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

Snakebite causes a variety of clinical sequelae. Local symptoms and signs include local bite site pain, swelling, and tender regional lymphadenopathy. Non-specific systemic symptoms include nausea, vomiting, headache, diaphoresis, abdominal pain, and diarrhoea. Systemic envenoming can cause major toxin syndromes, including neurotoxicity, myotoxicity, and coagulopathy. Different snake species are associated with characteristic patterns of these toxicities. These differences are conferred by their variable venom composition of non-enzymatic and enzymatic toxins [1], including cytotoxins, myotoxins, neurotoxins, and haemotoxins. Haemotoxins are associated with viper and Australian elapid envenomings, and with cardiovascular and haemostatic effects, including hypotension, cardiovascular collapse, coagulopathy, and bleeding [2].

The most common haemotoxin-mediated coagulopathy caused by snake envenoming is a venom-induced consumption coagulopathy (VICC), characterised by prolonged clotting times, hypofibrinogenaemia, and a raised d-dimer [2‐5]. VICC resolves at a rate consistent with synthesis of new clotting factors, after the toxins are neutralised. Its main complication is bleeding [5]. VICC is distinct from disseminated intravascular coagulopathy (DIC) [3]. Whilst VICC meets the definitions of commonly used diagnostic scoring systems for DIC, the differing pathophysiology, outcomes, and prognosis of VICC compared to DIC clearly differentiate it [3, 6, 7]. A small subset of snakebite patients with VICC develop a thrombotic microangiopathy (TMA) [3, 8‐17]. The reported cases of snakebite-associated TMA present with a delayed phase thrombocytopenia and a haemolysis in keeping with microangiopathic haemolytic anaemia (MAHA) [11]. There appears to be a predilection for renal end organ injury [3, 11]. The long-term outcomes and best treatment of snakebite-associated TMA are unclear, with most published studies being isolated case reports, small case series, or other small retrospective observational studies.

The TMA syndromes are a group of disorders with the unifying pathognomonic hallmark of vascular small vessel wall damage with microthrombosis [18‐20]. There is a resultant MAHA with mechanical red cell fragmentation which manifests as haemolysis with circulating red cell fragments (schistocytes) on examination of the blood film [18, 21]. Thrombocytopenia together with MAHA is sufficient for the diagnosis, and tissue biopsy for confirmation by the finding of TMA is only occasionally performed [18, 20]. Corroborating other signs of haemolysis include the presence of anaemia, a raised lactate dehydrogenase (LDH), unconjugated hyperbilirubinaemia, and lowered haptoglobin [20]. However, these are markers of haemolysis of any cause and are not specific to MAHA. The main complication of TMA is vaso-occlusive end organ injury [18]. This may be multi-organ in nature (commonly seen for example with DIC), or for certain forms of TMA, it may be more organ-specific: neurological for thrombotic thrombocytopenic purpura (TTP) [18, 21] and renal for haemolytic uraemic syndrome (HUS) [18, 20]. The aetiologies of TMA disorders differ. DIC is caused by complex mechanisms which culminate in generalised microvascular fibrin deposition due to thrombin generation triggered by a tissue factor stimulus in the intravascular space [6]. TTP is mediated by either a hereditary- or an autoimmune antibody-mediated deficiency of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS-13) [19]. Most cases of HUS are caused by Shiga toxin producing or enterohaemorrhagic Escherichia coli (typical HUS), or acquired or hereditary dysregulation of the alternative complement pathway in atypical HUS (aHUS) [20]. The TMAs are heterogeneous not only in both their clinical presentation and aetiology, but also in their best treatments and long-term outcomes.

Snakebite-associated TMA has been variably compared to both TTP and aHUS [11, 13, 22]. Plasmapheresis has a clearly established role in dramatically preventing mortality in TTP [11, 19, 21, 23]. Some published cases of snakebite-associated TMA with acute kidney injury (AKI) have reported successful treatment with plasmapheresis, with normalisation of renal function [11, 13]. Other published cases of snakebite-associated TMA with AKI report that the renal end organ damage resolves with renal replacement therapy alone [11]. Any association with respect to the pathophysiology or long-term outcomes of snakebite TMA with either aHUS or TTP is not established [3, 11]. The potential role of plasmapheresis in the treatment of snake TMA treatment is also unknown.

Interpretation of the published literature on snakebite TMA and VICC more broadly is complicated by historical differences and inconsistencies in nomenclature. Many studies use a variety of terms, often not overtly defined, including DIC, defibrination, and intravascular haemolysis [3, 5, 9, 12, 24, 25]. VICC is commonly but erroneously reported as DIC, and there is a lack of consistency in the case definition for snakebite-associated TMA. Various and often ill-defined haematological abnormalities together with AKI are also commonly reported in the setting of snakebite [26]. Complicating this further, AKI in snakebite is common and has a number of other possible causes including direct venom toxicity, shock, and myotoxicity with secondary rhabdomyolysis [9, 12, 27]. This leads to difficulties in establishing which cases are true TMA versus the more typical VICC of snake envenoming, and which represent other causes of snakebite with AKI and coincidental haematological findings. These challenges make the incidence, features, natural history, outcomes, and best treatment strategy for snakebite TMA difficult to elucidate.

The objective of this systematic review is to synthesise the features, outcomes, and evidence of any role for intervention with plasmapheresis, for snakebite-associated thrombotic microangiopathy, using a predetermined case definition. We hope to inform best practice via a descriptive synthesis of its features, outcomes, and any evidence for or against current reported approaches to its management.

Snakebite-associated TMA is a rare and poorly understood phenomenon. Existing literature consists of small observational studies with little to guide an understanding of its natural history, outcomes, and treatment. This is complicated by published studies which use varied and sometimes non-defined descriptors for both the coagulopathy and thrombotic microangiopathy of snake envenomation. Published cases have been likened to either aHUS or TTP. Plasmapheresis has been used in some studies with perceived benefit. Other studies report that the renal end organ damage is self-limiting.

This systematic review will provide the first descriptive synthesis of the international experience of snakebite-associated TMA. We will use a predefined case definition of snakebite-associated TMA, which will help inform an understanding of the clinical features and typical outcomes of this uncommon phenomenon. The most likely limitation to this systematic review will be the quality of included studies, which will likely be predominantly small observational studies.

We aim for this systematic review to help guide best intervention strategies including elucidating any role for plasmapheresis, which, whilst having a clear role in the prevention of mortality and morbidity in some types of TMA, is a resource-intense intervention which also carries some adverse risk.