Inhibition of tissue factor-activated platelets by low-molecular-weight heparins and glycoprotein IIb/IIIa receptor antagonist

Thrombotic disorders can lead to vascular distress and platelet activation eventually resulting in the rupture of the lesions where a sizable amount o f tissue factor (TF) is generated during the pathogenesis of arterial disea ses. Since low-molecular-weight heparins (LMWHs) and platelet glycoprotein (GP) IIb/III alpha inhibitors are clinically used for the management of acu te coronary syndrome (ACS), studies were taken to determine the effects of these agents on TF-mediated activation of platelets. Freshly drawn native w hole blood (WB) from normal healthy volunteers (n = 6) supplemented with a predetermined amount of TF was incubated with equivalent anti-Xa adjusted a mounts of various LMWHs at 0.01-1.0 U/ml and tirofiban from 10 to 100 ng/ml . Platelet activation was assessed by measuring the expression of P-selecti n (CD62) and the generation of platelet aggregates. At 0.01 U/ml, enoxapari n exhibited a stronger inhibition of TF-induced platelet activation compare d to ardeparin and dalteparin. At 0.1 U/ml, these LMWHs produced a comparab le inhibition of total P-selectin expression, and at 1.0 U/ml, a marked inh ibition was noted. Since enoxaparin produced the best concentration-depende nt inhibition of P-selectin expression (saline: 76 +/- 10% vs. 1.0 U/ml eno xaparin: 18 +/-7%; P < .02) and platelet aggregate formation (saline: 63 +/ -7% vs. 1.0 U/ml enoxaparin: 35 +/-6%, P < .035), this agent was used for a dditional studies. Unlike enoxaparin, tirofiban produced a weak concentrati on-dependent inhibition of platelet activation. At 100 ng/ml, tirofiban pro duced a 40% inhibition of P-selectin expression and about 60% inhibition of platelet aggregate formation. To elucidate the potential interaction betwe en tirofiban and enoxaparin, the effect of 10 and 100 ng/ml tirofiban was s tudied with enoxaparin-supplemented WE in a 0.01-1.0 U/ml range. Additive e ffects between these two agents were noted only at lower concentrations. Th us, at therapeutic concentrations (0.8-1.2 U/ml), enoxaparin itself was cap able of inhibiting TF-mediated activation of platelets to > 70%; whereas ti rofiban failed to produce such concentration-dependent inhibition. This sug gests that the simultaneous administration of GPIIb/ IIIa receptor antagoni st with LMWH may not have any added benefit in the clinical management of p atients with ACS. (C) 2001 Elsevier Science Ltd. All rights reserved.