Hematologic diseases

The absence of high quality evidence for basic clinical dilemmas in immune thrombocytopenic purpura underlines the need for contemporary guidelines relevant to the local treatment context

Philip YI Choi · Eileen Merriman · Ashwini Bennett · Anoop K Enjeti · Chee Wee Tan · Isaac Goncalves · Danny Hsu · Robert Bird

VITT is a potential complication of ChAdOx1-nCov-19 vaccination — early recognition is key to improved outcomes

Vivien M Chen · Jennifer L Curnow · Huyen A Tran · Philip Y‐I Choi

A 27-year-old man presented with right upper quadrant abdominal pain which had gradually worsened in the previous week

Muhajir Mohamed · Jeanette Koay

A public health unit in Sydney was notified of two unrelated patients who presented on the previous day with methaemoglobinaemia

Caitlin O’Neill · Zeina Najjar · Andrew Ingleton · Alan Edwards · Andrew Dawson · Leena Gupta

A 62-year-old man presented with left eye swelling and 3 weeks of intermittent epiphora without visual disturbance

Douglas Dunn · Sebastian Brown · Sartaj Sandhu · Domit Azar

Clinical record A 44‐year‐old male health care worker presented with fevers, fatigue and head “fogginess” with abdominal discomfort and increased bowel frequency 8 days after receiving his first dose of the COVID‐19 vaccine (ChAdOx1‐S [recombinant]) (AstraZeneca). He was previously well, with a past history of depression and was only taking escitalopram. He had no prior thrombosis or exposure to heparin. The low platelet count, 70 × 109/L (reference range, 150–400 × 109/L), and markedly elevated D‐dimer, 114 mg/L (upper limit of normal, 0.5 mg/L), with vague abdominal pains prompted a computed tomography (CT) venogram of the abdomen, which demonstrated thrombosis with complete occlusion of the portal and splenic veins and protrusion of a tongue of thrombus into the superior mesenteric vein (Box 1). CT venogram of the head did not show central venous sinus thrombosis. The rest of the full blood count and the blood film showed no features of microangiopathic haemolytic anaemia. The prothrombin time, activated partial thromboplastin and fibrinogen levels, liver and renal function tests were all normal. Antiphospholipid antibodies were negative and a heterozygous prothrombin G20210A mutation was identified. Antibodies to the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) nucleocapsid protein and the respiratory polymerase chain reaction (PCR) test for coronavirus disease 2019 (COVID‐19) were negative, ruling out active COVID‐19 infection as a potential thrombosis aetiology. Antibodies to the heparin–platelet factor 4 (PF4) complex in the patient’s plasma was strongly positive (optical density, 1.94) by enzyme‐linked immunosorbent assay (ELISA)‐based test (Asserachrom HPIA IgG; Stago). Three functional assays, including serotonin release assay (SRA; Hidex 300 SL, Hydex), multiple electrode aggregometry (MEA; Roche Diagnostics) and flow cytometry (BD Fortessa, ETH Zürich; procoagulant assay) all detected heparin‐independent PF4 antibody complexes that activated donor platelets.1 Immediate anticoagulation was started with the anti‐factor Xa agent fondaparinux 10 mg (weight, 105 kg) subcutaneously every 24 hours and intravenous immunoglobulin (1 g/kg) administered on days 2 and 3, and repeated on days 7 and 8 after admission. Despite achieving the anti‐factor Xa fondaparinux level 6 hours after receiving a dose of 0.94 U/mL (target range, 0.50–1.20 U/mL), the platelets remained between 6 × 109/L and 20 × 109/L for the initial 6 days. The patient subsequently developed an acute abdomen clinically and a repeat CT scan showed extension and occlusive thrombus into the superior mesenteric vein with venous outlet obstruction and bowel ischaemic features. He underwent an immediate laparotomy with resection of 1.8 m of ischaemic bowel. Contemporaneously, given clot extension had occurred on fondaparinux, anticoagulation was changed to thrombin inhibitor bivalirudin, which had a short half‐life (25 minutes) that allowed for titratable perioperative anticoagulation and an intravenous pulse of methylprednisolone 1 g administered to augment PF4 antibody immunosuppression. The patient returned to the theatre 48 hours after the first laparotomy, where further compromised bowel was resected. Methylprednisolone 1 g daily was reinstituted for 4 days, with an immediate platelet peak to 385 × 109/L at completion of this 4‐day pulse. He was discharged after 34 days without further complications. He has transitioned to warfarin and continues to be well while monitored in the haematology outpatient clinic. Box 2 summarises the time course of treatment and response. Discussion In March 2021, Australia began the roll‐out of the COVID‐19 vaccine (ChAdOx1‐S [recombinant]) to combat the COVID‐19 pandemic. In Europe, where more than 20 million doses of this vaccine had been administered by mid‐March 2021, there were case reports of thrombosis at unusual sites associated with thrombocytopenia, which occurred at day 4–28 after vaccination and had a mortality rate of up to 25%, at an estimated rate of 1:100 000.2 In Australia, the COVID‐19 vaccine (ChAdOx1‐S [recombinant]) was initially offered to people working in high risk professions without age restrictions. By the end of March 2021, about 350 000 first doses of the COVID‐19 vaccine (ChAdOx1‐S [recombinant]) had been administered Australia‐wide. This is the first reported case of thrombosis at an unusual site with thrombocytopenia following vaccination with the COVID‐19 vaccine (ChAdOx1‐S [recombinant]) in Australia. The temporal association, the detection of anti‐PF4 antibodies with platelet activation in the absence of heparin, which is neutralised at high dose heparin, is consistent with the most recent reports.3 This entity, currently labelled as vaccine‐induced thrombotic thrombocytopenia (VITT) — also known as thrombosis with thrombocytopenia syndrome (TTS) — has pathological similarity to autoimmune heparin‐induced thrombocytopenia but without prior heparin exposure. More evidence is needed to demonstrate if the serum of patients with VITT contains antibodies that can bind to PF4 independent of heparin following vaccination for COVID‐19. Furthermore, the mechanism responsible for profound platelet activation following vaccination with the COVID‐19 vaccine (ChAdOx1‐S [recombinant]), as evidenced by ELISA high optical densities, remains to be established.3 While the COVID‐19 vaccine (ChAdOx1‐S [recombinant]) is delivered via adenovirus vector, to the best of our knowledge, there are no reported VITT cases associated with mRNA COVID‐19 vaccines. It is doctrine in the management of heparin‐induced thrombocytopenia that, in addition to immediate cessation of all heparins, a non‐heparin anticoagulant is commenced to prevent (further) thrombosis. Given the pathogenic similarities of VITT cases to heparin‐induced thrombocytopenia, we initially used fondaparinux, as our patient was clinically stable with normal renal function at presentation. It is unclear if the clinical deterioration in our patient, despite achieving favourable therapeutic fondaparinux drug level, was resultant of anti‐factor Xa drugs non‐efficacy and/or because of the severity of the venous outflow obstruction with compromised ischaemic small bowel. In principle, the surgical removal of any ischaemic tissue would be associated with clinical improvement. The benefit of intravenous immunoglobulin remains debatable, but in vitro spiking experiments and observation of platelet increment after its administration suggest that there may be a role.3,4 It is possible that intravenous immunoglobulin displaces the binding of anti‐PF4 antibody complex to FcgammaRIIA (an Fc receptor for IgG) receptors on platelets.5 In our patient, it is difficult to ascribe a specific clinical and platelet recovery to intravenous immunoglobulin solely given the simultaneous timing of surgical removal of ischaemic intestine, the commencement of alternate anticoagulation with bivalirudin, and pulsed high dose steroids. It is noted that pulsed methylprednisolone was prescribed in the majority of recently reported cases.3 In line with evolving guidance documents, clinicians assessing patients who present with organ‐specific thrombotic symptoms 4–28 days following vaccination with the COVID‐19 vaccine (ChAdOx1‐S [recombinant]) should look for any combination of thrombocytopenia and elevated D‐dimer, and/or low fibrinogen, with a low threshold for requesting imaging of the appropriate organ — in particular, the brain central venous sinus and abdominal splanchnic venous systems — for thrombosis plus anti‐PF4 ELISA testing in consultation with haematology. Lessons from practice Vaccine‐induced immune thrombotic thrombocytopenia (VITT) is rare but potentially life‐threatening. VITT should be considered when patients present at day 4–28 after vaccination with unusual site thrombosis: splanchnic and/or central venous sinus thrombosis, or thrombocytopenia (or falling platelets) and markedly elevated D‐dimer. Specific testing to detect anti‐platelet factor 4 (PF4) antibody is needed to support VITT. Treat with non‐heparin anticoagulation, intravenous immunoglobulin, and consider pulsed methylprednisolone. Avoid platelet transfusions. Box 1 – Computed tomography venogram at presentation showing (A) a filling defect of portal vein, contrast in superior mesenteric vein and its tributaries (arrow, coronal plane) and (B) a thrombus in the superior mesenteric vein (the arrow shows the contrast, axial plane) Box 2 – Time course and management IV = intravenous; IVIg = intravenous immunoglobulin; SC = subcutaneous.

