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(Circulation. 2001;103:2528.)
© 2001 American Heart Association, Inc.

Editorial

Monitoring Platelet Function in Glycoprotein IIb/IIIa Inhibitor Therapy

Kenneth K. Wu, MD, PhD; James T. Willerson, MD

From the University of Texas Medical School at Houston (K.K.W.) and St Luke’s Episcopal Hospital/Texas Heart Institute (J.T.W.), Houston, Tex.

Correspondence to Kenneth Wu, MD, University of Texas Medical School at Houston, 6431 Fannin, MSB 5.016, Houston, TX 77030. E-mail Kenneth.K.Wu{at}uth.tmc.edu

Key Words: Editorials • platelets • glycoproteins

Platelet aggregation is a key step in thrombus formation on the ruptured atherosclerotic plaque and after percutaneous coronary intervention (PCI). It is induced and amplified by several potent agonists, such as collagen, ADP, thromboxane A₂, and thrombin. Each agonist binds to a specific platelet membrane receptor and signals the conformational change of glycoprotein IIb/IIIa (GP IIb/IIIa), which becomes an active receptor for fibrinogen. The binding of fibrinogen to GP IIb/IIIa mediates platelet aggregation.¹ At high shear stress, von Willebrand factor also binds to GP IIb/IIIa and contributes to platelet aggregation.² Thus, platelet surface GP IIb/IIIa plays a critical role in coronary arterial thrombosis and is a target for antithrombotic therapy.

Three classes of GP IIb/IIIa antagonists have been shown to be efficacious in reducing thrombotic events in patients with acute coronary syndromes. Abciximab is a "humanized" hybrid monoclonal antibody that binds to active GP IIb/IIIa, thereby blocking fibrinogen binding and subsequent platelet aggregation. Integrilin (eptifibatide) is a synthetic peptide containing a cyclic KGD (lysine-glycine-aspartic acid) sequence that blocks the GP IIb/IIIa complex without affecting the function of other integrins. Tirofiban is a nonpeptide GP IIb/IIIa receptor antagonist with a potent inhibitory effect on platelet aggregation.³ All 3 drugs (abciximab, eptifibatide, and tirofiban) have been shown by controlled, clinical trials to be beneficial in reducing thrombotic complications in patients with acute coronary artery syndromes who are treated with PCI.^{4 5 6} However, in each of these trials, many patients who received these treatments were not protected.

It has been suggested that the lack of a more protective clinical response is due to subtherapeutic inhibition of GP IIb/IIIa binding activity in these patients. The body-weight–adjusted doses of the GP IIb/IIIa inhibitors selected for previous clinical trials were based on the inhibition of platelet aggregation using in vitro platelet aggregometry. However, because of technical limitations, the dose for each drug was selected on the basis of platelet aggregometry tests in a small number of patients. The sample sizes used in earlier clinical trials was almost certainly too small to detect individual differences in response to these drugs.

Platelet aggregometry for determining in vitro platelet aggregability in response to physiological agonists is a time-honored technique for evaluating the pharmacological actions of platelet inhibitors and has provided valuable information on the clinical use of aspirin, ticlopidine, and clopidogrel. However, this technique assesses the global function of platelets and does not test specific platelet GP IIb/IIIa–binding activity. Furthermore, the procedure requires freshly prepared blood samples from patients and takes several hours to complete. The use of this technique in clinical trials is further limited by a high degree of intraindividual variation.⁷ Therefore, this procedure is not really suitable for selecting therapeutic doses for an individual patient on receptor blockers.

Tests are now available that provide a rapid, reliable, and more specific assessment of GP IIb/IIIa receptor occupancy.⁸ In this issue of Circulation, Steinhubl et al⁹ report the use of the Ultegra Rapid Platelet Function assay (RPFA) to evaluate the relationship between the degree of platelet function inhibition and the risk of thrombotic complications after PCI. The RPFA measures platelet GP IIb/IIIa interaction with fibrinogen-coated beads and is therefore a more specific test for determining the inhibitory activity of GP IIb/IIIa antagonists. A total of 500 patients who planned to receive abciximab, tirofiban, or eptifibatide after a PCI procedure had the RPFA done at several different time points during treatment with GP IIb/IIIa inhibitors. Each patient had a baseline RPFA, and the percentage of inhibition was determined at 10 minutes, 1 hour, 8 hours, and 24 hours after the GP IIb/IIIa inhibitor therapy was begun.

Abciximab was started with an intravenous bolus of 0.25 µg/kg followed by a continuous infusion of 0.125 µg · kg^–1 · min^–1 for a mean duration of 12 hours. Tirofiban was given as a 10 µg/kg bolus followed by a 0.15 µg · kg^–1 · min^–1 infusion for a mean of 12 hours. Eptifibatide was administered as a 180 µg/kg bolus followed by a 2 µg · kg^–1 · min^–1 infusion for a mean duration of 19 hours. Major cardiac events, including acute myocardial infarction, death, or urgent target vessel revascularization, that occurred during the 7 days of PCI were correlated with the degree of RPF inhibition. The results reveal that 25% of patients did not achieve >95% inhibition of RPF at 10 minutes after bolus treatment. These patients had more thrombotic complications than those who achieved >95% inhibition of RPF. The degree of RPF inhibition at 8 hours after treatment had the best predictive value for major cardiac complications. Patients whose RPF inhibition was <70% (6% of the patients studied) had a thrombotic risk 3-fold higher than those whose RPF inhibition was 70%. However, the degree of RPF inhibition at 1 hour and 24 hours after treatment did not predict thrombotic complications, although there was evidence of different responses to the inhibitors among the patients.

