Conclusions LJE & ZM and EMW & SJS contributed equally Patients undergoing treatment for hematologic malignancies continue to have a high burden of clinically significant bleeding (WHO grade 2 or above) despite receiving prophylactic platelet transfusions (43% in TOPPS trial, NEJM 2013). One potential approach to reduce the burden of bleeding is antifibrinolytic therapy, which has been shown to reduce bleeding and transfusion needs in patients undergoing surgery. The Trial to EvaluAte Tranexamic acid therapy in Thrombocytopenia (TREATT) is a double-blind randomized controlled trial evaluating the safety and efficacy of tranexamic acid (TXA) in patients with hematologic malignancies with severe thrombocytopenia (EudraCT number 2014-001513-35). We enrolled adults with hematologic malignancies having intensive chemotherapy or a hematopoietic stem cell transplant (HSCT) who were expected to have severe thrombocytopenia (platelet count ≤10x10 9/L for ≥5 days) at 16 UK and 11 Australian sites. We stratified randomization by site. We randomized participants to receive TXA (1g iv or 1.5g orally) or placebo (saline or capsule/tablet) 8-hourly from when platelet count ≤30x10 9/L or as soon as possible if the platelet count was already ≤ 30x10 9/L (no later than 72 hours after start of chemotherapy or HSCT). We stopped treatment if the unsupported platelet count reached ≥ 30x10 9/L, thrombosis occurred, or patient had received 30 days treatment. Patients received red cell and platelet transfusions according to national transfusion guidelines. Bleeding assessments were performed by trained research staff (inpatients) or via a patient diary, with significant bleeding reported to clinicians (outpatients), using validated tools. The primary outcome was the proportion of participants who died or had bleeding of WHO Grade 2 or above from study day 1 ([D1], first day of treatment) to D30. We used marginal Cox proportional hazards regression modelling (adjusted for site to account for clustering) to compare the two arms. Secondary outcomes included: safety outcomes (thrombotic events to D120) and use of blood components. Recruitment was affected by the COVID pandemic. We randomized 616 participants between June 2015 and February 2022 and included 597 in the modified intention to treat (mITT) analysis (platelet count ≤ 30x10 9/L for ≥ 1 day and no exclusion criteria). 16 participants were lost to follow-up prior to D120 (8 each arm); we included them in analyses if possible. Participant mean age was 55.6 years (SD12.2), 38.2% (236/616) were women, 42.9% (264/616) had AML, 35.1% (216/626) autograft and 25.4% (156/626) allograft. There was no evidence of a difference in the risk of death or ≥ Grade 2 bleeding between the TXA and placebo arms (HR 0.92; 95% CI: 0.67, 1.27; p-value 0.62). 29.0% (87/300) of participants in the TXA arm and 32.7% (97/297) in the placebo arm experienced ≥ Grade 2 bleeding, 66.0% (198/300) of participants in the TXA arm and 73.4% (218/297) in the placebo arm experienced ≥ Grade 1 bleeding. There was no evidence of a difference in the risk of death to D30 (HR 2.72; 95% CI 0.29, 25.36; p-value 0.38), however there were only 11 deaths overall. No patient died from bleeding (to D30) or thrombosis (to D120). The proportion of participants surviving to D30 without a platelet transfusion was 8.3% in TXA arm (95% CI: 5.4, 11.9), 6.4% placebo arm (95% CI 3.9, 9.7) (HR 0.92; 95% CI: 0.84, 1.02; p-value 0.10). The proportion of participants surviving to D30 without a red cell transfusion was 29.4% in TXA arm (95% CI: 24.1, 34.8), 20.5% placebo arm (95% CI 16.0, 25.4) (HR 0.82; 95% CI: 0.72, 0.93; p-value 0.003). 13 participants developed thrombosis to D120: 2 arterial events (1 each arm), and 11 venous (7 TXA arm, 4 placebo). 5 participants developed veno-occlusive disease (VOD) to D60 (3 TXA arm, 2 placebo). Additional secondary outcomes (Table 1). Prophylactic TXA had no effect on the incidence of WHO Grade ≥2 bleeding or death when given in addition to prophylactic platelet transfusions to severely thrombocytopenic patients undergoing therapy for hematologic malignancies. The results are consistent with those of a similar trial (A-TREAT, Blood 2022). These results indicate no role for TXA to prevent WHO ≥ Grade 2 bleeding in this patient population. There was no evidence that TXA increases the risk of venous or arterial thrombosis, or VOD, despite use for up to 30 days.

