The prevalence of alloantibodies and ABO RhD blood groups in a cohort of Aboriginal and non-Aboriginal cardiac surgery patients from Australia.

INTRODUCTION: Limited evidence exists on the distribution of ABO RhD blood groups and prevalence and specificity of red blood cell (RBC) alloantibodies in Aboriginal and Torres Strait Islander peoples of Australia. We investigated RBC alloantibody prevalence and ABO RhD groups in Aboriginal patients undergoing cardiac surgery at a South Australian (SA) tertiary hospital, a major cardiac surgical referral centre for Northern Territory (NT) patients METHODS: Retrospective analysis of all consecutive patients undergoing cardiac surgery at Flinders Medical Centre (FMC) between January 2014 and June 2019. ABO and RhD blood groups, and RBC alloantibody prevalence, specificity, and clinical significance in Aboriginal and non-Aboriginal cardiac patients were determined at time of surgery and on follow up to 2021. RESULTS: 2327 patients were included, 588 (25.3 %) were from NT, and 420 (18.0 %) were Aboriginal. Aboriginal patients had a higher prevalence of ABO group O (59.8 % vs 43.9 %) and RhD positive (99.0 % vs 83.8 %). One-hundred-and-eleven patients had 154 RBC alloantibodies, 57/420 (13.6 %) Aboriginal versus 54/1907 (2.8 %) non-Aboriginal (p < 0.0001). There were higher numbers of IgM alloantibodies in Aboriginal patients (59/77, 76.6 %), with Lewis, P1 and M more common. Sixty patients had antibodies detected at time of surgery, 14 NT patients with previously detected alloantibodies, prior to surgery, presented with a negative antibody screen and 37 had new antibodies detected after cardiac surgery. CONCLUSION: A high prevalence of IgM alloantibodies was found in Aboriginal compared to non-Aboriginal cardiac surgery patients. The clinical significance of these IgM alloantibodies in Aboriginal peoples requires further investigation.

Snakebite-associated thrombotic microangiopathy: a spotlight on pharmaceutical interventions.

INTRODUCTION: Snakebite is a neglected public health issue causing death and disability, disproportionately affecting tropical and subtropical resource poor countries globally. Snakebite-associated thrombotic microangiopathy (TMA) occurs in a subset of snakebites and is associated with acute kidney injury (sometimes requiring renal replacement therapy) and a risk of chronic kidney disease. AREAS COVERED: This expert review synthesizes current evidence on therapeutic interventions in snakebite-associated TMA via PubMed search for cohort studies and randomized controlled trials (RCTs) in snakebite-associated TMA from 1970 to October 2022. EXPERT OPINION: There are no interventional RCTs in snakebite-associated TMA. Recent cohort studies from Sri Lanka, India, and Australia report clinical and laboratory endpoint outcomes for intervention with antivenom and therapeutic plasma-exchange (TPE). TPE is a resource intense and costly treatment using large volumes of blood donor plasma. There is no consistent evidence supporting TPE in snakebite-associated TMA with respect to patient survival, dialysis-free survival, or hospital length of stay. Antivenom is the standard of care for patients with snake envenoming, but there is no specific evidence of benefit in snakebite-associated TMA. Emerging new therapies in snakebite more broadly are untested in snakebite-associated TMA. RCTs are needed to improve the evidence for treatment of snakebite-associated TMA.

A Retrospective Cohort Study of Red Cell Alloimmunisation in Rural, Remote, and Aboriginal and Torres Strait Islander Peoples Admitted to Intensive Care in the Northern Territory, Australia.

