Hematologic diseases

Summary Vegetarians who eat a varied and well balanced diet are not at any greater risk of iron deficiency anaemia than non-vegetarians. A diet rich in wholegrains, legumes, nuts, seeds, dried fruits, iron-fortified cereals and green leafy vegetables provides an adequate iron intake. Vitamin C and other organic acids enhance non-haem iron ...

Angela V Saunders BS(Dietetics), MA(Ldshp · Winston J Craig PhD, RD · Surinder K Baines BSc(Hons), APD, PhD · Jennifer S Posen MB BS, FRACP, FRCPA

A causal link is conceivable, but how strong is the evidence and how might this change clinical practice?

Bruce J Brew MB BS, MD, FRACP · Catriona A McLean MB BS, PhD, FRCPA · Eugene O Major PhD

On behalf of the Australasian Society of Thrombosis and Haemostasis, six experts present strategies for managing patients with complications of warfarin therapy in different clinical settings, including patients undergoing surgery.

on behalf of the Australasian Society of Thrombosis and Haemostasis

Tests for serum vitamin B12 and red cell folate levels are commonly requested in elderly inpatients to rule out reversible causes of cognitive impairment (eg, delirium). This imposes some cost on the community. The evidence for the association of cognitive impairment and vitamin B12 deficiency is inconclusive. It is also unclear whether other markers, such as elevated mean corpuscular volume (MCV) and ...

Celia S M Ting · John C Oldroyd · Michele R Levinson

Correction Potentially misleading statement and incorrect data: In “Splenectomy sequelae: an analysis of infectious outcomes among adults in Victoria”, published online first on 14 May and in the 21 May issue of the Journal (Med J Aust 2012; 196: 582-586), there was a potentially misleading statement. Under the heading “Mortality (all-cause)” (page 584), the second sentence should read: “The median survival for patients who died during the follow-up period after splenectomy was 3.1 years (interquartile range [IQR], 1.3–5.3).” In the same article, there was also an error in the Abstract (page 582). Under “Results”, the fourth sentence should read: “The risk of severe infection was highest among patients aged > 50 years (10.1 per 100 person-years; 95% CI, 9.3–11.1) and those splenectomised for malignancy (14.2 per 100 person-years; 95% CI, 11.8–17.1).” o

David F M Looke FRACP, FRCPA, MMedSci · Naomi J Runnegar MB BS, FRACP, FRCPA

Further studies are needed to develop evidence-based recommendations for vaccinations and prophylactic antibiotic regimensThroughout the ages, the function of the spleen was subject to much conjecture. It was variously thought to be both the centre of melancholy by the French and the centre for anger by the English (“to vent one’s spleen”). Of no doubt ...

David F M Looke FRACP, FRCPA, MMedSci · Naomi J Runnegar MB BS, FRACP, FRCPA

A new drug with great promise, but be very aware of the risksDabigatran is the first new oral anticoagulant for the prevention of embolism in patients with non-valvular atrial fibrillation (AF) that has been recently ...

Ross I Baker BMedSc, FRACP, FRCPA · Paul Harper MD, FRCP, FRACP · Claire McLintock MB ChB, FRACP, FRCPA

Objectives: To measure eligibility for medical thromboprophylaxis using two Australasian guidelines — the Australia and New Zealand Working Party Guidelines [WPG] and the National Health and Medical Research Council Guidelines [NHMRCG]) — and ...

J Alasdair Millar PhD, FRACP, FRCP · Joanne E Lett MB ChB · Leonard J Bagley BPharm · Ian K Densie BSR

This is the first report of endovascular therapy for acute ischaemic stroke in a patient with atrial fibrillation who was taking the direct thrombin inhibitor dabigatran for stroke prevention. As more of these agents will ...

