Hematologic diseases

In reply: I thank Ford and Close for highlighting additional points regarding the optimal management of anticoagulants in general practice. Indeed, neither of these points was raised by our study participants. Regarding the timing of doses, for medication safety reasons, in many hospitals the warfarin dose is listed for mid-evening administration; the recently introduced National Inpatient Medication Chart (NIMC), which incorporates a designated “warfarin section”, nominates 16:00 as the time. In the hospital setting, this timing is necessary to enable the treating medical team (rather than after-hours staff) to review the day’s blood test results, and subsequently prescribe the appropriate dose. The process ensures that treatment is optimally managed by those most knowledgeable about the patient’s regimen, prevents dose omissions, and reduces the time to dose stabilisation (and potentially, time to discharge). Ford and Close appropriately point out that this timing may not always be convenient for patients once they are discharged to the community setting. The optimal regimen should facilitate the patient’s adherence to treatment, and therefore should coordinate with the rational use of existing support services. This needs to be more carefully considered in discharge planning when warfarin therapy is involved. Point-of-care testing is an efficient mode of monitoring anticoagulation therapy, but we were unable to expand on this in our previous discussion (due to word limits). Internationally, point-of-care testing underpins many comprehensive monitoring services, whereby allied health professionals (eg, trained nurses or pharmacists) perform the blood tests, monitor results, adjust doses, and/or prescribe therapy, as well as educate patients, under the guidance of a medical officer. Such services are conventionally offered on an outpatient basis (eg, the Antithrombosis Center, University of Illinois Medical Center, Chicago, Ill, USA) or within the general practice setting, and are effective and safe models of care. Patient self-management using point-of-care testing devices has also been studied overseas,3 with reports of good control of international normalised ratio (INR) and high patient satisfaction. Locally, point-of-care testing has been trialled within community pharmacies. In a Sydney-based study, trained community pharmacists monitored INRs using point-of-care testing, reviewed doses according to standardised nomograms, and subsequently liaised with GPs regarding dose adjustments. The results showed that collaborative management effectively maintained INRs within the therapeutic range.4 There is scope to develop such models further, and we are currently investigating GPs’ preferences for models of care, as well as opportunities for mobile anticoagulation services.

Beata V Bajorek

Until recently, liver transplantation was contraindicated in Jehovah’s Witness patients because of recipient-imposed restrictions on use of blood products. However, recent improvements in surgical and anaesthetic techniques and new procoagulant agents challenge this practice. We describe two Jehovah’s Witness patients who had successful liver transplantation without blood transfusion. To our knowledge, these are the first such cases in Australasia. The techniques used to minimise blood loss and transfusion requirements could potentially benefit all patients undergoing major surgery. Clinical recordsPatient 1A 48-year-old farmer with end-stage cirrhosis due to α-1 antitrypsin deficiency had evidence of moderate portal hypertension with splenomegaly and ascites (Child–Pugh score B), but no significant lung disease. He met minimum recipient suitability criteria for liver transplantation, according to the Transplantation Society of Australia and New Zealand (TSANZ) liver standing committee.1 As a Jehovah’s Witness, he would not accept transfusion of red blood cells, fresh frozen plasma or platelets. However, he indicated that he would accept blood fractions and recirculated autologous blood and cell-saved blood. A relative, also a Jehovah’s Witness with similar restrictions on use of blood products, offered to be a live liver donor, but this offer was rejected by the treating team on the basis of unacceptable donor risk. The patient was placed on the transplantation waiting list, and was treated with erythropoietin. Over 6 months, this increased the haemoglobin concentration from 112 g/L to 151 g/L (reference range [RR], 135–180 g/L). Results of other preoperative blood tests included: platelet count, 74 × 109/L (RR, 150–400 × 109/L); international normalised ratio (INR), 1.2 (RR, 0.9–1.3); serum concentration of bilirubin, 60 μmol/L (RR, < 20 μmol/L); albumin, 26 g/L (RR, 35–50 g/L); alanine aminotransferase (ALT), 102 U/L (RR, < 40 U/L); and creatinine, 143 μmol/L (60–110 μmol/L). Liver transplantation was performed using an organ from a 54-year-old deceased donor. The piggyback implantation technique, without venovenous bypass, was used. Coagulation was monitored intraoperatively using routine coagulation tests and thromboelastography (Haemoscope, Skopie, Ill, USA). The latter technique measures the kinetics and tensile strength of clot formation. Prophylactic aprotinin was administered as a bolus followed by a constant infusion. The patient also received cryoprecipitate, albumin, haemodilution, and autotransfusion of cell-saved and recirculated blood. On arrival in the intensive care unit, haemoglobin concentration was 118 g/L. The patient received recombinant factor VIIa to treat an INR of 3.4, and erythropoietin was continued. There was significant primary graft dysfunction, and ascites was slow to resolve. Three months after transplantation, the patient developed a pulmonary embolism and required anticoagulation. Currently, at 4 years after transplantation, the patient is well and works full time. Patient 2A 43-year-old woman with chronic hepatitis B infection was found to have an unresectable multifocal hepatocellular carcinoma at laparotomy. She had well compensated cirrhosis (Child–Pugh score A) with no evidence of portal hypertension, and met listing criteria for transplantation. A Jehovah’s Witness, she would not accept transfusion of red blood cells, fresh frozen plasma or platelets, but determined that she would accept blood fractions and recirculated autologous blood and cell-saved blood. Pretransplant laboratory results were: haemoglobin concentration, 129 g/L; platelets, 203 × 109/L; INR, 0.9; bilirubin, 7 μmol/L; albumin, 38 g/L; ALT, 58 U/L; and creatinine, 70 μmol/L. Liver transplantation was performed using an organ from a 42-year-old deceased donor. An inferior vena cava interposition technique was used without venovenous bypass because of the proximity of the tumour to this vessel. The central venous pressure was maintained below 5 cmH2O to minimise blood loss. The patient received cryoprecipitate, haemodilution, autotransfusion, and cell-saved and recirculated blood. Unfortunately, she had an allergic reaction to the colloidal plasma-volume substitute, gelofusine; coagulation studies and thromboelastography showed fibrinolysis, which was treated with aprotinin and recombinant factor VIIa. On arrival in the intensive care unit, haemoglobin concentration was 75 g/L, and INR was 1.3. Erythropoietin and iron supplements were started. Postoperative recovery was uncomplicated, and the patient remains well 3 years after the operation. DiscussionTo our knowledge, these are the first reported cases of liver transplantation in Jehovah’s Witness patients in Australasia. While the two patients filled accepted criteria for recipient suitability for liver transplantation,1 the likely need for blood transfusion would until recently have precluded this procedure. Liver transplantation is a well established and successful intervention for liver failure that results in long-term survival (70% at 10 years) in individuals who otherwise have minimal 1-year survival.2 The shortage of deceased donor livers remains the major factor limiting the number of liver transplantation operations in Australia and New Zealand. In 2000, the death rate while waiting for a donor liver in Australia and New Zealand was 40% for acute liver failure and 5%–8% for chronic liver disease.3 This donor shortfall creates an ethical dilemma in which the potential benefit to individual patients has to be balanced against the need to maximise the benefits of this scarce resource. Following a well publicised case in Edinburgh of a death due to acute liver failure, a recommendation was made for a colloquium to address the question of patient selection for liver transplantation and the need for a uniform code of practice in the United Kingdom. The colloquium, held in 1999, recommended that liver transplantation should be performed in patients when their expected survival is less than 12 months and the expected post-transplant survival is over 50% at 5 years.4 These recommendations have been incorporated into the minimum recipient listing criteria used by the TSANZ liver standing committee,1 and were met by both the reported patients. Over the past decade, improvements in surgical and anaesthetic techniques, combined with new procoagulant agents, have resulted in a dramatic reduction in the requirement for transfusion of blood and blood products during liver transplantation. In selected patients, the need for blood transfusions can be avoided completely.5,6 These advances have resulted in reassessment of the use of liver transplantation in Jehovah’s Witness patients. The first-ever reported liver transplantation in a Jehovah’s Witness patient was in 1994.7 Since then, transplantation has been successfully performed in selected individuals for acute and chronic liver failure without the need for blood products.8,9 Outcomes of liver transplantation in adult Jehovah’s Witness patients have been reported as 92% survival with a mean follow-up of 2.2 years (range, 0.3–5.6 years).10 Live-donor liver transplantation using Jehovah’s Witness donor/recipient pairs has more recently been reported.10 However, the risk to the potential live donor in the case of our first patient through refusing blood products, added to the known 0.5% mortality associated with donation of the right lobe of the liver, was thought to be excessive, and this option was rejected.11 As always, careful selection of the recipient is required. Two other Jehovah’s Witness patients referred to us for liver transplant assessment rejected, or were rejected for, transplantation: one, after lengthy consideration, refused to accept a donor liver; while the other had multiple hepatocellular cancer tumours which fell outside the minimal listing criteria. By way of comparison, in a previously reported series, only nine of 29 Jehovah’s Witness patients were found to be suitable for liver transplantation.9 The Jehovah’s Witness church teaches that blood transfusion (whole blood, red blood cells, white blood cells, platelets and plasma) should not be accepted, but individuals themselves are to decide whether to accept organ transplantation and blood fractions. Both our patients accepted the use of cryoprecipitate, albumin, recombinant factor VIIa, recirculated autologous blood and cell-saved blood, and signed a preoperative agreement to this effect. Consent to the use of these factors and techniques were minimum listing criteria required by the treating teams to proceed with liver transplantation. In selected Jehovah’s Witness patients with hypersplenism (not present in our patients), the use of partial splenic artery embolism increased platelet count, allowing transplantation to proceed.9,10 Transjugular intrahepatic portosystemic shunt formation has been less successful in reversing hypersplenism, and should not be used for this indication.12 Jehovah’s Witness patients with severe decompensated liver disease and coagulopathy (Child–Pugh score C), severe portal hypertension and renal failure are at high risk for perioperative mortality and should not receive liver transplantation. Preoperative use of erythropoietin to increase haemoglobin levels has a number of potential benefits. The most obvious is that the patient begins the procedure with a higher blood haemoglobin level. This also enables use of haemodilution to minimise red cell loss during the explant procedure, and autotransfusion to raise the haematocrit after haemostasis is secure. Maintaining a low central venous pressure also decreases blood transfusion requirements during liver transplantation.13 Although recombinant factor VIIa is expensive (average $6000 per patient), it reduces coagulopathy and transfusion requirements.14 Overall, use of these blood conservation techniques may result in a cost benefit, compared with use of large volumes of blood product.7,10 Successful liver transplantation is possible in selected Jehovah’s Witness patients, but early referral before the development of severe, decompensated liver disease is mandatory. Also, we believe that techniques that minimise blood loss and transfusion requirements for liver transplantation should be more widely practised to benefit all those undergoing major surgery.

