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 of tissue factor (TF) is generated during the pathogenesis of arterial diseases. Since low-molecular-weight heparins (LMWHs) and platelet glycoprotein (GP) IIb/IIIa inhibitors are clinically used for the management of acute coronary syndrome (ACS), studies were taken to determine the effects of these agents on TF-mediated activation of platelets. Freshly drawn native whole blood (WB) from normal healthy volunteers (n = 6) supplemented with a predetermined amount of TF was incubated with equivalent anti-Xa adjusted amounts 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-selectin (CD62) and the generation of platelet aggregates. At 0.01 U/ml, enoxaparin exhibited a stronger inhibition of TF-induced platelet activation compared to ardeparin and dalteparin. At 0.1 U/ml, these LMWHs produced a comparable inhibition of total P-selectin expression, and at 1.0 U/ml, a marked inhibition was noted. Since enoxaparin produced the best concentration-dependent inhibition of P-selectin expression (saline: 76 +/- 10% vs. 1.0 U/ml enoxaparin: 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 additional studies. Unlike enoxaparin, tirofiban produced a weak concentration-dependent inhibition of platelet activation. At 100 ng/ml, tirofiban produced a 40% inhibition of P-selectin expression and about 60% inhibition of platelet aggregate formation. To elucidate the potential interaction between tirofiban and enoxaparin, the effect of 10 and 100 ng/ml tirofiban was studied with enoxaparin-supplemented WB in a 0.01-1.0 U/ml range. Additive effects between these two agents were noted only at lower concentrations. Thus, at therapeutic concentrations (0.8-1.2 U/ml), enoxaparin itself was capable of inhibiting TF-mediated activation of platelets to > 70%; whereas tirofiban failed to produce such concentration-dependent inhibition. This suggests that the simultaneous administration of GPIIb/IIIa receptor antagonist with LMWH may not have any added benefit in the clinical management of patients with ACS.
Ahmad
S
S
Department of Thoracic and Cardiovascular Surgery, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, USA.
Jeske
W P
WP
Ma
Q
Q
Walenga
J M
JM
Fareed
J
J
D001792:Blood Platelets / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D017984:Enoxaparin / Q000494:pharmacology; D006495:Heparin, Low-Molecular-Weight / Q000494:pharmacology*; D006801:Humans; D019007:P-Selectin / Q000378:metabolism; D015539:Platelet Activation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D013925:Thromboplastin / Q000494:pharmacology*; D000077466:Tirofiban; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000494:pharmacology
D017984:Enoxaparin; D006495:Heparin, Low-Molecular-Weight; D019007:P-Selectin; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D014443:Tyrosine; D013925:Thromboplastin; D000077466:Tirofiban