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Prepublished online as a Blood First Edition Paper on June 21, 2002; DOI 10.1182/blood-2002-04-1234.
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Blood, 15 October 2002, Vol. 100, No. 8, pp. 2839-2844
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
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
From the Departments of Internal Medicine and
Pediatrics, University of Iowa College of Medicine, and Veterans
Affairs Medical Center, Iowa City; Abramson Family Cancer Research
Institute, Department of Pathology and Laboratory Medicine, University
of Pennsylvania School of Medicine, Philadelphia.
The adapter protein SLP-76 is a critical mediator of signal
transduction via the platelet collagen receptor glycoprotein VI (GPVI)
and its coreceptor 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 < .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 < .001 versus unstimulated platelets). Similar
results were obtained with platelets from FcR null mice, for which
collagen, but not convulxin, induced procoagulant activity
(P < .01). Costimulation with thrombin and collagen
produced a further (2.3-fold) increase in procoagulant activity in
SLP-76+/ platelets (P < .05), but not in
SLP-76/ platelets. SLP-76/ platelets
also exhibited less annexin V binding than SLP-76+/
platelets after costimulation with thrombin and convulxin
(P < .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 costimulation with thrombin plus
collagen. Thus, both GPVI-dependent and GPVI-independent pathways
contribute to collagen-induced platelet procoagulant activity.
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