Increased Binding of von Willebrand Factor to Sub-Endothelial Collagen May Facilitate Thrombotic Events Complicating Bothrops lanceolatus Envenomation in Humans

Abstract

Consumption coagulopathy and hemorrhagic syndrome exacerbated by blood anticoagulability remain the most important causes of lethality associated with Bothrops snake envenomation. Bothrops venom also engages platelet aggregation on the injured endothelium via von Willebrand factor (vWF) interactions. Besides platelet aggregation, some Bothrops venom toxins may induce qualitative thrombopathy, which has been in part related to the inhibition of vWF activation. We tested whether B. lanceolatus venom impaired vWF to collagen(s) binding (vWF:CB) activity. Experiments were performed with B. lanceolatus crude venom, in the presence or absence of Bothrofav, a monospecific B. lanceolatus antivenom. Venom of B. lanceolatus fully inhibited vWF to collagen type I and III binding, suggesting venom interactions with the vWF A3 domain. In contrast, B. lanceolatus venom increased vWF to collagen type VI binding, suggesting the enhancement of vWF binding to collagen at the vWF A1 domain. Hence, B. lanceolatus venom exhibited contrasting in vitro effects in terms of the adhesive properties of vWF to collagen. On the other hand, the antivenom Bothrofav reversed the inhibitory effects of B. lanceolatus venom on vWF collagen binding activity. In light of the respective distribution of collagen type III and collagen type VI in perivascular connective tissue and the sub-endothelium, a putative association between an increase in vWF:CB activity for collagen type VI and the onset of thrombotic events in human B. lanceolatus envenomation might be considered.

A murine experimental model of the unique pulmonary thrombotic effect induced by the venom of the snakeBothrops lanceolatus

“…The proinflammatory effect of B. lanceolatus venom, reflected by its ability to activate the complement system and generate a variety of mediators, has been proposed as a possible mechanism of the thrombotic effect [16][17][18]. Alternative mechanisms of thrombosis might be related to the action of venom on von Willebrand factor, promoting its binding to type VI collagen in the subendothelial surface [15] or to platelet activation, perhaps associated with the thrombocytopenia observed in clinical cases in in our experimental conditions. Our observations concur with clinical laboratory findings in that this venom induces thrombocytopenia, which might be a consequence of the action of a C-type lectin-like component, similar to the one characterized from the closely related venom of B. caribbaeus [42].…”

“…It has been proposed that venom-induced alterations in the endothelium might be involved [12,13,14]. Other proposed mechanisms include platelet activation, the effect of venom on the binding of von Willebrand factor to type VI collagen in the subendothelium [15], and the proinflammatory activity of the venom [16][17][18]. Proteomic analysis of adult specimens of B. lanceolatus venom have revealed a pattern characteristic of viperid snake venoms, with predominance of P-III and P-I metalloproteinases (SVMPs), serine proteinases (SVSPs), phospholipases A 2 (PLA 2 s) and, to a lower extent, L-amino acid oxidases and C-type lectin like proteins (SNACLECs), disintegrins, and cysteine-rich secretory proteins (CRISPs) [14,19].…”

Plasma von Willebrand factor levels in patients with cancer: A meta‑analysis

“…Once in the bloodstream, the primary function of VWF is to facilitate hemostasis. This is primarily accomplished by its strong interaction with platelet receptor glycoprotein Ib (GPIb) and various constituents of the subendothelial connective tissue ( 8 , 9 ). Furthermore, VWF binds to another clotting protein, factor VIII, and serves as its carrier in the blood circulation ( 10 ).…”