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GDF ‐15 prevents platelet integrin activation and thrombus formation
Author(s) -
Rossaint J.,
Vestweber D.,
Zarbock A.
Publication year - 2013
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/jth.12100
Subject(s) - platelet activation , integrin , platelet , thrombus , chemistry , flow cytometry , microbiology and biotechnology , hemostasis , collagen receptor , fibrinogen , in vivo , immunology , medicine , receptor , biology , biochemistry
Summary 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.