Jay Hocking · Sanjeev D Chunilal · Vivien M Chen · Tim Brighton · James Nguyen · Jocelyn Tan · Stephen B Ting · Huyen Tran

To the Editor: We read with interest the analysis and comments by Shand and colleagues.1 The authors show a rise in the dispensing of intravenous iron agents in the period from 2013 to 2017 for women. They suggest that this may be an issue relating to the inappropriate use of this agent. However, we question whether the data can support this suggestion, and feel this should be viewed cautiously because of the study limitations. The study did not examine the reasons for the escalation in prescriptions. The rise in numbers is not surprising. Iron deficiency anaemia is common and undertreated.2 While dietary modifications and oral iron are the first line treatment, oral iron is limited by the high occurrence of side effects in up to 50% of users.3 The new intravenous agents allow a full treatment in one visit — often in primary care — which is safe and effective. The authors are rightly concerned about safety; however, it is reassuring that studies have demonstrated the relative safety of these agents.4 During the study period, ferric carboxymaltose became more widely available, with its listing on the Pharmaceutical Benefits Scheme easing a financial barrier to women who need treatment. A number of education programs and various patient blood management initiatives to detect and treat iron deficiency that occurred during the study period could influence the study findings. A noteworthy activity was the landmark Patient Blood Management Collaborative facilitated by the Australian Commission on Safety and Quality in Health Care.5 The assumption by the authors that the number of women receiving treatment is equivalent to the number of dispensing claims by pharmacy is likely incorrect, as there are situations when an individual can have multiple dispensing claims. The study is timely because it highlights a serious condition affecting a large proportion of Australian women that must be better managed. Despite the various endeavours to improve access to treatment for women, iron deficiency remains undertreated and under‐recognised.