Andrew W Moey MB BS · Simon A Koblar MB BS, FRACP, PhD · Steve Chryssidis MB BS, RANZCR · Martin Robinson MB BS, FRACP · Jim Jannes MB BS, FRACP, PhD

To the Editor: The past decade has seen significant change in the management of major haemorrhage, including earlier and more aggressive use of fresh frozen plasma (FFP). Australian guidelines now advocate high ratios of FFP to packed red blood cells (PRBC) from the outset of resuscitation.1 Preparation of one unit of FFP for every two units of PRBC is recommended. This approach is supported by a recent meta-analysis demonstrating a reduction in organ failure and mortality with high FFP : PRBC ratios.2 In Australia, 40% of major trauma incidents originate in rural areas,3 some distance from tertiary or even secondary care. Initial resuscitation often falls to general practitioners (with no blood bank) or aeromedical services. In a 2010 international survey of 29 aeromedical services conducted by the Royal Flying Doctor Service (RFDS) (Western Operations), the seven responding Australian services reported difficulty accessing blood products. Only three had immediate access to PRBC, although all could obtain it within 45 minutes. None could obtain FFP without delaying departure, and only four had access within 45 minutes. This difficulty in obtaining blood products, particularly FFP, was evident in an analysis of major haemorrhage management by the RFDS (Western Operations). Of 7585 patients transferred in the 2009–10 financial year, 610 (8%) had a diagnosis that put them at risk of major haemorrhage; of these, 58 (9.5%) demonstrated physiological derangement predictive of requiring massive transfusion and did receive transfusion in flight. However, the FFP : PRBC ratios fell short of accepted standards (Box), particularly in patients originating from non-regional hospital locations. As logistical difficulties with storage and preparation render FFP impractical in remote Australia, alternative sources of coagulation factors must be explored. European groups have proposed replacing FFP with freeze-dried factor preparations (fibrinogen concentrate and prothrombin complex concentrate),4 which are currently available in Australia. These are easier to store, transport and deliver, and may be safer and more efficacious than FFP.4 Evidence that tranexamic acid significantly reduces mortality in trauma-related haemorrhage5 has been met with a guarded response in Australia. The study was conducted in developing countries with limited access to blood products and its applicability here has been questioned, although it may be highly applicable to remote and regional areas where FFP is scarce. Ongoing research and the planned Australian Massive Transfusion Registry will contribute further to the debate. When devising major haemorrhage strategies, however, it should be remembered that managing bleeding in Melbourne and managing bleeding in Meekatharra (in remote Western Australia) are two very different prospects. Ratio of fresh frozen plasma (FFP) to packed red blood cells (PRBC) in patients at risk of requiring massive transfusion, 2009–10 Origin of patient All patients (n = 58) Regional hospital (n = 35) Non-regional hospital (n = 23) Mean number of FFP units delivered: In referring hospital 0.9 1.3 0.3 During transport 0.2 0.3 0.1 Mean number of PRBC units delivered: In referring hospital 2.5 3.3 1.3 During transport 1.8 1.6 2.0 Overall FFP : PRBC ratio 1 : 3.9 1 : 3.1 1 : 8.3

Stuart A Gillon · Cem R Kibar

Objective: To determine survival rates of patients with lymphoma in South Australia.Design and setting: De-identified data from the SA Cancer Registry on all patients with lymphoma were analysed, as well as the subgroup treated at the Royal Adelaide Hospital (RAH). For non-Hodgkin lymphoma (NHL), we used the International Working Formulation (IWF) grading. SA and RAH data on survival rates were compared with those for the whole of Australia and the United States.Patients: All patients diagnosed with lymphoma and treated in SA in 1977–2007.Outcome measures: 5-year survival rates for patients with lymphoma, by type of lymphoma and age.Results: Of the total of 8651 patients with lymphoma, 939 were classified as having Hodgkin lymphoma (HL) and 7712 as having NHL. Of those with NHL, 1805 had low-grade, 3576 intermediate-grade, and 510 high-grade NHL. In another 1821 patients, the data were insufficient to make an IWF grading. There was a substantial increase in 5-year survival rates for patients with lymphoma between 1977 and 2007 in SA. While the increase in 5-year survival rates for HL was 7.6 percentage points, survival rates peaked at 88%. For NHL, there was an 18.7 percentage points increase in 5-year survival rates. The first significant increase of 7 percentage points was associated with the introduction of bone marrow transplantation; this was maintained with the increase in 5-year survival rates reaching 14 percentage points by 1995–1999. Since 1999, there has been a further increase of 5 percentage points in 5-year survival rates with the introduction of rituximab.Conclusion: Outcomes in patients with NHL have improved significantly, most likely because of the use of bone marrow transplantation and rituximab. Hospital- and state-based cancer registry data reflect the reality of population outcomes and the impact of new technologies.

