Thrombin-mediated activation of Factor XI results in a thrombin-activatable fibrinolysis inhibitor-dependent inhibition of fibrinolysis

被引:184
作者
VondemBorne, PAK
Bajzar, L
Meijers, JCM
Nesheim, ME
Bouma, BN
机构
[1] UNIV UTRECHT HOSP,DEPT HAEMATOL,NL-3508 GA UTRECHT,NETHERLANDS
[2] UNIV VERMONT,DEPT BIOCHEM,BURLINGTON,VT 05405
[3] QUEENS UNIV,DEPT BIOCHEM,KINGSTON,ON K7L 3N6,CANADA
[4] QUEENS UNIV,DEPT MED,KINGSTON,ON K7L 3N6,CANADA
关键词
coagulation; fibrinolysis; Factor XI; thrombin; carboxypeptidase; COAGULATION FACTOR-XI; BLOOD-COAGULATION; PROTEIN-C; PLASMINOGEN-ACTIVATOR; CLOT LYSIS; PLASMA; CARBOXYPEPTIDASE; PURIFICATION; GENERATION; SYSTEM;
D O I
10.1172/JCI119412
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Recently, it has been shown that Factor XI can be activated by thrombin, and that Factor XIa significantly contributes to the generation of thrombin via the intrinsic pathway after the clot has been formed. This additional thrombin, generated inside the clot, was found to protect the clot from fibrinolysis. A plausible mechanism for this inhibitory effect of thrombin involves TAFI (thrombin-activatable fibrinolysis inhibitor, procarboxypeptidase B) which, upon activation, may inhibit fibrinolysis by removing carboxy-terminal lysines from fibrin. We studied the role of Factor XI and TAFI in fibrinolysis using a clot lysis assay. The lysis time was decreased two-fold when TAFI was absent, when TAFI activation was inhibited by anti-TAFI antibodies, or when activated TAFI was inhibited by the competitive inhibitor (2-guanidinoethylmercapto)succinic acid. Inhibition of either TAFI activation or Factor XIa exhibited equivalent profibrinolytic effects. In the absence of TAFI, no additional effect of anti-Factor XI was observed on the rate of clot lysis. We conclude that the mechanism of Factor XI-dependent inhibition of fibrinolysis is through the generation of thrombin via the intrinsic pathway, and is dependent upon TAFI. This pathway may play a role in determining the fate of in vivo formed clots.
引用
收藏
页码:2323 / 2327
页数:5
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