Gary P Jeffrey FRACP, MD, MRCP · John McCall FRACS · Edward Gane MD, FRACP · Andrew W Mitchell FRACS · Neville M Gibbs MD, FANZCA · Vanessa Beavis FANZCA · Kerry Gunn FANZCA · Stephen Munn FRACS · Anthony K House MS, FRACS

A 45-year-old woman presented with a 6-month history of dysphagia. Pallor and koilonychia were present on examination. Laboratory tests revealed microcytic hypochromic anaemia (haemoglobin, 59 g/L; mean cell volume, 65 fL), with decreased iron stores (on serum iron studies and bone marrow examination). Barium swallow (Figure A) and oesophagoscopy (Figure B) revealed an upper oesophageal web, which was fractured using Savary–Gilliard dilators. A diagnosis of Plummer–Vinson syndrome (oesophageal web, dysphagia and sideropenic anaemia) was made. As further investigations gave negative results (oesophagoduodenoscopy, colonoscopy, duodenal biopsy, measurement of anti-tissue transglutaminase antibodies, and stool examination for occult blood, ova and cysts), we attributed the iron deficiency to inadequate iron intake. This syndrome is associated with upper alimentary tract cancer, and surveillance endoscopy is recommended. A: Barium swallow showing oesophageal web (arrow). B: Oesophageal web seen on upper gastrointestinal endoscopy (arrows).

Sandeep Chauhan MD(Med) · Atul Sachdev MD(Med), DM(Gastro) · Sanjay D’Cruz MD(Med), DNB(Med), DM(Nephrol) · Ram Singh MD(Med) · Sandeep Singla MD(Med)

To the Editor: The recent article by Miller and colleagues regarding adverse drug events (ADEs) in general practice highlights the high frequency and considerable morbidity associated with ADEs in the general community.1 The authors identified recognised side effects, drug sensitivity, and allergy as responsible for most ADEs. The contribution of the patient’s genotype to drug response, via altered metabolism or responsiveness to pharmaceuticals, is increasingly recognised as potentially responsible for a significant proportion of ADEs. The science of determination of the genetic contribution to an individual’s response to drug action is referred to as pharmacogenomics,2 and represents a potentially beneficial diagnostic tool to aid in the prevention of ADEs. Treatment with warfarin, one of the most frequently prescribed drugs in Australia, has been estimated to account for up to15.1% of all severe ADEs, manifest as minor and major bleeding.3 We have recently determined the presence, frequency and laboratory sequelae of genetic variants (single nucleotide polymorphisms) in two genes responsible for the metabolism (cytochrome P450 2C9 [CYP2C9]) and potency (vitamin K epoxide reductase complex, subunit 1 [VKORC1]) of warfarin4 in an Australian population. In our study of 120 patients in an anticoagulation clinic, the frequencies of allelic variants of the CYP2C9 and VKORC1 genes responsible for altered warfarin activity were 31%5 and 59% (unpublished data), respectively, in keeping with previously published studies.4 Detection of these variants was associated with increased induction international normalised ratio (INR) readings compared with controls, and reduced overall warfarin requirements.6 These findings support previous studies,7 and suggest that genotype determination may be of benefit in identification of patients with increased sensitivity to empiric induction phase warfarin dosing schedules. This may allow for a reduction of induction doses of warfarin, decreasing the risk of excessive INR and bleeding sequelae, commonly observed with induction of warfarin treatment. Furthermore these benefits may aid in reduced time to stabilisation. Additional cost–benefit analysis8,9 will enable determination of the economic viability of genotype determination as an adjunct to management of warfarin dosing. The high population frequency of genetic variants associated with warfarin response emphasises the significant contribution genetic factors can play in patient reaction to drugs and highlights their involvement as potential causes of ADEs.

Keith A Byron · Anthony E Dear

To the Editor: In reference to the letter by Kennedy et al, reporting two patients who tested positive to human T-lymphotropic virus I/II (HTLV-I/HTLV-II) antibodies after administration of the intravenous immunoglobulin, Octagam (Octapharma Australia, Sydney, NSW),1 the Therapeutic Goods Administration (TGA) would submit that: This product was accepted for review by the TGA at a time when plasma products sourced from overseas had to demonstrate superiority over the local product. This requirement was fulfilled by Octagam on grounds that included pathogen safety issues. HTLV-I and HTLV-II are entirely cell-associated viruses and are thus irrelevant to the safety of plasma derivatives. They are in a group of pathogens for which risks, implied by epidemiological factors, apply to cellular but not to plasma products. Another common example is malaria. The Australian plasma pool includes donations from individuals who are at risk of transmitting malaria, so their cells are not used but their plasma is used for fractionation. This situation is well understood and managed by regulators, none of whose standards internationally include the need to test plasma donors for HTLV-I/HTLV-II infection. As the bulk of Australia’s fractionation pool is derived as a by-product of whole blood, blood is tested for HTLV-I/HTLV-II in this country, but it is not a mandatory requirement in Australia or anywhere else. The exclusion of antibody from the plasma pool, as occurs for HTLV-I/HTLV-II in Australia, may actually lead to the loss of potentially protective antibodies, which may well have a therapeutic effect in protecting patients from HTLV-I/HTLV-II infection.2 Such considerations apply, for example, in the requirements of the Food and Drug Administration in the United States for source plasma for fractionation. The requirements take care to allow the inclusion of antibody-positive units for some viruses that would be excluded from blood transfusion. The incident referred to by Kennedy et al was appropriately reported to the TGA’s Adverse Drug Reactions Unit, which concluded that this was not an adverse event. A Northern Territory Government document on HTLV reports: “In Central Australia the prevalence of HTLV-I is estimated to be up to 14%, compared to 4.7% in the Northern Territory cattle country . . .”3 The residual risk of transmission of HTLV-I/HTLV-II infection, while low,4 clearly varies across the potential donor population, and comparisons that are irrelevant in relation to the safety of specific products would appear to be unwise. It is recommended that practitioners seeking to assess causality in putative infectious disease transmission by plasma products follow rigorous scientific processes, such as those recommended by the German regulatory authority.5

