Segers Olivier, Castoldi Elisabetta
Department of Biochemistry, Maastricht University, Maastricht, The Netherlands.
Adv Clin Chem. 2009;49:121-57. doi: 10.1016/s0065-2423(09)49006-1.
Activated protein C (APC) proteolytically inactivates factors Va (FVa) and VIIIa (FVIIIa), which in turn control two key steps of the coagulation cascade. The pathophysiological importance of this anticoagulant mechanism is illustrated by the severe prothrombotic diathesis associated with the congenital deficiencies of protein C and its cofactor protein S. A poor anticoagulant response of plasma to APC (APC resistance) was first described in a thrombotic patient in 1993 and soon recognized as the most common risk factor for venous thrombosis. The underlying genetic defect was identified one year later as the FV Arg506Gln mutation (FV Leiden), which abolishes one of the APC-cleavage sites on FVa. These ground-breaking discoveries have stimulated numerous researches into the workings of the protein C pathway, the molecular mechanisms of APC resistance in carriers and noncarriers of FV Leiden, and the clinical significance of APC resistance. This chapter reviews the most important findings, summarizes the state of the art, and discusses new developments in this rapidly evolving research area.
活化蛋白C（APC）可通过蛋白水解作用使因子Va（FVa）和因子VIIIa（FVIIIa）失活，而这两种因子又分别控制着凝血级联反应的两个关键步骤。蛋白C及其辅助因子蛋白S先天性缺乏所导致的严重血栓形成素质，说明了这种抗凝机制在病理生理学上的重要性。1993年，在一名血栓形成患者中首次描述了血浆对APC的抗凝反应不佳（APC抵抗），并且很快被认为是静脉血栓形成最常见的危险因素。一年后，潜在的基因缺陷被确定为FV Arg506Gln突变（FV莱顿突变），该突变消除了FVa上的一个APC切割位点。这些开创性的发现激发了众多关于蛋白C途径的作用机制、FV莱顿突变携带者和非携带者中APC抵抗的分子机制以及APC抵抗的临床意义的研究。本章回顾了最重要的研究发现，总结了当前的技术水平，并讨论了这个快速发展的研究领域的新进展。
