Angiotensin II exacerbates intracerebral hemorrhage in mice via heparin-like antithrombin activation and coagulation...

Hypertension has paradoxical prothrombotic-hemorrhagic predisposition toward cerebral infarction and intracerebral hemorrhage (ICH), but the mechanism remains poorly understood. We observed Angiotensin II (Ang II) inhibited coagulation by activating antithrombin through heparin-like acceleration of antithrombin-thrombin interaction. Ang II allosterically modulates the 386-397 loop of antithrombin to enhance thrombin inhibition. In vivo, single injection of Ang II inhibited coagulation, alleviating thrombosis and aggravating ICH. Conversely, anti-Ang II monoclonal antibody promoted coagulation, aggravating thrombus formation and alleviating ICH. Notably, the blockage or deficiency of Ang II receptor had no significant effect on the alleviated thrombus formation or aggravated hemorrhage elicited by Ang II, suggesting the phenotypes were independent of Ang II receptor. In hypertensive mice, anti-Ang II monoclonal antibody significantly promoted coagulation and ameliorated ICH. These results identify Ang II as a key coagulation regulator with heparin-like function, suggesting that targeting Ang II-coagulation pathway could be a novel strategy to mitigate cerebral bleeding.