Red cell (RC) alloantibodies occur on exposure to non-self RC antigens in transfusion and pregnancy (typically IgG and clinically significant) or in association with non-RC immune environmental factors (typically IgM and not clinically significant). In Australia, the risk of RC alloimmunisation in First Nations peoples is unknown. We assessed the epidemiology, specificity, and antecedents of RC alloimmunisation via a data linkage retrospective cohort study of Northern Territory (NT) intensive care unit (ICU) patients (2015-2019). Of 4183 total patients, 50.9% were First Nations. In First Nations versus non-First Nations patients, the period prevalence of alloimmunisation was 10.9% versus 2.3%, with 390 versus 72 prevalent alloantibodies detected in 232 versus 48 alloimmunised patients, of which 135 (34.6%) versus 52 (72.2%) were clinically significant specificities. Baseline and follow-up alloantibody testing were available for 1367 patients, in whom new incident clinically significant alloantibodies developed in 4.5% First Nations versus 1.1% non-First Nations patients. On Cox proportional hazards modelling, adjusted hazard ratios (HR) showed First Nations status (HR 2.67 (95% CI 1.05-6.80), p = 0.04) and cumulative RC unit transfusion exposure (HR 1.03 (95% CI 1.01-1.05), p = 0.01) were independent predictors of clinically significant alloimmunisation. First Nations Australian patients are at increased risk of alloimmunisation due to RC transfusion, underscoring the importance of very judicious use of RC transfusions and shared decision-making with patients. Further studies are recommended to explore the role of other (non-RC) immune host factors, given the relative high prevalence of non-clinically significant IgM alloantibodies within alloimmunised First Nations patients.

Antiphospholipid syndrome in rural, remote, and First Nations peoples in the Top End of the Northern Territory, Australia.

Background: The Northern Territory of Australia has a high proportion of First Nations peoples living in remote communities and a high burden of chronic autoimmune diseases. The epidemiology and clinical outcomes of antiphospholipid syndrome (APS) in First Nations Australians are poorly characterized. Objectives: To determine the epidemiology, presenting features, and outcomes of patients with APS using an 18-year retrospective cohort of newly diagnosed patients presenting to Royal Darwin Hospital (2002-2020). Methods: Patients admitted to Royal Darwin Hospital with a new incident diagnosis of APS between January 2002 and December 2020 were identified and followed until December 2022, with data on baseline demographics, clinical and laboratory features, and overall survival extracted from electronic and paper medical records. Results: Fifty-three patients with APS were included, of whom 40 (75%) were First Nations and 46 (87%) were female. Thirty (75%) of First Nations patients with APS resided in very remote Australia vs 0 (0%) non-First Nations patients. Eighteen cases (34%) had primary APS, and 35 cases (66%) had secondary APS, most in association with lupus. Eight (15%) cases developed catastrophic APS (CAPS), all in First Nations patients. There were 13 deaths (of which 11 were among First Nations patients). Patients with CAPS had significantly shorter median overall survival (8.3 years from diagnosis), with median survival in non-CAPS patients not reached (P = .003). Conclusion: There is a high prevalence of APS in First Nations patients living in very remote Australia admitted for tertiary care in the tropical north of the Northern Territory, Australia. The rate of CAPS in First Nations patients was high, and CAPS was associated with significantly shorter survival. Larger prospective studies are required to inform improved models of care for First Nations and remote Australians living with APS.

D-dimer testing for early detection of venom-induced consumption coagulopathy after snakebite in Australia (ASP-29).