The bone marrow failure syndromes (BMFS) are a diverse group of acquired and inherited diseases which may manifest in cytopenias, haematological malignancy and/or syndromic multisystem disease. Patients with BMFS frequently experience poor outcomes, and improved treatment strategies are needed. Collation of clinical characteristics and patient outcomes in a national disease-specific registry represents a powerful tool to identify areas of need and support clinical and research collaboration. Novel treatment strategies such as gene therapy, particularly in rare diseases, will depend on the ability to identify eligible patients alongside the molecular genetic features of their disease that may be amenable to novel therapy. The Australian Aplastic Anaemia and other Bone Marrow Failure Syndromes Registry (AAR) aims to improve outcomes for all paediatric and adult patients with BMFS in Australia by describing the demographics, treatments (including supportive care) and outcomes, and serving as a resource for research and practice improvement.

BACKGROUND:Sickle cell disease (SCD) is the most common monogenic disorder worldwide. In deoxygenated conditions, the altered beta chain (haemoglobin S [HbS]) polymerises and distorts the erythrocyte, resulting in pain crises, vasculopathy and end-organ damage. Clinical complications of SCD cause substantial morbidity, and therapy demands expertise and resources. Optimising care for patients and planning resource allocation for the future requires an understanding of the disease in the Australian population. The Australian Haemoglobinopathy Registry (HbR) is a collaborative initiative of specialist centres collating and analysing data on patients with haemoglobin disorders. AIMS:To provide a snapshot of SCD in Australia over a 12-month period based on data from the HbR. METHODS:Patients with a clinically significant sickling disorder across 12 clinical sites were included for analysis. Data include demographic and diagnostic details, as well as details of the clinical management of the condition over a 12-month period. RESULTS:Data on 359 SCD patients demonstrate a shift in the demographic of patients in Australia, with a growing proportion of sub-Saharan African ethnicities associated with the HbSS genotype. Acute and chronic complications are common, and patients require significant outpatient and inpatient support. Prevalence of disease complications and therapeutic trends are in keeping with other high-income countries. CONCLUSIONS:This study provides the first national picture of SCD in Australia, describing the characteristics and needs of SCD patients, elucidating demand for current and novel therapy and facilitating the planning of services for this vulnerable population.

Key Points Question Can levels of perfluoroalkyl and polyfluoroalkyl substances (PFASs) in the blood be reduced by blood or plasma donations? Findings In this randomized clinical trial of 285 firefighters, both blood and plasma donations resulted in significantly lower PFAS levels than observation alone. Plasma donation was the most effective intervention, reducing mean serum perfluorooctane sulfonate levels by 2.9 ng/mL compared with a 1.1-ng/mL reduction with blood donation, a significant difference; similar changes were seen with other PFASs. Meaning Blood or plasma donations may be used to reduce serum PFAS levels.

Direct acting oral anticoagulants (DOAC) are now commonly prescribed medications. Urgent reversal of their anticoagulant effect is sometimes required in emergency situations. In Australia, a specific reversal agent for factor Xa (FXa)‐inhibitor DOAC is not available. Instead, two non‐specific haemostatic agents, activated prothrombin complex concentrate (aPCC) and 3 factor‐prothrombin complex concentrate (3F‐PCC), are used off‐label despite a paucity of evidence for their effectiveness or safety.

Introduction: Aside from peripheral cytopenias, the presence of morphologic dysplasia is an integral component in the diagnosis of MDS. The degree and significance of dysplastic changes in bone marrow aspirate (BMA) smears is often subjected to inter-observer variability. The use of cytogenetics is an important tool to diagnose MDS in the absence of sufficient morphologic criteria. Methods: The Cytogenetic database from the Victorian Cancer Cytogenetic Service was interrogated for BMA samples received between August 2019 to June 2021. We identified samples that proceeded with cytogenetic testing when the degree of morphology and/or cytopenias did not fulfil the morphologic criteria for an MDS diagnosis. MDS defining cytogenetic abnormalities were identified based on the 2017 WHO classification. Results: 942 cases were identified, of which 905 had results available at time of analysis. The common reasons for BMAT performance was isolated cytopenia (39%), pancytopenia (23%), unexplained macrocytosis (13%) and clinical suspicion of MDS (12%). The most common reason for proceeding with cytogenetics was insufficient morphological evidence for MDS (83%), differentiating MDS with aplastic anaemia (8%) and differentiating MDS with idiopathic thrombocytopenia purpura (ITP) (3%). Of the 905 cases with cytogenetics results available, 671 (74%) had a normal karyotype, 90 (10%) had no mitoses and 143 (16%) had a detectable cytogenetic abnormality. 75 (8.3%) had an abnormality confined to loss of chromosomes X or Y, 12 (1.3%) had an isolated deletion in 20q or trisomy of chromosome 8. 5 (6%) cases had a clonal abnormality not reported in myeloid neoplasms. Of the 905 cases identified, only 41 (4.5%) had an MDS defining abnormality (7 with complex karyotype). Of these patients, 17 had a history of malignancy and prior exposure to chemotherapy and 7 had exposure to immunosuppressive drugs. Conclusion: The overall detection rate of an MDS defining cytogenetic abnormality where there is insufficient morphological evidence is low in this group. This may, however, be higher in cases with higher pre-test probability such as in patients with previous exposure to chemotherapy or immunosuppressive therapy.

