · Bernadette Modell PhD, MB BChir, FRCP

Objective: To evaluate the management, clinical outcomes and adherence to chelation therapy in adult transfusion-dependent patients with thalassaemia major.Design, setting and participants: We reviewed all transfusion-dependent adults with thalassaemia major (n = 44) attending the Haematology Department at the Prince of Wales Hospital, Sydney, in 2005. Data were collected retrospectively (2000–2005) and prospectively (2005) for cross-sectional clinical audit from clinical reviews, patient questionnaires, pharmacy dispensing records and routine laboratory investigations.Main outcome measures: Iron overload and its complications; complications of transfusion; adherence to subcutaneous and oral chelation therapy (expressed as a percentage based on the ratio of the amount dispensed to the prescribed dose).Results: The prevalence of diabetes mellitus was 18%; hypothyroidism, 16%; hypogonadism, 32%; cardiomyopathy, 9%; and osteopenia/osteoporosis, 83%. Serological evidence of exposure to hepatitis C and hepatitis B was present in 41% and 14% of patients, respectively, and 23% of patients had active hepatitis C infection. Predictors of complications included increasing number of years of transfusion, increasing age, coprescription of desferrioxamine and deferiprone, and poor adherence to desferrioxamine treatment. There was a wide range of adherence to therapy with desferrioxamine (0–100% of prescribed dose; mean, 46%; median, 49%) and deferiprone (29%–214% of prescribed dose; mean, 117%; median 112.5%).Conclusion: The health outcomes in our patients were similar to or better than those of patients in other cohorts, but, despite the availability of effective chelating agents, our patients had marked iron overload and a high incidence of complications.

Giselle L Kidson-Gerber MB BS, BSc · Sally Francis DipAppSc(Nursing) · Robert Lindeman FRACP, FRCPA, PhD

Objective: To measure the safety and acceptability of providing written advice (WA) for selected patients referred to a haematology service, as an alternative to inpatient or outpatient assessment.Design, setting and participants: Review of the initial management and subsequent course of patients newly referred to a tertiary referral hospital in Christchurch, New Zealand, between 16 October 2003 and 8 June 2006. Structured questionnaires were sent to all referring doctors and patients recently managed with WA.Main outcome measures: Numbers and diagnoses of patients managed with WA, early assessment or delayed assessment; re-referral and treatment details; characteristics of WA letters; and opinions of referring doctors and their patients on the WA process.Results: 26% of new referrals (714/2785) were managed with prompt WA, while 16% (455/2785) received the alternative of delayed assessment. After a median follow-up of 23 months (range, 8–40 months), 13% of those managed with WA (91/714) were re-referred back to the same haematologists; 7% (52/714) were assessed in hospital and 2% (15/714) eventually required treatment. There were no deaths due to haematological causes. Over 90% of responding referring doctors said the WA process was rapid and effective, and 77% of recently managed patients were pleased to be treated by their own doctors.Conclusions: Using WA to manage a substantial minority of patients referred to haematologists can be rapid and safe. It is widely accepted by referring doctors.

Peter S Ganly PhD, FRACP, FRCPA · Helen Keeman · Ruth L Spearing FRACP, FRCPA · Mark P Smith FRACP, FRCPA · Nigel Patton MD, FRACP, FRCPA · Eileen G Merriman MB ChB, BMLSc · Steve S Gibbons FRACP, FRCPA

A positron emission tomography scan of this patient’s lymphoma revealed a surprisingly “Australian” distribution of disease.

