RESUMO
BACKGROUND: The dramatic clinical improvement offered by mechanical thrombectomy raised questions about the relevance of prior intravenous thrombolysis in large-vessel occlusion strokes. Hence, studying intravenous thrombolysis susceptibility and its dependence on thrombus composition is crucial. We used an observational proteomic study of whole thrombi retrieved by mechanical thrombectomy to identify factors associated with fibrin content and fibrinolytic activity (FA). METHODS: In 104 stroke patients, the thrombi proteome was established by mass spectrometry coupled to liquid chromatography. FA was estimated in clots both outside (FAout) by measuring D-dimer levels at the blood-thrombus interface and inside (FAin) by evaluating the ratio of fibrinogen α to its plasmin-cleaved forms using proteomics coupled with protein electrophoresis. The factors associated with fibrin content, FAin, and FAout were determined by intravenous thrombolysis-adjusted linear regression. RESULTS: FAout (P<0.0001) and FAin (P=0.0147) were driven by recombinant tissue-type plasminogen activator (r-tPA) administration (47/104) and thrombus composition. Indeed, FAout was greater with fibrin-rich than erythrocyte-rich thrombi, presumably because of more (r)tPA substrates. Thus, FAout was increased with cardioembolic thrombi (72/104), which are rich in fibrin (P=0.0300). Opposite results were found inside the thrombus, suggesting that (r)tPA penetrability was hampered by the density of the fibrinous cap. Moreover, blood cells had a strong impact on thrombus structure and susceptibility to (r)tPA. Indeed, fibrin content was negatively associated with erythrocyte-specific proteins in the thrombus, admission hematocrit (P=0.0139), and hemoglobin level (P=0.0080), which underlines the key role of erythrocytes in thrombus composition. Also, an increased number of neutrophils impaired FAout (P=0.0225), which suggests that their aggregation around the thrombus prevented the (r)tPA attack. Only FAout was significantly associated with reduced thrombus weight (P=0.0310), increased recanalization rate (P=0.0150), good clinical outcome (P=0.0480), and reduced mortality (P=0.0080). CONCLUSIONS: Proteomics can offer new insights into the close relationship between thrombus composition and susceptibility to fibrinolysis, paving the way for new adjuvant therapies.
Assuntos
Fibrinólise , Trombose Intracraniana , Proteômica , Acidente Vascular Cerebral , Humanos , Masculino , Feminino , Fibrinólise/efeitos dos fármacos , Idoso , Pessoa de Meia-Idade , Trombose Intracraniana/metabolismo , Trombose Intracraniana/tratamento farmacológico , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/tratamento farmacológico , Trombectomia/métodos , Ativador de Plasminogênio Tecidual , Fibrina/metabolismo , Idoso de 80 Anos ou mais , Terapia Trombolítica , Trombose/metabolismoAssuntos
Infarto Cerebral , Trombose Intracraniana , Imageamento por Ressonância Magnética , Trombose Venosa , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Estudos Retrospectivos , Trombose Venosa/patologia , Trombose Intracraniana/patologia , Trombose Intracraniana/diagnóstico por imagem , Trombose Intracraniana/metabolismo , Adulto Jovem , Infarto Cerebral/patologia , Infarto Cerebral/diagnóstico por imagem , Infarto Cerebral/metabolismo , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Cefaleia/etiologia , Córtex Cerebral/patologia , Córtex Cerebral/irrigação sanguínea , Córtex Cerebral/diagnóstico por imagem , Diagnóstico Diferencial , Lobo Temporal/patologia , Lobo Temporal/diagnóstico por imagem , Hemorragia Cerebral/diagnóstico por imagem , Hemorragia Cerebral/patologia , Convulsões/etiologia , Edema Encefálico/patologia , Lobo Frontal/patologia , Lobo Frontal/diagnóstico por imagem , Lobo Frontal/irrigação sanguíneaRESUMO
Cerebral venous thrombosis (CVT) is a neurovascular disease with recently increasing incidence. Aseptic inflammatory responses play an important role in the pathology of CVT. Recent studies report that neutrophil extracellular traps (NETs) are major triggers of thrombosis and inflammation in stroke, but their effect on brain injury in CVT requires further validation. In this study, two CVT animal models were used to simulate superior sagittal sinus thrombosis and cortical vein thrombosis. The effects of brain tissue infiltration of NETs and the molecular mechanisms associated with NET formation were deeply explored in combination with proteomics, histology, and serology. The results showed that the cortical vein thrombosis model could be combined with more severe blood-brain barrier (BBB) disruption and showed more severe cerebral hemorrhage. Decreased Sirtuin 1 (SIRT1) expression promotes high mobility group box 1 (HMGB1) acetylation, causing increased cytosolic translocation and extracellular release, and HMGB1 can promote NET formation and recruitment. In addition, corticocerebral accumulation of NETs contributes to BBB damage. This establishes a vicious cycle between BBB damage and NET accumulation. SIRT1 mediated-HMGB1 deacetylation may play a critical role in attenuating BBB damage following CVT. This study employed a combined validation using models of venous sinus thrombosis and cortical vein thrombosis to investigate the deacetylation role of SIRT1, aiming to offer new insights into the pathological mechanisms of brain injury following CVT.