Albert Farrugia

To the Editor: We read with great interest the article by Bambrick et al relating to the potential impact of the Australia–United States Free Trade Agreement (AUSFTA) on supply of blood products in Australia.1 Our recent experience with Octagam (Octapharma Australia, Sydney, NSW), an intravenous immunoglobulin (IVIg) product produced overseas, highlights some of the quality concerns raised in their article. Routine practice in our bone marrow transplant unit is to administer IVIg weekly for 100 days after allogeneic stem cell transplantation. Until December 2004, locally produced IVIg, Intragam-P (CSL, Melbourne, Vic), was used exclusively as the IVIg product for these patients. From October 2005, because of limitations in the supply of Intragam-P, the Australian Red Cross Blood Service (ARCBS) also provided Octagam for IVIg replacement therapy in transplant recipients. It has also been routine practice within our transplant unit to repeat serological tests for a variety of transfusion-transmitted viral infections, including human T-lymphotropic virus type I and type II (HTLV-I and HTLV-II), in all transplant patients 100 days after transplantation. Until 2006, none of our patients had ever tested positive for HTLV-I or HTLV-II antibodies. After the introduction of Octagam, the first two transplant patients who received this product for IVIg replacement tested positive for HTLV-I/HTLV-II antibodies at 100 days after transplant (signal to cut-off [S/CO] ratios, 4.36 and 6.33, respectively). Subsequent investigation revealed that these results were probably secondary to passive transfer of HTLV antibodies from the IVIg product used. Both patients received Octagam from the same batch, and subsequent testing of this batch was positive for the presence of HTLV-I/HTLV-II antibodies. Of note, both patients tested negative for HTLV-I/HTLV-II antibodies before transplantation (S/CO ratio < 1.00). Their stem cell donors were also negative for HTLV on testing immediately before stem cell donation, and the only other blood product shared between the two patients (platelets from a common donor) also tested negative for HTLV. Follow-up testing for HTLV-I/HTLV-II antibodies at about 12 months after transplantation gave a negative result in both patients (S/CO ratio < 1.00). Given that Octagam is a plasma (acellular) product processed with appropriate viral inactivation steps,2 we believed it to be extremely unlikely that direct transfer of HTLV virus had occurred. The most likely explanation was the passive transfer of HTLV antibodies. It followed that Octagam must have been sourced from HTLV-positive plasma donors — a practice that is in direct conflict with current ARCBS policy, which specifies that all blood and plasma donors must be screened for HTLV-I and HTLV-II, and that any donors testing positive should be excluded from blood or plasma donation.3 The HTLV-I/HTLV-II serostatus of donors used to source plasma for Octagam are not reported on the product information sheet.2 Testing of one patient sample at the National Serology Reference Laboratory (Melbourne, Vic) suggested the positive serological results in our patients were due to the presence of HTLV-II antibodies. In collaboration with Octapharma, it was subsequently determined that plasma for Octagam was sourced from paid donors from the southern United States, an area where HTLV-I and HTLV-II seropositivity is known to be prevalent among blood donors.4 The clinical implications of our findings are unclear. Our results were reported rapidly to the ARCBS and subsequently to the Therapeutic Goods Administration. Our main concerns are that Octagam plasma is sourced from donors who would normally be excluded from plasma donation within Australia,3 and that there appears to be no current mechanism for addressing this issue. Some of the quality concerns raised by Bambrick et al appear to be not so theoretical after all.

Glen A Kennedy · Judy Cummings · Simon T Durrant

In reply: I would like to respond to the letter by Kennedy et al regarding the passive transfer of human T-lymphotropic virus (HTLV) antibodies following Octagam (intravenous immunoglobulin [IVIg]) administration. Octapharma does not routinely test Octagam for HTLV antibodies — this is in line with Australian regulatory requirements.1 Furthermore, in accordance with global regulatory requirements (including those defined by the Australian Therapeutic Goods Administration), plasma from sources in Europe and the United States is also not routinely tested for HTLV antibodies.2,3 It is important to note that the patients described by Kennedy et al tested positive for HTLV antibodies rather than the HTLV virus, and that the presence of antibodies in the finished product does not pose an infection risk. As noted by the authors, the manufacturing process for Octagam includes viral inactivation. There are two dedicated viral inactivation and removal steps: Solvent/detergent treatment, which is a highly effective step for inactivating lipid-enveloped viruses; Incubation at pH 4 and 37°C for 24 hours. The combination of these two processes ensures that lipid-enveloped and several non-lipid-enveloped viruses are inactivated. Since the initial launch of Octagam in Europe in 1993, more than 33 million grams of the product have been infused, corresponding to more than 2.5 million infusions. During this time, there have been no documented cases of viral transmission resulting from the use of Octagam. Since the launch of Octagam in Australia in 2005, Octapharma has supplied over 600 kg of IVIg, representing about 40 000 infusions to Australian patients. Therefore, taking into account the steps used to remove and/or inactivate lipid- and non-lipid-enveloped viruses, the fact that there have been no documented cases of transmission of any virus since the launch of Octagam, and that plasma sources and testing meet both Australian and global regulatory requirements, the positive HTLV antibody results reported by Kennedy et al have no bearing on either the quality or safety of Octagam.

Wolfgang Frenzel

To the Editor: Bambrick et al1 suggest that the importation of overseas plasma products or the processing of Australian plasma overseas may pose a threat to the safety and security of Australia’s supply of plasma products. The National Blood Authority (NBA) and the Therapeutic Goods Administration (TGA) would like to respond to these issues to ensure that clinicians have confidence in the safety of products currently available in Australia and a better understanding of current blood processing and supply arrangements. Australia is largely self-sufficient in plasma products, a position supported by all Australian governments.2 The governments also agree to the supply arrangements for imported plasma products when demand exceeds domestic supply (as in the case of intravenous immunoglobulin [IVIg]), and for products not supplied by Australian manufacturers (eg, fibrin sealant and other coagulation products). All these products are purchased by the NBA on behalf of Australian governments. Standards applied in Australia ensure that all products on the Australian market are derived from sources — in Europe, the United States and Australia — approved by the relevant authorities. The TGA regulates all plasma products to ensure that they meet international standards of safety, quality and efficacy, irrespective of their source.3 No centres sourcing blood from countries in the developing world, as cited by Bambrick et al, are used. National health systems around the world strive to attain degrees of self-sufficiency that suit their particular economic and policy objectives. However, as the US supplies 60%–70% of global plasma (while consuming only 40% of products sourced from this plasma4), many patients outside the US are dependent on the system of both compensated and uncompensated donors operating in the US. It is worth noting that definitions of “remuneration” vary across countries. The Commission of the European Communities reported in 2006 that “the principle of voluntary and unpaid donations does not exclude compensation for donors, if it is limited to making good the expenses and inconveniences related to the donation”.5 Examples of compensation that this article cites include tax relief of up to €70 per annum in the Czech Republic, an expense allowance of up to €25 for a whole blood donation in Germany, and up to €50 for an apheresis donation in Austria. Thus, the boundary between compensated and non-compensated donors is not distinct globally. Bambrick and colleagues’ contention that products manufactured from paid donors may be less safe is not supported by evidence. The history of blood safety clearly demonstrates that there were major safety issues with both fresh blood and blood products in the 1980s. These problems were more a result of pathogen epidemiology and governments’ blood safety policies than whether donors were paid or unpaid. For example, the Canadian and French blood systems relied entirely on volunteer donors, but the delayed implementation of safety measures and good governance measures led to pathogen risks that exceeded those of the US.6,7 In Australia, the incidence of HIV/AIDS in people with haemophilia exposed to only one type of product in the 1980s approached that of the same patient group in the US, despite the product being sourced entirely from domestic voluntary donors.8 Currently, robust plasma product safety measures in the US have proved to be effective in minimising contamination from both known and emerging pathogens, such as West Nile virus. This virus did not infect the recipients of plasma products from compensated donors, but did infect the recipients of (uncompensated) fresh blood transfusions.9 The equivalence in safety between plasma products sourced from compensated and uncompensated donors has been confirmed by the European Medicines Agency.10 Ensuring the security of supply is central to Australia’s plasma fractionation arrangements. The NBA’s contracts include provisions to ensure product supply security and product safety, including compliance with TGA requirements. Under Australia’s emergency response plans, plasma could be supplied from fresh stock, while the inventory of product in the system and the national reserve of products (funded by the NBA to cover contingencies) could provide fractionated products. A range of other supply security measures is implemented by the NBA on behalf of Australian governments, including secondary suppliers for critical products. These measures take into account the fact that Australian plasma used to manufacture fractionated products is not produced in sufficient quantities to permit storage of excess. Thus, Bambrick and colleagues’ concern that geographical factors may restrict access to Australian plasma has limited relevance in an emergency situation. In summary, Australia has a comprehensive system that draws on international best practice and national jurisdictional arrangements to ensure the supply of high-quality, safe, efficacious plasma products, irrespective of their source.

