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

Abstract

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: an Australian prospective cohort study [ASP30]

“…A subset of patients with VICC develop thrombotic microangiopathy (TMA), which is associated with acute kidney injury (AKI) [5,6]. Snakebite-associated TMA presents with microangiopathic hemolytic anemia (MAHA) evidenced by red cell fragments (schistocytes) on the blood film [7].…”

“…Our current understanding of the epidemiology, clinical and laboratory features and treatment of snakebite-associated TMA are limited. Most existing studies are case reports and case series [6]. The few cohort studies available are typically small, single centre, and/or based in highly selected settings such as tertiary hospital renal specialist centres [8,9].…”

“…The few cohort studies available are typically small, single centre, and/or based in highly selected settings such as tertiary hospital renal specialist centres [8,9]. Long-term follow-up has been limited, particularly with respect to renal outcomes [6,8,9]. Any association between TMA secondary to snakebite, and treatment based on approaches used in either HUS or TTP, is unsubstantiated [6].…”

“…Long-term follow-up has been limited, particularly with respect to renal outcomes [6,8,9]. Any association between TMA secondary to snakebite, and treatment based on approaches used in either HUS or TTP, is unsubstantiated [6]. TPE has been used for the treatment of D-AKI due to snakebite-associated TMA, with little supporting evidence [8][9][10]20].…”

“…Similarly, the role of antivenom in the prevention of TMA or AKI in TMA is uncertain. Whilst antivenom is the standard of care in snake envenoming, there is no clear evidence supporting its efficacy in VICC [21], nor TMA specifically [6].…”