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

Author summary Thrombotic microangiopathy (TMA) is an important complication of snakebite. It occurs in a subset of patients envenomed by snake species associated with blood clotting abnormalities. TMA is a disorder marked the formation of blood clots and blood vessel wall damage in the micro-circulation, and it carries a risk of organ damage and failure. Prior to our systematic review, evidence predominantly consisted of case reports and case series studies, and one landmark literature review on TMA following snakebite. Recent studies increasingly reported the use of resource intense treatment with therapeutic plasmapheresis (TPE), with limited supporting evidence of benefit. Our systematic review is the first to collate the worldwide experience of TMA in snakebite. We found TMA reported in at least 5.4% of Hypnale bites in Sri Lanka, and 10-15% of Australian elapid envenomings. The main complication was kidney failure. The kidney failure improved in most cases, irrespective of treatment with either antivenom or TPE. The major limitation of our review was the quality of included studies. Whilst antivenom remains the standard of care for snake envenoming irrespective of any evidence for specific benefit in snakebite associated TMA, our systematic review raises questions about whether the use of TPE represents a wise use of resources. There is a high resourcing cost of TPE, potential risks of the treatment, and lack of evidence for benefit. As a neglected tropical disease, it is imperative that treatment strategies for snakebite make efficient use of limited resources. Follow up studies, including good quality prospective cohort or interventional studies, would be best placed to confirm our findings. 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.