Sickle cell disease in Australia: a snapshot from the Australian Haemoglobinopathy Registry.

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.

Role of bone marrow biopsy for fever of unknown origin in the contemporary Australian context.

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.

Revisiting acquired aplastic anaemia: current concepts in diagnosis and management.

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.

Platelet transfusion is not associated with increased mortality or morbidity in patients undergoing cardiac surgery.

BACKGROUND: Transfusion 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 METHODS: A 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. RESULTS: A 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). CONCLUSION: Platelet 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.

Predicting blood loss and transfusion requirement in patients undergoing surgery for musculoskeletal tumors.

BACKGROUND: Few studies have systematically identified factors associated with blood loss in musculoskeletal tumor surgery. We aimed to identify risk factors for requiring large-volume transfusion in musculoskeletal tumor surgery and created an interactive model to predict red blood cell transfusion requirements based on patient characteristics. These data will facilitate planning in hospital blood banks and aid identification of specific groups for future interventions targeted at reducing blood utilization. Only one similar study has been published and there are minimal data surrounding interventions designed to minimize blood loss in musculoskeletal tumor surgery. STUDY DESIGN AND METHODS: We retrospectively analyzed a database containing 1322 consecutive surgeries, performed at a quaternary referral center in Melbourne, Australia. Using logistic regression analysis and a negative truncated binomial logistic regression model, we developed prediction models for transfusion requirement. RESULTS: The following factors were associated with large-volume transfusion: malignant tumors, bone tumors, sacral and pelvic tumors, high American Society of Anesthesiologists (ASA) score, and tumor size of more than 5 cm. High ASA score was also strongly associated with 30-day mortality. CONCLUSIONS: Preoperative planning in high-risk patients is critical to ensure adequate blood product supply, minimize wastage, and optimize the patient's general health before surgery. These patients would be ideal targets for future randomized studies aimed at reducing blood utilization.

Clinical transfusion practice update: haemovigilance, complications, patient blood management and national standards.

Blood transfusion is not without risk. Although the risks of HIV and hepatitis transmission have diminished, haemovigilance programs highlight that other significant transfusion hazards remain. Sepsis from bacterial contamination is the most common residual infectious hazard in developed countries, and events due to clerical error are problematic. Unnecessary transfusions should be avoided. New national guidelines on patient blood management (PBM) emphasise holistic approaches, including strategies to reduce transfusion requirements. Perioperative PBM should incorporate preoperative haemoglobin and medication optimisation, intraoperative blood conservation, and consideration of restrictive postoperative transfusion and cell-salvage techniques. When massive transfusion is required, hospitals should implement massive transfusion protocols. These protocols reduce mortality, improve communication and facilitate adequate provision of blood products. They should include multidisciplinary team involvement and guidelines for use of blood components and adjunctive agents. Although fresh frozen plasma to red blood cell and platelet to red blood cell ratios of ≥ 1 : 2 appear to reduce mortality in trauma patients who receive massive transfusion, there is insufficient evidence to recommend specific ratios. Systematic reviews have found no significant benefit of recombinant activated factor VII in critical bleeding, and an increase in thromboembolic events; specialist haematology advice is therefore recommended when considering use of this agent. The National Safety and Quality Health Service Standards address use of blood and blood products, and provide important transfusion principles for adoption by all clinicians. Storage of red cells in additive solution results in changes, known as the "storage lesion", and studies to determine the clinical effect of the age of blood at transfusion are ongoing.

The Australian Aplastic Anaemia and other Bone Marrow Failure Syndromes Registry.

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.

Hospital blood bank information systems accurately reflect patient transfusion: results of a validation study.

