Studies of the variable expressivity of the factor V Leiden mutation

V因子Leiden突变的可变表达性研究

• 批准号: 419450023
• 负责人: Professor Dr. Bernd Pötzsch
• 金额: --
• 依托单位: Institut für Experimentelle Hämatologie und Transfusionsmedizin (IHT)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2023-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/419450023?language=en
• 关键词: Studies; variable; expressivity; factor; Leiden

The factor V Leiden mutation (FVL) is the most common thrombophilic risk factor in the Caucasian population. Our group has recently shown that stimulation of thrombin formation in vivo, using recombinant activated factor VII (rFVIIa), resulted in significantly higher plasma concentrations of activated protein C (APC) in FVL carriers than in non-FVL carriers. Furthermore, there was a significant difference between the APC response of FVL carriers with a history of thrombosis and those without. The aim of this research project is to identify the underlying causes of these observed differences. In order to achieve this objective, we will systematically analyze various mechanisms, that regulate APC formation, including the thrombin formation capacity, the endothelial APC generation potential of the endothelium, and APC inhibition kinetics. Using both the patients’ plasma and cells, data will be obtained in the purified system and in the cell culture model, that will be directly compared with already available in vivo data to identify inter-individual differences in the reactivity of the APC system. Causal characterization of the different APC response phenotypes would provide a basis to develop biomarkers for the assessment of the thrombophilic potential of FVL, which would substantially improve treatment of FVL patients.

凝血因子V Leiden突变（FVL）是高加索人群中最常见的血栓形成危险因素。我们的小组最近表明，在体内凝血酶形成的刺激，使用重组活化因子VII（rFVIIa），导致FVL载体中的活化蛋白C（APC）的血浆浓度显着高于非FVL载体。此外，有血栓形成史的FVL携带者与无血栓形成史的FVL携带者之间的APC反应存在显著差异。本研究项目的目的是确定这些观察到的差异的根本原因。为了实现这一目标，我们将系统地分析调节APC形成的各种机制，包括凝血酶形成能力、内皮细胞的内皮APC生成潜力和APC抑制动力学。使用患者的血浆和细胞，将在纯化系统和细胞培养模型中获得数据，将其与已经获得的体内数据直接比较，以鉴定APC系统反应性的个体间差异。不同APC反应表型的因果表征将为开发用于评估FVL的血栓形成潜力的生物标志物提供基础，这将大大改善FVL患者的治疗。