Brendon J Kearney FRACP, FRACMA, AM · Luen Bik To MB BS, MD, FRACP · Daniel J Kearney MB BS, FRCPA · David Roder MPH, DDSc · Colin G Luke MB BS, MPH, MD · Ian D Lewis PhD, FRACP · Pratyush Giri FRACP, FRCPA

Clinical record A 17-year-old girl presented to her general practitioner with a 1-week history of fever, arthralgia, general malaise and dry cough. She had a history of systemic onset juvenile idiopathic arthritis (SOJIA), diagnosed at age 2 years and treated with aspirin, and had been in remission for 13 years. She was initially treated by her GP with oral roxithromycin, and admitted to hospital 3 days later with worsening of her symptoms. Her admission chest x-ray (Box 1) revealed bilateral perihilar infiltrates. A diagnosis of severe community-acquired pneumonia was made and broad spectrum antibiotics were commenced, including vancomycin, moxifloxacin, and oseltamivir. Despite this treatment, her condition deteriorated. On Day 3 of admission she required endotracheal intubation and circulatory support with noradrenaline 18–50 μg/kg/min, and was admitted to the intensive care unit (ICU). She remained hypotensive, with a mean arterial pressure of 50 mmHg, and with sinus tachycardia of 132 beats/min, and subsequently required renal replacement therapy. She remained febrile for the first 3 days after admission (temperature range 37.5°C–39°C), and her temperature settled to normal after appropriate therapy was initiated. Investigations included a computed tomography scan of her abdomen, which showed hepatosplenomegaly, and liver function tests, which showed elevated conjugated bilirubin (36 mmol/L; reference range [RR], < 4 mmol/L), γ-glutamyl transferase (84 U/L; RR, < 24 U/L), lactate dehydrogenase (3540 U/L; RR, 150–280 U/L), alanine aminotransferase (108 U/L; RR, 10–30 U/L) and aspartate transaminase (388 U/L; RR, < 30 U/L). Other abnormal parameters were her haemoglobin level (93 g/L; RR, 120–160 g/L), platelet count (65 x 109/L; RR, 150–400 109/L), white cell count (2.9 x 109/L; RR, 4.5–13 x 109/L), international normalised ratio (2.1; RR, 0.9–1.2) and fibrinogen level (0.9 g/L; RR, > 2.5 g/L). Elevated inflammatory markers included C-reactive protein (301 mg/L; RR, < 5 mg/L) and serum ferritin (50 500 μg/L; RR, 7–140 μg/L). A transthoracic echocardiogram showed a left ventricular ejection fraction of 60%, a mild reduction in right ventricular contractility, and a right ventricular systolic pressure of 48 mmHg. A full screen for sepsis was performed, including a nasopharyngeal aspirate, bronchoalveolar lavage, blood cultures and serological testing; all were unremarkable. Other immunological tests performed were for Mycoplasma pneumoniae antibodies, Streptococcus pneumoniae urinary antigen, Legionella pneumophila urinary antigen, herpes simplex virus, cytomegalovirus, Epstein–Barr virus (EBV) IgM and IgG, influenza A and B, H1N1 influenza RNA, respiratory syncytial virus, parainfluenza and adenovirus DNA, Q fever (Coxiella burnetti) IgM and IgG, and serological tests for hepatitis, dengue fever IgM and Leptospira IgM, all of which were non-reactive. Urinalysis revealed a white blood cell count of 140 x 106/L (RR, < 10 x 106) and an erythrocyte count of > 500 x 106/L (RR, < 10 x 106/L) with no microbial growth on culture. A bone marrow aspirate with trephine was performed on Day 4 (Day 2 in the ICU), and EBV DNA was detected in the resulting sample using a qualitative DNA test. The patient’s failure to improve, in combination with her past history of SOJIA, hepatosplenomegaly and a very high ferritin level led to a preliminary diagnosis of macrophage activation syndrome (MAS). Immunosuppressive treatment in the form of high-dose methylprednisolone (10 mg/kg daily) and intravenous immunoglobulin (1 g/kg daily) were commenced. Inotrope and ventilatory requirements improved within 24 hours of this treatment. On Day 9 of admission she was extubated, and was discharged home on high-dose steroids 8 days later with no complications. Her bone marrow aspirate histological examination showed haemophagocytosis which confirmed the diagnosis of MAS (Box 2). Macrophage activation syndrome (MAS) is a severe, potentially fatal condition associated with paediatric rheumatic diseases. It is a form of secondary haemophagocytic lymphohistiocytosis (HLH) with uncontrolled activation and proliferation of well differentiated macrophages and T-lymphocytes.1,2 The central pathophysiological abnormality in HLH is cytokine dysfunction, resulting in uncontrolled accumulation of activated T-lymphocytes