SDF-1α is a novel autocrine activator of platelets operating through its receptor CXCR4

Platelets store and secrete the chemokine stromal cell-derived factor (SDF)-1 alpha upon platelet activation, but the ability of platelet-derived SDF-1 alpha to signal in an autocrine/paracrine manner mediating functional platelet responses relevant to thrombosis and haemostasis is unknown. We sought to explore the role of platelet-derived SDF-1 alpha and its receptors, CXCR4 and CXCR7 in facilitating platelet activation and determine the mechanism facilitating SDF-1 alpha-mediated regulation of platelet function. Using human washed platelets, CXCR4 inhibition, but not CXCR7 blockade significantly abrogated collagen-mediated platelet aggregation, dense granule secretion and thromboxane (Tx) A(2) production. Time-dependent release of SDF-1 alpha from collagen-activated platelets supports a functional role for SDF-1 alpha in this regard. Using an in vitro whole blood perfusion assay, collagen-induced thrombus formation was substantially reduced with CXCR4 inhibition. In washed platelets, recombinant SDF-1 alpha in the range of 20-100 ng/mL(-1) could significantly enhance platelet aggregation responses to a threshold concentration of collagen. These enhancements were completely dependent on CXCR4, but not CXCR7, which triggered TxA(2) production and dense granule secretion. Rises in cAMP were significantly blunted by SDF-1 alpha, which could also enhance collagen-mediated Ca(2 +) mobilisation, both of which were mediated by CXCR4. This potentiating effect of SDF-1 alpha primarily required TxA(2) signalling acting upstream of dense granule secretion, whereas blockade of ADP signalling could only partially attenuate SDF-1 alpha-induced platelet activation. Therefore, this study supports a potentially novel autocrine/paracrine role for platelet-derived SDF-1 alpha during thrombosis and haemostasis, through a predominantly TxA(2)-dependent and ADP-independent pathway. (C) 2014 The Authors. Published by Elsevier Inc.