Pradeep Jayasuriya · Toby Richards · Bernd Froessler

An 81-year-old woman presented with subacute chorea as a paraneoplastic neurological syndrome

Rebecca Nothrop · Will Lee · Denise Lee · Amanda K Gilligan

Although VTE risk in minor gynaecological procedures is low, a systematic approach to prophylaxis is necessary

Esther MC Johns · Alex Ades · Pavitra Nanayakkara

A 75-year-old man was referred to our centre with a history of sudden onset painless loss of vision in the right eye, on a background of recent jaw claudication and weight loss

Khizar Rana · Carmen Oakley · David M Ross · Sumu Simon

Recent proposals to adopt tenecteplase as the recommended thrombolytic agent for stroke reperfusion will reduce its availability for patients with acute myocardial infarction

Mark Parsons · Leonid Churilov · Aletta E Schutte · Christopher Levi

An 83-year-old male non- smoker presented with chronic purulent cough

Adrián López Alba · Agustín Blanco Echevarría

The advent of CAR T‐cell therapy has seen significant improvements in survival and is a potential cure for patients with advanced haematological malignancies Cancer immunotherapy is a burgeoning field which, in the last decade, has produced unprecedented improvements in outcomes across a variety of advanced malignancies. The eventual translation of decades of research into clinically available immunotherapies stems from the expanded knowledge of the role that the immune system plays in preventing tumour initiation and progression as well as the mechanisms by which tumours learn to evade this immune surveillance.1 Immunotherapies that have reached the clinic include monoclonal antibodies and, more recently, their augmented counterparts including antibody–drug conjugates and bi‐specific T‐cell engagers. Other treatments are immunomodulatory, meaning that they augment endogenous anti‐tumour immune activity. These include immune checkpoint inhibitors such as pembrolizumab, which are prolonging survival in melanoma and several solid organ malignancies as well as relapsed or refractory Hodgkin lymphoma. Cellular immunotherapies offer the potential to overcome immune tolerance and generate immune memory.1 Allogeneic stem cell transplantation (ASCT), a largely unmanipulated form of cellular immunotherapy, acts by completely replacing the recipient’s entire haematopoeitic and immune systems, leveraging differences between the recipient and donor to produce a graft‐versus‐tumour effect, with the potential negative consequence of immune attack on recipient’s normal tissues, known as graft‐versus‐host disease, as well as other serious toxicities. ASCT has been the only curative option for many patients with haematological malignancies. However, it is generally considered a consolidative therapy; that is, the patient’s malignancy must be in or near complete remission in order to be effective. This is not always possible in refractory cases. For others, ASCT may be contraindicated because of age or comorbidities. With advances in genetic manipulation technology, the notion of combining the specificity of a monoclonal antibody with the cytotoxicity and memory of a T‐cell came to fruition in the chimeric antigen receptor (CAR) T‐cell. “Chimeric” here means that the DNA comes from two or more sources; the antigen‐binding domain of the CAR construct is an antibody fragment, tethered to the intracellular signalling domain of the T‐cell receptor, with an additional co‐stimulatory domain acting to improve their expansion and persistence in vivo. The fundamental steps in generating and delivering CAR T‐cell therapy are summarised in Box 1.2 Specific toxicities are characteristic of CAR T‐cell therapy, the two most important being cytokine release syndrome and neurotoxicity. Cytokine release syndrome is an inflammatory state induced by the rapid proliferation of CAR T‐cells and tumour cell death, releasing an array of inflammatory cytokines. The hallmark is a fever, with the potential for hypotension, hypoxia and organ dysfunction. As one of the key cytokines driving the syndrome is interleukin‐6, its blockade using the interleukin‐6 receptor antagonist tocilizumab is now routinely used for more severe grades of cytokine release syndrome. The pathogenesis of neurotoxicity has not been fully elucidated; however, it most often manifests with speech disturbance or aphasia, dysgraphia and attention deficits, with more severe manifestations including altered level of consciousness, seizures and, rarely, cerebral oedema. Fortunately, even patients with severe neurotoxicity who are adequately supported in intensive care settings most often have complete neurological recovery. By far the most successful antigen target of all CAR T‐cell therapies developed to date is the pan‐B‐cell antigen CD19, as it arguably comes closest to the characteristics of an ideal target. CD19 is widely expressed across the full maturation spectrum of B‐cell malignancies, from B‐cell lymphoblastic leukaemia cells to mature B‐cell lymphomas, giving broad applicability. Second, CD19 is only expressed on B‐cells (normal and malignant) and not other tissues. Third, the toxicity resulting from the on‐target, off‐tumour effects, in this case normal B‐cell aplasia, is manageable by immunoglobulin replacement in patients who experience recurrent or severe infections. The decision for health authorities to fund a personalised, genetically engineered treatment is a complex one, taking into account considerations such as cost, efficacy, safety, the level of evidence and the maturity of outcome data, alternative therapies, equity of access, and resource utilisation. The cost of a single product is measured in hundreds of thousands of dollars and the mechanism by which such therapies will be funded is certainly not self‐evident. In the Australian context, the new therapy is evaluated by the Medical Services Advisory Committee, an independent committee that appraises new medical services proposed for public funding, taking into account all the above‐mentioned considerations, and providing advice to government. Moreover, given the high cost and limited, immature data, regulatory bodies worldwide have come to unprecedented outcomes‐based reimbursement agreements with pharmaceutical companies — such as rebates and staged payments according to defined response criteria — in order to mitigate risk. Two CAR T‐cell products targeting CD19 were approved by the United States Food and Drug Administration in 2017 and 2018: tisagenlecleucel and axicabtagene ciloleucel. The landmark studies which led to their approval, and a summary of their key outcomes, are shown in Box 2.3,4,5,6 In Australia, tisagenlecleucel is approved by the Therapeutic Goods Administration for paediatric and young adult patients up to 25 years of age with B‐cell lymphoblastic leukaemia that is refractory, in relapse after transplant or in second or later relapse, as well as adult patients with relapsed or refractory diffuse large B‐cell lymphoma after two or more lines of