Intracerebral hemorrhage and thrombin-induced alterations in cerebral microvessel matrix. Issue 9 (September 2022)

• Record Type: Journal Article
• Authors: Gu, Yu-Huan; Hawkins, Brian T; Izawa, Yoshikane; Yoshikawa, Yoji; Koziol, James A; del Zoppo, Gregory J
• Is Part Of: Journal of cerebral blood flow & metabolism. Volume 42:Issue 9(2022)
• Page Start: 1732
• Page End: 1747
• Publication Date: 2022-09
• Subjects: Cerebral microvessels -- dabigatran etexilate -- extracellular matrix -- hemorrhage -- thrombin; Cerebral circulation -- Periodicals; Brain -- Metabolism -- Periodicals; Brain -- Blood-vessels -- Periodicals; Cerebrovascular disease -- Periodicals; 612.824
• DOI: 10.1177/0271678X221099092
• Languages: English
• ISSNs: 0271-678X

Abstract

Four phase III clinical trials of oral direct factor Xa or thrombin inhibitors demonstrated significantly lower intracranial hemorrhage compared to warfarin in patients with nonvalvular-atrial fibrillation. This is counter-intuitive to the principle that inhibiting thrombosis should increase hemorrhagic risk. We tested the novel hypothesis that anti-thrombin activity decreases the risk of intracerebral hemorrhage by directly inhibiting thrombin-mediated degradation of cerebral microvessel basal lamina matrix, responsible for preventing hemorrhage. Collagen IV, laminin, and perlecan each contain one or more copies of the unique α-thrombin cleavage site consensus sequence. In blinded controlled experiments, α-thrombin significantly degraded each matrix protein in vitro and in vivo in a concentration-dependent fashion. In vivo stereotaxic injection of α-thrombin significantly increased permeability, local IgG extravasation, and hemoglobin (Hgb) deposition together with microvessel matrix degradation in a mouse model. In all formats the direct anti-thrombin dabigatran completely inhibited matrix degradation by α-thrombin. Fourteen-day oral exposure to dabigatran etexilate-containing chow completely inhibited matrix degradation, the permeability to large molecules, and cerebral hemorrhage associated with α-thrombin. These experiments demonstrate that thrombin can degrade microvessel matrix, leading to hemorrhage, and that inhibition of microvessel matrix degradation by α-thrombin decreases cerebral hemorrhage. Implications for focal ischemia and other conditions are discussed.