Alison Turner · Albert Farrugia

In reply: Turner and Farrugia highlight important issues about the safety and supply of Australia’s blood and plasma that constituted key findings of the recent Australian Government review of Australia’s plasma fractionation arrangements.1 These included the desirability of self-sufficiency and the need for a viable contingency plan in the event of local supply failing to meet demand, in the context of probable increased uncertainty in relevant security and supply circumstances. The authors note the importance of a rapid regulatory response to new risks, and rightly emphasise the important role of our National Blood Authority and the Therapeutic Goods Administration in relevant safety assurance processes. However, a crucial issue highlighted in the review that they fail to address is the difficulty of relying on the application and enforcement of regulatory standards if the bulk of Australia’s fractionation occurs offshore.1 After an exhaustive study of arrangements in Europe and the United States, the review concluded that overseas fractionation of Australian plasma would involve significant costs in moving away from the current local arrangements ($75 million) and, because of yield considerations, there would be the potential for an ongoing shortfall in the supply of intravenous immunoglobulin (IVIg) and other plasma-derived products. The review also found that overseas fractionation was potentially associated with major risks to the supply chain, with increased distance and handling providing more opportunities for loss and error, while a doubling or tripling of the turnaround period would have implications for continuity of supply. The review recommended that the federal government maintain the reservation exempting plasma fractionation services from the government procurement provisions of Chapter 15 of the Australia–United States Free Trade Agreement.1 The review confirmed that volunteering for blood donation should be institutionally reinforced as an important exemplar and means of sustaining Australia’s national culture, and that donor payment endorsed a very different set of values and was unlikely to assure sustainability of supply.2 It did, however, suggest initiatives such as tax relief or other institutional ways to encourage donation.1 We fully endorse the summary assessment of the review that: [T]he current structural arrangements, whereby domestically collected plasma is fractionated by CSL Bioplasma, are, subject to careful monitoring of prices, in Australia’s best interests. The present system is well entrenched in the “hearts and minds” of the Australian population and of the Australian medical community and, particularly, in the strategy, thinking and reliance of all end user groups.1

Hilary J Bambrick · Thomas A Faunce

Objective: To evaluate the outcomes of and barriers to implementing standard guidelines (Caring for Australasians with renal impairment [CARI]), using iron management in patients having dialysis as an example.Design and setting: On-site review of iron management processes at six Australian dialysis units varying in size and locality. Patients’ iron indices and haemoglobin levels were obtained from the Australian and New Zealand Dialysis and Transplant Registry.Participants: Patients with chronic kidney disease who were dependent on dialysis.Main outcome measures: Processes for assessing indices of iron stores and iron supplementation; comparison with target indices in the CARI guidelines.Results: There was considerable variability among the units in achievement of haemoglobin and iron targets, with 25%–32% of patients achieving haemoglobin targets of 110–120 g/L, 30%–68% achieving ferritin targets of 300–800 μg/L, and 65%–73% achieving transferrin saturation targets of 20%–50%. Implementation barriers included lack of knowledge, lack of awareness of or trust in the CARI guideline, inability to implement the guideline, and inability to agree on a uniform unit protocol. Factors associated with achieving the CARI guideline targets included nurse-driven iron management protocols, use of an iron management decision aid, fewer nephrologists per dialysis unit, and a “proactive” (actively keeping iron levels within target range) rather than “reactive” (only reacting if iron levels are out of the range) protocol.Conclusions: Variability in achievement of iron targets, despite the availability of a clinical practice guideline, may be explained by variability in processes of care for achieving and maintaining adequate iron parameters.

Michelle J Irving MHSciEd · Jonathan C Craig MMed, PhD, FRACP · Martin Gallagher MB BS, MMEpi, FRACP · Stephen McDonald MB BS(Hons), PhD, FRACP · Kevan R Polkinghorne MB ChB, FRACP, MClinEpi · Rowan G Walker MD, MB BS, FRACP · Simon D Roger MD, FRACP

Objective: To assess the potential for dose-reduction of prophylactic anti-D postpartum.Design: Retrospective audit of fetomaternal haemorrhage (FMH) quantitation by flow cytometry.Participants and setting: 5148 consecutive Rhesus D-negative women aged 15–45 years who had FMH estimation by flow cytometry at a central laboratory in Western Australia in the 65 months between 1 August 1999 and 31 January 2005.Main outcome measures: Quantitation of FMH volume for adequate prophylactic anti-D administration in a timely fashion.Results: 90.4% (4651/5148) of the women had an FMH volume of 1.0 mL or less of Rh D-positive red cells, and 98.5% (5072/5148) had a volume of less than 2.5 mL. Only 0.4% of cases had an FMH volume of 6.0 mL or greater (range, 6.0–92.4 mL).Conclusions: This large retrospective audit shows that a currently available dose of 250 IU (50 mg) of anti-D would have been sufficient for 98.5% of the 5148 Rh D-negative women. On the basis of this evidence, a reduction in the recommended routine postpartum dose of anti-D from 625 IU to 250 IU when flow cytometric quantitation for FMH is available should be considered. Adopting such a strategy would ensure the ongoing provision of a valuable human blood product currently in limited supply.

Bradley M Augustson FRACP, FRCPA · Elizabeth A Fong BappSc, PGradDip(MBiol), GradDip(BCom) · Dianne E Grey FAIMS, BAppSc · Janine I Davies BAppSc, PGradDip(MSc) · Wendy N Erber MD, FRCPA

To the Editor: Reading the excellent Christmas edition of the Journal, I was struck by the symmetry of the computed tomography scans of rectus sheath haematomas in a husband and wife, reported by James and colleagues1 (Box). I was wondering if the couple had not been involved in a minor car accident or incident of heavy braking several days earlier, where the lap–sash or buckle of a seatbelt might explain the mirror injuries?

Mark R Nelson

In reply: The rare and spontaneous nature of rectus sheath haematoma leaves its origins open to such interesting questions. Neither of our patients was able to recall a history of motor vehicle trauma, but minor braking trauma certainly remains a possibility, as does respiratory infection leading to protracted cough. Computed tomography scans of matching rectus sheath haematomas in a 62-year-old woman (A) and her husband (B).

