Bajzar L
Hamilton Civic Hospitals Research Centre and McMaster University, Hamilton, Ontario, Canada.
Arterioscler Thromb Vasc Biol. 2000 Dec;20(12):2511-8. doi: 10.1161/01.atv.20.12.2511.
Coagulation and fibrinolysis are processes that form and dissolve fibrin, respectively. These processes are exquisitely regulated and protect the organism from excessive blood loss or excessive fibrin deposition. Regulation of these cascades is accomplished by a variety of mechanisms involving cellular responses, flow, and protein-protein interactions. With respect to regulation mediated by protein-protein interaction, the coagulation cascade appears to be more complex than the fibrinolytic cascade because it has more components. Yet each cascade is regulated by initiators, cofactors, feedback reactions, and inhibitors. Coagulation is also controlled by an anticoagulant pathway composed of (minimally) thrombin, thrombomodulin, and protein C.(1) Protein C is converted by the thrombin/thrombomodulin complex to activated protein C (APC), which catalyzes the proteolytic inactivation of the essential cofactors required for thrombin formation, factors Va and VIIIa. An analogous antifibrinolytic pathway has been identified recently. This pathway provides an apparent symmetry between coagulation and fibrinolysis and is also composed of thrombin, thrombomodulin, and a zymogen that is activated to an enzyme. The enzyme proteolytically inactivates a cofactor to attenuate fibrinolysis. However, unlike APC, which is a serine protease, the antifibrinolytic enzyme is a metalloprotease that exhibits carboxypeptidase B-like activity. Within a few years of each other, 5 groups independently described a molecule that accounts for this antifibrinolytic activity. We refer to this molecule as thrombin activatable fibrinolysis inhibitor (TAFI), a name that is based on functional properties by which it was identified, assayed, and purified. (Because of the preferences of some journals "activatable" is occasionally referred to as "activable.") This review will encompass a historical account of efforts to isolate TAFI and characterize it with respect to its activation, activity, regulation, and potential function in vivo.
凝血和纤维蛋白溶解分别是形成和溶解纤维蛋白的过程。这些过程受到精确调控，可保护机体避免失血过多或纤维蛋白过度沉积。这些级联反应的调控是通过多种机制实现的，包括细胞反应、血流以及蛋白质 - 蛋白质相互作用。就蛋白质 - 蛋白质相互作用介导的调控而言，凝血级联反应似乎比纤维蛋白溶解级联反应更为复杂，因为它有更多的组分。然而，每个级联反应都由启动子、辅因子、反馈反应和抑制剂调控。凝血还受一条抗凝途径控制，该途径（至少）由凝血酶、血栓调节蛋白和蛋白C组成。（1）蛋白C被凝血酶/血栓调节蛋白复合物转化为活化蛋白C（APC），后者催化凝血酶形成所需的关键辅因子因子Va和VIIIa的蛋白水解失活。最近发现了一条类似的抗纤维蛋白溶解途径。该途径在凝血和纤维蛋白溶解之间呈现出明显的对称性，同样由凝血酶、血栓调节蛋白和一种被激活为酶的酶原组成。该酶通过蛋白水解作用使一种辅因子失活，从而减弱纤维蛋白溶解。然而，与作为丝氨酸蛋白酶的APC不同，抗纤维蛋白溶解酶是一种具有羧肽酶B样活性的金属蛋白酶。在几年时间里，5个研究小组分别独立描述了一种具有这种抗纤维蛋白溶解活性的分子。我们将这种分子称为凝血酶激活的纤维蛋白溶解抑制剂（TAFI），这个名称是基于其被鉴定、检测和纯化所依据的功能特性而来。（由于一些期刊的偏好，“activatable”偶尔也被称为“activable”。）本综述将涵盖分离TAFI以及对其激活、活性、调控和体内潜在功能进行表征的研究历程。
