INSIGHTS INTO THE MECHANISM OF HEMORRHAGE CAUSED BY SNAKE-VENOM METALLOPROTEINASES

Local and systemic haemorrhage are common consequences of crotaline an d viperine envenoming. Several studies carried out using purified toxi ns have indicated that local haemorrhage can be attributed to a distin ct class of venom metalloproteinases. Analyses of their cDNAs pr-edict multi-domain enzymes, with an N-terminal metalloproteinase domain, a disintegrin-like domain and a Cys-rich C-terminus. Haemorrhagic metall oproteinases are responsible for degrading proteins of the extracellul ar matrix and they also have cytotoxic effects on endothelial cells. H owever, to date very few investigations have been carried out on the e ffects of venom haemorrhagic metalloproteinases on components of the h aemostatic system. We describe here the effects of a high molecular we ight haemorrhagic metalloproteinase, jararhagin, from the venom of a S outh American pit viper Bothrops jararaca, on platelet and plasma comp onents involved in haemostasis. Jararhagin, which is not inhibited in plasma, causes the loss of the platelet collagen receptor alpha(2) bet a(1), integrin (gpIa/IIa or VLA-2) and degrades the adhesive plasma pr otein von Willebrand factor. Alterations of these haemostatic componen ts are known to result in bleeding. This suggests that venom haemorrha gic metalloproteinases, in addition to causing local bleeding, may als o contribute to systemic haemorrhage. Copyright (C) 1996 Elsevier Scie nce Ltd