systemic therapy. In April 2019, a joint state and federal government funding initiative commenced for tisagenlecleucel for the B‐cell lymphoblastic leukaemia indication, and in January 2020, the government announced its funding for diffuse large B‐cell lymphoma. Soon after, the Therapeutic Goods Administration approved axicabtagene ciloleucel in February 2020 and the Medical Services Advisory Committee made a positive recommendation for its public funding for the lymphoma indication. Further, Novartis announced an agreement with an Australian cell and gene therapy manufacturing company for manufacture of tisagenlecleucel for the region to commence in late 2020 (https://www.celltherapies.com.au/kymriah-to-be-manufactured-at-cell-therapies-pty-ltd-marking-australias-first-on-shore-commercial-production-of-car-t-therapy/). In the case of tisagenlecleucel for relapsed or refractory B‐cell lymphoblastic leukaemia, evaluation began with a comparison with best available therapy. In the ELIANA trial4 outcomes compared very favourably with other chemo‐ or immunotherapeutic salvage options such as clofarabine7 and blinatumumab,8 respectively. For example, blinatumomab, a bispecific T‐cell engager, in the paediatric relapsed or refractory setting produced a complete remission rate of 39% within the first two cycles, with a relapse‐free survival at 6 months of 42%, and this therapy is considered to be a bridging therapy to ASCT. Tisagenlecleucel on the other hand can be used as a stand‐alone therapy; however, it is notable that a substantial proportion of responders do relapse, particularly between 6 and 12 months, which raises the question of whether this treatment should also serve as a bridge to ASCT. The available evidence is currently insufficient to confidently provide an answer, and practice therefore varies among treating centres worldwide. However, a major concern is the financial implications of CAR T‐cell therapy as a bridge to ASCT, which itself is a highly resource‐intensive therapy, with some suggestion that the cost‐effectiveness may be unbalanced if this practice were routine. In the case of high grade B‐cell lymphomas, patient outcomes also appear to be superior to other available treatments in the third line setting. In the ZUMA‐1 trial, the recently updated 3‐year overall survival rate of 47% does likely reflect a significant cure fraction.6 In comparison, the SCHOLAR‐1 retrospective study of the outcomes of patients with refractory diffuse large B‐cell lymphoma showed that this pooled patient population only achieved complete remission rates of 7% with conventional therapies and had a median overall survival of 6.3 months.9 One concern is that the outcomes of the CAR T‐cell trials may not be generalisable to the real‐world population where patient selection may not be as strict as in clinical trials. Interestingly, the real‐world data seems to be conflicted on this, with the US experience from the Center for International Blood and Marrow Transplant Research registry being comparable to trial data for both tisagenlecleucel and axicabtagene ciloleucel, while preliminary United Kingdom experience appears to be considerably worse.10,11,12 The cause of this discrepancy is unclear. In terms of future directions, many clinical trials are assessing CAR T‐cells in earlier lines of therapy. For example, two trials are randomising patients in first relapse of large B‐cell lymphoma to receive either CAR T‐cell therapy or standard salvage plus autologous stem cell transplant: ZUMA‐7 (NCT03391466) and BELINDA (NCT03570892). The results of these trials, if favourable, could greatly alter treatment paradigms. Other trials are assessing CAR T‐cells in other B‐cell lymphomas, such as follicular non‐Hodgkin lymphoma (ELARA [NCT03568461]) and mantle cell lymphoma.13 The response to KTE‐X19, an anti‐CD19 CAR T‐cell therapy with a manufacturing process that removes circulating tumour cells, seen in the ZUMA‐2 trial in relapsed or refractory mantle cell lymphoma (overall response rate of 93%) is the highest reported response rate in patients with mantle cell lymphoma who failed previous BTK inhibitor treatment, with a high proportion of durable responses in this very challenging malignancy.13 Strategies to improve the availability and timeliness of CAR T‐cell therapy include the development of third party allogeneic CAR T‐cells, which could produce off‐the‐shelf treatments for many patients. Other alterations to the CAR construct aim to improve characteristics such as persistence and safety, as well as addressing the problem of antigen escape, where the malignancy loses the targeted antigen, potentially through multi‐antigen targeting. Others are combining CAR T‐cells with immunomodulatory therapies such as immune checkpoint inhibition to improve efficacy. Finally, there is great interest in CAR T‐cell therapies for malignancies such as multiple myeloma, acute myeloid leukaemia and T‐cell lymphomas and leukaemias, many of which are at various phases of clinical trials. The furthest advanced are CAR T‐cell therapies targeting B‐cell maturation antigen in multiple myeloma. JNJ‐4528, an investigational B‐cell maturation antigen CAR T‐cell therapy, has recently demonstrated very high response rates in the phase 1b/2 CARTITUDE‐1 study in relapsed or refractory myeloma.14 In the 29‐patient cohort, the overall response rate was 100%, with 69% complete remission, the median time to complete remission being 1 month, and measurable residual disease negativity in all 17 evaluable patients. These are very promising times in cancer immunotherapy and the task ahead for regulatory authorities will be immense as evidence rapidly accumulates for these high cost therapies. In the meantime, we are pleased to add CD19 CAR T‐cell therapy to our armamentarium and await the results of trials across a wide range of haematological and solid organ malignancies. Box 1 – Overview of the processes for manufacture and delivery of a chimeric antigen receptor (CAR) T‐cell product Procurement of T-cells, usually via leukapheresis (1); transduction of the CAR genes via viral vector or non-viral methods (2); ex vivo expansion of the CAR T-cells (3); preconditioning with lymphodepleting chemotherapy (4); and infusion into a patient (5). ◆ Box 2 – Summary of data from pivotal CD19 chimeric antigen receptor (CAR) T‐cell trials Trial name CAR T‐cell product Disease Complete response rate Other response parameters Safety ELIANA4 Tisagenlecleucel Relapsed or refractory paediatric B‐ALL 81% 12‐month OS, 76%; 12‐month EFS, 50% Grade ≥ 3 CRS, 47% Grade ≥ 3 NT, 13% JULIET5 Tisagenlecleucel Relapsed or refractory DLBCL 38% Median OS, 12 months Grade ≥ 3 CRS, 23% Grade ≥ 3 NT, 11% ZUMA‐13,6 Axicabtagene ciloleucel Relapsed or refractory DLBCL 58% 3‐year OS, 47% Grade ≥ 3 CRS, 13% Grade ≥ 3 NT, 28% B‐ALL = B‐cell acute lymphoblastic leukaemia; CRS = cytokine release syndrome; DLBCL = diffuse large B‐cell lymphoma; EFS = event‐free survival; NT = neurotoxicity; OS = overall survival.

