von Willebrand factor–mediated platelet adhesion is critical for deep vein thrombosis in mouse models

Alexander Brill; Tobias A Fuchs; Anil K Chauhan; Janie J Yang; Simon F De Meyer; Maria Köllnberger; Thomas W Wakefield; Bernhard Lämmle; Steffen Massberg; Denisa D Wagner

doi:10.1182/blood-2010-05-287623

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von Willebrand factor–mediated platelet adhesion is critical for deep vein thrombosis in mouse models

Journal article

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von Willebrand factor–mediated platelet adhesion is critical for deep vein thrombosis in mouse models

Alexander Brill, Tobias A Fuchs, Anil K Chauhan, Janie J Yang, Simon F De Meyer, Maria Köllnberger, Thomas W Wakefield, Bernhard Lämmle, Steffen Massberg and Denisa D Wagner

Blood, Vol.117(4), pp.1400-1407

Thrombosis and Hemostasis

01/27/2011

DOI: 10.1182/blood-2010-05-287623

PMCID: PMC3056477

PMID: 20959603

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Abstract

Deep vein thrombosis (DVT) and its complication, pulmonary embolism, are frequent causes of disability and mortality. Although blood flow disturbance is considered an important triggering factor, the mechanism of DVT initiation remains elusive. Here we show that 48-hour flow restriction in the inferior vena cava (IVC) results in the development of thrombi structurally similar to human deep vein thrombi. von Willebrand factor (VWF)–deficient mice were protected from thrombosis induced by complete (stasis) or partial (stenosis) flow restriction in the IVC. Mice with half normal VWF levels were also protected in the stenosis model. Besides promoting platelet adhesion, VWF carries Factor VIII. Repeated infusions of recombinant Factor VIII did not rescue thrombosis in VWF −/− mice, indicating that impaired coagulation was not the primary reason for the absence of DVT in VWF −/− mice. Infusion of GPG-290, a mutant glycoprotein Ibα-immunoglobulin chimera that specifically inhibits interaction of the VWF A1 domain with platelets, prevented thrombosis in wild-type mice. Intravital microscopy showed that platelet and leukocyte recruitment in the early stages of DVT was dramatically higher in wild-type than in VWF −/− IVC. Our results demonstrate a pathogenetic role for VWF-platelet interaction in flow disturbance-induced venous thrombosis.

Thrombosis and Hemostasis

Details

Title: Subtitle: von Willebrand factor–mediated platelet adhesion is critical for deep vein thrombosis in mouse models
Creators: Alexander Brill - Immune Disease Institute, Boston, MA
Tobias A Fuchs - Immune Disease Institute, Boston, MA
Anil K Chauhan - Immune Disease Institute, Boston, MA
Janie J Yang - Immune Disease Institute, Boston, MA
Simon F De Meyer - Immune Disease Institute, Boston, MA
Maria Köllnberger - Deutsches Herzzentrum, Technische Universität München, Munich, Germany
Thomas W Wakefield - Cardiovascular Center, University of Michigan, Ann Arbor, MI; and
Bernhard Lämmle - Immune Disease Institute, Boston, MA
Steffen Massberg - Deutsches Herzzentrum, Technische Universität München, Munich, Germany
Denisa D Wagner - Immune Disease Institute, Boston, MA
Resource Type: Journal article
Publication Details: Blood, Vol.117(4), pp.1400-1407
Series: Thrombosis and Hemostasis
DOI: 10.1182/blood-2010-05-287623
PMID: 20959603
PMCID: PMC3056477
NLM abbreviation: Blood
ISSN: 0006-4971
eISSN: 1528-0020
Publisher: American Society of Hematology
Grant note: R01 HL095091; R01 HL041002 / National Institutes of Health
Language: English
Date published: 01/27/2011
Academic Unit: Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
Record Identifier: 9984094639502771

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