and activated histiocytes (macrophages) in many organs. High levels of cytokines are found in these patients due to ineffective natural killer cells and T-lymphocytes (a positive feedback loop started by ineffective T-cells, triggering an unopposed release of cytokines that attracts further T-cells).3 Hyperactivated macrophages cause damage in different tissues, and this is thought to be the origin of the high serum ferritin levels characteristic of these conditions. The cause of the macrophage activation is multifactorial. Ineffective cytotoxic immunity is due to underactive natural killer cells and reduced perforin production. Secondary HLH can be precipitated by infection, drugs, malignancy and rheumatic diseases. SOJIA has been linked to polymorphisms in genes controlling production of cytokines, such as tumour necrosis factor. This could in turn be a cause for MAS, leading some authors to postulate that MAS and SOJIA could be part of the same disease.4 Clinical manifestations include fever (91%–100%), hepatomegaly (90%–92.3%), splenomegaly (77%–84%), lymphadenopathy (41%–62%), neurological symptoms (47%) and rash (43%).5,6 The central nervous system is commonly affected,7 and patients may present with agitation, seizures, coma, respiratory failure from adult respiratory distress syndrome, and multiorgan failure.7 MAS has a mortality of up to 22%.8 To our knowledge, this is the only reported case of MAS in a patient nearing adult age and with a long inactive rheumatic disease period. MAS is well described in the paediatric population with SOJIA, and has a median age of 5 years at the time of presentation.9 The mean time between initial diagnosis of SOJIA and presentation with MAS is 4 years.8 Our patient was aged 17 years at the time of presentation with MAS, and had not had symptoms of, nor required treatment for, SOJIA for 13 years. Diagnosis was described by Ravelli and colleagues,7 and is based on clinical findings such as organomegaly and laboratory findings such as hypofibrinogenaemia, thrombocytopenia and elevated serum liver enzymes. A bone marrow aspirate can aid diagnosis in uncertain cases, the pathognomonic feature being the presence of well differentiated macrophages actively phagocytosing haemopoietic cells.8 Infections, medications and malignancies have all been identified as triggers for MAS. EBV DNA was found in the patient’s bone marrow aspirate, and EBV has been identified as one of the more common triggers for MAS.5,7 It is likely that EBV was the trigger for this patient’s MAS. Treatment is based on immunosuppression using steroid therapy. Cyclosporin has been used as the first-line treatment, or used in combination with corticosteroids. Other treatment options include plasma exchanges or intravenous immunoglobulins.10 This patient presented with fever, prominent respiratory failure and cardiovascular collapse. Her initial systemic symptoms and radiological findings suggested severe sepsis, most likely respiratory in origin, her SOJIA had been in remission for over 10 years, and there was no neurological involvement. These factors made clinical suspicion of MAS difficult, but her hepatosplenomegaly and highly raised ferritin levels suggested the diagnosis, which was supported by her laboratory test results (leucopenia, thrombocytopenia, hypofibrinogenaemia and abnormal liver function test results) and bone marrow aspirate histological findings (Box 2). Despite MAS predominantly presenting in a paediatric population with active disease, this case report emphasises the need to exercise diagnostic vigilance in treating young adult patients with multiorgan failure and a distant history of rheumatic disease. Lessons from practice Multiorgan dysfunction and vasodilatory shock may not be of infectious origin. If a patient fails to improve when treated with broad spectrum antimicrobials, alternative diagnoses should be sought. Although macrophage activation syndrome (MAS) primarily affects children with active rheumatic disease close to the time of diagnosis, it may occur in adults after a prolonged disease-free period. Diagnosis of MAS is based on history, clinical examination and laboratory findings. Demonstrating haemophagocytosis in a bone marrow aspirate can aid uncertain diagnosis. 1 Chest x-ray of the 17-year-old patient, taken on admission, showing bilateral perihilar infiltrates 2 Macrophage (long arrow), containing a red blood cell (arrow head), seen in the bone marrow aspirate taken from the 17-year-old patient (May–Grünwald–Giemsa stain x 100)

