title: Anti-glycoprotein VI treatment severely compromises hemostasis in mice with reduced alpha2beta1 levels or concomitant aspirin therapy.
abstract: 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.
  
  
  RESULTS
  Mice lacking (-/-) or expressing half-levels (+/-) of the other major platelet collagen receptor, integrin alpha2beta1, 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 alpha2-/- or alpha2+/- 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 alpha2-/- or alpha2+/- 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 gamma-chain-deficient but not control mice.
  
  
  CONCLUSIONS
  Anti-GP VI therapy may result in defective hemostasis in patients with reduced alpha2beta1 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.
authors.affiliation: Rudolf Virchow Center, DFG Research Center for Experimental Biomedicine, University of Würzburg, Würzburg, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Grüner
authors.forename: Miroslava
authors.initials: M
authors.lastname: Prostredna
authors.forename: Barsom
authors.initials: B
authors.lastname: Aktas
authors.forename: Alexandra
authors.initials: A
authors.lastname: Moers
authors.forename: Valerie
authors.initials: V
authors.lastname: Schulte
authors.forename: Thomas
authors.initials: T
authors.lastname: Krieg
authors.forename: Stefan
authors.initials: S
authors.lastname: Offermanns
authors.forename: Beate
authors.initials: B
authors.lastname: Eckes
authors.forename: Bernhard
authors.initials: B
authors.lastname: Nieswandt
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity*; D001241:Aspirin / Q000008:administration & dosage / Q000633:toxicity*; D001760:Bleeding Time; D003094:Collagen / Q000494:pharmacology / Q000502:physiology; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D005343:Fibrinolytic Agents / Q000633:toxicity*; D044365:GTP-Binding Protein alpha Subunits, G12-G13 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D006470:Hemorrhage / Q000139:chemically induced* / Q000517:prevention & control; D006487:Hemostasis / Q000187:drug effects* / Q000502:physiology; D038982:Integrin alpha2beta1 / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D015539:Platelet Activation / Q000187:drug effects / Q000502:physiology; D010973:Platelet Adhesiveness / Q000187:drug effects; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000502:physiology; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction; D013927:Thrombosis / Q000517:prevention & control*
chemical_list: D000911:Antibodies, Monoclonal; D005343:Fibrinolytic Agents; D038982:Integrin alpha2beta1; D010980:Platelet Membrane Glycoproteins; D044244:Receptors, Thromboxane A2, Prostaglandin H2; C098341:platelet membrane glycoprotein VI; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D003094:Collagen; D044365:GTP-Binding Protein alpha Subunits, G12-G13; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D001241:Aspirin