David James

Haematopoietic stem cell transplantation is an accepted curative therapy for many cancers and inherited non-malignant diseases, including bone marrow failure syndromes, haemoglobinopathies, and inborn errors of metabolism. Stem cells can be used from the bone marrow or blood of matched siblings or appropriately matched unrelated volunteers, but many patients do not have a suitably matched donor. Umbilical cord blood (UCB) has been successfully used as an alternative stem cell source. It has the advantage of tolerance for a degree of human leukocyte antigen (HLA) incompatibility not possible with adult bone marrow, resulting in greater likelihood of finding an appropriate match. UCB is also stored fully tested and cryopreserved, leading to rapid availability. Greatest clinical experience in UCB transplants has been in treating paediatric leukaemia. Results using well matched UCB grafts are equivalent or better than with unrelated bone marrow transplant. Cell dose and the degree of HLA matching are critical determinants in the success of UCB transplant. The use of UCB in older children and adult patients has been limited by the fixed, low cell dose available in a UCB unit, relative to recipient weight. This can be overcome by strategies such as using two or more UCB units. Early animal studies suggest that UCB may have the potential to differentiate into other cell types, including nervous tissue, and may in future play a role in the treatment of disorders such as Alzheimer disease and Parkinson disease.

Tracey A O’Brien FRACP, MB ChB, MHL, BSc · Karin Tiedemann OAM, MB BS, FRACP · Marcus R Vowels AM, MB BS, MD, FRACP

To the Editor: Current Australian guidelines for urgent warfarin reversal recommend withholding warfarin, and giving vitamin K as well as factor replacement (Prothrombinex HT; PTX) with or without fresh frozen plasma (FFP).1 PTX administration without FFP is recommended only when FFP is unavailable, as PTX factor VII levels are low and unquantified.2 Transfusion of 25–50 IU/kg PTX and 150–300 mL of FFP is advised. We examined the effectiveness of warfarin reversal using PTX alone or combined with FFP. One hundred and fifty-five patients given PTX were identified from the transfusion medicine unit’s computer records. Fifty patients were excluded — no warfarin (19), non-hospital patients (11), no record of PTX administration (14), no monitoring (5), normal international normalised ratio (INR) (1). One hundred and five patients who had received warfarin were reviewed. The reasons for anticoagulation were atrial fibrillation (45 patients), venous thromboembolism (22 patients), cardiac valve replacement (21 patients), myocardial infarction (9 patients), and other (8 patients). PTX was administered for bleeding in 51 patients (32 had major bleeds), suspected bleeding in eight patients, high INR in 11 patients, and before a procedure in 35 patients. Bleeding severity was graded using published criteria.3 Post-treatment INR and patient details were used to determine clinically significant INR lowering and haemostasis. The patients were divided into two groups — patients administered PTX without FFP (n = 74) and patients administered PTX and FFP (n = 31) (Box 1). Seventy-four patients (71% receiving PTX; 67.7% PTX + FFP) were given vitamin K (71 intravenously) to ensure ongoing correction of coagulopathy. This was administered within 2 hours of PTX (77%), with doses 1–2.5 mg (44 patients), 3–6 mg (13 patients), and 10 mg (17 patients). The mean PTX dose used was 862 IU or 12.9 IU/kg. Slightly higher PTX doses were administered to patients in the PTX group (913 IU or 13.1 IU/kg) than to patients receiving PTX and FFP (742 IU or 12.3 IU/kg) (Box 1). Seven of 89 patients (7.9%) received the published recommended PTX dose.1 The remaining patients received < 25 IU/kg. Neither the degree of warfarin coagulopathy nor FFP transfusion appeared to influence PTX doses administered. One patient in the PTX group with end-stage renal impairment failed to show any reduction in INR, but did achieve haemostasis. All patients with bleeding achieved haemostasis after PTX. The degree of INR correction after PTX varied considerably, with the percentage reduction in INR after PTX ranging from 0 to > 90% per vial of PTX transfused (Box 2). Achievement of haemostasis did not require normalisation of INR (Box 2). The INR is designed for monitoring therapeutic warfarin levels and its accuracy declines with excessively prolonged clotting times. As PTX is more likely to produce correction of coagulopathy through increased thrombin rather than through factor VII replacement, INR may not be the best test for monitoring haemostatic changes after PTX. Our data suggest that FFP may be unnecessary when PTX is used to reverse warfarin coagulopathy. We have also shown that doses of PTX under 25 IU/kg are effective. Administration of low-dose PTX will produce cost savings and may reduce PTX-associated adverse events (including infusional reactions, thrombocytopenia [secondary to heparin], and thrombosis). The risks associated with FFP transfusion (including allergic reaction, transfusion-related acute lung injury, fluid overload, and infection transmission) would be eliminated. A prospective study is necessary to confirm our findings and assess the efficacy of lower PTX doses, so that, if our results are confirmed, warfarin reversal guidelines can be reviewed. 1 International normalised ratio (INR) before transfusion of Prothrombinex HT (PTX) and dose of PTX in patients in the two groups (PTX and PTX + fresh frozen plasma [FFP]) at increasing levels of anticoagulation INR before PTX PTX group (n = 74) PTX + FFP group (n = 31) No. of patients PTX dose IU (range) PTX IU/kg* (range) No. of patients PTX dose IU (range) PTX IU/kg† (range) FFP units (range) < 2.0 8 556 7.69 1 500 9.09 2 (500–1000) (5.32–11.1) — — — 2.0–3.9 22 929 12.81 16 562 8.48 2.2 (500–2000) (4.85–31.25) (500–1000) (5.1–17.54) (1–10) 4.0–5.9 12 1083 16.2 7 1000 15.51 4 (500–3000) (6.67–34.8) (500–2000) (7.14–44.4) (2–6) 6.0 + 32 1187 14.17 7 929 12.65 4.7 (500–2000) (4.17–27.03) (500–1000) (7.69–19.23) (2–10) * PTX doses calculated for the 89% of patients in the PTX group whose weight was recorded in notes. † Doses calculated for the 77% of patients in the PTX + FFP group whose weight was recorded in notes. 2 Absolute and percentage reduction in international normalised ratio (INR) per vial of Prothrombinex HT (PTX) transfused for the 74 patients in the PTX group (treated with PTX without fresh frozen plasma) INR after PTX INR before PTX < 1.5 1.5–1.9 2.0–2.9 3.0–3.9 4.0–5.9 6.0 + < 2.0 No. of patients (no. with bleeding) 5 (0) 3 (1) — — — — Mean percentage reduction in INR (range) 18.6% (7.1%–31.3%) 9.3% (0–16.7%) — — — — 2.0–3.9 No. of patients (no. with bleeding) 7 (4) 9 (2) 6 (1) — — — Mean percentage reduction in INR (range) 35.9% (21.4%–53.6%) 23.5% (9.1%–44.4%) 30.5% (9.6%–40.0%) — — — 4.0–5.9 No. of patients (no. with bleeding) 1 (1) 7 (5) 3 (3) 1 (1) — — Mean percentage reduction in INR (range) 33.8% 34.4% (9.9%–65.5%) 31.7% (25.5%–39.5%) 21.8% — — 6.0 + No. of patients (no. with bleeding) 8 (4) 4 (1) 8 (5) 8 (2) 2 (1) 2 (0) Mean percentage reduction in INR (range) 52.8% (19.4%–86.4%) 66.9% (44.5%–90.1%) 55.7% (33.6%–82.5%) 37.8% (19.9%–40.2%) 39.6% (35.7%–43.5%) 26.7% (19.0%–34.4%)