BACKGROUND: Hospital transfusion laboratories collect information regarding blood transfusion and some registries gather clinical outcomes data without transfusion information, providing an opportunity to integrate these two sources to explore effects of transfusion on clinical outcomes. However, the use of laboratory information system (LIS) data for this purpose has not been validated previously. STUDY DESIGN AND METHODS: Validation of LIS data against individual patient records was undertaken at two major centers. Data regarding all transfusion episodes were analyzed over seven 24-hour periods. RESULTS: Data regarding 596 units were captured including 399 red blood cell (RBC), 95 platelet (PLT), 72 plasma, and 30 cryoprecipitate units. They were issued to: inpatient 221 (37.1%), intensive care 109 (18.3%), outpatient 95 (15.9%), operating theater 45 (7.6%), emergency department 27 (4.5%), and unrecorded 99 (16.6%). All products recorded by LIS as issued were documented as transfused to intended patients. Median time from issue to transfusion initiation could be calculated for 535 (89.8%) components: RBCs 16 minutes (95% confidence interval [CI], 15-18 min; interquartile range [IQR], 7-30 min), PLTs 20 minutes (95% CI, 15-22 min; IQR, 10-37 min), fresh-frozen plasma 33 minutes (95% CI, 14-83 min; IQR, 11-134 min), and cryoprecipitate 3 minutes (95% CI, -10 to 42 min; IQR, -15 to 116 min). CONCLUSIONS: Across a range of blood component types and destinations comparison of LIS data with clinical records demonstrated concordance. The difference between LIS timing data and patient clinical records reflects expected time to transport, check, and prepare transfusion but does not affect the validity of linkage for most research purposes. Linkage of clinical registries with LIS data can therefore provide robust information regarding individual patient transfusion. This enables analysis of joint data sets to determine the impact of transfusion on clinical outcomes.

Combination Treatment of p53-Null HL-60 cells with Histone Deacetylase Inhibitors and Chlorambucil Augments Apoptosis and Increases BCL6 and p21 Gene Expression.

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.

Major haemorrhage fatalities in the Australian national coronial database.

OBJECTIVE: The aim of the study is to describe the epidemiology of major bleeding fatalities. METHODS: A 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. RESULTS: A total of 427 cases of major bleeding causing death were identified. The cohort was predominately men (69%), with a median age of 63 years (interquartile range 45-77 years). 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. CONCLUSIONS: Major 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.

Blood transfusion requirements for patients undergoing chemotherapy for acute myeloid leukemia how much is enough?

Although essential in the management of AML, there is little information quantitating transfusion requirements for these patients. We evaluated 111 consecutive adults treated for AML, showing that approximately 150 blood donors are required to adequately cater for a single patient's complete therapy with little variation for age, prognostic group or intensity of treatment.

Introduction of universal prestorage leukodepletion of blood components, and outcomes in transfused cardiac surgery patients.

OBJECTIVE: To assess whether introduction of universal leukodepletion (ULD) of red blood cells (RBCs) for transfusion was associated with improvements in cardiac surgery patient outcomes. METHODS: Retrospective study (2005-2010) conducted at 6 institutions. Associations between leukodepletion and outcomes of mortality, infection, and acute kidney injury (AKI) were modeled by logistic regression, and intensive care unit length of stay (LOS) in survivors was explored using linear regression. To examine trends over time, odds ratios (ORs) for outcomes of transfused were compared with nontransfused patients, including a comparison with nontransfused patients who were selected based on propensity score for RBC transfusion. RESULTS: We studied 14,980 patients, of whom 8857 (59%) had surgery pre-ULD. Transfusions of RBCs were made in 3799 (43%) pre-ULD, and 2525 (41%) post-ULD. Administration of exclusively leukodepleted, versus exclusively nonleukodepleted, RBCs was associated with lower incidence of AKI (adjusted OR 0.80, 95% confidence interval [CI] 0.65-0.98, P = .035), but no difference in mortality or infection. For post-ULD patients, no difference was found in mortality (OR 0.96, 95% CI 0.76-1.22, P = .76) or infection (OR 0.91, 95% CI 0.79-1.03, P = .161); however, AKI was reduced (OR 0.79 95% CI 0.68-0.92, P = .003). However, ORs for post-ULD outcomes were not significantly different in nontransfused, versus transfused, patients. Furthermore, those who received exclusively nonleukodepleted RBCs were more likely to have surgery post-ULD. CONCLUSIONS: Universal leukodepletion was not associated with reduced mortality or infection in transfused cardiac surgery patients. An association was found between ULD and reduced AKI; however, this reduction was not significantly different from that seen in nontransfused patients, and other changes in care most likely explain such changes in renal outcomes.

