Activated platelet-based inhibition of fibrinolysis via thrombin-activatable fibrinolysis inhibitor activation system
| Autor: | Tetsumei Urano, Liina Mochizuki, Yuko Suzuki, Naoki Honkura, Hideto Sano |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Blood Platelets
0301 basic medicine Carboxypeptidase B2 medicine.medical_treatment Thrombogenicity 030204 cardiovascular system & hematology Fibrin Thrombosis and Hemostasis Mice 03 medical and health sciences 0302 clinical medicine Fibrinolysis medicine Animals Platelet Platelet activation Blood Coagulation Whole blood biology Chemistry Hematology 030104 developmental biology biology.protein Biophysics Fibrin Clot Lysis Time Plasminogen activator |
| Zdroj: | Blood Adv |
| ISSN: | 2473-9537 2473-9529 |
| DOI: | 10.1182/bloodadvances.2020002923 |
| Popis: | Our previous real-time imaging studies directly demonstrated the spatiotemporal regulation of clot formation and lysis by activated platelets. In addition to their procoagulant functions, platelets enhanced profibrinolytic potential by augmenting the accumulation of tissue-type plasminogen activator (tPA) and plasminogen, in vivo in a murine microthrombus model, and in vitro in a platelet-containing plasma clot model. To clarify the role of thrombin-activatable fibrinolysis inhibitor (TAFI), which regulates coagulation-dependent anti-fibrinolytic potential, we analyzed tPA-induced clot lysis times in platelet-containing plasma. Platelets prolonged clot lysis times in a concentration-dependent manner, which were successfully abolished by a thrombomodulin-neutralizing antibody or an activated TAFI inhibitor (TAFIaI). The results obtained using TAFI- or factor XIII–deficient plasma suggested that TAFI in plasma, but not in platelets, was essential for this prolongation, though its cross-linkage with fibrin was not necessary. Confocal laser scanning microscopy revealed that fluorescence-labeled plasminogen accumulated on activated platelet surfaces and propagated to the periphery, similar to the propagation of fibrinolysis. Plasminogen accumulation and propagation were both enhanced by TAFIaI, but only accumulation was enhanced by thrombomodulin-neutralizing antibody. Labeled TAFI also accumulated on both fibrin fibers and activated platelet surfaces, which were Lys-binding-site-dependent and Lys-binding-site-independent, respectively. Finally, TAFIaI significantly prolonged the occlusion times of tPA-containing whole blood in a microchip-based flow chamber system, suggesting that TAFI attenuated the tPA-dependent prolongation of clot formation under flow. Thus, activated platelet surfaces are targeted by plasma TAFI, to attenuate plasminogen accumulation and fibrinolysis, which may contribute to thrombogenicity under flow. |
| Databáze: | OpenAIRE |
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