REGULATION OF COAGULATION BY A MULTIVALENT KUNITZ-TYPE INHIBITOR
REGULATION OF COAGULATION BY A MULTIVALENT KUNITZ-TYPE INHIBITOR
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DOI：
10.1021/bi00485a001
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发表时间：
1990-08-21
期刊：
影响因子：
2.9
通讯作者：
NOVOTNY, WF
中科院分区：
文献类型：
--
作者：
BROZE, GJ;GIRARD, TJ;NOVOTNY, WF
^ 血液凝固通过一系列反应进行，其中丝氨酸酶的血浆酶原通过有限的蛋白水解裂解依次激活。从机制上讲，凝血的启动分为“外在”和“内在”两条途径，它们在 X 因子激活时汇聚，随后通过单一“共同”途径生成凝血酶（MacFarlane，1964 年；Davie 和 Ratnoff，1964 年）（图 1）。在外源途径中，VIIa因子与其辅因子组织因子(TF)结合，可直接激活X因子。在内源途径中，接触因子（因子 XII、前激肽释放酶和高分子量激肽原）暴露于带负电的表面会导致因子 XI 的激活，随后因子 IX 的激活。活化的因子 IX 在其辅助因子因子 VIII 存在的情况下，然后将因子 X 裂解为因子 Xa。由于个体缺乏其中一种接触因子的人不会出血，因此外源性或 TF 介导的途径很可能提供了体内生理凝血的触发因素。尽管因子 VII 和 TF 可能负责凝血的启动，但很明显，仅由因子 VIIa/TF 催化复合物产生因子 Xa 不足以实现最终止血，因为缺乏因子 IX 或因子 VIII 的血友病患者患有严重的出血素质。体内对通过因子 VIII 和 IXa 的作用产生的额外因子 Xa 的需求可以通过产生 VIIa/TF 复合物的反馈抑制的新型抑制剂来解释。这种抑制剂最近被称为外源性途径抑制剂 (EPI) (Rao & Rapaport, 1987) 或脂蛋白相关凝血抑制剂 (LACI) (Broze 等人, 1987a)。之前已经发表了对该主题的精彩评论（Rapaport，1989）。
^ Jlood coagulation proceeds through a series of reactions in which plasma zymogens of serine enzymes are sequentially activated by limited proteolytic cleavage. Mechanistically, the initiation of coagulation has been separated into two pathways,“extrinsic” and “intrinsic”, that converge at the activation of factor X with subsequent generation of thrombin proceeding through a single,“common”, pathway (MacFarlane, 1964; Davie & Ratnoff, 1964)(Figure 1). In the extrinsic pathway, factor VIIa boundto its cofactor, tissue factor (TF), can ac-tivate factor X directly. In the intrinsic pathway, exposure of the contact factors (factor XII, prekallikrein, and high molecular weight kininogen) to a negatively charged surface leads to the activation of factor XI with subsequent activation of factor IX. Activated factor IX, in the presence of its co-factor factor VIII, then cleaves factor X to factor Xa. Since people individually deficient in one of the contact factors do not bleed, it appears most likely that the extrinsic, or TF-mediated, pathway provides the trigger for physiologic coagulation in vivo. Whereas factor VII and TF may be responsible for the initiation of coagulation, however, it is clear that the generation of factor Xa by the factor VIIa/TF catalytic complex alone is not sufficient forultimate hemostasis since hemophiliacs, who lack either factor IX or factor VIII, suffer a severe hemorrhagic diathesis. The in vivo requirement for additional factor Xa produced through the action of factors VIII and IXa may be explained by a novel inhibitor that produces feedback inhibition of the VIIa/TF complex. This inhibitor has most recently been called extrinsic pathway in-hibitor (EPI)(Rao & Rapaport, 1987) or lipoprotein-asso-ciated coagulation inhibitor (LACI)(Broze et al., 1987a). An excellent review of the subject has been published previously (Rapaport, 1989).