Natural Variation in VWF and FVIII

描述(由申请人提供)：关键血浆凝血蛋白von Willebrand因子(VWF)和因子(FVIII)的水平在人类中有很大的差异。VWF和FVIII的高水平会增加血栓形成的风险，而低水平的VWF和FVIII会导致出血。VWF数量变异的广泛范围已经被很好地描述，但VWF功能变异的程度和性质以及它与FVIII的相互作用尚不清楚。我们假设VWF在数量和质量上都是可变的。有证据表明，VWF分子的自然变异影响了VWF在循环中的存活和/或可能改变了与其两个关键配体--血小板和FVIII的相互作用的性质。我们建议通过测量与VWF的主要止血功能相关的属性来研究来自通用淋巴细胞和血浆库(GLPR)的500名受试者样本中VWF的自然变异。我们将评估与VWF存活率、VWF与血小板结合、VWF多聚体结构以及VWF与FVIII的相互作用相关的参数。已知的VWF修饰物ABO血型和性别将在分析中进行评估和考虑。我们将检验一个新的假设，即FVIII/VWF比率通常是可变的，并对H血型抗原系统对VWF分子特征的影响进行新的研究。这项研究的结果将为VWF和FVIII的生物学提供新的见解，并可能导致新的预后凝血生物标志物的开发，用于未来的临床试验研究。此外，这项工作可以为出血和凝血障碍的治疗药物的设计或优化提供基础。

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.