Prinomastat

While scorpion venoms are well-characterised as being potently neurotoxic, their effects upon blood coagulation are understudied. Here, we report novel procoagulant toxicological functions for Androctonus amoreuxi, A. australis, A. bicolor and A. crassicauda venoms. Factor activation tests with A. amoreuxi venom revealed cofactor-dependent activation of Factor VII (FVII) and Factor X (FX) to be the primary zymogen targets, with FX the more potently activated. Activation of both factors was demonstrated to be dependent upon the proteinaceous cofactor Factor Va (FVa) and the biochemical cofactors calcium and phospholipid. It was also shown that venom was able to convert Factor V (FV) into a form of FVa that was equipotent to endogenous FVa, suggestive of the venom cleaving FV at the same activation site as thrombin. Intriguingly, low level FXII activation only proceeded with the venom-activated form of FVa and was not reliant upon calcium or phospholipid. Antivenom produced with Androctonus species included in the immunising mixture failed to neutralise procoagulation. However, neutralisation of procoagulant activities was achieved by the metalloprotease inhibiting drugs marimastat and prinomastat, thereby not only revealing the enzyme type responsible for the effects upon blood coagulation, but also suggesting therapeutic options. These results indicate that venom-induced coagulopathy resulting from scorpion envenomation may require greater consideration in pathophysiological profiling of envenomed patients. The implications extend beyond the field of toxinology, building a foundation for evolutionary studies into the selection pressures that have resulted in some species having potent effects upon blood biochemistry, whether as a weapon for predation or defence.