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Blood, 15 April 2001, Vol. 97, No. 8, pp. 2314-2322
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Antiplatelet agents in tissue factor-induced blood
coagulation
Saulius Butenas,
Kevin M. Cawthern,
Cornelis van't
Veer,
Maria E. DiLorenzo,
Jennifer B. Lock, and
Kenneth
G. Mann
From the Department of Biochemistry, College of
Medicine, University of Vermont, Burlington.
Several platelet inhibitors were examined in a tissue factor
(TF)-initiated model of whole blood coagulation. In vitro coagulation of human blood from normal donors was initiated by 25 pM TF while contact pathway coagulation was suppressed using corn trypsin inhibitor. Products of the reaction were analyzed by immunoassay. Preactivation of platelets with the thrombin receptor activation peptide did not influence significantly the clotting time or
thrombin-antithrombin III complex (TAT) formation. Addition of
prostaglandin E1 (5 µM) caused a significant delay in
clotting (10.0 minutes) versus control (4.3 minutes). The prolonged
clotting time is correlated with delays in platelet activation,
formation of TAT, and fibrinopeptide A (FPA) release. In blood from
subjects receiving acetylsalicylic acid (ASA or aspirin), none of the
measured products of coagulation were significantly affected.
Similarly, no significant effect was observed when 5 µM dipyridamole
(Persantine) was added to the blood. Antagonists of the platelet
integrin receptor glycoprotein (gp) IIb/IIIa had intermediate effects
on the reaction. A 1- to 2-minute delay in clot time and FPA formation
was observed with addition of the antibodies 7E3 and Reopro (abciximab)
(10 µg/mL), accompanied by a 40% to 70% reduction in the maximal
rate of TAT formation and delay in platelet activation. The
cyclic heptapetide, Integrilin (eptifibatide), at 5 µM
concentration slightly prolonged clot time and significantly attenuated
the maximum rate of TAT formation. The disruption of the
gpIIb/IIIa-ligand interaction not only affects platelet aggregation,
but also decreases the rate of TF-initiated thrombin generation in
whole blood, demonstrating a potent antithrombotic effect
superimposed on the antiaggregation characteristics.
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