von Willebrand factor-cleaving protease ADAMTS13 reduces ischemic brain injury in experimental stroke.

Abstract:

:Stroke is a leading cause of death and disability. The only therapy available is recombinant tissue plasminogen activator, but side effects limit its use. Platelets play a crucial role during stroke, and the inflammatory reaction promotes neurodegeneration. von Willebrand factor (VWF), an adhesion molecule for platelets, is elevated in patients with acute stroke. The activity of VWF is modulated by ADAMTS13 (a disintegrin-like and metalloprotease with thrombospondin type I repeats-13) that cleaves VWF to smaller less-active forms. We recently documented that ADAMTS13 negatively regulates both thrombosis and inflammation. We report that deficiency or reduction of VWF reduces infarct volume up to 2-fold after focal cerebral ischemia in mice, thus showing the importance of VWF in stroke injury. In contrast, ADAMTS13 deficiency results in larger infarctions, but only in mice that have VWF. Importantly, infusion of a high dose of recombinant human ADAMTS13 into a wild-type mouse immediately before reperfusion reduces infarct volume and improves functional outcome without producing cerebral hemorrhage. Furthermore, recombinant ADAMTS13 did not enhance bleeding in a hemorrhagic stroke model. Our findings show the importance of VWF in regulating infarction and suggest that recombinant ADAMTS13 could be considered as a new therapeutic agent for prevention and/or treatment of stroke.

journal_name

Blood

journal_title

Blood

authors

Zhao BQ,Chauhan AK,Canault M,Patten IS,Yang JJ,Dockal M,Scheiflinger F,Wagner DD

doi

10.1182/blood-2009-03-213264

subject

Has Abstract

pub_date

2009-10-08 00:00:00

pages

3329-34

issue

15

eissn

0006-4971

issn

1528-0020

pii

blood-2009-03-213264

journal_volume

114

pub_type

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