AN OVERVIEW OF THE MECHANISM OF ACTION OF ANTITHROMBIN AND ITS INHERITED DEFICIENCY STATES
AN OVERVIEW OF THE MECHANISM OF ACTION OF ANTITHROMBIN AND ITS INHERITED DEFICIENCY STATES
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DOI：
10.1097/00001721-199401000-00002
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发表时间：
1994-01-01
影响因子：
1.1
通讯作者：
BLAJCHMAN, MA
中科院分区：
文献类型：
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作者：
BLAJCHMAN, MA
抗凝血酶是各种激活的丝氨酸蛋白酶凝血因子，尤其是凝血酶的最重要的生理性抑制物。在体外，抗凝血酶对凝血酶的抑制非常缓慢，但肝素和相关的糖胺多糖大大增强了凝血酶的抑制作用。当丝氨酸蛋白酶与抗凝血酶相互作用时，这两种蛋白质形成一个共价稳定的化学计量比为1：1的复合体，该复合体很快就会从循环中移除。这种稳定的共价复合体的形成涉及精氨酸393-丝氨酸394处抑制剂的反应中心被蛋白酶的活性部位丝氨酸残基切割。紧随其后的是在酶的活性部位丝氨酸残基和被切割的抗凝血酶分子的精氨酸393残基之间形成的酯键。抗凝血酶缺乏状态的存在最早是在1965年，在一个家庭中，该家庭的一些成员患有反复发作的静脉血栓。随后，从不同的地理位置描述了许多抗凝血酶缺乏症家族。此外，据报道，普通人群中抗凝血酶缺乏症的患病率从1：500到1：5000不等。随着重组DNA技术的出现，抗凝血酶缺乏症分子病理学的定义已经允许在150多个家系中描述特定突变的特征。据报道，大约有60种不同的突变，导致抗凝血酶基因产物缺失或病理性。遗传性抗凝血酶缺乏是公认的静脉血栓易感性的原因，在带有丙氨酸382苏氨酸突变(抗凝血酶-汉密尔顿)的2型抗凝血酶缺乏的大家族中，只有不到20%的受影响个体被发现有既往血栓事件的客观证据。在大多数情况下，最初的血栓发作发生在存在易感因素时(怀孕、手术、口服避孕药、创伤等)。因此，遗传性抗凝血酶缺乏症患者血栓事件的发生率似乎明显低于迄今估计的水平；此外，此类事件的发生似乎主要与易感因素有关。对遗传性抗凝血酶缺乏症患者的研究可以为治疗获得性抗凝血酶缺乏症患者提供有用的信息。
Antithrombin is the most important physiological inhibitor of the various activated serine protease clotting factors, particularly thrombin. In vitro, the inhibition of thrombin by antithrombin is very slow; but greatly enhanced by heparin and related glycosaminoglycans. When a serine protease interacts with antithrombin, the two proteins form a covalent stable stoichiometric 1:1 complex that is rapidly removed from the circulation. The formation of this stable covalent complex involves the cleavage of the reactive centre of the inhibitor at arginine 393-serine 394 by the active site serine residue of the protease. This is followed by the formation of an ester linkage between the active site serine residue of the protease and the arginine 393 residue of the cleaved antithrombin molecule. The existence of an antithrombin deficiency state was first recognized in 1965, in a family some of whose members suffered from recurrent episodes of venous thrombosis. Subsequently, many kindreds with antithrombin deficiency have been described from diverse geographic locations. Moreover, the prevalence of antithrombin deficiency in the general population has been reported to vary from 1:500 to 1:5000. With the advent of recombinant DNA techniques, the definition of the molecular pathology of antithrombin deficiency has allowed the characterization of the specific mutation in more than 150 kindreds. Approximately 60 different mutations, resulting in either an absent or a pathological antithrombin gene product, have been reported. Inherited antithrombin deficiency is a well-recognized cause of predisposition to venous thrombosis and in a large type 2 antithrombin-deficient kindred with an alanine 382 threonine mutation (antithrombin-Hamilton), less than 20% of affected individuals were found to have objective evidence for past thrombotic events. In most of these, the initial thrombotic episode occurred when a predisposing factor was present (pregnancy, surgery, oral contraception, trauma, etc.). The incidence of thrombotic events in subjects with inherited antithrombin deficiency thus appears to be significantly lower than heretofore estimated; moreover, such events appear to occur predominantly in association with predisposing factors. Insights from studies of patients with inherited antithrombin deficiency could provide useful information in the management of those with acquired antithrombin deficiency.