ABSTRACT As a marker of cellular proliferation, 18F-fluorothymidine (FLT) PET can detect the distribution of proliferating hematopoiesis and has an emerging role in the investigation of hematopoietic disorders. These images demonstrate the novel utility of 18F-FLT PET for imaging sites of extramedullary hematopoiesis (EMH) in a patient with Chuvash-type polycythemia and suggest a role for 18F-FLT PET in response assessment following radiotherapy. Further, the discordant response observed in the irradiated marrow and sites of EMH is a unique discovery, possibly suggesting the influence of the microenvironment favoring more rapid recovery of proliferative function within EMH sites.

Hematology is the study of blood and bone marrow disorders. These conditions affect the structure, quantity, and/or function of the cellular and plasma components of blood and include inherited and acquired cytopenias/cytoses, coagulation/hemostatic and immune dysregulation disorders, and malignancies. Significant iatrogenic hematological effects can also result from various drug therapies commonly prescribed in the elderly.

Acquired aplastic anaemia is a rare, serious, immunologically mediated bone marrow failure syndrome, characterised by marrow hypoplasia of varying severity and significant pancytopenia. Careful attention and investigation, including molecular testing, is required to confirm the diagnosis and exclude other mimicking conditions, such as inherited bone marrow failure syndromes. In a proportion of patients, the disease evolves to myelodysplasia or acute myeloid leukaemia and in some there is an association with paroxysmal nocturnal haemoglobinuria. The disease has a major impact on patient quality of life. Haemopoietic stem/progenitor cell transplantation for eligible patients with an available donor is the only current curative therapy. Other patients may receive immunosuppression, most commonly with anti-thymocyte globulin and cyclosporin. An initial response to immunosuppression is often encouraging, but relapse is common. Supportive care, including management of transfusion requirements and infections, is central to management. Promising new diagnostic tools and emerging therapies will likely transform approaches to this important, chronic and life-threatening condition.

BACKGROUND:Bone marrow biopsy (BMB) is an accepted investigation in fever of unknown origin (FUO) to uncover haematological malignancies, such as lymphoma, and sometimes infections. With the advance in imaging modalities, such as 18-fluoro-2-deoxyglucose positron emission tomography (FDG-PET) to identify the focus of lymphoma, BMB may not contribute to the diagnosis when there are no other clinical features to suggest an underlying haematological disease.AIM:To investigate the utility of BMB in determining the cause of FUO, when there are no other indications for BMB.METHODS:Medical records of adult patients who had BMB performed for FUO or febrile illness from 1 January 2005 to 31 December 2014 in four metropolitan tertiary hospitals in Melbourne, Australia were reviewed. Patients with other concurrent indications for BMB, known human immunodeficiency virus infection and previously diagnosed connective tissue diseases were excluded.RESULTS:Seventy-three patients were included in the study. Fifty-one patients had a final diagnosis for fever (systemic inflammatory diseases, infective, malignancy or other) while 22 patients had no diagnoses. In only 10 patients (13.7%) did BMB contribute to the diagnosis, finding either malignancy or granulomata. However, all these diagnoses could have been made without BMB. Two patients with diffuse large B-cell lymphoma had normal BMB. FDG-PET was helpful in making a diagnosis in eight (25%) out of 32 patients.CONCLUSION:Performing BMB in patients with FUO and no other haematological abnormalities is of very limited value, and other investigations, such as FDG-PET, may be more likely to help establish a definitive diagnosis.

