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Prepublished online as a Blood First Edition Paper on June 21, 2002; DOI 10.1182/blood-2002-04-1234.
Submitted April 24, 2002
Accepted June 7, 2002
Role of the adapter protein SLP-76 in GPVI-dependent platelet procoagulant responses to collagen
Lorie Leo, Jorge Di Paola, Barbi A Judd, Gary A Koretzky, and Steven R Lentz*
Department of Internal Medicine, University of Iowa, Iowa City, IA, USA
Department of Pediatrics, University of Iowa, Iowa City, IA, USA
Abramson Family Cancer Research Institute, Department of Pathology and Laboratory Medicine, University of Pennsylvannia School of Medicine, Philadelphia, PA, USA
Department of Internal Medicine, University of Iowa, Iowa City, IA, USA; Veterans Affairs Medical Center, Iowa City, IA, USA
* Corresponding author; email: steven-lentz{at}uiowa.edu.
The adapter protein SLP-76 is a critical mediator of signal transduction via the platelet collagen receptor GPVI and its co-receptor FcR . We tested the hypothesis that SLP-76 is required for collagen-induced procoagulant responses in murine platelets. Platelets from SLP-76 null (SLP-76-/-) or heterozygous (SLP-76+/-) mice were activated with the GPVI agonist convulxin, and surface expression of P-selectin (a marker of granule release) and annexin V binding (a marker of procoagulant phospholipid) were determined by flow cytometry. Convulxin induced surface expression of P-selectin in SLP-76+/- platelets, but not SLP-76-/- platelets (p<0.01), and failed to stimulate annexin V binding to either SLP-76+/- or SLP-76-/- platelets. Platelet procoagulant activity was measured in a prothrombinase assay. Convulxin did not stimulate procoagulant activity in either SLP-76+/- or SLP-76-/- platelets, but fibrillar collagen produced a 1.9-fold increase in procoagulant activity in both SLP-76+/- and SLP-76-/- platelets (p<0.001 vs. unstimulated platelets). Similar results were obtained with platelets from FcR null mice, for which collagen, but not convulxin, induced procoagulant activity (p<0.01). Co-stimulation with thrombin and collagen produced a further (2.3-fold) increase in procoagulant activity in SLP-76+/- platelets (p<0.05), but not in SLP-76-/- platelets. SLP-76-/- platelets also exhibited less annexin V binding than SLP-76+/- platelets after co-stimulation with thrombin and convulxin (p<0.05). These findings demonstrate that an intact GPVI/FcR/SLP-76 signal transduction pathway is not essential for platelet procoagulant activity induced by collagen but is necessary for maximal procoagulant response to co-stimulation with thrombin plus collagen. Thus, both GPVI-dependent and GPVI-independent pathways contribute to collagen-induced platelet procoagulant activity.
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