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J Thromb Haemost. 2011 Oct;9(10):2077-86. doi: 10.1111/j.1538-7836.2011.04474.x.

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

Author information

  • 1Department of Medicine and Cardeza Foundation for Hematologic Research, Thomas Jefferson University, Philadelphia, PA, USA.

Abstract

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.

© 2011 International Society on Thrombosis and Haemostasis.

PMID:
21848641
[PubMed - indexed for MEDLINE]
PMCID:
PMC3184355
Free PMC Article

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