Intracerebral hemorrhage and thrombin-induced alterations in cerebral microvessel matrix.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Gu, Y-H; Hawkins, BT; Izawa, Y; Yoshikawa, Y; Koziol, JA; Del Zoppo, GJ

Published Date

  • September 2022

Published In

Volume / Issue

  • 42 / 9

Start / End Page

  • 1732 - 1747

PubMed ID

  • 35510668

Pubmed Central ID

  • PMC9441730

Electronic International Standard Serial Number (EISSN)

  • 1559-7016

International Standard Serial Number (ISSN)

  • 0271-678X

Digital Object Identifier (DOI)

  • 10.1177/0271678x221099092


  • eng