Bothrops jararaca snake venom: A reappraisal of its coagulant activity in humans, mice, and rats

BACKGROUND: Bothrops jararaca snake venom (BjV) contains toxins that both activate and inhibit blood coagulation and platelets, leading to consumption coagulopathy, thrombocytopenia, endothelial dysfunction, and secondary fibrinolysis in human and animal victims of snakebite. Herein, we aimed to investigate the in vitro coagulant activity of BjV in human, mouse, and rat plasmas. METHODOLOGY/PRINCIPAL FINDINGS: The coagulant activity of BjV was evaluated using normal human plasma and plasmas deficient in coagulation factors II, V, VII, VIII, IX, or X; in mice, normal plasma as well as plasma from F8-/-, F9-/-, Vwf-/-, and pearl (Ap3b1-/-) strains were analyzed, in addition to normal plasma from Wistar rats. The contributions of calcium ions, phospholipids, and blood cells to BjV-induced coagulant activity were assessed. Pharmacological inhibitors were used to investigate the generation of factor Xa and/or thrombin, and their roles in the coagulant activity of BjV. Statistical analyses were performed to compare minimum coagulant dose (MCD) values and their corresponding clotting curves. Human and rat plasmas showed greater sensitivity to the coagulant activity of BjV than mouse plasmas. Calcium ions and phospholipids significantly enhanced the coagulant activity of BjV. Remarkably, both red blood cells and platelets in whole blood markedly potentiated the coagulant activity of BjV. Pre-incubation of plasma samples with rivaroxaban and/or dabigatran demonstrated that the coagulant activity of BjV in rat plasmas primarily depended on prothrombin activation, whereas in human and mouse plasmas it involved both thrombin-like enzymes and prothrombin activators. CONCLUSIONS/SIGNIFICANCE: This study reveals key differences in the coagulant activity of BjV in human and rodent plasmas, underscoring the need to considering these interspecies disparities when using animal models in comparative envenomation research.