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J Thromb Haemost. 2013 Feb;11(2):335-44. doi: 10.1111/jth.12100.

GDF-15 prevents platelet integrin activation and thrombus formation.

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1
Department of Anaesthesiology, Intensive Care and Pain Medicine, University Hospital Münster, Münster, Germany.

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.

CONCLUSION:

GDF-15 specifically inhibits platelet integrin activation. These findings may have profound clinical implications for the treatment of hemostatic conditions involving platelets.

PMID:
23231375
DOI:
10.1111/jth.12100
[Indexed for MEDLINE]
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