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(Circulation. 2004;110:2946-2951.)
© 2004 American Heart Association, Inc.

Vascular Medicine

Anti–Glycoprotein VI Treatment Severely Compromises Hemostasis in Mice With Reduced ₂ß₁ Levels or Concomitant Aspirin Therapy

Sabine Grüner, MD^*; Miroslava Prostredna, MSc^*; Barsom Aktas, PhD; Alexandra Moers, PhD; Valerie Schulte, PhD; Thomas Krieg, MD; Stefan Offermanns, MD; Beate Eckes, PhD; Bernhard Nieswandt, PhD

From the Rudolf Virchow Center, DFG Research Center for Experimental Biomedicine, University of Würzburg, Würzburg (S.G., M.P., B.A., V.S., B.N.); the Institute of Pharmacology, University of Heidelberg, Heidelberg (A.M., S.O.); and the Department of Dermatology, University of Cologne, Cologne (T.K., B.E.), Germany.

Correspondence to Bernhard Nieswandt, PhD, Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, Versbacher Straße 9, 97078 Würzburg, Germany. E-mail bernhard.nieswandt{at}virchow.uni-wuerzburg.de

Received March 5, 2004; revision received May 13, 2004; accepted May 21, 2004.

Background— Platelet inhibition is a major strategy to prevent arterial thrombosis, but it is frequently associated with increased bleeding because of impaired primary hemostasis. The activating platelet collagen receptor, glycoprotein VI (GP VI), may serve as a powerful antithrombotic target because its inhibition or absence results in profound protection against arterial thrombosis but no major bleeding in mice.

Methods and Results— Mice lacking (–/–) or expressing half-levels (+/–) of the other major platelet collagen receptor, integrin ₂ß₁, were injected with the anti–GP VI antibody JAQ1 and analyzed on day 5. Anti–GP VI treatment resulted in a marked hemostatic defect in ₂^–/– or ₂^+/– mice, as shown by dramatically prolonged tail bleeding times. Platelet adhesion to collagen was studied in an ex vivo whole-blood perfusion system under high shear conditions. Weak integrin activation by thromboxane A₂ (TxA₂) receptor stimulation restored defective adhesion of anti–GP VI–treated wild-type but not ₂^–/– or ₂^+/– platelets to collagen. This process required the simultaneous activation of the G_q and G₁₃ signaling pathways, as demonstrated by use of the respective knockout strains. Conversely, inhibition of TxA₂ production by aspirin severely compromised hemostasis in anti–GP VI–treated or GP VI/Fc receptor -chain–deficient but not control mice.

Conclusions— Anti–GP VI therapy may result in defective hemostasis in patients with reduced ₂ß₁ levels or concomitant aspirin therapy. These observations may have important implications for a potential use of anti–GP VI–based therapeutics in the prevention of cardiovascular disease.

Key Words: collagen • glycoproteins • receptors • platelets • thrombosis

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