Role of crotoxin in coagulation: novel insights into anticoagulant mechanisms and impairment of inflammation-induced coagulation

Abstract

Background: Snake venom phospholipases A 2 (svPLA 2) are biologically active toxins, capable of triggering and modulating a wide range of biological functions. Among the svPLA 2 s, crotoxin (CTX) has been in the spotlight of bioprospecting research due to its role in modulating immune response and hemostasis. In the present study, novel anticoagulant mechanisms of CTX, and the modulation of inflammation-induced coagulation were investigated. Methods: CTX anticoagulant activity was evaluated using platelet poor plasma (PPP) and whole blood (WB), and also using isolated coagulation factors and complexes. The toxin modulation of procoagulant and pro-inflammatory effects was evaluated using the expression of tissue factor (TF) and cytokines in lipopolysaccharide (LPS)-treated peripheral blood mononuclear cells (PBMC) and in WB. Results: The results showed that CTX impaired clot formation in both PPP and WB, and was responsible for the inhibition of both intrinsic (TF/factor VIIa) and extrinsic (factor IXa/factor VIIIa) tenase complexes, but not for factor Xa and thrombin alone. In addition, the PLA 2 mitigated the prothrombinase complex by modulating the coagulation phospholipid role in the complex. In regards to the inflammation-coagulation cross talk, the toxin was capable of reducing the production of the pro-inflammatory cytokines IL-1β, IL-6 and TNF-α, and was followed by decreased levels of TF and procoagulant activity from LPS-treated PBMC either isolated or in WB. Conclusion: The results obtained in the present study recognize the toxin as a novel medicinal candidate to be applied in inflammatory diseases with coagulation disorders.

Integrating pharmacokinetics and network analysis to investigate the mechanism of Moutan Cortex in blood-heat and blood stasis syndrome

“…It has been previously reported that the coagulation system and the inflammatory system interact with each other. Not only does inflammation led to the activation of coagulation, but coagulation in turn affects inflammation [ 61 ]. MAPK10 and MAPK14 are members of the MAPK family that is widely involved in the inflammatory response and platelet activation.…”

Crotalus Durissus Ruruima: Current Knowledge on Natural History, Medical Importance, and Clinical Toxinology

“…The venom is a cocktail of toxins capable of interefering with hemostatic components, leading to coagulopathy. Prolonged clotting times are associated with antagonistic behavior of toxins, which can induce anticoagulant activity, as described for crotoxin and crotamine ( 79 , 141 ), and procoagulant toxins, reported by serine proteases with thrombin-like activity, which induces the consumption of coagulation factor and hypofibrinogenemia ( 78 , 79 ). The overall activity induces blood incoagulability, an important factor in bleeding genesis.…”