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Molecular regulation of blood coagulation factor V: from snakes to humans

Final Report Summary - MOREFV (Molecular regulation of blood coagulation factor V: from snakes to humans)

The blood coagulation response is a uniquely complex process that protects organisms form significant blood loss following vascular damage. A failure of the system to respond at the appropriate time or place can result in life-threatening bleeding disorders, such as hemophilia. In addition to cellular participation, there are numerous proteins involved in the enzymatic reactions that lead to the formation of a blood clot. Most of these enzymes are large complexes consisting of a protease and a cofactor, the latter making the protease much more effective by enhancing its activity several orders of magnitude. These enzymatic complexes assemble on a negatively charged membrane surface, such as that of platelets or endothelial cells. Apart from directing these enzyme complexes to the site of injury, the precise mechanisms by which the membrane surface propagates the coagulation reactions are incomplete. Therefore, the overall goal of this proposal is to provide new information on the molecular mechanisms that regulate the assembly of enzyme-cofactor complexes driving blood coagulation. To do so, we will use a novel strategy based on a naturally occurring variant of a cofactor found in the venom of the Australian common brown snake P. textilis. Strikingly, this cofactor does not require a membrane surface for its enzymatic complex assembly.
Using this variant as a model and tool we have generated several panels of snake-human and human-snake chimeras of the blood coagulation cofactor V. In these chimeras we have introduced or removed specific regions that may play a role in the membrane-independent characteristics of snake venom V. Biochemical analysis of these variants revealed that the targeted regions do not play a role in the unique capacity of the snake venom cofactor to function in the absence of lipids. They do suggest, however, that the snake venom enzyme complex functions in a different way altogether as compared to the human enzyme complex, thereby potentially challenging the current paradigm.

In addition, these studies have led to novel questions and opened up new avenues of research that are currently being explored. A better understanding of the enzyme complexes that are essential to blood coagulation will provide ground for translational studies aimed at exploring novel therapeutics and targets to restore hemostasis in cases of a deficient (bleeding) or overactive (thrombosis) coagulation system.

Mettine H.A. Bos, Ph.D.

Assistant Professor

Leiden University Medical Center
Dept. of Thrombosis and Hemostasis
Einthoven Laboratory for Experimental Vascular Medicine Room C7-14
Albinusdreef 2
2333 ZA Leiden
The Netherlands

Ph: +31 71 526 8133