David Gutierrez MD · Louis Guy MB BS · Veera S Katikireddi MB ChB(Hons), MRCP(UK) · Jason P Butler MMedSci, FRACP, FRCPA · John Gowardman FRACP, FCICM

The clinical usefulness of laboratory testing of adult patients with venous thromboembolism (VTE) for heritable thrombophilia needs to be critically evaluated. At present, some clinicians use testing to identify patients at higher risk of recurrence (who may benefit from an extended period of anticoagulation beyond the usual 3–6 months) and their relatives at risk of a first VTE episode. As prevalence of heritable thrombophilia is related to age and ethnic origin, the pretest probability of detecting heritable thrombophilia may be low in unselected populations. Interpretation of laboratory results may not be straightforward. Apparent deficiencies of a natural anticoagulant may be due to acute thrombosis and “consumption”, concomitant therapy with heparin and/or warfarin and other clinical factors. The predictive value of recurrent VTE conferred by the most common types of heritable thrombophilia (factor V Leiden and the G20210A prothrombin mutation) is limited. Risk of recurrence associated with deficiencies of a natural anticoagulant is less certain due to their rarity. Clinical risk factors (eg, the presence or otherwise of provoking factor(s) and whether or not the risk factor for VTE is reversible or permanent) appear to be the most important predictors of VTE recurrence. Duration of anticoagulation should be determined by clinical risk factors rather than the presence, or otherwise, of heritable thrombophilia. The benefit of identifying relatives who are carriers of thrombophilia is uncertain, as VTE is a multifactorial disease resulting from the interaction of various risk factors, some well recognised and others as yet unknown.

Wai Khoon Ho MMedSc, FRACP, FRCPA · Graeme J Hankey MD, FRCP, FRACP · John W Eikelboom MSc, FRACP, FRCPA