OBJECTIVE: To assess the accuracy and marginal value of quantitative D-dimer testing for diagnosing venom-induced consumption coagulopathy (VICC) in people bitten by Australian snakes. DESIGN, SETTING: Analysis of data for suspected and confirmed cases of snakebite collected prospectively by the Australian Snakebite Project, 2005-2019, from 200 hospitals across Australia. PARTICIPANTS: 1363 patients for whom D-dimer was quantitatively assessed within 24 hours of suspected or confirmed snakebite. MAIN OUTCOME MEASURES: Diagnostic performance of quantitative D-dimer testing for detecting systemic envenoming with VICC (area under the receiver operating characteristic curve, AUC); optimal D-dimer cut-off value (maximum sum of sensitivity and specificity). RESULTS: D-dimer values exceeded 2.5 mg/L within three hours of the bite for 95% of patients who developed VICC, and were lower than 2.5 mg/L for 95% of non-envenomed patients up to six hours after snakebite. The AUC for diagnosing envenoming with VICC on the basis of quantitative D-dimer testing within six hours of snakebite was 0.97 (95% CI, 0.96-0.98; 944 patients). Diagnostic performance increased during the first three hours after snakebite; for quantitative D-dimer testing at 2-6 hours, the AUC was 0.99 (95% CI, 0.99-1.0); with a cut-off of 2.5 mg/L, sensitivity was 97.1% (95% CI, 95.0-98.3%) and specificity 99.0% (95% CI, 97.6-99.6%) for VICC. For 36 patients with normal international normalised ratio (INR) and activated partial thromboplastin time (aPTT) values 2-6 hours after snakebite, the AUC was 0.97 (95% CI, 0.93-1.0); with a cut-off of 1.4 mg/L, sensitivity was 94% (95% CI, 82-99%) and specificity 96% (95% CI, 94-97%). In all but one of 84 patients who developed VICC-related acute kidney injury, D-dimer values exceeded 4 mg/L within 24 hours of the bite. CONCLUSION: D-dimer concentrations assessed 2-6 hours after snakebite, with a cut-off value of 2.5 mg/L, could be useful for diagnosing envenoming with VICC.

Snakebite Associated Thrombotic Microangiopathy and Recommendations for Clinical Practice.

Snakebite is a significant and under-resourced global public health issue. Snake venoms cause a variety of potentially fatal clinical toxin syndromes, including venom-induced consumption coagulopathy (VICC) which is associated with major haemorrhage. A subset of patients with VICC develop a thrombotic microangiopathy (TMA). This article reviews recent evidence regarding snakebite-associated TMA and its epidemiology, diagnosis, outcomes, and effectiveness of interventions including antivenom and therapeutic plasma-exchange. Snakebite-associated TMA presents with microangiopathic haemolytic anaemia (evidenced by schistocytes on the blood film), thrombocytopenia in almost all cases, and a spectrum of acute kidney injury (AKI). A proportion of patients require dialysis, most survive and achieve dialysis free survival. There is no evidence that antivenom prevents TMA specifically, but early antivenom remains the mainstay of treatment for snake envenoming. There is no evidence for therapeutic plasma-exchange being effective. We propose diagnostic criteria for snakebite-associated TMA as anaemia with >1.0% schistocytes on blood film examination, together with absolute thrombocytopenia (<150 × 109/L) or a relative decrease in platelet count of >25% from baseline. Patients are at risk of long-term chronic kidney disease and long term follow up is recommended.

Snakebite-associated thrombotic microangiopathy: an Australian prospective cohort study [ASP30].

BACKGROUND: Snakebite-associated thrombotic microangiopathy (TMA) occurs in a subset of patients with venom-induced consumption coagulopathy (VICC) following snakebite. Acute kidney injury (AKI) is the commonest end-organ manifestation of TMA. The epidemiology, diagnostic features, outcomes, and effectiveness of interventions including therapeutic plasma-exchange (TPE), in snakebite-associated TMA are poorly understood. METHODS: We reviewed all patients with suspected or confirmed snakebite recruited to the Australian Snakebite Project (2004-2018 inclusive), a prospective cohort study, from 202 participating Australian hospitals across the country. TMA was defined as anemia with schistocytosis. RESULTS: 2069 patients with suspected snakebite were enrolled, with 1158 (56.0%) systemically envenomed, of which 842 (72.7%) developed VICC, from which 104 (12.4%) developed TMA. Of those systemically envenomed, TMA occurred in 26% (13/50) taipan, 17% (60/351) brown, and 8% (16/197) tiger snakebites. Thrombocytopenia was present in 90% (94/104) of TMA cases, and a further eight (8%) had a > 25% decrease in platelets from the presentation. Patients with TMA were significantly older than non-TMA patients with VICC (53 [35-61] versus 41 [24-55] years, median [IQR], p < 0.0001). AKI developed in 94% (98/104) of TMA patients, with 34% (33/98) requiring dialysis (D-AKI). There were four deaths. In D-AKI TMA cases, eventual dialysis-free survival (DFS) was 97% (32/33). TPE was used in five D-AKI cases, with no significant difference in DFS or time to independence from dialysis. >90-day follow-up for 25 D-AKI cases (130 person-years) showed no end-stage kidney disease but 52% (13/25) had ≥ stage 3 chronic kidney disease (CKD). CONCLUSION: Our findings support a definition of snakebite-associated TMA as anemia with schistocytosis and either thrombocytopenia or >25% drop in platelet count. AKI occurring with snakebite-associated TMA varied in severity, with most achieving DFS, but with a risk of long-term CKD in half. We found no evidence of benefit for TPE in D-AKI.

