Normal hemostasis is maintained by a highly regulated complex mechanism involving plasma, platelets, and endothelial cells. von Willebrand factor represents an important regulatory protein that promotes the adhesion of platelets to the vessel wall after injury and serves as a carrier protein for plasma factor VIII. Thus, von Willebrand factor serves to regulate the initial events of platelet deposition as well as the major regulatory protein, factor VIII, of the clotting process. The synthesis and multimerization of von Willebrand factor is directed by a large propolypeptide of 741 amino acids that we initially termed as von Willebrand's antigen II (vW AgII). This grant will study how natural and other mutations of the propolypeptide result in the production of mature von Willebrand factor with abnormal structure and/or function. Site-directed mutations of vW AgII will be used to determine the role of the propolypeptide in multimerization, cellular trafficking, and storage of both von Willebrand factor and FVIII. Through these studies, we expect to increase our understanding of the cellular and molecular biology of this important regulatory protein and its role in both hemorrhagic and thrombotic disorders.
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