Julie H Crawford MB BS · Bradley M Augustson FRACP, FRCPA

Heather E Robinson,* Ellen L Maxwell,† H Miles Prince,‡ Mary A O'Reilly,§ Andrew Jakobovits¶ * Haematology Registrar, ‡ Chair of Haematology Service, Peter MacCallum Cancer Centre, Locked Bag 1, A'Beckett Street, East Melbourne, VIC 8006; † Haematologist, Melbourne Pathology, Melbourne, VIC; § Infectious Diseases Physician, ¶ Physician, Cabrini Health, Melbourne, VIC. Miles. PrinceATpetermac.org To the Editor: A 32-year-old woman presented with fatigue and jaundice 12 days after an uncomplicated elective caesarean delivery. She had a haemoglobin level of 76 g/L (reference range [RR], 110–160 g/L), reticulocytosis (202 × 109/L, 12.6%; RR, 20–100 × 109/L) and hyperbilirubinaemia (139 μmol/L, 97% unconjugated; RR, < 20 μmol/L). Within 24 hours, her haemoglobin level fell to 37 g/L, and a blood film showed spherocytes and polychromasia consistent with haemolysis (Box). A direct antiglobulin test was strongly positive for IgG and complement. The patient’s obstetric case notes revealed administration of a single intravenous dose of cefotetan at the time of delivery. Donor red cells treated in vitro with this antibiotic reacted dramatically with the patient’s serum, indicating the presence of antibody to the drug–red cell combination. The patient was admitted to the intensive care unit and received 6 units of red cells over 24 hours, until the haemolysis resolved. Cefotetan disodium is a broad-spectrum second-generation cephalosporin commonly used as prophylaxis in abdominal and pelvic surgery. It is given as a single intravenous dose at the start of the operation, and 50%–80% of the dose is excreted within 24 hours.1-3 A positive direct antiglobulin test is seen in one in 250 patients treated with cefotetan, although this in itself does not always imply active haemolysis. The true incidence of symptomatic haemolysis is difficult to determine for several reasons: the severity of haemolysis varies between patients, and, if mild, may go undiagnosed; the process is self-limiting; and, when the drug has been used perinatally, symptoms may not be distinguished from the fatigue and anaemia expected (and therefore accepted) by most new mothers. Furthermore, as in our case of caesarean delivery, the obstetrician is not always aware of drugs administered by the anaesthetist, making the link between the antibiotic and haemolysis easy to miss. The Adverse Drug Reactions Advisory Committee has 15 listings of haemolytic anaemia caused by cefotetan in Australia, which probably represents significant under-reporting. Indeed, the recognition of cefotetan-induced haemolysis prompted a US Food and Drug Administration review of its incidence in 2002, which revealed more than 85 reports worldwide, including 15 fatal cases.4 Cephalosporins are the most common group of drugs to cause haemolytic anaemia (93% of all cases), with cefotetan alone accounting for 83%.5 A patient with haemolytic anaemia induced by one cephalosporin carries a 10% risk of cross-reactivity with other cephalosporins and consequently should avoid further exposure if possible. First-generation cephalosporins are less likely to cause significant haemolysis than second- and third-generation cephalosporins, yet are equally efficacious in surgical prophylaxis.1,3 We therefore recommend the use of cefazolin as an alternative to cefotetan. Blood film in a woman with drug-induced haemolytic anaemia Blood film taken on Day 1 of admission shows features of immune-mediated haemolysis, with polychromasia (vertical arrow) and spherocytosis (horizontal arrow).

Heather E Robinson · Ellen L Maxwell · H Miles Prince · Mary A O'Reilly · Andrew Jakobovits

Henry Ekert Haematologist, Children's Cancer Centre and Department of Haematology, Royal Children's Hospital, PO Box 2096, Brighton North, Melbourne, VIC 3186; and Haematology Advisor, Australian Government Department of Health and Ageing. ekerthenryAToptushome.com.au To the Editor: The editorial on mandatory fortification of flour with folic acid by Maberly and Stanley is subtitled: “The scientific benefit is clear, but translating this into practice requires advocacy”.1 The only benefit that is scientifically clear is the reduction in the incidence of neural tube defects. All the other “benefits” listed by the authors are observational and have occurred in a setting where myriad environmental changes have occurred concurrent with folic acid fortification. To imply that the reduction in the rate of heart attacks and stroke is the result of folic acid fortification is, at best, anecdotal, because it is not supported by any randomised controlled studies, and is an extrapolation from the relationship between reduced homocysteine levels and the incidence of stroke and heart disease. The authors also did not mention the increased incidence of multiple pregnancies that has been observed with folate supplementation (relative risk, 1.02; 95% CI, 0.97–1.07).2 While this represents only a slight increase in the risks associated with the birth process, it should not be ignored when considering perceived risks. It is also possible that in a planned pregnancy where the mother is prescribed folic acid before conception, the additional folate intake from fortified flour may further increase the risk of multiple pregnancy. It seems to me that the editorial was in fact an item of advocacy rather than a dispassionate scientific assessment of the arguments for and against mandatory folic acid fortification. At the very least, if mandatory folic acid fortification is implemented, prospective mothers will have to be made aware of the increased risk of multiple pregnancy and the as yet unknown risk of combining the fortified diet with medically prescribed folic acid.

Henry Ekert

Fiona J Stanley,* Glen F Maberly† * Director, Telethon Institute for Child Health Research, PO Box 855, West Perth, WA 6872. † Professor of Global Health, Rollins School of Public Health, Emory University, Atlanta, Georgia, USA. fionaATichr.uwa.edu.au In reply: Ekert suggests that in our article advocating for mandatory fortification with folate to reduce neural tube defects,1 we omitted to mention the “increased risk of multiple pregnancies”. He then misquotes the Lumley meta-analysis “(relative risk, 1.02; 95% CI, 0.97–1.07)” — the real relative risk was 1.40 (95% CI, 0.93–2.11). This Cochrane systematic review shows that folate supplementation does not carry a statistically significant risk for multiple births, but confirms the dramatic reduction in neural tube defects.2 Another study, which did suggest an increased risk, did not control for the known increased risk of multiple births following infertility treatments, which could explain the increase observed.3 Ekert suggests that we inform women about this unsubstantiated risk and “the as yet unknown risk” which mandatory fortification might add to “medically prescribed folic acid”. Folic acid is found in leafy green vegetables and in many fruits, nuts and other components of a healthy diet. Tablets are available over the counter. What advice would he give to women about these “risks”? Our evidence is that we are not reaching many women in our society by education and voluntary fortification, and that countries that have fortified their flour have achieved much better reductions in these major defects than we have in Australia. Hence our advocacy. We acknowledge that the evidence for stroke and heart disease reduction is not as solid as that for neural tube defects. However, there is an increasing literature on the protective effects of folate on cardiovascular risk and possible mechanisms.4-8 Hence, with consideration of the proven benefits and the unsubstantiated risks, we will continue to advocate for the mandatory fortification of flour with folate.

Fiona J Stanley · Glen F Maberly

A 62-year-old woman presented to the emergency department with a persistent cough and severe abdominal pain. Computed tomography showed the rare condition of a spontaneous rectus sheath haematoma on the right side (Figure A). The patient commented that her husband had been suffering the same symptoms for days, and that he was taking warfarin therapy. Six hours later, he presented to the same hospital with a matching rectus sheath haematoma on the left side (Figure B), and required blood transfusion. This completed a “marriage of inconvenience”, but did bring them closer to marital bliss — they shared a room in hospital, although in separate beds! Spontaneous rectus sheath haematoma is very rare. Coughing can rub the inferior epigastric artery or its perforating branches against the free posterior edge of the rectus sheath. Clinical suspicion should be raised in the elderly patient taking anticoagulant therapy. To our knowledge, this is the first reported case of simultaneous presentation of rectus sheath haematoma in family members. Computed tomography scans of matching rectus sheath haematomas in a married couple.

David James FRACGP, GradDipSurgAnat · D Ong Hii FRACS · Nathan Lawrentschuk MB BS

Making films from bone marrow aspirates is often a challenge for haematologists and oncologists in training (particularly oncologists). This aspirate taken from a child’s ilium ended up looking more like a femur.

