Abstract
Background/AimsBleeding tendency, coagulopathy and platelet disorders are recurrent manifestations in snakebites occurring worldwide. We reasoned that by damaging tissues and/or activating cells at the site of the bite and systemically, snake venom toxins might release or decrypt tissue factor (TF), resulting in activation of blood coagulation and aggravation of the bleeding tendency. Thus, we addressed (a) whether TF and protein disulfide isomerase (PDI), an oxireductase involved in TF encryption/decryption, were altered in experimental snake envenomation; (b) the involvement and significance of snake venom metalloproteinases (SVMP) and serine proteinases (SVSP) to hemostatic disturbances.Methods/Principal FindingsCrude Bothrops jararaca venom (BjV) was preincubated with Na2-EDTA or AEBSF, which are inhibitors of SVMP and SVSP, respectively, and injected subcutaneously or intravenously into rats to analyze the contribution of local lesion to the development of hemostatic disturbances. Samples of blood, lung and skin were collected and analyzed at 3 and 6 h. Platelet counts were markedly diminished in rats, and neither Na2-EDTA nor AEBSF could effectively abrogate this fall. However, Na2-EDTA markedly reduced plasma fibrinogen consumption and hemorrhage at the site of BjV inoculation. Na2-EDTA also abolished the marked elevation in TF levels in plasma at 3 and 6 h, by both administration routes. Moreover, increased TF activity was also noticed in lung and skin tissue samples at 6 h. However, factor VII levels did not decrease over time. PDI expression in skin was normal at 3 h, and downregulated at 6 h in all groups treated with BjV.ConclusionsSVMP induce coagulopathy, hemorrhage and increased TF levels in plasma, but neither SVMP nor SVSP are directly involved in thrombocytopenia. High levels of TF in plasma and TF decryption occur during snake envenomation, like true disseminated intravascular coagulation syndrome, and might be implicated in engendering bleeding manifestations in severely-envenomed patients.
Highlights
Snakebites, which have been considered a neglected tropical disease by the World Health Organizaton since 2009, frequently evoke hemostatic disturbances
Snake venom metalloproteinases (SVMP) induce coagulopathy, hemorrhage and increased tissue factor (TF) levels in plasma, but neither SVMP nor SVSP are directly involved in thrombocytopenia
High levels of TF in plasma and TF decryption occur during snake envenomation, like true disseminated intravascular coagulation syndrome, and might be implicated in engendering bleeding manifestations in severely-envenomed patients
Summary
Snakebites, which have been considered a neglected tropical disease by the World Health Organizaton since 2009, frequently evoke hemostatic disturbances. Thrombocytopenia, platelet dysfunction, and coagulation disorders are major laboratory findings observed in victims of Bothrops jararaca bites [2,3,4]. Snake venom metalloproteinases (SVMP) and serine proteinases (SVSP), the two main protein families found in BjV with anti-hemostatic activity [6], have been implicated in the hemostatic disorders associated with envenomation [7]. SVMP present in Bothrops venoms belong to a zincdependent enzyme family, which contributes to the inflammatory, proteolytic, hemorrhagic and procoagulant (prothrombin and factor X activators) activities in snake venoms [8,9,10]. SVSP have been reported to affect platelet aggregation, blood coagulation and fibrinolysis, and several SVSP purified from BjV show anti-hemostatic activities [11].
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