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Relative contributions of stromal interaction molecule 1 and CalDAG‐GEFI to calcium‐dependent platelet activation and thrombosis
Author(s) -
AHMAD F.,
BOULAFTALI Y.,
GREENE T. K.,
OUELLETTE T. D.,
PONCZ M.,
FESKE S.,
BERGMEIER W.
Publication year - 2011
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/j.1538-7836.2011.04474.x
Subject(s) - platelet , platelet activation , medicine , orai1 , stim1 , thrombosis , thrombin , fibrin , platelet adhesiveness , calcium , immunology , platelet aggregation
Summary. Background: Stromal interaction molecule 1 (STIM1) was recently identified as a critical component of store‐operated calcium entry (SOCE) in platelets. We previously reported the Ca 2+ ‐sensing guanine nucleotide exchange factor CalDAG‐GEFI as a critical molecule in Ca 2+ signaling in platelets. Objective: To evaluate the contribution of STIM1/SOCE to Ca 2+ ‐dependent platelet activation and thrombosis, we here compared the activation responses of platelets lacking STIM1 and platelets lacking CalDAG‐GEFI. Methods: The murine Stim1 gene was conditionally deleted in the megakaryocyte/platelet lineage. CalDAG‐GEFI –/– and Stim1 fl/fl PF4‐Cre mice, along with littermate control mice, were used for in vitro and in vivo experiments under flow as well as static conditions. Results: Integrin α IIb β 3 ‐mediated aggregation was markedly impaired in CalDAG‐GEFI‐deficient but not STIM1‐deficient platelets, under both static and flow conditions. In contrast, deficiency in either STIM1 or CalDAG‐GEFI significantly impaired the ability of platelets to express phosphatidylserine on the cell surface. When subjected to a laser injury thrombosis model, mice lacking STIM1 in platelets were characterized by the formation of unstable platelet‐rich thrombi and delayed and reduced fibrin generation in injured arterioles. In CalDAG‐GEFI –/– mice, fibrin generation was also delayed and reduced, but platelet accumulation was almost abolished. Conclusions: Our studies suggest that: (i) STIM1/SOCE is critical for the procoagulant activity but not the proadhesive function of platelets; and (ii) at the site of vascular injury, STIM1 and CalDAG‐GEFI are critical for the first wave of thrombin generation mediated by procoagulant platelets.