Therapeutic heparin concentrations augment platelet reactivity: implications for the pharmacologic assessment of the glycoprotein IIb/IIIa antagonistabciximab

Background This study evaluated the effect of heparin on the platelet react ivity and the pharmacodynamic profile of abciximab. Methods and Results Ex vivo studies were performed on patients undergoing e lective percutaneous coronary intervention (n = 26) who were at moderate to high risk of ischemic complications, Patients received a 12,000-U bolus of heparin followed by a 0.25-mg/kg bolus of abciximab. Before abciximab trea tment, platelet aggregation responses to a variety of stimuli were assessed immediately before and 10 minutes after the heparin bolus. Heparin increas ed platelet aggregation to 2 and 5 mu mol/L adenosine diphosphate (ADP) and 5 mu g/mL collagen by 36%, 25%, and 46%, respectively (P less than or equa l to .001), but did not influence platelet reactivity to thrombin receptor- activating peptide or 20 mu mol/L ADP and had no appreciable effect on plat elet surface glycoprotein (GP) IIb/IIIa receptor numbers. To assess the imp act of heparin on the pharmacodynamic profile of abciximab, GP IIb/IIIa rec eptor blockade and platelet aggregation inhibition estimates obtained after abciximab administration were calculated relative to the basal levels obse rved both before and after the heparin bolus. At 2 and 24 hours after the a bciximab bolus, GP IIb/IIIa receptor blockade measurements normalized to ei ther the preheparin or postheparin baseline determinations were equivalent. For all ADP concentrations tested, the 2-hour post-abciximab bolus platele t aggregation inhibition estimates based on the preheparin and postheparin baseline values were comparable. However, for 2 and 5 mu mol/L ADP, the 24- hour post-abciximab platelet aggregation inhibition measurements based on p reheparin baseline values were significantly lower than postheparin baselin e determinations (both P less than or equal to .003). In vitro studies reve aled that therapeutic heparin doses induced a concentration-dependent reduc tion in the extent of platelet inhibition produced by amounts of abciximab that elicit partial inhibition of platelet aggregation. However, at abcixim ab concentrations that achieved platelet aggregation blockade of >80%, the levels of inhibition of platelet aggregation in the presence and absence of heparin were equivalent. Conclusions The cumulative ex vivo and in vitro data indicate that for cert ain stimuli, heparin alters the platelet inhibitory profile of abciximab at concentrations of the agent that yield partial suppression of platelet fun ction.