Colin K F Tan · Tim Y Demetriades

Objective: To assess efficacy and safety of a 24-hour comprehensive protocol-driven model for rapid assessment and thrombolysis of stroke patients in the emergency department.Design: Prospective open observational study.Participants and setting: All patients with acute stroke presenting within 3 hours to the St Vincent’s Hospital (Sydney) emergency department between 1 December 2004 and 30 July 2005.Main outcome measures: Proportion of patients treated, patient demographics, clinical outcome, adverse events and time to treatment parameters.Results: 134 patients (100 stroke; 34 transient ischaemic attack) were admitted to the stroke unit during the study period. Of the 100 stroke patients, 40 presented within 3 hours of symptom onset. Fifteen patients had no contraindications and received intravenous thrombolysis. At 3 months, 10 patients (67%) were independent (modified Rankin score [mRS], 0–2) and seven (47%) had an excellent functional outcome (mRS ≤ 1). Symptomatic intracranial haemorrhage was not observed. The median time from symptom onset to tissue plasminogen activator treatment was 155 minutes (range, 105–197 min). Median onset-to-door, door-to-computed tomography, and door-to-needle times were 48, 25, and 87 minutes, respectively.Conclusion: Rapid assessment of stroke in the emergency department according to a comprehensive protocol allows identification and treatment of acute ischaemic stroke patients eligible for thrombolysis.

Julia J Batmanian BSc(Med), MB BS(Hons) · Meeyin Lam BAppSc(Physio), MIPH · Caitlin Matthews BSc(Hons), MB BS(Hons) · Andrew Finckh MB BS, FACEM · Martin Duffy MB BS, MMed(ClinEdi), FACEM · Robert Wright FRACP, FFARACS, FJFICM · Bruce J Brew MB BS, MD, FRACP · Romesh Markus PhD, FRACP, MB ChB

