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Platelet-Derived Factor Va/VaLeiden Cofactor Activities
Are Sustained on the Surface of Activated Platelets Despite the
Presence of Activated Protein C
Rodney M. Camire,
Michael Kalafatis,
Paolo Simioni,
Antonio Girolami, and
Paula B. Tracy
From the Department of Biochemistry, University of Vermont, College
of Medicine, Burlington, VT; and the Institute of Medical Semeiotics,
University-Hospital of Padua Medical School, Padua, Italy.
We investigated the role of the thrombin-activated platelet in
modulating the rate and extent of activated protein C (APC)-catalyzed inactivation of platelet-derived factor Va and factor
VaLeiden. Platelet-derived factor Va and factor
VaLeiden were inactivated by APC at near identical rates;
however, complete inactivation of the cofactors was never achieved.
Greater residual cofactor activity remained when using
thrombin-activated platelets compared with that observed with synthetic
phospholipid vesicles and platelet-derived microparticles, suggesting
that thrombin-activated platelets protect the cofactors from
APC-catalyzed inactivation. This apparent protection was not due to (1)
an insufficient number of membrane binding sites for APC or factor Va;
(2) the destruction of these sites; or (3) the presence of a
platelet-associated APC inhibitor. Results from a plasma-based clotting
assay (with or without APC) with platelets or PCPS vesicles added to
induce clot formation indicated that, even in the presence of high
concentrations of APC, platelets offered protection of the cofactor by
delaying cleavage at Arg506. This resulted in incomplete
proteolysis of the heavy chain, suggesting that platelets can also
protect plasma-derived factor Va from APC-catalyzed inactivation.
However, additional experiments indicated that the plasma-derived
cofactor, bound to thrombin-activated platelets, was completely
inactivated by APC, suggesting that the plasma and platelet-derived
cofactor pools represent different substrates for APC. Collectively,
these results indicate that platelets sustain procoagulant events by
providing a membrane surface that delays cofactor inactivation and by
releasing a cofactor molecule that displays an APC resistant phenotype.
Thus, at sites of arterial injury, the factor VLeiden
mutation may not as readily predict arterial thrombosis, because the
normal and variant platelet-derived cofactors are equally resistant to
APC at the activated platelet surface.
Blood, Vol. 91 No. 8 (April 15), 1998:
pp. 2818-2829
© 1998 by The American Society of Hematology.
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