RESUMO
Essentials Activated clotting factor X (FXa) acquires fibrinolytic cofactor function after cleavage by plasmin. FXa-mediated plasma fibrinolysis is enabled by active site modification blocking a second cleavage. FXa-directed oral anticoagulants (DOACs) alter FXa cleavage by plasmin. DOACs enhance FX-dependent fibrinolysis and plasmin generation by tissue plasminogen activator. BACKGROUND: When bound to an anionic phospholipid-containing membrane, activated clotting factor X (FXa) is sequentially cleaved by plasmin from the intact form, FXaα, to FXaß and then to Xa33/13. Tissue-type plasminogen activator (t-PA) produces plasmin and is the initiator of fibrinolysis. Both FXaß and Xa33/13 enhance t-PA-mediated plasminogen activation. Although stable in experiments using purified proteins, Xa33/13 rapidly loses t-PA cofactor function in plasma. Bypassing this inhibition, covalent modification of the FXaα active site prevents Xa33/13 formation by plasmin, and the persistent FXaß enhances plasma fibrinolysis. As the direct oral anticoagulants (DOACs) rivaroxaban and apixaban bind to the FXa active site, we hypothesized that they similarly modulate FXa fibrinolytic function. METHODS: DOAC effects on fibrinolysis and the t-PA cofactor function of FXa were studied in patient plasma, normal pooled plasma and purified protein experiments by the use of light scattering, chromogenic assays, and immunoblots. RESULTS: The plasma of patients taking rivaroxaban showed enhanced fibrinolysis correlating with FXaß. In normal pooled plasma, the addition of rivaroxaban or apixaban also shortened fibrinolysis times. This was related to the cleavage product, FXaß, which increased plasmin production by t-PA. It was confirmed that these results were not caused by DOACs affecting activated FXIII-mediated fibrin crosslinking, clot ultrastructure and thrombin-activatable fibrinolysis inhibitor activation in plasma. CONCLUSION: The current study suggests a previously unknown effect of DOACs on FXa in addition to their well-documented anticoagulant role. By enabling the t-PA cofactor function of FXaß in plasma, DOACs also enhance fibrinolysis. This effect may broaden their therapeutic indications.
Assuntos
Fator Xa/química , Pirazóis/farmacologia , Piridonas/farmacologia , Rivaroxabana/farmacologia , Administração Oral , Anticoagulantes/química , Coagulação Sanguínea/efeitos dos fármacos , Domínio Catalítico , Reagentes de Ligações Cruzadas/química , Inibidores do Fator Xa/farmacologia , Fibrina/química , Fibrinolisina/química , Fibrinólise , Humanos , Fosfolipídeos/química , Trombina/química , Terapia Trombolítica , Trombose , Ativador de Plasminogênio Tecidual/químicaAssuntos
Terapia Antirretroviral de Alta Atividade/efeitos adversos , Infecções por HIV/tratamento farmacológico , Doenças Mitocondriais/induzido quimicamente , Doenças Mitocondriais/fisiopatologia , Oftalmoplegia Externa Progressiva Crônica/induzido quimicamente , Oftalmoplegia Externa Progressiva Crônica/fisiopatologia , Fármacos Anti-HIV/efeitos adversos , Blefaroptose/induzido quimicamente , Blefaroptose/metabolismo , Blefaroptose/fisiopatologia , DNA Mitocondrial/efeitos dos fármacos , Didanosina/efeitos adversos , Predisposição Genética para Doença/genética , Humanos , Lipodistrofia/induzido quimicamente , Lipodistrofia/metabolismo , Lipodistrofia/fisiopatologia , Masculino , Pessoa de Meia-Idade , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Doenças Mitocondriais/genética , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/patologia , Músculo Esquelético/fisiopatologia , Mutação/genética , Músculos Oculomotores/efeitos dos fármacos , Músculos Oculomotores/patologia , Músculos Oculomotores/fisiopatologia , Oftalmoplegia/induzido quimicamente , Oftalmoplegia/metabolismo , Oftalmoplegia/fisiopatologia , Oftalmoplegia Externa Progressiva Crônica/metabolismo , Recuperação de Função Fisiológica/fisiologia , Fatores de Risco , TempoRESUMO
Statins are generally well tolerated, but can cause myopathy and have been associated with mitochondrial abnormalities. The aim of this study was to determine whether muscle mitochondrial DNA (mtDNA) levels are altered during statin therapy. We retrospectively quantified mtDNA in 86 skeletal muscle biopsy specimens collected as part of a previously published clinical trial of high-dose simvastatin or atorvastatin versus placebo.