An evaluation of existing manual blood film schistocyte quantitation guidelines and a new proposed method.

Schistocytosis is the morphological hallmark of the microangiopathic haemolytic anaemia of thrombotic microangiopathy (TMA). Consensus guidelines for manual schistocyte quantitation are available, but limited research has evaluated them. The 2012 International Council for Standardization in Haematology (ICSH) recommends a schistocyte quantitation of 1% as a robust cut-off for significance, with the quantitation including helmet, crescent, triangle and keratocyte poikilocytes; and microspherocytes only in the presence of helmets, crescents/triangles, and keratocytes. We aimed to evaluate the relative contribution of these different poikilocytes to schistocyte counting; compare the ICSH method with our proposed method which counts only cells most specific for red cell fragmentation (helmet, crescent and triangular schistocytes); and evaluate inter- and intra-observer agreement. Blood films were sourced from the Australian Snakebite Project, including non-envenomed and envenomed cases, with and without TMA. In blood films across the range of schistocytosis, the predominant poikilocytes present were helmets and crescents. Triangles, keratocytes and microspherocytes were typically only present when ICSH schistocyte count was >1%. With results dichotomised as <1.0% or ≥1.0%, our proposed new method versus the ICSH method showed almost perfect agreement [observed agreement 95%, Cohen's kappa (κ)=0.84, SE 0.04, 95% CI 0.76-0.92, p<0.005]. Inter-observer strength of agreement for our method was moderate (Fleiss' κ for comparisons between three non-unique microscopists κ=0.50, SE 0.05, 95% CI 0.41-0.59, p<0.005). Intra-observer reproducibility assessed in two microscopists ranged from substantial (Cohen's κ=0.71, SE 0.08, 95% CI 0.55-0.86, p<0.005) to borderline almost perfect agreement (Cohen's κ=0.81, SE 0.07, 95% CI 0.68-0.93, p<0.005). Schistocyte quantitation using our new method is simpler than the 2012 ICSH method and had almost perfect agreement. Our finding of moderate inter-observer agreement in quantitating helmet, triangle and crescent schistocytes is applicable to both the ICSH and our newly proposed method. This finding underscores the importance of clinicopathological correlation and repeated examinations in the context of a clinically suspected TMA.

Schistocyte quantitation, thrombotic microangiopathy and acute kidney injury in Australian snakebite coagulopathy [ASP28].

