Broze G J, Higuchi D A
Division of Hematology, Jewish Hospital, Washington University Medical Center, St Louis, MO 63110, USA.
Blood. 1996 Nov 15;88(10):3815-23.
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 micrograms/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.
凝血由因子VIIa与组织因子结合启动，导致有限的因子IX和X激活以及凝血酶生成。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作用，额外的因子X激活和凝血酶生成必须通过涉及因子VIII、IX和XI的途径进行。旨在阐明正常止血中放大的因子Xa和凝血酶生成需求的实验表明，血浆凝块对组织型纤溶酶原激活剂（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、凝血酶激活的纤维蛋白溶解抑制剂）介导，这是一种前酶，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。在尿激酶（100 U/mL）存在的情况下，用有限量的组织因子在因子IX缺乏的血浆中诱导形成的凝块过早溶解，通过向缺乏的血浆中补充因子IX（5微克/毫升）或血栓调节蛋白（20纳克/毫升）可纠正此缺陷。这些添加物提高了CPU激活的速率和程度：就因子IX而言，大概是通过允许放大的因子Xa和凝血酶生成；就血栓调节蛋白而言，大概是通过增加在缺乏因子IX时产生的低水平凝血酶所产生的CPU激活程度。用特异性抗CPU抗体对因子IX缺乏的血浆进行预处理可防止因添加因子IX和血栓调节蛋白而产生的对纤维蛋白溶解抵抗力的增加。同样，当在tPA（60 U/mL）存在的情况下由凝血酶（2 U/mL）诱导凝血时，除非缺失的因子被替代或添加血栓调节蛋白（20纳克/毫升），否则由因子VIII、IX、X或XI缺乏的血浆形成的凝块会过早溶解。
