Bleeding and Thrombosis: Insights into Pathophysiology of Bothrops Venom-Related Hemostasis Disorders

Abstract

Toxins from Bothrops venoms targeting hemostasis are responsible for a broad range of clinical and biological syndromes including local and systemic bleeding, incoagulability, thrombotic microangiopathy and macrothrombosis. Beyond hemostais disorders, toxins are also involved in the pathogenesis of edema and in most complications such as hypovolemia, cardiovascular collapse, acute kidney injury, myonecrosis, compartmental syndrome and superinfection. These toxins can be classified as enzymatic proteins (snake venom metalloproteinases, snake venom serine proteases, phospholipases A2 and L-amino acid oxidases) and non-enzymatic proteins (desintegrins and C-type lectin proteins). Bleeding is due to a multifocal toxicity targeting vessels, platelets and coagulation factors. Vessel damage due to the degradation of basement membrane and the subsequent disruption of endothelial cell integrity under hydrostatic pressure and tangential shear stress is primarily responsible for bleeding. Hemorrhage is promoted by thrombocytopenia, platelet hypoaggregation, consumption coagulopathy and fibrin(ogen)olysis. Onset of thrombotic microangiopathy is probably due to the switch of endothelium to a prothrombotic phenotype with overexpression of tissue factor and other pro-aggregating biomarkers in association with activation of platelets and coagulation. Thrombosis involving large-caliber vessels in B. lanceolatus envenomation remains a unique entity, which exact pathophysiology remains poorly understood.

Clinical and Evolutionary Implications of Dynamic Coagulotoxicity Divergences in Bothrops (Lancehead Pit Viper) Venoms

“…However, while the prey capture role is unresolved, the direct action upon fibrinogen is of relevance to human envenomations, as bite victims survive long enough for fibrinogen depletion to become a significant variable, and thereby contribute to consumptive coagulopathy [ 24 , 52 ]. Other activities of clinical significance have been documented in Bothrops venoms, including direct actions upon platelets, and vessel damage [ 53 ].…”

Plant-Derived Toxin Inhibitors as Potential Candidates to Complement Antivenom Treatment in Snakebite Envenomations

“…In addition to the protease domain and other domains such as disintegrin-like and lectin-like domains, they are also responsible for the action on platelets. The effect of the series of actions on hemostasis is characterized by the installation of consumption coagulopathy responsible for local and systemic bleeding ( 42 , 43 ). Toxins are responsible for the direct stimulation of leukocytes, acting as VAMPs (venom associated molecular patterns), and acting on inflammatory components of the complement system, in addition to indirect action via the production of DAMPs (damage-associate molecular patterns) through proteolytic action on cellular and extracellular components ( 44 , 45 ).…”

Cerebral Complications of Snakebite Envenoming: Case Studies

“…Snaclecs are mainly expressed in the venoms of vipers and colubrids [ 73 , 74 ]. Regarding the vipers reported in this review, snaclecs were identified in Bothrops [ 75 , 76 ], Daboia [ 77 ], Crotalus [ 78 ], and Trimeresurus [ 71 ]. In addition, procoagulant proteases, one type of snake-venom serine proteases (SVSPs), were reported to be involved in affecting blood coagulation [ 79 , 80 ].…”

“…SVMPs are zinc-dependent enzymes belonging to the metzincin family [ 85 ] that are mainly expressed in Viperinae and Crotalinae [ 6 ]. Based on the size and domain structure, three known SVMPs are identified in P-I (20–30 kDa), P-II (30–60 kDa) and P-III (60–100 kDa) classes [ 7 , 75 ]. In some vipers, SVMPs and anticoagulant toxins exist in their venoms [ 75 ].…”

“…Based on the size and domain structure, three known SVMPs are identified in P-I (20–30 kDa), P-II (30–60 kDa) and P-III (60–100 kDa) classes [ 7 , 75 ]. In some vipers, SVMPs and anticoagulant toxins exist in their venoms [ 75 ]. Once bitten by those vipers, patients are likely to suffer from a severe cerebral hemorrhage ( Figure 1 B) due to vascular endothelium damage and coagulation disorder.…”