Adrian G Selim · Constantine S Tam

To the Editor: The recent article by Akram and Sadashiv1 presents a timely and most welcome opportunity to enhance awareness, in the medical community at large, of the investigation and treatment options for proximal deep vein thrombosis (DVT) of the lower extremity. Diagnosis of lower extremity DVT is generally made or confirmed with duplex ultrasound assessment. Standards in Australia and New Zealand state that duplex ultrasound for DVT should determine the proximal extent of the thrombus, as well as identify structures causing extrinsic compression that may have contributed to the thrombosis.2 This information assists the clinician in determining the need to consider specific treatments, such as venous stenting for May–Thurner syndrome or placement of a caval filter in cases where there is a free‐floating thrombus in the inferior vena cava. Duplex ultrasound can play a key role in the diagnosis of May–Thurner syndrome.3 Technical factors, such as the presence of bowel gas, may inhibit ultrasonographic views of the abdominal and pelvic vasculature, and may therefore prevent attainment of the required information. Further, clinical experience in vascular surgery services in Australia and overseas has shown that, despite the above‐mentioned standards, it is common for there to be no attempt to obtain adequate proximal views during ultrasound DVT scans. Clinicians should therefore be wary of the limitations of ultrasound DVT scans and consider alternate imaging modalities such as computed tomography venography in cases where ultrasound has yielded inadequate information. Clinicians should also be aware of the potential of clot removal therapies such as catheter‐directed thrombolysis to improve long term outcomes for patients with proximal lower extremity DVT, whether or not May–Thurner syndrome is identified as a predisposing factor. Recent studies have reported improvements in the incidence and/or severity of post‐thrombotic syndrome in patients receiving catheter‐directed thrombolysis compared with those treated with anticoagulation alone.4,5 The appropriateness of catheter‐directed thrombolysis for some patients is acknowledged in the relevant guidelines,6 although patient selection remains a topic of debate. Lower extremity DVT is a common condition encountered in both inpatient and community settings. Due to technical considerations and quality variations, ultrasound DVT scans do not always yield adequate information to determine the optimal therapeutic approach. In such situations, consultation with a vascular specialist is strongly encouraged.

Trevor MY Kwok

Elevated serum angiotensin‐converting enzyme (ACE) activity, a biomarker for epithelioid granuloma, has a supportive role in the diagnosis and management of sarcoidosis,1 although in population‐based studies its diagnostic usefulness is modest, with positive and negative predictive values of 25.4% and 89.9% respectively.2 Further, elevated ACE activity is non‐specific; it is also found in people with tuberculous and other infectious granulomata, liver disease, lymphoma, diabetes, or hyperthyroidism, and also as a benign familial condition. However, elevated ACE activity can facilitate some clinical decisions, including the diagnosis of Löfgren syndrome or adults with uveitis.1,3 Serum ACE can be assessed by measuring its enzymatic activity or its protein concentration. Most Australian pathology laboratories measure ACE activity, which is predictably inhibited by ACE inhibitor (ACEI) drugs commonly prescribed for people with high blood pressure,4,5 whereas ACE protein level is not affected by these agents. In this study, we investigated the prevalence of ACEI influencing ACE activity results; for cases of markedly elevated ACE, we also evaluated the clinical performance of the two ACE measures with respect to sarcoidosis. In a preliminary evaluation, all discrepant paired results (high mass with low activity) were for patients using ACEIs at the time of sample collection. Between January 2017 and February 2019, we measured ACE activity and protein concentration in parallel; all test requests were initiated by clinicians as part of routine clinical care. Formal ethics approval was not required for collecting and analysing data to assess the quality of routine care. Further details of the study design and laboratory methods are included in the online Supporting Information. A total of 8882 paired test results were retrieved from the Pathology Queensland database for 4206 women (median age, 53.3 years; interquartile range [IQR], 36.0–65.6 years) and 4014 men (median age, 55.2 years; IQR, 42.2–67.3 years). Two discrete populations were evident in the scatterplot of paired results; for 1346 pairs (15.2%; 95% CI, 14.4–15.9%; green in Box 1), ACE activity was low relative to ACE protein, pathognomonic of ACEI interference. The upper reference limits for the two tests and the regression line for samples not affected by ACEIs nearly intersected, suggesting the general biologic equivalence of the two analytic methods and that the discordant results were not attributable to mismatched reference limits (Box 1). The correlation of values for the unaffected samples was moderate (R2 = 0.71) and the differences between the methods greater than predicted by their variances (Supporting Information, figure), indicating that the assays were not interchangeable. The monthly rate of ACEI interference was fairly consistent throughout the study period, despite comments to requesting physicians about the discrepancy between activity and protein levels included in pathology laboratory reports (Box 2). Of the 50 patients with high ACE protein levels (more than 300 μg/L) and ACE activity below the upper reference limit (70 IU/L), 27 (54%; 95% CI, 40–67%) had sarcoidosis (including 16 with ACE activity below the lower reference limit of 20 IU/L). In contrast, four of 16 people (25%; 95% CI, 10–50%) with high ACE activity (greater than 100 IU/L) and ACE protein within the reference interval had sarcoidosis. From a diagnostic perspective, ACEIs erode the negative predictive value of ACE activity, the most useful characteristic of this biomarker (Box 1; Supporting Information, table). Given that ACEI therapy interferes with ACE activity assessment, we recommend measuring ACE protein in routine practice, with the added benefit of convenience and safety of uninterrupted therapy for people taking ACEIs. The lack of influence of laboratory comments on testing behaviour is disappointing, but perhaps unsurprising given the information overload typical of modern medicine.6 Box 1 – Effect of angiotensin‐converting enzyme inhibitor (ACEI) therapy on serum ACE activity: scatterplot of paired ACE activity and protein assay results Pathology test reference intervals are indicated by the dotted lines. The shaded areas indicate result pairs included in the clinical audit (numbers of patients with sarcoidosis/total number audited). Blue: ACE activity not affected by ACEI therapy; 7536 samples, R2 = 0.71. Green: ACE activity affected by ACEI therapy; 1346 samples, R2 = 0.21. Box 2 – Influence of angiotensin‐converting enzyme (ACE) inhibitor (ACEI) therapy on serum ACE activity, by month

