Effects of GP IIb/IIIa receptor antagonists on the activated clotting time of heparinized blood

The activated clotting time (ACT) is a functional measure of the intrinsic coagulation pathway that has become a standard monitoring device of heparin. In the Evaluation of c7E3 Fab in the Prevention of Ischemic Complications (EPIC) study, ACT has been measured during percutaneous transluminal coronary angioplasty (PTCA)to minimize thrombotic events and hemorrhagic complications.1,2 To investigate whether a GP IIb/IIIa receptor antagonist influences ACT, Moliterno et al3reviewed data from the EPIC trial and demonstrated that ACT was more prolonged in heparinized patients treated with c7E3 Fab(abciximab-Reopro) than in those treated with placebo. Subsequently, it was shown in vitro that the addition of c7E3 Fab significantly prolonged ACT of blood anticoagulated with heparin, hirudin, and D-phenylalanine-L-propyl-L-arginyl chloromethyl ketone (PPACK),suggesting that in vivo c7E3 Fab acts not only as an antiplatelet but also as an anticoagulant agent.4 The ACT of in vitro heparinized blood obtained from healthy donors or obtained from patients during cardiopulmonary bypass was prolonged when a platelet inhibitor (prostacyclin or carbacyclin, respectively) was added.5 Since platelet activation leads to generation of thrombin,6 it is not surprising that a coagulation time measured in whole blood might be dependent on platelet function. Consequently, the presence of platelet inhibitors can influence ACT.

In current practice, 2 automated devices, HemoTec (Medtronic Inc,Parker, CO) and Hemochron (ITC Technidyne Corp, Edison, NJ) are commonly used for measuring ACT, each one using a different technique to determine clot formation in the presence of diatomaceous earth or kaolin as contact activator.7 As shown in patients undergoing coronary angioplasty,8 HemoTec and Hemochron ACT measurements cannot be used interchangeably after heparin administration because Hemochron values are about 28% higher than the HemoTec values.

Here we report that when ACT is determined by the Hemochron device(Figure 1A, B), the time elapsed between blood sampling in heparin and the actual measurement plays a crucial role: the longer the delay time, the shorter the ACT. In the presence of a GP IIb/IIIa antagonist such as c7E3 Fab or the nonpeptide antagonist lamifiban9 in the heparinized blood, a clear prolongation of ACT was observed as compared to the heparinized blood without GP IIb/IIIa antagonist, and in addition the ACT values became more constant over time. In contrast, the ACT of heparinized blood determined by the HemoTec device (Figure 1C, D) was stable for at least 40 minutes. In the presence of the GPIIb/IIIa antagonist no additional prolongation of ACT was measured.

The differences in the ACT observed between the Hemochron and the HemoTec devices can be explained by in vitro platelet activation occurring when the Hemochron FTK-ACT cartridges are used,because vigorous shaking of the tube is required to disperse the activator (kaolin) in the blood (instructions of the manufacturer). Under these conditions the continuous decrease of the ACT of the heparinized blood over time might be indicative of increased thrombin generation due to the platelet activation. In the presence of an antiplatelet agent such as c7E3 or lamifiban, the thrombin generation is inhibited,10 resulting in a prolongation of ACT that maintains constant ACT values over 40 minutes. In contrast, when the HemoTec High Range (HR)-ACT cartridges(activator: kaolin) are used, no manual agitation is required to activate the coagulation process (instructions of the manufacturer). Because of this softer handling of the blood samples, less or no platelet activation occurs, which explains why the ACT of heparinized blood remains stable over 40 minutes and is independent of the presence of a GP IIb/IIIa antagonist.

Which of the two ACT devices is more exact for measuring the in vivo anticoagulation is difficult to assess. Use of the Hemochron device means that the platelets contribute to the coagulation time, and therefore, GPIIb/IIIa antagonists are prolonging the ACT. One could argue that this device mimics the situation at a site of injury where platelets become activated and contributes to the coagulation process. In contrast, in the HemoTec system the platelet function appears to play a minor role because GPIIb/IIIa antagonists have no influence on the ACT.

The analysis of the EPIC trial pointed to the importance of ACT measurements for patients undergoing concomitant heparin and GPIIb/IIIa antagonist therapy.3 Based on our findings, we conclude that the optimal adjustment of the anticoagulation in patients treated with heparin and a GPIIb/IIIa antagonist depends on the ACT device used. Thus, there is a need for a standardized method for ACT measurements in the case of this combination therapy.