INTRODUCTION: The major systemic manifestation of hemotoxicity in human snakebite envenoming is venom-induced consumption coagulopathy (VICC). A subset of patients with VICC develop thrombotic microangiopathy (TMA), in which acute kidney injury (AKI) occurs. We aimed to investigate the association between schistocytosis in snakebite patients with VICC and AKI, compared to non-envenomed patients. METHODS: Serial blood films collected from a prospective cohort of snakebite patients (Australian Snakebite Project) were examined. Cases were classified a priori as non-envenomed snakebites (normal controls), envenomed without VICC, partial VICC without AKI, complete VICC without AKI, and VICC with AKI based on defined clinical and laboratory criteria. The percentage of schistocytes between groups was compared and correlated by Kendall's tau b test. RESULTS: Seven hundred and eighty blood films from 234 snakebite cases were analyzed. There was a statistically significant correlation (τ = .69, SE .03, P < .001) for schistocytosis between the ordered groups of non-envenomed snakebites, envenomed without VICC, partial VICC without AKI, complete VICC without AKI, and VICC with AKI groups. Patients with VICC and AKI had a platelet nadir median of 42 × 109 /L (interquartile range [IQR] :25-130 × 109 /L), hemoglobin nadir of median 107 g/L (IQR 66-122 g/L), and maximum LDH median of 1128 U/L (IQR 474-3255 U/L). A 1.0% threshold for schistocytosis yielded 90% sensitivity (95% CI: 67%-98%) and 71% specificity (95% CI: 62%-79%) for predicting AKI in patients with VICC. CONCLUSION: Schistocyte quantitation has good diagnostic utility in snakebite patients with VICC. A definition of snakebite TMA as MAHA with ≥1.0% schistocytes and thrombocytopenia, would appear to be appropriate.

Snakebite associated thrombotic microangiopathy: a systematic review of clinical features, outcomes, and evidence for interventions including plasmapheresis.

Snakebite is a neglected tropical disease with significant morbidity and mortality. Thrombotic microangiopathy (TMA) is an important but poorly understood complication of snakebite associated with acute kidney injury (AKI). Numerous treatments have been attempted based on limited evidence. We conducted a systematic review of TMA following snakebite using a pre-determined case definition of blood film red cell schistocytes or histologically diagnosed TMA. The search strategy included major electronic databases and grey literature. We present a descriptive synthesis for the outcomes of AKI, dialysis free survival (DFS), other end-organ damage, overall survival, and interventions with antivenom and therapeutic plasmapheresis (TPE). This study was prospectively registered with PROSPERO (CRD42019121436). Seventy-two studies reporting 351 cases were included, predominantly small observational studies. Heterogeneity for study selection, design, reporting and outcomes were observed. The commonest envenoming species were hump-nosed vipers (Hypnale spp.), Russell's viper (Daboia russelii) and Australian brown snakes (Pseudechis spp.). The prevalence of TMA was at least 5.4% in proven and probable Hypnale bites, and 10-15% of Australian elapid envenomings, AKI occurred in 94% (293/312) of TMA cases, excluding case reports. The majority of cases with AKI required dialysis. Included prospective and retrospective cohort studies reporting interventions and renal outcomes showed no evidence for benefit from antivenom or TPE with respect to DFS in dialysis dependant AKI. The Grading of Recommendations, Assessment, Development and Evaluations (GRADE) assessment for quality of accumulated evidence for interventions was low. The major complication of TMA following snakebite is AKI. AKI improves in most cases. We found no evidence to support benefit from antivenom in snakebite associated TMA, but antivenom remains the standard of care for snake envenoming. There was no evidence for benefit of TPE in snakebite associated TMA, so TPE cannot be recommended. The quality of accumulated evidence was low, highlighting a need for high quality larger studies.

Snakebite associated thrombotic microangiopathy: a protocol for the systematic review of clinical features, outcomes, and role of interventions.