Carel J Pretorius · Jacobus PJ Ungerer

Iron deficiency anaemia, which affects 14–22% of women of reproductive age,1 has adverse effects on pregnant women and their infants. Oral iron supplementation is the first‐line treatment, but intravenous iron therapy is sometimes preferred because of gastrointestinal effects, low patient adherence, and the delayed effect of oral iron therapy. Further, guidelines now recommend intravenous iron therapy in certain situations,2 and more rapidly infusible intravenous iron preparations have recently become available in Australia. We investigated the use of intravenous iron by women of reproductive age, analysing dispensing data for a 10% random sample of Australians eligible to receive subsidised medicines under the Pharmaceutical Benefits Scheme (PBS).3 We included data for all women aged 18–44 years with a dispensing claim for intravenous iron during January 2013 to December 2017. Three preparations were available: iron polymaltose and iron sucrose during 2013–2017, and ferric carboxymaltose from June 2014. We calculated the annual number and rate of intravenous iron dispensing claims and iron preparation types by age group, using Australian Bureau of Statistics 2017 population data,4 and estimated overall dispensing rates by extrapolating these numbers to the national level (Supporting Information). The study was approved by the New South Wales Population and Health Services Research Ethics Committee (reference, 2013/11/494) and the federal Department of Human Services External Request Evaluation Committee. An estimated 259 700 intravenous iron dispensing claims were made for 190 490 women of reproductive age during 2013–2017; the annual number of dispensing claims increased from 17 920 in 2013 to 97 040 in 2017, and the annual rate of intravenous iron dispensing rose from 0.4 per 100 women in 2013 to 2.1 claims per 100 women in 2017 (Box). By iron type, 187 800 dispensing claims were for ferric carboxymaltose (72.3%), 71 110 for iron polymaltose (27.4%), and 790 for iron sucrose (0.3%). Most preparations were prescribed by general practitioners (111 870 claims, 43%), specialists (54 640 claims, 21%), and other medical practitioners (50 868 claims, 20%). The number of dispensing claims increased with age (18–24 years, 1.6 per 100 women; 35–44 years, 2.5 per 100 women). In 2017, intravenous iron was dispensed to one in fifty Australian women of reproductive age, five times the proportion in 2013; in 2017, 90% of these women received ferric carboxymaltose. The optimal rate of intravenous iron treatment is unknown, and there are no comparable overseas data. As possible adverse outcomes include permanent skin staining and the risk (albeit rare) of potentially fatal anaphylaxis,5 intravenous iron should be administered in settings where allergic reactions can be treated promptly, but whether this is generally the case is not known. Intravenous iron therapy for women of reproductive age also has considerable financial implications: based on average PBS prices,6 its total annual cost increased 35‐fold, from $0.75 million in 2013 to $26.9 million in 2017. However, we have probably underestimated the use of intravenous iron therapy, as we included only PBS‐subsidised dispensing, which may not include preparations administered to public hospital inpatients. The reasons for the rise in the use of intravenous iron are unclear, but may include increased awareness of patient blood management guidelines, the ease of treatment, and the perception that its side effect profile is more favourable than for oral iron therapy. The rapid growth raises concerns about whether it is being employed appropriately and cost‐effectively, given the potential harms and the lack of strong evidence for its value for improving quality of life and reproductive health outcomes. Box – Pharmaceutical Benefits Scheme dispensing claims for intravenous iron preparations for women aged 18–44 years, Australia, 2013–2017 *The small numbers of dispensing claims for iron sucrose are not separately depicted, but were included when calculating the rates of dispensing.