Combining clinical diagnostic scoring with D-dimer analysis Venous thromboembolism (VTE) occurs in one to two people per 1000 annually in Caucasian populations.1 About a third of these patients will have symptomatic pulmonary embolism (PE), which is associated with a mortality rate of about 30% if left untreated.2 Anticoagulant therapy is highly effective for preventing death in patients with symptomatic PE,3 but causes major bleeding in 2% of patients during the first 3 months. The mortality rate among patients who suffer major bleeding is about 10%.4 Accurate diagnosis is thus critical to ensure that patients with PE receive effective treatment and that patients without PE do not receive unnecessary anticoagulant therapy, with its associated risks and inconvenience. The diagnosis of PE is challenging because of the wide spectrum of symptoms and signs, and because most patients with suggestive clinical features do not have the disease.5,6 Major risk factors for PE include trauma, surgery, and a diagnosis of cancer, but half of patients with symptomatic PE do not have an identifiable risk factor.1 Typical symptoms of PE include dyspnoea or acute chest pain and, less commonly, cough or haemoptysis, while typical signs include tachycardia, tachypnoea and, less commonly, right ventricular dysfunction.5 However, none of the typical clinical symptoms and signs are unique to the disorder or invariably present in patients with confirmed PE. Thus, the clinical diagnosis of PE is unreliable and additional testing is required to confirm or refute the diagnosis. The accuracy of non-invasive testing, which has almost completely replaced pulmonary angiography in the diagnosis of PE, is substantially improved when combined with an assessment of clinical pre-test probability and the results of a sensitive D-dimer assay.5 Experienced clinicians can use clinical judgment (“gestalt”) to assign a pre-test probability of PE with reasonable accuracy, but simple clinical prediction rules, such as the one developed by Wells and colleagues,7 perform equally well and can be used by less experienced clinicians.5 To date, the Wells model has not been evaluated in an Australian setting. In this issue of the Journal, Yap and colleagues report the results of a prospective cohort study in which they evaluated the use of Wells’ model in 633 consecutive inpatients and outpatients with suspected PE referred for lung scanning at a major Australian teaching hospital (→ A prospective reassessment of the utility of the Wells score in identifying pulmonary embolism).8 Lung scans and multidetector computed tomography (MDCT) were used as the reference standard to establish the diagnosis of PE (positive lung scan or positive MDCT) or to exclude PE (negative lung scan or non-diagnostic scan with negative MDCT). They found that a low clinical pre-test probability of PE (Wells score < 2) was associated with a 4.3% prevalence of PE; a moderate clinical pre-test probability of PE (Wells score 2–6) was associated with a 13% prevalence of PE; and a high clinical pre-test probability of PE (Wells score > 6) was associated with a 67% prevalence of PE. There was no follow-up of patients once diagnostic imaging was completed, and PE may have remained undiagnosed in some patients. Nonetheless, the prevalence of PE in the low, moderate and high pre-test probability categories reported by Yap and colleagues is almost identical to the prevalence reported in the original study by Wells and colleagues,7 and confirms the ability of the Wells score to accurately classify patients according to their clinical pre-test probability of PE. Some investigators9,10 have suggested that patients with a low pre-test probability of PE do not require further investigation because the prevalence of disease in this group is low. However, the risk of missing a diagnosis of PE in such patients can be further minimised by combining the clinical assessment of pre-test probability with the results of a D-dimer assay. Depending on the sensitivity of the D-dimer assay, patients with low or moderate pre-test probability for PE may not require diagnostic imaging if they have a negative D-dimer test. Patients with a low pre-test probability and a negative moderately sensitive D-dimer assay, or patients with a low or moderate pre-test probability and a negative highly sensitive D-dimer assay do not require diagnostic imaging because the prevalence of disease in these patients is very low (less than 2%).11 By contrast, patients with a positive D-dimer test and/or those with a high pre-test probability require diagnostic imaging. For the past 20 years, clinicians have used lung scanning as the first-line non-invasive imaging test for patients with suspected PE. A normal or near-normal lung scan reliably excludes PE, while a high-probability lung scan confirms the diagnosis. However, as many as half of patients with suspected PE have a non-diagnostic lung scan result, and a quarter of these have PE.12 Newer lung scanning techniques may reduce the proportion of non-diagnostic scans, although the number of non-diagnostic scans reported by Yap and colleagues is unexpectedly low. MDCT is more rapid and convenient than lung scanning, but requires intravenous injection of contrast medium that is potentially nephrotoxic. The test can also yield non-diagnostic results.13 Clinicians must interpret non-diagnostic results of imaging studies in the context of the clinical pre-test probability of PE: patients with a moderate or high pre-test probability of PE and a non-diagnostic scan generally require additional or serial testing to establish or refute the diagnosis.12,13 Patients for whom there is a marked discrepancy between the pre-test probability of PE and the results of diagnostic imaging should also undergo further testing.13 The outcomes for patients with suspected PE can be improved by routine use of written diagnostic algorithms that incorporate a clinical probability scoring system.14 Yap and colleagues have validated the Wells probability scoring system in the Australian setting, and their data should encourage efforts by clinicians and institutions to implement standardised diagnostic strategies that combine assessment of clinical probability with measurement of a sensitive D-dimer in all patients with suspected PE.

Simon J McRae MB BS, FRACP, FRCPA · John W Eikelboom MB BS, MSc, FRACP

To the Editor: Bajorek et al1 did not address two aspects of compliance that may be an issue in community care of patients with atrial fibrillation taking warfarin: time of dose, and point-of-care testing. There is no pharmacological reason requiring warfarin administration in the evening. This practice arose to facilitate dose adjustment on the day of testing, initially in hospitals, and subsequently flowed on to community care. We know that compliance is better with once-daily administration re-gimens, and this patient group invariably needs other medications, such as diuretics, that require morning doses. Concomitant morning administration of warfarin would be logical. In addition, it would reduce attendances by domiciliary nurses to cognitively impaired patients, who may otherwise require twice-daily visits for administration of medications. This would alleviate a significant burden on this stretched resource. The implementation of point-of-care testing at the general practitioner’s surgery by a registered nurse can be of great benefit in the liaison required to manage therapy, and facilitates instant dose adjustments by the doctor, who has comprehensive knowledge of the patient’s pharmaceutical and health circumstances.2

Peter W Ford · Angela Close