Coagulation-dependent inhibition of fibrinolysis: Role of carboxypeptidase-U and the premature lysis of clots from hemophilic plasma
Coagulation-dependent inhibition of fibrinolysis: Role of carboxypeptidase-U and the premature lysis of clots from hemophilic plasma
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DOI：
10.1182/blood.v88.10.3815.bloodjournal88103815
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发表时间：
1996-11-15
期刊：
影响因子：
20.3
通讯作者：
Higuchi, DA
中科院分区：
文献类型：
--
作者：
Broze, GJ;Higuchi, DA
凝血是由因子VIIa与组织因子结合引发的，结果是有限的因子IX和X活化和凝血酶产生。由于组织因子途径抑制剂（TFPI）对因子VIIa/组织因子复合物的反馈抑制，额外的因子X活化和凝血酶产生必须通过涉及因子VIII、IX和XI的途径进行。旨在阐明正常止血中放大因子Xa和凝血酶生成的要求的实验表明，血浆凝块对组织纤溶酶原激活物（tPA）和尿激酶诱导的纤维蛋白溶解的抵抗力与凝血酶生成的程度有关。纤维蛋白溶解的抑制部分由血浆羧肽酶-U（[CPU]羧肽酶-R，羧肽酶原-B，凝血酶可激活的纤维蛋白溶解抑制剂）介导，这是一种酶原，在辅因子血栓调节蛋白显著增强的过程中被凝血酶蛋白水解激活。在存在尿激酶（100 U/mL）的情况下，在具有有限量组织因子的因子IX缺乏血浆中诱导的凝块过早溶解，并且该缺陷通过补充因子IX（5 μ g/mL）或血栓调节蛋白（20 ng/mL）来校正。这些添加物提高了CPU活化的速率和程度：在因子IX的情况下，可能是通过允许因子Xa和凝血酶的扩增产生，而在血栓调节蛋白的情况下，可能是通过增加在因子IX不存在的情况下产生的低水平凝血酶产生的CPU活化程度。用特异性抗CPU抗体预处理IX因子缺乏的血浆可防止对添加IX因子和血栓调节蛋白产生的纤维蛋白溶解的抵抗增加。同样，当凝血酶（2 U/mL）在tPA（60 U/mL）存在下诱导凝血时，由因子VIII、IX、X或XI缺陷的血浆形成的凝块过早溶解，除非替换缺失的因子或添加血栓调节蛋白（20 ng/mL）。(C)1996年，美国血液学会。
Coagulation is initiated by the binding of factor VIIa to tissue factor, with resultant limited factor IX and X activation and thrombin production. Owing to the feedback inhibition of the factor VIIa/tissue factor complex by tissue factor pathway inhibitor (TFPI), additional factor X activation and thrombin generation must proceed through a pathway involving factors VIII, IX, and XI. Experiments designed to elucidate the requirement for amplified factor Xa and thrombin generation in normal hemostasis show that the resistance of plasma clots to tissue plasminogen activator (tPA)- and urokinase-induced fibrinolysis is related to the extent of thrombin generation. Inhibition of fibrinolysis is mediated in part by plasma carboxypeptidase-U ([CPU] carboxypeptidase-R, procarboxypeptidase-B, thrombin-activatable fibrinolysis inhibitor), a proenzyme that is proteolytically activated by thrombin in a process enhanced dramatically by the cofactor thrombomodulin. A clot induced in factor IX-deficient plasma with limited amounts of tissue factor in the presence of urokinase (100 U/mL) lyses prematurely, and this defect is corrected by supplementation of the deficient plasma with factor IX (5 mu g/mL) or thrombomodulin (20 ng/mL). These additions enhance the rate and extent of CPU activation: in the case of factor IX, presumably by permitting amplified generation of factor Xa and thrombin, and in the case of thrombomodulin, presumably by increasing the degree of CPU activation produced by the low levels of thrombin generated in the absence of factor IX. Pretreatment of the factor IX-deficient plasma with specific anti-CPU antibodies prevents the increased resistance to fibrinolysis produced by addition of factor IX and thrombomodulin. Likewise, when coagulation is induced by thrombin (2 U/mL) in the presence of tPA (60 U/mL), clots formed from plasmas deficient in factors VIII, IX, X, or XI lyse prematurely unless the missing factor is replaced or thrombomodulin (20 ng/mL) is added. (C) 1996 by The American Society of Hematology.