BACKGROUND: Thrombotic microangiopathy is an uncommon complication of snake envenoming associated with a subset of snakebite cases presenting with venom-induced consumption coagulopathy. It presents with microangiopathic haemolytic anaemia and thrombocytopenia. Available studies are predominantly small retrospective observational studies only. Renal end organ injury appears common. It has variably been likened to either thrombotic thrombocytopenic purpura or atypical haemolytic uraemic syndrome. Many studies report acute kidney injury, with dialysis required in a subset of patients. Some studies suggest a role for treatment with plasmapheresis. Interpretation of the literature is complicated by variable nomenclature and historically poor case definitions of both venom-induced consumption coagulopathy and thrombotic microangiopathy associated with snake envenoming. METHODS: The main objective of this systematic review is to synthesise the worldwide experience of snakebite-associated thrombotic microangiopathy with respect to its features and outcomes, and collate any evidence for the role of plasmapheresis as treatment. A predetermined case definition of confirmed or suspected snakebite with either blood film evidence of microangiopathic haemolytic anaemia or histological evidence of thrombotic microangiopathy will be used. This case definition will determine the search terms and study inclusion criteria. Relevant studies will be identified by electronic database, published conference abstracts, and grey literature search. This systematic review will be performed and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist. The quality of included studies will be assessed by a proposed tool for evaluating the methodological quality of case reports and case series. Results will be reported by a descriptive synthesis with a focus on the presenting features; outcomes of acute kidney injury, dialysis-free survival, other end organ damage, and overall survival; and any evidence of a role for treatment with plasmapheresis. The quality of accumulated evidence will be assessed via the Grading of Recommendations, Assessment, Development, and Evaluations framework. DISCUSSION: It is anticipated that eligible studies will consist of small observational studies. Evidence gathered from this review will provide the first broader understanding of the clinical features, outcomes, prognosis, and management of snakebite-associated thrombotic microangiopathy. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42019121436.

The Northern Territory Medical Program - growing our own in the NT.

CONTEXT: The Northern Territory (NT) is characterised by major health inequalities. A high proportion of the population is Indigenous, with poor socioeconomic conditions and a high burden of disease. The small NT population - 1% of the total Australian population - is dispersed over one-sixth of Australia's land mass. Given this very low population density and the geographical isolation of many small communities, access to services is often difficult. Medical workforce recruitment and retention have been persistent problems. Prior to 2011, NT residents who aspired to study medicine had to leave the NT. This was the only Australian state or territory that did not have the capacity for students to complete an entire medical degree within the jurisdiction. This article describes the development, implementation and outcomes of the Northern Territory Medical Program (NTMP), which commenced in Darwin in 2011. This was a major development of the Flinders University distributed program, which aimed to develop the medical workforce for the challenging NT environment. ISSUES: Based on evidence regarding the importance of selection in achieving rural workforce outcomes, and a national priority to graduate more Indigenous Australian doctors, NT residents and Indigenous applicants to the NTMP were prioritised in the selection process. Aspiring doctors would not now have to move interstate to study. The curriculum of Flinders University, based in Adelaide, South Australia, would be contextualised to the NT. The NTMP was developed and implemented in collaboration with Charles Darwin University, the major university in the NT. LESSONS LEARNED: Some of the lessons learned may be useful to others contemplating the delivery of a distributed program that includes a full medical program in a remote area. These include: Leadership at the highest levels of the university is crucial. Expect faculty turnover and avoid single person vulnerabilities. Actively engage local clinicians. Ensure a strong focus on new or alternative selection processes that are able to predict progression. Provide preparatory skills and support for students, especially Indigenous students, with non-science backgrounds. Appreciate and accommodate the community and family pressures experienced by some Indigenous students. Anticipate that the first pioneering cohort of students will not be typical of future cohorts, and work with them to adapt the curriculum, teaching and selection methods. Whilst exemplary telecommunications are needed, some elements of the curriculum will be able to be delivered far better locally than at the larger campus. Do not underestimate the level of student and staff support required both locally and centrally. Develop a 'network' rather than a 'hub and spoke' model. The network may include multiple dispersed placement sites, requiring infrastructure, staffing and ongoing support. The 'new kid' will mean the 'older sibling' will change for the better and use the small size and agility to explore innovations. Focus on the goals. We wanted to contribute to improved economic, social and health outcomes for NT residents by developing an appropriately prepared medical workforce, thereby eliminating the need to recruit doctors from interstate and overseas, and by graduating more Indigenous doctors - potential medical leaders for Australia. Build your expectation for success based on past successes in innovation. Flinders University was able to build on its experience in developing the first 4-year medical program in Australia.