Relative contributions of stromal interaction molecule 1 and CalDAG‐GEFI to calcium‐dependent platelet activation and thrombosis

• Published in: Journal of thrombosis and haemostasis 2011-10, Vol.9 (10), p.2077-2086
• Main Authors: AHMAD, F., BOULAFTALI, Y., GREENE, T. K., OUELLETTE, T. D., PONCZ, M., FESKE, S., BERGMEIER, W.
• Format: Article
• Language: English
• Subjects: Animals; Blotting, Western; Calcium - metabolism; Calcium Channels; Guanine Nucleotide Exchange Factors - physiology; Male; Membrane Glycoproteins - physiology; Mice; platelet; Platelet Activation; procoagulant; store‐operated calcium entry; Stromal Interaction Molecule 1; stromal interaction molecule 1; thrombosis; Thrombosis - physiopathology
• ISSN: 1538-7933; 1538-7836; 1538-7836
• DOI: 10.1111/j.1538-7836.2011.04474.x

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 Ca2+‐sensing guanine nucleotide exchange factor CalDAG‐GEFI as a critical molecule in Ca2+ signaling in platelets. Objective: To evaluate the contribution of STIM1/SOCE to Ca2+‐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 Stim1fl/flPF4‐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 αIIbβ3‐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.