Potent Thrombolytic Effect of N -Acetylcysteine on Arterial Thrombi

• DOI: 10.1161/circulationaha.117.027290
• Publication Date: 2017-05-10T00:30:29Z
• Authors: Sara Martinez de ...; Clément Gakuba; Bradley A. Herbig; Yohann Repessé; Carine Ali; Cécile V. Denis; Peter J. Lenting; Emmanuel Touzé; Scott L. Diamond; Denis Vivien; Maxime Gauberti
• Keywords: Thromboelastography; Fibrinolytic agent

Platelet cross-linking during arterial thrombosis involves von Willebrand Factor (VWF) multimers. Therefore, proteolysis of VWF appears promising to disaggregate platelet-rich thrombi and restore vessel patency in acute thrombotic disorders such as ischemic stroke, coronary syndrome, or limb ischemia. N-Acetylcysteine (NAC, a clinically approved mucolytic drug) can reduce intrachain disulfide bonds large polymeric proteins. In the present study, we postulated that NAC might cleave multimers inside occlusive thrombi, thereby leading their dissolution recanalization.Experimental models stroke induced by either intra-arterial thrombin injection ferric chloride application followed measurement cerebral blood flow using combination laser Doppler flowmetry MRI were performed uncover effects on thrombi. To investigate effect larger vessels, also chloride-induced carotid artery thrombosis. vitro experiments study molecular bases thrombolytic effect, including platelet aggregometry, lysis assays, thromboelastography (ROTEM), high-shear string formation microfluidic devices. We investigated putative prohemorrhagic mouse model intracranial hemorrhage situ collagenase type VII injection.We demonstrated intravenous administration promotes are resistant conventional approaches recombinant tissue-type plasminogen activator, direct inhibitors, antiplatelet treatments. Through vivo experiments, provide evidence target underlying is principally cross-link platelets Coadministration nonpeptidic GpIIb/IIIa inhibitor further improved its efficacy, essentially accelerating thrombus preventing rethrombosis. Thus, new large-vessel thromboembolic mice, this cotreatment significantly lesion size neurological outcome. It important note did not worsen hemorrhagic outcome, suggesting it exerts without impairing normal hemostasis.We an effective safe alternative currently available antithrombotic agents after occlusion.