Anthony R Herbert MB BS, BMedSc

Major advances continue apace in therapy and in understanding its molecular pathogenesis Myeloma is a malignancy of plasma cells in the bone marrow and presents with bone lesions, renal failure, anaemia and hypercalcaemia. Back pain, often associated with vertebral body collapse, is the most common presenting feature. In Australia, about 1200 new patients are diagnosed with multiple myeloma each year, with a median age at diagnosis in the early 60s. The aetiology of myeloma remains essentially unknown, although recent studies suggest links to agricultural exposures and lifestyle factors, such as low socioeconomic status and obesity.1 The major risk factor is the presence of a monoclonal immunoglobulin (paraprotein) in the blood. The incidence of paraproteins increases with age, and they are found in up to 3%–5% of people aged over 80 years. They are termed “benign paraproteins” or, more commonly, MGUS (monoclonal gammopathy of undetermined significance). By definition, this condition is not associated with other myeloma abnormalities. A patient with this type of gammopathy has an annual risk of about 1%–1.5% of developing active myeloma.2 A variant of myeloma — smouldering or indolent multiple myeloma — is associated with an infiltrate of over 10% monoclonal plasma cells in the bone marrow, but no organ dysfunction. Patients with this variant can be safely monitored for the onset of increasing paraprotein levels or organ dysfunction, suggesting transformation from smouldering myeloma to active disease. Melphalan chemotherapy was introduced in the 1960s, but there was little further change in our ability to affect the natural history of myeloma until the past decade, which has witnessed dramatic therapeutic advances. Currently, all patients aged under 65 years are offered autologous stem cell transplantation, using bone marrow stem cells harvested from the peripheral blood, unless precluded by other comorbidities. Stem cell transplantation is usually preceded by 3–6 months of induction therapy aimed at reducing tumour load and contamination of stem cell harvests by malignant cells.3 The role of a second stem cell transplant 3–6 months after the first is under investigation; it appears to benefit patients who do not have a full response to the initial transplant.4 The effect of a second transplant is also being compared with the new targeted drug therapies (see below). While allogeneic transplantation is usually precluded by age at presentation of myeloma, new techniques that require less intensive chemotherapy and gain their efficacy from the immunological effect of the stem cell graft on the malignant plasma cells (so-called “non-myeloablative” transplants) are now being used for patients who have a suitable matched sibling donor, are young, and have relapsed after autologous stem cell transplantation. The role of ongoing chemotherapy after transplant is unknown at present and the subject of a number of clinical trials. Lytic bone disease, bone pain and hypercalcaemia are major clinical manifestations of myeloma. In the past, no effective therapy was available for bone disease, but now all patients with myeloma receiving chemotherapy are also treated with a bisphosphonate. This reduces the number of skeletal events, such as vertebral collapse and pathological fracture of long bones, and reduces bone pain. Despite the increasing recognition of the uncommon side effect of osteonecrosis of the jaw, bisphosphonate therapy continues to be a standard intervention for all patients with myeloma who are receiving active chemotherapy.5,6 Of great interest are the new targeted therapies. Currently, three drugs — thalidomide, its analogue lenalidomide, and the proteasome-inhibitor bortezomib — are available for use in North America and are undergoing clinical trials in Australia. Extensive clinical experience with these drugs in refractory disease shows that they have a response rate of about 30%, which rises to 60%–70% when combined with dexamethasone.7 Major side effects include neuropathy (thalidomide and bortezomib) and myelotoxicity (lenalidomide). Current investigations are assessing the value of these drugs at initial diagnosis and as maintenance therapy after stem cell transplantation.7-9 Thalidomide and dexamethasone have been shown to be as effective for induction before stem cell transplantation as standard therapies. However, as they may be administered orally they are considered more convenient than therapies requiring venous access. Current studies involve the use of lenalidomide and bortezomib in induction therapy, while a recent French study has shown that thalidomide taken after stem cell transplantation both prolongs event-free survival and prevents relapse compared with no therapy.10 In April this year, the 10th International Myeloma Workshop in Sydney was attended by over 1000 experts in myeloma, indicating the current research interest in this condition. Abstracts and presentations of the meeting are available at the Haematologica website (www.haematologica-thj.org/supplements.html). The work presented at the meeting offered great hope for the future, both in our understanding of the molecular pathogenesis of multiple myeloma and, more importantly, in new therapies for our patients.

Douglas E Joshua DPhil(Oxon), FRACP, FRCPA

A 25-year-old man presented with macroscopic haematuria associated with a body mass index of 20 kg/m2 and a severe coagulopathy consistent with vitamin K deficiency. The diagnosis of a profound malabsorption syndrome secondary to coeliac disease was confirmed by small bowel histology and positive coeliac serology. Clinical recordA 25-year-old man presented to our hospital’s emergency department with frank haematuria and bilateral loin pain. He had been unwell for 10 days with abdominal pain and vomiting. Two days before presentation, he sought medical attention and was prescribed naproxen for the abdominal pain (he only took two of these tablets); he was on no other medications. Two years previously, a diagnosis of irritable bowel syndrome had been made by his doctor, based on a history of loose bowel motions over 2 years and a normal colonoscopy. 1 Angular cheilitis This image is similar to but is not of the patient described in this article. At the time of his hospital presentation, our patient had a body mass index (BMI) of 20 kg/m2 and appeared pale, but had no sign of bruising. He was apyrexial and well hydrated, with unremarkable cardiovascular and respiratory findings. Gastrointestinal examination revealed a red swollen tongue and angular cheilitis (Box 1). There was some mild left renal angle tenderness. Urinalysis revealed > 500 ×106 non-glomerular red blood cells per litre (normal range < 13 ×106/L) but no pyuria. Abdominal ultrasound performed on the day of review was unremarkable. Peripheral blood tests revealed normal electrolyte levels and renal function, with a coagulopathy reflected by an international normalised ratio (INR) of > 10 (reference range, < 1.4) and activated partial thromboplastin time (APTT) of 115 seconds (reference range, 25–38 seconds) (Box 2). These results were verified with repeat testing. Clotting factor studies revealed severe deficiencies in factors II, VII, IX and X. There were also deficiencies in iron, vitamin B12, and serum folate, vitamin A and vitamin E concentrations (Box 2). Vitamin D levels were normal, but the serum alkaline phosphatase level was twice the upper limit of normal. Results of other liver function tests were normal. Endomysial antibody test results were positive, and tissue transglutaminase antibody (IgA) levels were more than five times the upper limit of normal. A preliminary diagnosis of vitamin K deficiency, leading to a profound coagulopathy, secondary to a malabsorption syndrome from coeliac disease was made. Duodenal biopsies confirmed the diagnosis of coeliac disease (Box 3). Gastroscopy showed no gastritis or peptic ulcer disease. The duodenal mucosa appeared abnormal and was consistent with villous atrophy. No conclusion could be reached regarding the nonspecific abdominal pain the patient experienced on presentation. Inflammatory bowel disease was a differential diagnosis, but inflammatory markers were only marginally elevated (Box 2). Parenteral vitamin K was administered, and the prothrombin time reduced to 15 seconds (INR, 1.3) and APTT became normal within 24 hours. The macroscopic haematuria resolved. The patient was also given parenteral iron and vitamin B12 and oral multivitamin replacement. He was reviewed by the dietetic services and educated about coeliac disease. He also started a gluten-free diet. On clinical review 2 months later, he was feeling well and had put on 15 kg in weight (BMI, 26 kg/m2). Duodenal biopsies 6 months after the initial presentation revealed variable villous abnormality, consistent with partially treated coeliac disease. The vitamin deficiencies had all resolved, and clotting factor studies were normal. Endomysial antibodies had become negative, and tissue transglutaminase antibody levels (IgA) were within the normal reference range. Bone mineral density at this time was normal. Genotyping revealed the presence of the HLA DQ2 allele. DiscussionThe most common presentation of coeliac disease is diarrhoea (43%); other reasons for presentation include anaemia (8%), bone disease (6%), weight loss (6%), and abdominal pain (5%).1 The remaining 32% of patients are asymptomatic or present with vague symptoms. Delay in the diagnosis of coeliac disease is common (mean, 11 years).2 About 47% of patients will have been misdiagnosed, and of those with classical symptoms of coeliac disease, 59% have been misdiagnosed as having irritable bowel syndrome.3 The clinical diversity of coeliac disease is recognised, and disorders involving nearly every organ system have been described with this condition.4 Haematuria is an unusual presenting symptom of coeliac disease.5 The haematuria in our patient indicated a systemic bleeding diathesis due to malabsorption of vitamin K, with subsequent prolongation of the prothrombin time and APTT.6 In patients with untreated coeliac disease, the prothrombin time is prolonged (INR, ≥ 1.4) in about 20%,7 and the coagulopathy is usually asymptomatic,8,9 but corrects quickly with administration of vitamin K.10 In the long-term treatment of coeliac disease, a gluten-free diet is paramount and leads to resolution of the underlying small bowel villous abnormality. A partial histological response to a gluten-free diet may reflect poor compliance, accidental exposure to gluten-containing food products, or slow recovery. Our patient claimed close adherence to the diet and was provided with adequate education and dietetic review. Histological recovery can be delayed, with 35% of patients still showing features of coeliac disease up to 2 years after commencing a gluten-free diet.11,12 Failure to achieve histological recovery can occur in the absence of gluten.13 The use of serology tests as surrogate markers for histological resolution is controversial.14-16 Some coeliac patients with negative results for endomysial and tissue transglutaminase antibodies have persistent villous abnormalities, necessitating the use of biopsies to monitor the response to a gluten-free diet (as in our patient). On HLA genotyping, our patient possessed the HLA DQ2 allele, which is present in more than 90% of patients with coeliac disease, but in only 20% of the general population.17 Endomysial IgA antibodies have a sensitivity of 90% and specificity of 100%, tissue transglutaminase IgA has a sensitivity and specificity of 98%. Sensitivities for the IgG class endomysial and tissue transglutaminase antibodies are around 40%.18 Deficiency of IgA occurs in 1.7%–2.6% of coeliac patients, and these patients have negative results on IgA antibody testing. Total serum IgA levels should be tested together with IgG (endomysial, tissue transglutaminase) to improve the overall sensitivity of antibody testing.19 Our patient demonstrates the need to be aware of the various presenting features of coeliac disease, and reminds us that coeliac disease is often misdiagnosed. 2 Results of laboratory tests Investigation Result Reference range Haemoglobin 123 130–180 g/L White cell count 12.4 4.0–11.0 × 109/L Platelets 727 150–400 × 109/L Mean corpuscular volume 73 82–95 fL Mean corpuscular haemoglobin 23.3 24–32 pg Reticulocytes 74 10–90 × 109/L Differential white cell count Neutrophils 9.52 2.0–7.5 × 109/L Lymphocytes 1.48 1.0–4.0 × 109/L Monocytes 1.25 0.1–0.8 × 109/L Eosinophils 0.12 < 0.4 × 109/L Basophils 0.02 < 0.2 × 109/L Blood film Microcytosis with moderate hypochromasia, and small numbers of elongated cells. Neutrophilia with no left shift and thrombocytosis. CRP 22.4 1.6–8.7 mg/L ESR 14 5–12 mm/hour Alkaline phosphatase 249 40–129 U/L Tissue transglutaminase antibody 101 < 20 U/mL Serum folate 4.7 > 6.8 nmol/L Red cell folate Not measured Vitamin B12 93 132–857 pmol/L Vitamin A 0.1 0.8–3.1 μmol/L Vitamin D 38 30–110 nmol/L Vitamin E 4.9 > 18.6 μmol/L Ferritin 10 24–336 μg/L International normalised ratio > 10 < 1.4 Activated partial thromboplastin time 115 25–38 seconds Factor II 15% 50%–120% Factor VII 3% 50%–120% Factor IX 17% 50%–120% Factor X 5% 50%–120% 3 Duodenal biopsies A At time of diagnosis. There is severe villous abnormality associated with marked enterocyte damage (black arrows), in keeping with untreated coeliac disease. B After 6 months of gluten-free diet. There is partial improvement of the previous villous abnormality, but a moderate villous abnormality with associated crypt hyperplasia remains.

