title: GDF-15 prevents platelet integrin activation and thrombus formation.
abstract: BACKGROUND
  Integrin-mediated platelet function plays an important role in primary hemostasis. Growth-differentiation factor 15 (GDF-15) has been shown to inhibit β(2) -integrin activation in leukocytes.
  
  
  METHODS
  We investigated the effect of GDF-15 on platelet integrin activation in vitro and in different in vivo models of thrombus formation.
  
  
  RESULTS
  GDF-15(-/-)  mice showed an accelerated thrombus formation and a reduced survival rate after collagen-induced pulmonary thromboembolism. In reconstitution experiments, recombinant GDF-15 decelerated thrombus formation and prolonged the bleeding time. In vitro experiments demonstrated that GDF-15 pretreated, agonist-stimulated platelets showed decreased binding to fibrinogen in flow chamber assays and reduced activation of β(1) - and β(3) -integrins in flow cytometry experiments. Pretreating human and mouse platelets with GDF-15 reduced platelet aggregation. Mechanistically, GDF-15 prevents agonist-induced Rap1- dependent α(II)             (b) β(3)  activation by activating PKA. Platelet P-selectin expression and dense granule secretion after stimulation were unaffected by GDF-15, indicating a specific effect of GDF-15 on integrin activation.
  
  
  CONCLUSIONS
  GDF-15 specifically inhibits platelet integrin activation. These findings may have profound clinical implications for the treatment of hemostatic conditions involving platelets.
authors.affiliation: Department of Anaesthesiology, Intensive Care and Pain Medicine, University Hospital Münster, Münster, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Rossaint
authors.forename: D
authors.initials: D
authors.lastname: Vestweber
authors.forename: A
authors.initials: A
authors.lastname: Zarbock
mesh_terms: D000818:Animals; D001760:Bleeding Time; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D002712:Chlorides; D003094:Collagen; D017868:Cyclic AMP-Dependent Protein Kinases / Q000097:blood; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005290:Ferric Compounds; D005434:Flow Cytometry; D055436:Growth Differentiation Factor 15 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006487:Hemostasis / Q000187:drug effects; D006801:Humans; D019012:Integrin beta1 / Q000097:blood; D039661:Integrin beta3 / Q000097:blood; D016023:Integrins / Q000097:blood*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019007:P-Selectin / Q000097:blood; D015539:Platelet Activation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism; D011655:Pulmonary Embolism / Q000097:blood / Q000139:chemically induced / Q000235:genetics / Q000517:prevention & control*; D011994:Recombinant Proteins / Q000378:metabolism; D013927:Thrombosis / Q000097:blood / Q000139:chemically induced / Q000235:genetics / Q000517:prevention & control*; D013997:Time Factors; D020827:rap1 GTP-Binding Proteins / Q000097:blood
chemical_list: D002712:Chlorides; D005290:Ferric Compounds; C526141:Gdf15 protein, mouse; D055436:Growth Differentiation Factor 15; D019012:Integrin beta1; D039661:Integrin beta3; D016023:Integrins; D019007:P-Selectin; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D011994:Recombinant Proteins; D003094:Collagen; D017868:Cyclic AMP-Dependent Protein Kinases; D020827:rap1 GTP-Binding Proteins; C024555:ferric chloride