In patients with anemia, transfusion of red blood cells (RBCs) can save lives and improve quality of life. The choice to transfuse should be cautiously made owing to risks of transfusion, economic costs, and limitations on the blood supply. Until the 1980s, the decision for RBC transfusion was guided by Hb threshold, with the aim of maintaining the patient's blood Hb level over 100 grams per liter. Since then, multiple randomized controlled trials and key systematic reviews have provided evidence-based guidelines as to appropriate transfusion thresholds in a number of clinical settings. Here, we aimed to address the outcome of defining different anemia criteria in specific clinical populations exclusively on the basis of the need for RBC transfusion based on Hb concentration. We focused on the patient populations, where there were the most available data on differing transfusion thresholds, which looked at transfusing to a higher or liberal transfusion threshold in comparison with a lower or restrictive transfusion threshold. These included patients in intensive care with or without septic shock, hip fracture surgery, cardiovascular surgery, and upper gastrointestinal bleeding, the pediatric population, and also those with malaria, by reviewing key randomized controlled trials and systematic reviews. Twenty-four randomized controlled studies and 12 systematic reviews have been included, and these are discussed below.

Introduction: Therapeutic plasma exchange (TPE) involves bulk removal of diseased plasma and replacement with a substitute fluid. Albumin is typically used for this purpose with fresh frozen plasma (FFP) reserved for replacement of ADAMTS13 in thrombotic thrombocytopenia purpura (TTP) or replacement of clotting factors in deficiency or coagulopathy.

ObjectiveThe aim of the study is to describe the epidemiology of major bleeding fatalities. MethodsA case series analysis of Australia's National Coronial Information System was conducted. Keywords were used to search for closed cases of major haemorrhage in the state of Victoria for the period 1 January 2009 to 31 December 2011. Coroners' findings, autopsy reports and police reports of cases were reviewed. Demographic data were extracted, and cases were assigned to a clinical bleeding context. ResultsA total of 427 cases of major bleeding causing death were identified. The cohort was predominately men (69%), with a median age of 63years (interquartile range 45-77years). Trauma accounted for 38%, gastrointestinal haemorrhage 28%, surgical/procedural bleeding 14%, ruptured/leaking aneurysms 12% and other 8%. Most events began in homes (46%), hospitals (22%) and at the roadside (17%). Of those whose haemorrhage began in the community, 69% did not survive to hospital. ConclusionsMajor bleeding fatalities occurred across a diverse range of contexts, with trauma and gastrointestinal bleeding accounting for most deaths. The majority of patients did not survive to reach hospital. Major haemorrhage occurring entirely outside hospital may be underrecognised from analyses of datasets based primarily on traumatic or in-hospital bleeding. These findings have implications for management of pre-hospital resuscitation and development of clinical practice guidelines for identification and management of major bleeding in the community.

In recent years, the anti-CD38 monoclonal antibody daratumumab (Darzalex; Janssen-Cilag Pty Ltd) has been shown to be highly efficacious in relapsed and refractory multiple myeloma, with the final results of treatment in newly diagnosed patients awaited. Despite awareness of the potential interference of daratumumab in pre-transfusion immunohaematology testing during phase I and II clinical studies, there was a degree of unpreparedness in the community upon the introduction of this drug into the clinics, particularly the impact that it has on the operational processes in hospital transfusion laboratories and timely issue of red blood cells (RBCs). Anti-CD38 interference in pre-transfusion immunohaematology tests is a particular problem in patients being treated with daratumumab for multiple myeloma as many will require RBC transfusions during their disease treatment. Panagglutination caused by anti-CD38 monoclonal antibody during the indirect antiglobulin test may mask the presence of a clinically significant RBC alloantibody in the patient's plasma during the antibody screen and identification process, which may be overlooked, particularly in urgent situations, subsequently resulting in a delayed or acute haemolytic transfusion reaction. Here, we summarise daratumumab's effects on pre-transfusion immunohaematology testing and its impact on clinical practice and make practical recommendations based on a consensus from medical and scientific transfusion experts and myeloma specialists on behalf of the Australian and New Zealand Society of Blood Transfusion and Myeloma Scientific Advisory Group to Myeloma Australia, respectively.