To the Editor: A recent study of adult bodyweights recorded in 199 countries showed an increase in mean body mass index (BMI) of 0.4 kg/m2 per decade between 1980 and 2008.1 The increase in Australia was even greater: 0.9 kg/m2 for men and 1.2 kg/m2 for women.1 This increase in BMI, sometimes referred to as an “obesity epidemic”, has also been reported in coronial cases in South Australia, with the percentage of morbidly obese individuals (BMI > 40 kg/m2) undergoing autopsy rising from 1.3% to 4.8% between 1986 and 2006.2 While attention is often focused on complications of obesity such as diabetes mellitus, hypertension and cardiac disease, there is also a link to pulmonary thromboembolism (PTE). A recent prospective forensic autopsy series found that 24 of 32 cases of fatal PTE were in individuals who were overweight or obese.3 To examine this association further, we performed two analyses. First, we recorded the numbers of sudden deaths subject to coronial autopsies in SA from 2000 to 2009 (inclusive) where the cause of death was PTE. These were divided into two periods (2000–2004 and 2005–2009) and expressed as the percentage of the total number of coronial autopsies. Second, we analysed all deaths due to PTE that were the subject of coronial autopsies in SA in 2008 (the most recent year for which complete autopsy data were available at the time that the study was initiated). Age, sex and BMI were recorded, and the group was compared with an age- and sex-matched control group taken from other coronial autopsy cases. Despite considerable yearly fluctuations, the death rate due to PTE showed a small increase over time (Box). The rate of deaths due to PTE per total number of autopsies increased from 3.59% (198/5521) in 2000–2004 to 3.71% (239/6442) in 2005–2009. In 2008, there were 44 individuals (21 men, 23 women) with PTE as cause of death. The age range of this group and the 44 matching controls was 27–93 years (mean, 67 years). The mean BMI for individuals dying of PTE (29.6 kg/m2; range, 19.0–51.8 kg/m2) was significantly higher than for the controls (25.9 kg/m2; range, 17.7–44.6 kg/m2) (Student t test, P < 0.05). If PTE is conclusively found to be associated with BMI, there may be significant effects on hospital diagnostic services, coronial forensic investigation units and public expenditure in the future. Coronial cases in South Australia where death was due to pulmonary thromboembolism, 2000–2009

Roger W Byard · Hannah Rosenfeld

To the Editor: Warfarin is an orally administered vitamin K antagonist and has many well described interactions with commonly prescribed medications.1 However, only a handful of case reports worldwide have shown that flucloxacillin, a widely used antibiotic, may affect warfarin therapy by reducing its anticoagulant effect — in one instance contributing to the development of ischaemic stroke.2,3 There are several reports describing potential mech-anisms of interaction for flucloxacillin with warfarin.4,5 We describe the case of a 64-year-old man who was diagnosed with infective endocarditis on the basis of mitral valve vegetations and blood cultures that were positive for methicillin-sensitive Staphylococcus aureus. The patient underwent mitral valve replacement with a prosthetic valve and received prolonged antibiotic therapy with intravenous flucloxacillin for 8 weeks. Initially, for nearly 4 weeks, therapeutic anticoagulation with warfarin was difficult to achieve with warfarin doses ranging between 5 and 10 mg per day (target international normalised ratio [INR], 2.5–3.5). During this time, the patient was receiving intravenous flucloxacillin at a total daily dose of 8 g (2 g every 6 h). Flucloxacillin was increased to 12 g per day (2 g every 4 h) and there was a subsequent fall in the patient’s INR, which was sustained despite increasing the dose of warfarin to 25 mg per day (Box). Completion of flucloxacillin therapy was associated with a rise in the patient’s INR and a reduction in his warfarin dose requirement. No other relevant medications were commenced during this period of observation. This case highlights the potential for a dose-related effect of intravenous high-dose flucloxacillin (up to 12 g per day) on warfarin metabolism and the need for vigilance when prescribing antibiotics in conjunction with oral vitamin K antagonists. Other penicillins such as amoxicillin can, conversely, enhance the anticoagulant effects of warfarin, so the warfarin–flucloxacillin interaction may not be intuitive for many clinicians. Doses* for oral warfarin and intravenous flucloxacillin administered to a 64-year-old man with infective endocarditis, and corresponding INR INR = international normalised ratio. * Graph shows abbreviated, not daily, data. Intervals are weekly up to Week 9, then vary according to when INR was measured.

Philip Y-I Choi · Katherine L Phillips · Ian Rae