Reduced Plasminogen Binding and Delayed Activation Render γ′-Fibrin More Resistant to Lysis than γA-Fibrin
Reduced Plasminogen Binding and Delayed Activation Render γ′-Fibrin More Resistant to Lysis than γA-Fibrin
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DOI：
10.1074/jbc.m114.588640
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发表时间：
2014-10-03
影响因子：
4.8
通讯作者：
Weitz, Jeffrey I.
中科院分区：
文献类型：
--
作者：
Kim, Paul Y.;Vu, Trang T.;Weitz, Jeffrey I.
Background: When compared with degradation of the predominant (A)-fibrin, lysis of variant -fibrin is delayed. Results: Thrombin-mediated fibrinopeptide B release is slower from -fibrinogen than from (A)-fibrinogen, resulting in delayed binding and activation of plasminogen. Conclusion: Delayed plasmin generation renders -fibrin resistant to lysis. Significance: The association between slower clotting and delayed lysis highlights the links between coagulation and fibrinolysis.Fibrin (Fn) clots formed from -fibrinogen (-Fg), a variant with an elongated -chain, are resistant to lysis when compared with clots formed from the predominant (A)-Fg, a finding previously attributed to differences in clot structure due to delayed thrombin-mediated fibrinopeptide (FP) B release or impaired cross-linking by factor XIIIa. We investigated whether slower lysis of -Fn reflects delayed plasminogen (Pg) binding and/or activation by tissue plasminogen activator (tPA), reduced plasmin-mediated proteolysis of -Fn, and/or altered cross-linking. Clots formed from -Fg lysed more slowly than those formed from (A)-Fg when lysis was initiated with tPA/Pg when FPA and FPB were both released, but not when lysis was initiated with plasmin, or when only FPA was released. Pg bound to -Fn with an association rate constant 22% lower than that to (A)-Fn, and the lag time for initiation of Pg activation by tPA was longer with -Fn than with (A)-Fn. Once initiated, however, Pg activation kinetics were similar. Factor XIIIa had similar effects on clots formed from both Fg isoforms. Therefore, slower lysis of -Fn clots reflects delayed FPB release, which results in delayed binding and activation of Pg. When clots were formed from Fg mixtures containing more than 20% -Fg, the upper limit of the normal level, the delay in lysis was magnified. These data suggest that circulating levels of -Fg modulate the susceptibility of clots to lysis by slowing Pg activation by tPA and provide another example of the intimate connections between coagulation and fibrinolysis.