Antonia W Shand · Jane Bell · Amanda Henry · Luke E Grzeskowiak · Giselle Kidson‐Gerber · Sallie Pearson · Natasha Nassar

Advice for clinicians managing patients with cancer during the pandemic

Robert Weinkove · Zoe K McQuilten · Jonathan Adler · Meera R Agar · Emily Blyth · Allen C Cheng · Rachel Conyers · Gabrielle M Haeusler · Claire Hardie · Christopher Jackson · Steven W Lane · Tom Middlemiss · Peter Mollee · Stephen P Mulligan · David Ritchie · Myra Ruka · Benjamin Solomon · Jeffrey Szer · Karin A Thursky · Erica M Wood · Leon J Worth · Michelle K Yong · Monica A Slavin · Benjamin W Teh

An integrated approach that includes a central role for pathology laboratories is necessary Mass casualty events (MCEs) are defined as events or other circumstances “where the normal major incident response of one or several health organisations must be augmented by extraordinary measures to maintain an efficient, suitable and sustainable response”.1 Haemorrhage is a leading cause of mortality in MCEs, accounting for almost 50% of deaths in the first 24 hours,2,3 and transfusion emergency preparedness is increasingly recognised as a critical element of an integrated approach to MCEs,4 with timely availability and appropriate delivery of blood components being an essential part of management. On 20 January 2017, an MCE occurred in Melbourne, Victoria, when a car struck pedestrians in the Bourke Street Mall in the central business district, killing six people and injuring more than 30. The injured were taken to various adult and paediatric hospitals around Melbourne, including designated trauma centres and non‐trauma hospitals, both public and private. A Code Brown was activated at some of these hospitals. This is a hospital alert activated internally when notification of an external incident is received, usually by emergency services or health departments, which requires mobilisation of additional capability and capacity within that facility to receive an influx of patients.5 In Victoria, the users of blood products, including public and private hospitals and pathology laboratories, are represented by the Victorian Blood User Group. The Blood User Group meets quarterly with Australian Red Cross Lifeblood (previously Australian Red Cross Blood Service) to discuss issues relevant to the use and supply of blood products. In February 2017, Blood User Group members highlighted concerns with communication during the Bourke Street incident. Poor communication from hospitals to their pathology laboratories was noted during activation of hospital Code Brown alerts. There was also uncertainty and lack of transparency surrounding supply of blood components from Lifeblood to hospitals in Victoria, not only to those involved in the incident but also those awaiting delivery of routine blood inventory. In response to these concerns, the Blood User Group held a forum in August 2017 to discuss these issues and to make recommendations to assist planning for future incidents. Blood User Group representatives and invited guests, including National Blood Authority representatives, heard presentations from the Victorian Department of Health and Human Services, Lifeblood and four hospitals that received patients, outlining issues and learnings from the incident, followed by further discussion. A summary of recommendations was circulated to forum attendees. This article highlights issues and recommendations pertinent to hospitals and associated pathology laboratories, in particular their haematology and transfusion laboratories. Recommendations Pathology staff must form part of hospital critical incident management teams In some hospitals, the associated pathology laboratory is not part of the critical incident management team, and when these hospitals were notified of the Bourke Street MCE by emergency services, this was only communicated to the pathology laboratory via public address systems or other informal means. Updates received by hospitals from emergency services throughout the event were similarly not always communicated in a planned way. Key pathology representatives in some hospitals also attended their emergency departments in person, which was invaluable for communication but occurred on an ad hoc basis rather than being part of a documented protocol. Without streamlined communication, pathology representatives can often only respond to blood component requests and transfusion specimens when they arrive, leading to potential delays in blood product provision. As transfusion support remains a core component of management in MCEs, a key recommendation is that pathology staff must form part of any hospital's critical incident management team. This should be documented in the critical incident protocol, and involves active pathology staff participation during critical incidents. Further formalised pathology roles, such as physical attendance at critical sites in the hospital (eg, emergency department) to streamline communication with the laboratory, are also encouraged. This ensures that pathology services receive adequate notification of critical events, and enables direct involvement in ongoing management of the incident in a systematic way with clear lines of communication. It also allows pre‐emptive action such as pre‐thawing of clinical plasma, and review and management of current inventory including appropriate use of emergency blood components. Implement safe, non‐sequential allocation of unit record numbers for consecutive emergency patients One hazard noted at the forum was a lack of specific labelling protocols for identifying patients presenting to some emergency departments, resulting in potentially dangerous patient identifiers being used; for example, consecutive unit record numbers for consecutive patients, or the same prefix on all patients. This may facilitate clerical errors and patient misidentification. It is recommended that institutions ensure that allocation of unit record numbers for consecutive unknown patients is performed in a safe way, which minimises the risk of patient misidentification. Ensure adequate levels of pathology staff familiar with critical event management Staffing levels were an issue at some sites during the Bourke Street MCE, owing to senior staff being on leave. Similarly, when critical incidents occur after‐hours, staffing is often limited and senior personnel may not be on site, resulting in less experienced staff enacting their critical incident management plans. Extra staff may be required and there may be difficulty of access to workplaces if the incident results in road closures. Working during the incident can be physically and emotionally tiring, and replacement staff will be required after the event.4,6 Therefore, it is recommended that all staff, irrespective of experience, should be familiar with their local critical incident management plan, and that consideration be given to how staffing levels are managed during and after a critical incident. Include pathology staff in practice disaster scenarios All hospitals should practise responses to disaster scenarios and involve pathology representatives. During the Bourke Street event, hospitals other than the major trauma centres received multiple casualties. “Walking wounded” may also present at nearby hospitals, irrespective of whether these have emergency departments. Performing practice scenarios is therefore important to familiarise staff with their critical incident plans. Limitations of these scenarios are recognised, as they often do not encompass the practical issues faced by pathology teams, such as time taken to run multiple pathology samples, perform multiple crossmatches and accept into inventory large numbers of blood products. Despite these limitations, it is recommended that hospitals perform practice disaster scenarios and involve pathology staff to highlight areas of potential weakness. Consider standby phase in Code Brown responses One hospital activated their Standby Code Brown during the Bourke Street MCE, when it was first notified by emergency services of the possible arrival of casualties, but before patient numbers or severity of injuries were known. This standby phase alerted the critical response areas of the hospital, including the emergency department and pathology services, to an external incident, allowing review of department response plans such as staffing levels and blood product inventory without activating a full Code Brown response. The standby code remained in place until the hospital was advised of further details of presenting patients. It is recommended that hospitals incorporate such a standby phase in their emergency response plan. This alerts relevant departments to plan and prepare for escalation of an event when a critical incident is first notified to the hospital, but before further details are known or casualties have presented, without activating the full series of Code Brown activities which can be disruptive. Discussion Effective communication during MCEs is critical. It is common for many more blood components to be requested than are eventually transfused, and the overall requirement for products in these events is often lower than expected.7,8 Most blood use in MCEs occurs within the first 24 hours, particularly in the first 4 hours as the majority of severe casualties arrive within this time frame.2,7 Therefore, the key to managing these chaotic and rapidly evolving events is early, accurate and ongoing updated communication between emergency services, state health departments, hospitals, pathology laboratories and Lifeblood to ensure that blood components are urgently allocated to appropriate patients while limiting unnecessary ordering and cross‐matching of products. Local communication between hospital departments and pathology laboratories can be improved by implementing the above recommendations, in particular by involving pathology laboratories in critical incident management. Hospitals may use existing communication channels including email, intranet and paging or other messaging services; however, the protocol for using these should be clearly documented in the critical incident management plan. Broader statewide communication via health departments and Lifeblood would also allow other health care services to respond appropriately; for example, by managing blood inventory conservatively until the extent and impact of the MCE is known. This requires effective communication between health departments and Lifeblood, and it is imperative that information circulated via state jurisdictions and Lifeblood is consistent to avoid confusion. Forum attendees recommended that the National Blood Authority enable Lifeblood to disseminate information to pathology services through a web‐based blood product ordering system, BloodNet, which is used by transfusion laboratories throughout Australia. Health departments should similarly ensure that existing channels for communicating emergency information to hospitals, such as hospital personnel contact details, are current. Any communication must also be effective outside standard business hours. Fax or email messages are unreliably received after‐hours, and phone contact with appropriate hospital personnel may be more effective. The Bourke Street Mall MCE highlighted the challenges involved in supplying blood components during such events. The recommendations are similar to those published in a previous review on transfusion preparedness for MCEs4 and recognise the requirement for an integrated approach that includes a central role for pathology laboratories. Incorporating the lessons learnt from this incident will allow for more organised responses and streamlined communications between all departments and institutions.