The probability analysis provides convincing evidence for maintaining RPF inhibition at a level 70% at 8 hours after abciximab treatment, because the probability of having a complication increased linearly when the level of inhibition was <70%. Probability analyses for the eptifibatide and tirofiban treatment groups was less clear, probably because the sample sizes for these 2 groups were much smaller than that of the abciximab treatment group (84% of patients received abciximab; 9% and 7% received tirofiban and eptifibatide, respectively). The results from this study clearly show that some patients who receive a standard dose of abciximab do not achieve a level of RPFA inhibition that will be therapeutic. The clinical implication of these results is that the dose of abciximab and other GP IIb/IIIa inhibitors should be tailored to provide individual platelet aggregation inhibition. This idea was proposed in the 1970s,¹⁰ and it is gratifying that it may now be taken into practice.

Why do some patients have a subtherapeutic response to GP IIb/IIIa inhibitors? Many factors may influence the response of platelets to GP IIb/IIIa antagonists in these patients. Basal platelet aggregability before treatment among these patients may vary because of underlying risk factors, such as hypertension, hypercholesterolemia, cigarette smoking, stress, and medications used. These factors enhance platelet aggregability, which may render platelets less (or sometimes more) sensitive to GP IIb/IIIa antagonists. Another factor is that all patients generally receive aspirin, which blocks the synthesis of thromboxane A₂ by inhibiting platelet cyclooxygenase-1 activity. Thromboxane A₂ plays an important role in recruiting platelets and amplifying platelet aggregation. Several clinical trials suggest that there are individual differences in the response to aspirin and that some patients are resistant to the standard aspirin dose used in clinical trials. It may be assumed that patients who are less sensitive to aspirin will produce a higher level of platelet thromboxane A₂, thereby amplifying GP IIb/IIIa activity and requiring a higher dose of GP IIb/IIIa inhibitors to suppress such activity.

Another important factor that has attracted increasing attention is the influence of genetic polymorphisms on the response to drugs. GP IIb/IIIa is a complex of 2 gene products, GPIIb and GPIIIa, and both genes are highly polymorphic, with multiple single nucleotide polymorphisms (SNPs) in their coding regions.¹¹ Several SNPs have resulted in coding for proteins exhibiting distinct epitopes, which accounts for the development of alloimmune antibodies.¹¹ The influence of these SNPs on platelet GP IIb/IIIa expression levels and activity has not been evaluated in detail. A common GP IIIa polymorphism (Leu33pro or P1^A1/A2) is reportedly associated with an increased risk of coronary thrombosis.¹² Individuals with the P1^A2 polymorphism (GP IIIa 33-pro) reportedly had a higher incidence of acute myocardial infarction in a cross-sectional, case-control study.¹² However, 2 prospective, cohort-case studies did not show that this allele increased the risk of coronary heart disease.^{13 14} Whether this allele increases thrombotic complications after PCI has not been assessed in prospective clinical trials. In vitro studies reveal that the P1^A2 platelets are more sensitive to platelet agonists.¹⁵ This allele could potentially contribute to relative resistance to treatment with GP IIb/IIIa inhibitors. However, it should be mentioned that single SNPs such as P1^A1/A2 are likely to have only a weak influence on the coded protein function or level. A genomic approach may be needed to determine the influence of multiple SNPs of GPIIb and GPIIIa on the response to GP IIb/IIIa inhibitor treatment.

Other platelet function monitoring techniques have been reported. For example, a shear-dependent platelet function test, which was recently reported in Circulation, was shown to be a reliable test for monitoring GP IIb/IIIa inhibition, especially during long-term therapy with GP IIb/IIIa inhibitors.⁸ This technique does not require a baseline reference and takes shear stress into consideration. Furthermore, it can be used at the bedside. The availability of rapid, reliable, and specific platelet function tests has made possible individualized dose selection to achieve a therapeutic level of inhibition of GP IIb/IIIa binding activity. This approach will improve the efficacy and reduce the bleeding complications of GP IIb/IIIa inhibitors for treating and preventing thrombotic complications in patients undergoing PCI and those with acute coronary artery syndromes. It should also be kept in mind that although the GP IIb/IIIa antagonists potentially inhibit platelet aggregation in response to most mediators (thromboxane, serotonin, ADP, thrombin, platelet-activating factor, collagen, etc.), they do not prevent the activation, adhesion, or secretion of platelets at sites of vascular injury. These physical responses of platelets are almost certainly important in some clinical situations, and they maybe require somewhat different and/or additional therapeutic interventions, including glycoprotein Ib inhibitors and/or inhibitors of platelet adhesion to collagen and/or von Willebrand factor binding domains on injured vascular surfaces.

Footnotes

The opinions expressed in this editorial do not necessarily reflect the views of the editors or of the American Heart Association.

References

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