GDF-15 prevents platelet integrin activation and thrombus formation
Article first published online: 7 FEB 2013
© 2012 International Society on Thrombosis and Haemostasis
Journal of Thrombosis and Haemostasis
Volume 11, Issue 2, pages 335–344, February 2013
How to Cite
GDF-15 prevents platelet integrin activation and thrombus formation. J Thromb Haemost 2013; 11: 335–44., , .
- Issue published online: 7 FEB 2013
- Article first published online: 7 FEB 2013
- Accepted manuscript online: 11 DEC 2012 10:28AM EST
- Manuscript Accepted: 22 NOV 2012
- Manuscript Received: 1 AUG 2012
- German Research Foundation. Grant Numbers: AZ 428/3-1, AZ 428/6-1, AZ 428/8-1 to A.Z.
- Else Kröner-Fresenius-Stiftung. Grant Number: A69/07 to A.Z.
- Innovative Medizinische Forschung. Grant Number: A.Z.
- Interdisciplinary Clinical Research Center. Grant Number: SEED01/12 to J.R.
Integrin-mediated platelet function plays an important role in primary hemostasis. Growth-differentiation factor 15 (GDF-15) has been shown to inhibit β2-integrin activation in leukocytes.
We investigated the effect of GDF-15 on platelet integrin activation in vitro and in different in vivo models of thrombus formation.
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 β1- and β3-integrins in flow cytometry experiments. Pretreating human and mouse platelets with GDF-15 reduced platelet aggregation. Mechanistically, GDF-15 prevents agonist-induced Rap1- dependent αIIbβ3 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.
GDF-15 specifically inhibits platelet integrin activation. These findings may have profound clinical implications for the treatment of hemostatic conditions involving platelets.