Linda Saravanan · Amanda Ormerod

A 48-year-old Chinese woman with obesity and no significant past medical history presented to the emergency department with acute onset pain and swelling in the entire left leg

Farooq Akram · Roshni G Sadashiv

There is no strong evidence that first-line therapy with intravenous iron is superior to oral administration

Alaa Qassim · Rosalie M Grivell · Amanda Henry · Giselle Kidson‐Gerber · Antonia Shand · Luke E Grzeskowiak

To the Editor: We read with interest the recent review by Adie and colleagues1 discussing the optimisation of patients planned for total knee arthroplasty (TKA) and the prevention of adverse post‐operative outcomes. However, anaemia, which is a common, major and modifiable risk factor for this patient cohort,2 was not addressed by the authors. A recent observational study found pre‐operative anaemia — defined as haemoglobin concentration < 130 g/L — in 32% of patients undergoing elective TKA, and, based on the results for the orthopaedic surgical cohort from this study, it is likely that most of these patients were iron depleted.3 A 2017 single‐centre retrospective study similarly reported anaemia in 24% of a similar cohort of patients, and found it was associated with an increased risk of hospital stay in excess of 6 days (unadjusted odds ratio [OR], 1.97; 95% confidence interval [CI], 1.53–2.53; P < 0.001), which escalated further and proportionally with decreasing haemoglobin cconcentration.4 In another observational study, anaemia was associated with an increased risk of post‐operative complications in aseptic revision joint arthroplasty (OR, 1.45; 95% CI, 1.24–1.70; P < 0.001), mortality (OR, 2.18; 95% CI, 1.09–4.36; P = 0.028), and increased hospital length of stay (adjusted coefficient, 1.02 days; 95% CI, 0.73–1.31; P < 0.001).5 Perhaps the most compelling argument for the recognition of anaemia in the pre‐operative TKA patient is that it is a risk factor that can be addressed even as little as 2–5 days pre‐operatively. A retrospective review of ultrashort term parenteral iron supplementation in major orthopaedic surgery suggested intravenous iron reduced allogeneic blood transfusion rates (8.9% v 30.1%; P = 0.001), which are a likely contributor to post‐operative outcome. Intravenous iron was also associated with reduced length of hospital stay (8.4 days v 10.7 days; P = 0.001).6 Newer parenteral iron preparations are widely used as pre‐operative rehabilitative interventions, are characterised by their ease of administration and favourable side‐effect profile, and are recommended as part of best practice patient blood management guidelines.7 At present, large scale prospective and randomised data assessing the safety and efficacy of iron supplementation for correction of anaemia before elective TKA remain lacking. The importance of this area and the potential capacity for clinical and economic effect warrant both further prospective research and consideration by clinicians practising perioperative medicine.

Lachlan F Miles · Kate L Burbury · David A Story