Studies of the variable expressivity of the factor V Leiden mutation

因子V Leiden突变(FVL)是高加索人群中最常见的亲血栓危险因素。我们的团队最近发现，使用重组激活因子VII(RFVIIa)刺激体内凝血酶形成，导致FVL携带者的激活蛋白C(APC)浓度显著高于非FVL携带者。此外，有血栓病史的FVL携带者和无血栓病史的FVL携带者的APC反应有显著差异。这项研究项目的目的是找出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，这些数据将直接与已有的体内数据进行比较，以确定APC系统的反应性的个体间差异。不同的APC反应表型的因果特征将为开发生物标记物来评估FVL的血栓形成潜力提供基础，这将显著改善FVL患者的治疗。

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.