Activated thrombin-activatable fibrinolysis inhibitor (TAFIa) attenuates fibrin-dependent plasmin generation on thrombin-activated platelets.
Activated thrombin-activatable fibrinolysis inhibitor (TAFIa) attenuates fibrin-dependent plasmin generation on thrombin-activated platelets.
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DOI：
10.1111/jth.14950
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发表时间：
2020-09
期刊：
影响因子：
--
通讯作者：
Kim PY
中科院分区：
文献类型：
--
作者：
Ni R;Neves MAD;Wu C;Cerroni SE;Flick MJ;Ni H;Weitz JI;Gross PL;Kim PY
Thrombin-activated platelets can promote fibrinolysis by binding plasminogen in a fibrinogen-dependent manner and enhancing its activation by tissue-type plasminogen activator (t-PA). Whether t-PA also binds to activated platelets and the mechanism for regulation of platelet-dependent fibrinolysis remain unknown. Determine the mechanism of plasminogen and t-PA binding on thrombin-activated platelets and its regulation by activated thrombin-activatable fibrinolysis inhibitor (TAFIa). Plasminogen and t-PA binding with or without TAFIa treatment was quantified using flow cytometry. Plasmin generation on platelets was quantified using a plasmin-specific substrate. Mass spectrometry analyses identified fibrinogen as a potential target of TAFIa. Thrombus formation was studied in mice lacking fibrinogen (Fg−/−) using intravital microscopy. Plasminogen and t-PA bind to platelets activated by thrombin but not by other agonists, including protease-activated receptor agonists (PAR-AP). Plasminogen binds via its kringle domains because ε-aminocaproic acid eliminates binding, whereas t-PA binds via its finger and kringle domains. Plasminogen binding is fibrinogen-dependent because it is abolished on (a) Fg−/− platelets, and (b) thrombi in Fg−/− mice. Binding requires thrombin-mediated fibrinogen modification because addition of batroxobin to PAR-AP activated platelets has no effect on plasminogen binding but induces t-PA binding. TAFIa reduces plasminogen and t-PA binding to thrombin-activated platelets and attenuates plasmin generation in a concentration-dependent manner. Mass spectrometry identified K556 on the fibrinogen alpha-chain as a potential thrombin cleavage site that generates a TAFIa sensitive C-terminal lysine residue. These findings provide novel mechanistic insights into how platelets activated by thrombin at sites of vascular injury can influence fibrinolysis.
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影响因子：
20.3
作者：
Ni, HY;Papalia, JM;Wagner, DD
通讯作者：
Wagner, DD
影响因子：
3.7
作者：
Brzoska T;Tanaka-Murakami A;Suzuki Y;Sano H;Kanayama N;Urano T
通讯作者：
Urano T
影响因子：
4.8
作者：
Kim, Paul Y.;Vu, Trang T.;Weitz, Jeffrey I.
通讯作者：
Weitz, Jeffrey I.
影响因子：
3.7
作者：
Brzoska T;Suzuki Y;Mogami H;Sano H;Urano T
通讯作者：
Urano T
DOI：
10.1084/jem.20071827
发表时间：
2007-12-24
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Nieswandt B;Moser M;Pleines I;Varga-Szabo D;Monkley S;Critchley D;Fässler R
通讯作者：
Fässler R