Transfusion practice varies widely in cardiac surgery: Results from a national registry.

OBJECTIVES: Evidence is accumulating of adverse outcomes associated with transfusion of blood components. If there are differences in perioperative transfusion rates in cardiac surgery, and what hospital factors may contribute, requires further investigation. METHODS: Analysis of 42,743 adult patients who underwent 43,482 procedures from 2005 to 2011 at 25 Australian hospitals, according to the Australian and New Zealand Society of Cardiac and Thoracic Surgeons Cardiac Surgery Database. Multiple logistic regression examined associations of patient and hospital characteristics with transfusion of ≥1 red blood cell (RBC) unit; platelet (PLT), fresh frozen plasma (FFP), and cryoprecipitate (CRYO) doses; and ≥5 RBC units, from surgery until hospital discharge. RESULTS: Procedures included 24,222 (55%) isolated coronary artery bypass grafts, 7299 (17%) isolated valve, 4714 (11%) coronary artery bypass graft and valve, and 7247 (17%) other procedures. After adjustment for various patient and procedure characteristics, transfusion rates varied across hospitals for ≥1 RBC unit from 22% to 67%, ≥5 RBC units from 5% to 25%, ≥1 PLT dose from 11% to 39%, ≥1 FFP dose from 11% to 48% and ≥1 CRYO dose from 1% to 20%. Hospital characteristics, including state or territory, private versus public, and teaching versus nonteaching, were not associated with variation in transfusion rates. CONCLUSIONS: Variation in transfusion of all components and large volume RBC was identified, even after adjustment for patient and procedural factors known to influence transfusion, and this was not explained by hospital characteristics.

Palliative care and the hemato-oncological patient: can we live together? A review of the literature.

Current evidence suggests that patients with hematological malignancies less frequently access palliative care services, and for those who do, this tends to occur later in their illness than their counterparts with solid malignancies. These patients are also more likely to die in hospital following escalating interventions. This approach to care that considers palliative care referral after most treatments are exhausted has implications for the quality of palliative care intervention possible. An episodic approach engaging palliative care according to needs rather than prognosis may be more valuable. The successful integration of palliative care into the care of hemato-oncological patients requires recognition by palliative care physicians of the particular issues encountered in care, namely, the difficulty in individual prognostication; ongoing therapeutic goals of curability or long term survival; the technical nature and complications of treatment; the speed of change to a terminal event; the need for pathology testing and transfusion of blood products as death approaches; the potentially reversible nature of intercurrent events such as infection; and the long relationships that develop between patients and their hematologists. Meanwhile, hematologists should be aware of the benefits of palliative care earlier in an illness trajectory and that palliative care does not equate to terminal care only. This review summarizes current practices and barriers to referral, and suggests recommendations for collaborative care and further research in the palliation of hemato-oncological patients. In doing so, it highlights to palliative care and hematology physicians how successful integration of their disciplines may improve their care of these patients.

Appearance of del(11q) in two patients with acute promyelocytic leukaemia treated with all-trans retinoic acid and combination chemotherapy.

Two acute promyelocytic leukaemia patients, treated with all-trans retinoic acid and combination chemotherapy, acquired a deletion of 11q within 12 months of diagnosis. One patient died in relapse, with both t(15;17) and del(11q) cell lines co-existing. Patient 2 remains in remission with del(11q) in 70% metaphases, despite normal marrow morphology. No deletion of the MLL gene was identified in the latter patient. The early appearance of a del(11q) is unusual, particularly without morphological evidence of myelodysplasia. We hypothesize that the del(11q) was therapy-induced but the absence of other genetic lesions has resulted in no accompanying morphological changes.