Natural Variation in VWF and FVIII

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DESCRIPTION (provided by applicant): Levels of the critical plasma clotting proteins von Willebrand Factor (VWF) and Factor VIII (FVIII) are widely variable in humans. High levels of VWF and FVIII confer an increased risk of thrombosis, while low levels are associated with bleeding. The wide range of quantitative variation in VWF has been well described, but the degree and nature of functional variation in VWF and its interaction with FVIII is less clear. We hypothesize that VWF is both quantitatively and qualitatively variable. There is some evidence that natural variation in the VWF molecule influences survival of VWF in circulation and/or may shift the nature of interactions with two of its key ligands, platelets and FVIII. We propose to study the natural variation of VWF in samples from 500 subjects from the General Lymphocyte and Plasma Repository (GLPR) by measuring attributes associated with the major hemostatic functions of VWF. We will evaluate parameters related to VWF survival, VWF platelet binding, VWF multimeric structure, and the interaction of VWF with FVIII. The known VWF modifiers ABO blood group and gender will be assessed and accounted for in the analysis. We will test a novel hypothesis that the FVIII/VWF ratio is normally variable, and pursue a new investigation into the influence of the blood group H antigen system on VWF molecular characteristics. The results of this study should lend new insights into the biology of VWF and FVIII, and may lead to the development of novel prognostic coagulation biomarkers for study in future clinical trials. Furthermore, this work could provide the foundation for the design or optimization of therapeutic agents in bleeding and clotting disorders.