BACKGROUNDTransfusion of platelets is common in cardiac surgery, and while there are guidelines for their use, there are concerns about potential risks. We aimed to assess the impact of platelet transfusion on mortality, thrombosis, and infection in this patient group.STUDY DESIGN AND METHODSA retrospective cohort study of all patients at St Vincent's Hospital Melbourne who underwent a first cardiac surgery procedure from June 2001 to June 2014 was conducted. A propensity‐weighted analysis was performed to examine the association between intraoperative platelet transfusion and outcomes.RESULTSA total of 5233 patients met inclusion criteria, and 531 (10.15%) received intraoperative platelet transfusion (median two platelet doses, interquartile range, 1‐17). Patients receiving platelets were older, had higher body mass index, lower rates of diabetes and dyslipidemia, higher rates of infective endocarditis, recent myocardial infarction and unstable angina, and exposure to aspirin or clopidogrel. On univariable analysis, platelet transfusion was associated with increased 30‐day mortality (2.4% vs. 10.55%, p < 0.001), return to theatre for bleeding (3.23% vs. 13.37%, p < 0.001), and rates of any infection (9.26% vs. 19.17%, p < 0.001). After adjusting for confounders, platelet transfusion was not associated with increased risk of 30‐day mortality or infective complications. Platelet transfusion was associated with higher rates of return to theatre (relative risk [RR], 2.46; confidence interval [CI], 1.42, 4.04; p = 0.001) and decreased risk of thromboembolic events (RR, 0.28; CI, 0.15, 0.51; p < 0.001).CONCLUSIONPlatelet transfusion was not associated with increased mortality or infective complications following first cardiac surgery. Further prospective studies are required to identify patients most likely to benefit from platelet transfusion.

EDTA-dependent changes include platelet clumping, satellism and more rarely, platelet phagocytosis by neutrophils.1,2 Our case describes a clinically well young patient who presented with significant neutrophil vacuolation on full blood examination (FBE) due to EDTA-dependent platelet phagocytosis.

BACKGROUND:Treatment of hematological malignancies with conventional DNA-damaging drugs, such as chlorambucil (CLB), commonly results in p53-dependent chemo-resistance. Chromatin modifying agents, such as histone deacetylase inhibitors (HDACIs), sodium butyrate (NaBu) and trichostatin A (TSA), may reverse chemo-resistance by modulating the activity of chromatin remodeling enzymes and/or genes that control cell proliferation, differentiation and survival.OBJECTIVE:This study examined the potential use of HDACIs and CLB combination therapies in an in vitro chemo-resistant leukemia model.METHODS:The p53-null promyelocytic leukemia cell line, HL60, was used as an in vitro model of chemo-resistant leukemia. Drug cytotoxicity was determined by tetrazolium salt-based colorimetric assays and Annexin V/propidium iodide staining (flow cytometry). The level of mRNA expression of the chromatin modifying genes was measured by quantitative real-time PCR.RESULTS:Micromolar concentrations of CLB combined with either NaBu or TSA triggered synergistic cytotoxic effects in HL-60 cells (p < 0.001). The effects of the combination treatments resulted in upregulated p21 gene expression (up to 59-fold; p<0.001) that preceded an increase in BCL6 gene expression (up to 20-fold; p < 0.001). Statistically significant but smaller magnitude changes (≤ 2-fold; p <0.05) were noted in the expression of other genes studied regardless of the treatment type.CONCLUSION:The combination treatment of p53-null HL-60 cells with DNA-damaging agent CLB and HDACIs NaBu and TSA triggered additive to synergistic effects on apoptosis and upregulated BCL6 and p21 expression. These findings reveal BCL6 and p21 as potential targets of chemo-resistance for the development of anti-leukemic drugs.

The hospital environment, across multidisciplinary transfusion processes, is complex involving various organizations and agencies, staff and patients. A comprehensive, robust, collaborative, inclusive and effective clinical governance framework for transfusion/blood management activities is essential for patient safety and optimal outcomes; this should include integrated systems across the transfusion chain which is intrinsically high risk, given the possible severe adverse outcomes of error, multiple potential vulnerabilities and various components not being supported by electronic systems. Strong, informed clinician leadership provides inspiration, motivation and support to staff to achieve excellence in transfusion practice; key leaders should be involved with patient care and facilitate a culture of collaborative teamwork, accountability, openness, engagement and improvement. The transfusion committee (TC) should focus on actions, outcomes, improvement and staff/consumer engagement and be integral to the hospital's overall governance structure; clear accountability to executive is essential so that effective change can be supported, resourced, implemented and maintained. TC membership, activities and reporting lines should be clearly documented. Key clinical personnel, the laboratory, quality and executive all contribute as well as relevant external agencies, for example the blood supplier. The TC leadership team should have expertise in transfusion, leadership qualities and should include a haematologist, transfusion nurse/officer and laboratory scientist. The TC agenda should encompass regular items and reports, policy review, illustrative cases, improvement projects, education, guidelines/research and information sharing/benchmarking with other groups. Small TC working groups facilitate progress between meetings. Enablers and barriers to good transfusion practice include system issues, evidence barriers and individual factors.