Blood Journal
Leading the way in experimental and clinical research in hematology

Cooperative integrin/ITAM signaling in platelets enhances thrombus formation in vitro and in vivo

  1. Huiying Zhi1,
  2. Lubica Rauova2,
  3. Vincent Hayes2,
  4. Cunji Gao1,
  5. Brian Boylan1,
  6. Debra K. Newman1,3,4,
  7. Steven E. McKenzie5,
  8. Brian C. Cooley6,
  9. Mortimer Poncz2, and
  10. Peter J. Newman1,4,7,8
  1. 1Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI;
  2. 2Division of Hematology, Children’s Hospital of Philadelphia, Philadelphia, PA;
  3. 3Department of Microbiology and
  4. 4Department of Pharmacology, Medical College of Wisconsin, Milwaukee, WI;
  5. 5Cardeza Foundation for Hematological Research, Department of Medicine, Thomas Jefferson University, Philadelphia, PA; and
  6. 6Department of Orthopaedic Surgery,
  7. 7Department of Cellular Biology, and
  8. 8The Cardiovascular Research Center, Medical College of Wisconsin, Milwaukee, WI

Key Points

  • These data establish FcγRIIa as a physiologically important functional conduit for αIIbβ3-mediated outside-in signaling.

Abstract

The integrin family is composed of a series of 24 αβ heterodimer transmembrane adhesion receptors that mediate cell-cell and cell-extracellular matrix interactions. Adaptor molecules bearing immunoreceptor tyrosine-based activation motifs (ITAMs) have recently been shown to cooperate with specific integrins to increase the efficiency of transmitting ligand-binding–induced signals into cells. In human platelets, Fc receptor γ-chain IIa (FcγRIIa) has been identified as an ITAM-bearing transmembrane receptor responsible for mediating “outside-in” signaling through αIIbβ3, the major adhesion receptor on the platelet surface. To explore the importance of FcγRIIa in thrombosis and hemostasis, we subjected FcγRIIa-negative and FcγRIIa-positive murine platelets to a number of well-accepted models of platelet function. Compared with their FcγRIIa-negative counterparts, FcγRIIa-positive platelets exhibited increased tyrosine phosphorylation of Syk and phospholipase Cγ2 and increased spreading upon interaction with immobilized fibrinogen, retracted a fibrin clot faster, and showed markedly enhanced thrombus formation when perfused over a collagen-coated flow chamber under conditions of arterial and venous shear. They also displayed increased thrombus formation and fibrin deposition in in vivo models of vascular injury. Taken together, these data establish FcγRIIa as a physiologically important functional conduit for αIIbβ3-mediated outside-in signaling, and suggest that modulating the activity of this novel integrin/ITAM pair might be effective in controlling thrombosis.

  • Submitted July 13, 2012.
  • Accepted December 2, 2012.
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