John S Lubel BDS, MB BS, MRCP · Louise M Burrell MBChB, MD, FRACP · Vicki Levidiotis MB BS, FRACP, PhD.

To the Editor: A 47-year-old woman presented with a 1-week history of spontaneous prominent and painful bruising and haematomata, 5–6 weeks after commencing meloxicam 15 mg daily for osteoarthritis and plantar fasciitis. The bruises varied in size from 2 cm × 2 cm to 3 cm × 4 cm. She had a past history of acne rosacea, for which she was taking clonidine 100 μg daily, and reflux oesophagitis, for which she was taking pantoprazole 40 mg daily. Meloxicam, being the only new drug taken by the patient, was suspected as the causative agent and was therefore discontinued. Activated partial thromboplastin time (APTT) at presentation was 58 s (reference range, 22 s –38 s). A week after stopping meloxicam, it had fallen to 37 s. All other haematological parameters, including platelet count and international normalised ratio, were normal, as were renal and liver function. New bruises and haematomata stopped appearing 2 days after the patient stopped taking meloxicam. She continued taking clonidine and pantoprazole. Meloxicam is a selective nonsteroidal anti-inflammatory drug (NSAID) (a cyclo-oxygenase 2 [COX-2] inhibitor). It was chosen for this patient in view of her reflux oesophagitis and because she had already been unresponsive clinically to one of the other COX-2 inhibitors. Unlike non-selective NSAIDs, meloxicam has been shown to have negligible effect on platelet function as measured by bleeding time.1-3 Rinder et al4 reported no prolongation of APTT or prothrombin time after 8 days of regular administration of meloxicam at 7.5 mg, 15 mg or 30 mg. In spite of these contrary findings, I believe the prolongation of APTT and spontaneous bruising and haematomata in this patient were directly attributable to meloxicam, as the bruises disappeared 2–3 days after stopping the drug (with no other changes in the patient’s existing medication) and a repeat APTT a week after cessation of the drug was normal.

Anil M Kurien

To the Editor: The clinical update on venous thromboembolism by Lee and colleagues advises that “Ventilation perfusion (V/Q) isotope scanning reliably establishes the diagnosis of PE [pulmonary embolism] if the V/Q features suggest a high probability of PE . . .”.1 Although this is probably true for patients with intermediate or high pretest probability, a discordant result (low pretest probability and high probability V/Q) should be regarded with suspicion. From the original PIOPED data, high probability V/Q was predictive of angiographically confirmed PE in 80% of patients,2 which drops to 56% by Bayesian analysis if the pretest probability is low. False positive results may be due to previous PE or unrelated parenchymal lung disease. There is significant potential morbidity associated with a false positive result for PE, both from the acute anticoagulation and for future presentations with PE-type symptoms, where PE will be accorded a higher probability because of the previous documented diagnosis. As Lee and colleagues also state, D-dimer testing must be combined with an estimate of pretest probability to be useful. They advocate excluding PE on the basis of low pretest probability and negative D-dimer result. However, a negative D-dimer result (rapid enzyme-linked immunosorbent assay [ELISA] type) may be used to exclude PE in intermediate as well as low probability patients.3 This is dependent on the type of assay available as well as the local PE prevalence, and local guidelines should therefore be developed.

Matthew J Bragg

To the Editor: I read with interest the article by Lee et al regarding the investigation and treatment of pulmonary embolism (PE).1 The investigation of patients presenting with PE as a diagnostic possibility is of great interest to emergency physicians, and such presentations are a daily occurrence in emergency departments around the country. Unfortunately, only a small amount of text is devoted to describing the relative merits of ventilation perfusion (V/Q) scanning and computed tomography pulmonary angiography (CTPA), and no guidance is provided as to which is the test of choice when both are available. The British Thoracic Society has recommended CTPA as the lung imaging modality of first choice for patients presenting with non-massive PE.2 There is a large and increasing body of evidence that CTPA provides superior specificity to V/Q scanning in the detection of PE. CTPA also provides the opportunity of establishing diagnoses other than PE and, in addition, a negative multi-slice CTPA is of sufficient sensitivity to enable the withholding of anticoagulation.3 It is also my experience that CTPA is easier to obtain out of hours, compared with V/Q scanning. The authors state that V/Q scanning “reliably establishes the diagnosis of PE if the V/Q scan features suggest a high probability of PE . . .”.1 Unfortunately, this statement is incorrect. It is essential that V/Q scan results be interpreted in the light of the patient’s clinical probability for PE. In the PIOPED study, only 56% of patients with high probability V/Q scan reports had pulmonary embolism if the pretest probability was low.4 No mention is made of the special situation of pregnant women presenting with pleuritic pain, or which lung imaging test is considered “safest” for both mother and baby. Although the risks of PE are generally agreed to be increased in pregnancy, it is my experience that pregnant women are extremely reluctant to undergo any form of diagnostic investigation that exposes the fetus to radiation. The Wells criteria have been validated for the assessment of PE in emergency department patients only, and provide a means for clinicians with little experience to make an accurate assessment of an individual patient’s clinical probability of PE.5 Once initiated, clinical assessment of the patient with possible PE is straightforward. The key question facing emergency physicians is this: is there a group of patients that have such low probability for PE that no investigation at all is required?

Paul M Bailey