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Blood, Vol. 93 No. 11 (June 1), 1999:
pp. 3792-3797
Activated Protein C Resistance: Effect of Platelet Activation,
Platelet-Derived Microparticles, and Atherogenic Lipoproteins
Janis Taube,
Nicola McWilliam,
Roger Luddington,
Christopher D. Byrne, and
Trevor Baglin
From the Department of Haematology and the University
Department of Clinical Biochemistry, Addenbrooke's NHS Trust,
Cambridge, UK.
Plasma and platelet factor Va represent different substrates for
activated protein C (APC). In this study, we have measured platelet-dependent APC resistance and the effect of aspirin and a
platelet glycoprotein IIbIIIa antagonist (GR144053F) on this phenomenon. In platelet rich plasma (PRP), progressive APC resistance was observed with increasing platelet activation. APC sensitivity ratios of 1.8, 1.7, and 1.4 were observed after platelet activation with thrombin receptor activating peptide (TRAP), collagen, and A23187,
respectively. Ultracentrifugation at 77,000g for 1 hour abolished APC resistance indicating that the phenotype is associated exclusively with the platelet membrane. APC resistance was not observed
in the presence of phosphatidylcholine-phosphatidylserine (PCPS)
vesicles or purified human plasma lipoproteins. APC resistance was
observed in the presence of platelet-derived microparticles, but to a
lesser degree than that in the presence of activated platelets. The
platelet-dependent APC resistance phenotype was also observed when
endogenous APC was generated by Protac (American Diagnostica,
Inc, Greenwich, CT). In vitro inhibition of platelet activation with aspirin had no effect, but the fibrinogen receptor antagonist, GR144053F, inhibited platelet-dependent APC resistance. These results indicate that platelet activation results in an APC-resistant phenotype comparable to that observed in the plasma of
patients with factor V gene mutations affecting critical APC cleavage
sites. This suggests that platelet activation at the site of
endothelial damage downregulates a critical natural anticoagulant mechanism. The antithrombotic effect of aspirin may be due to an
indirect effect on platelet-dependent APC resistance with reduced platelet retention within a developing thrombus. The more potent antithrombotic effect of glycoprotein IIbIIIa antagonists may in
addition be the result of reduced platelet factor Va expression and
modulation of the platelet-dependent APC resistance phenotype.
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