AbstractSnakebite is a significant 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. Occasional patients with VICC appear to develop a poorly understood thrombotic microangiopathy (TMA) with peripheral blood film schistocytes. This thesis investigated snakebite associated TMA via a systematic review and series of laboratory and clinical studies from the Australian Snakebite Project (ASP).
TMA occurred in ≥9% of snake envenoming, and 8-23% of VICC, presenting with anaemia and thrombocytopenia. Acute kidney injury (AKI) developed in 77-94% of TMA. Blood film schistocytes appeared by 24 hours post bite. Manual schistocyte quantitation using existing international consensus methods versus a new and simpler proposed method showed almost perfect agreement. Interobserver agreement for schistocyte quantitation between four microscopists was moderate. A 1.0% cut-off for schistocytes using the newly proposed method was 84.2% sensitive and 81.7% specific for AKI in Australian snakebite patients with VICC.
The systematic review found 69-95% of AKI TMA cases required dialysis (D-AKI), compared to 33% in the ASP prospective cohort study. Dialysis free survival (DFS) was achieved in 80-97% of D-AKI cases. Death and non-renal other end organ damage were uncommon. There was no evidence for intervention with antivenom in preventing TMA, nor for benefit with therapeutic plasma-exchange (TPE) in D-AKI with respect to DFS or time to dialysis independence. Prevalence of ≥Stage 3 chronic kidney disease (CKD) on long term follow up was ≥39% in ASP D-AKI TMA cases.
Thesis findings support a definition of snakebite associated TMA as anaemia with schistocytes >1.0% and either thrombocytopenia or >25% drop in platelet count. TMA presents as a spectrum disorder with respect to AKI severity. Whilst data need to be interpreted with caution given low sample sizes, TPE cannot be recommended for snakebite-associated TMA, although antivenom remains the standard of care for snake envenoming more broadly. Patients require long term follow up for CKD. The exact pathophysiology of snakebite TMA remains unclear; and is a recommended area for future research.
|Date of Award||2021|
|Supervisor||Bart Currie (Supervisor) & Geoffrey K. Isbister (Supervisor)|