Bertina R M, Koeleman B P, Koster T, Rosendaal F R, Dirven R J, de Ronde H, van der Velden P A, Reitsma P H
Hemostasis and Thrombosis Research Center, University Hospital, Leiden, The Netherlands.
Nature. 1994 May 5;369(6475):64-7. doi: 10.1038/369064a0.
Activated protein C (APC) is a serine protease with potent anticoagulant properties, which is formed in blood on the endothelium from an inactive precursor. During normal haemostasis, APC limits clot formation by proteolytic inactivation of factors Va and VIIIa (ref. 2). To do this efficiently the enzyme needs a nonenzymatic cofactor, protein S (ref. 3). Recently it was found that the anticoagulant response to APC (APC resistance) was very weak in the plasma of 21% of unselected consecutive patients with thrombosis and about 50% of selected patients with a personal or family history of thrombosis; moreover, 5% of healthy individuals show APC resistance, which is associated with a sevenfold increase in the risk for deep vein thrombosis. Here we demonstrate that the phenotype of APC resistance is associated with heterozygosity or homozygosity for a single point mutation in the factor V gene (at nucleotide position 1,691, G-->A substitution) which predicts the synthesis of a factor V molecule (FV Q506, or FV Leiden) that is not properly inactivated by APC. The allelic frequency of the mutation in the Dutch population is approximately 2% and is at least tenfold higher than that of all other known genetic risk factors for thrombosis (protein C (ref. 8), protein S (ref. 9), antithrombin10 deficiency) together.
活化蛋白C（APC）是一种具有强大抗凝特性的丝氨酸蛋白酶，它由血管内皮上的一种无活性前体在血液中形成。在正常止血过程中，APC通过对因子Va和VIIIa进行蛋白水解失活来限制血栓形成（参考文献2）。为了高效地完成这一过程，该酶需要一种非酶辅因子，即蛋白S（参考文献3）。最近发现，在21%未经选择的连续性血栓形成患者以及约50%有个人或家族血栓形成病史的选定患者的血浆中，对APC的抗凝反应（APC抵抗）非常弱；此外，5%的健康个体表现出APC抵抗，这与深静脉血栓形成风险增加7倍相关。我们在此证明，APC抵抗的表型与因子V基因中的一个单点突变的杂合性或纯合性有关（核苷酸位置1691处，G→A替换），该突变预测会合成一种不能被APC正常失活的因子V分子（FV Q506，或FV Leiden）。该突变在荷兰人群中的等位基因频率约为2%，至少比所有其他已知的血栓形成遗传风险因素（蛋白C（参考文献8）、蛋白S（参考文献9）、抗凝血酶缺乏）的频率总和高10倍。
