Use Of Platelet Function Testing Research Articles

Receptor Inhibitors in Acute Coronary Syndromes: What Is New on the Horizon?

Dual antiplatelet therapy with aspirin and a P2Y12 receptor inhibitor represents the cornerstone therapy for patients with acute coronary syndromes or undergoing percutaneous interventions, leading to a reduction of subsequent ischemic events. Variable response to clopidogrel has received close attention, and pharmacokinetic, pharmacodynamic, and pharmacogenomic factors have been identified as culprits. This led to the introduction of newer, potentially safer, and more effective antiplatelet agents (prasugrel and ticagrelor). Additionally, several point-of-care assays of platelet function have been developed in recent years to rapidly screen individuals on antiplatelet therapy. While the routine use of platelet function testing is uncertain and not currently recommended, it may be useful in instances when the degree of platelet inhibition may be uncertain such as high-risk patients undergoing percutaneous coronary intervention or when there may be a suspected pharmacodynamic interaction with other drugs. The current paper focuses on the P2Y12 receptor inhibitors and their pharmacogenetics and indications in patients with acute coronary syndromes or receiving percutaneous coronary interventions as well as the applicability of platelet function testing in this clinical context.

New anti-platelet agents: The end of resistance?

Despite improved clinical outcomes from dual anti-platelet therapy with aspirin plus the CYP12 ADP receptor antagonist clopidogrel in patients undergoing coronary revascularisation, ex-vivo platelet function testing consistently reveals a proportion of patients with apparent resistance or non-response to clopidogrel loading and maintenance therapy who are at increased risk of coronary thrombosis.Treatment regimens using the newer CYP12 antagonists prasugrel and ticagrelor demonstrate improved ex-vivo platelet inhibition and superior clinical efficacy in large-scale clinical trials—even in patients demonstrating clopidogrel resistance. However, improved efficacy comes at the cost of an increased overall risk of bleeding for both drugs. Further analysis of the outcomes from large scale clinical studies suggests that individual patient sub-groups differ both in their liklehood of bleeding with newer anti-platelet agents and with regard to efficacy outcomes.Therefore when deciding anti-platelet regimens in suspected acute coronary syndrome, particular consideration must be given to patient's risk of thrombosis (STEMI, previous stent thrombosis), the procedure (complex PCI, thrombus in-situ, strategy of pre-treatment), and factors affecting safety (patient age, patient weight, previous stroke, liklehood of surgical revascularisation). Placing the focus on individualised patient risk-benefit assessment with appropriate use of platelet function testing when indicated, in combination with the ongoing assessment of prasugrel and ticagrelor in larger numbers of patients should be the key strategies governing use of dual anti-platelet therapy.

Clinical Use of Clopidogrel

In patients with stable and unstable coronary disease and those undergoing coronary stenting, the activation of platelets plays a central role in the occurrence of major thrombotic events such as death, myocardial infarction and stent thrombosis. Antiplatelet therapy for primary and secondary prevention of thromboembolic events is a cornerstone for the management of these patients and for many years the cyclooxygenase-1 (COX-1) inhibitor aspirin and the second generation thienopyridine clopidogrel which targets the ADP P2Y12 receptor on platelets served as the main antiplatelet agents for these indications. Clopidogrel in particular is very efficient in reducing ischemic cardiovascular events but exposes patients to an increased risk of bleeding. Therefore the optimal dosage and duration of clopidogrel therapy is of utmost importance. Furthermore, platelet function studies have revealed that responsiveness to clopidogrel is not uniform and that a low response is linked to a higher incidence of thrombotic events. Causes are multifactorial and several genetic and non-genetic factors including patients' co-morbidities and co-medications have been identified. As a result clopidogrel's long lasting monopole as the only antiplatelet agent in patients undergoing coronary stenting is currently challenged by the newer P2Y12 blockers such as prasugrel and ticagrelor, which provide a stronger and more consistent inhibition of platelets. In the setting of acute coronary syndromes, this more potent platelet inhibition led to less thrombotic events with these newer agents, but at the cost of a higher bleeding risk. This review provides an overview of the indication, dosage and duration of clopidogrel therapy and discusses its role in light of the recent introduction of newer P2Y12 receptor antagonists, the combination with newer oral anticoagulants such as dabigatran, apixaban and rivaroxaban as well as the emerging use of platelet function testing in clinical practice.

Evolving role of platelet function testing in coronary artery interventions

The substantial reduction in ischemic events provided by the dual antiplatelet regimen with aspirin and clopidogrel is well documented in patients with acute coronary syndrome and patients undergoing percutaneous coronary intervention. Recently the variable response to the antiplatelet agents has received considerable attention after several “boxed warnings” on clopidogrel. This led to intense controversy on pharmacokinetic, pharmacodynamic, and pharmacogenomic issues of antiplatelet drugs, especially clopidogrel. Research use of platelet function testing has been successfully validated in identifying new antiplatelet drugs like prasugrel and ticagrelor. These platelet function assays are no longer regarded just as a laboratory phenomenon but rather as tools that have been shown to predict mortality in several clinical trials. It is believed that suboptimal response to an antiplatelet regimen (pharmacodynamic effect) may be associated with cardiovascular, cerebrovascular, and peripheral arterial events. There has been intense controversy about this variable response of antiplatelet drugs and the role of platelet function testing to guide antiplatelet therapy. While the importance of routine platelet function testing may be uncertain, it may be useful in high-risk patients such as those with diabetes mellitus, diffuse three vessels coronary artery disease, left main stenosis, diffuse atherosclerotic disease, and those with chronic renal failure undergoing percutaneous coronary intervention. It could also be useful in patients with suspected pharmacodynamic interaction with other drugs to assure the adequacy of platelet inhibition. While we wait for definitive trials, a predictive prognostic algorithm is necessary to individualize antiplatelet therapy with P2Y12 inhibitors based on platelet function assays and genetic testing.

Relationship between clopidogrel-induced platelet P2Y12 inhibition and stent thrombosis or myocardial infarction after percutaneous coronary intervention—A case-control study

Insufficient platelet inhibition is a major determinant of stent thrombosis (STh), although the etiology is multifactorial. On-clopidogrel platelet reactivity was investigated in patients with previous angiographically confirmed STh, myocardial infarction (MI), and controls. Using the Swedish Coronary Angiography and Angioplasty Registry, we identified patients with angiographically confirmed STh (n = 48) or MI (n = 30) while on dual antiplatelet therapy within 6 months of percutaneous coronary intervention (PCI) and matched control patients (n = 78). On-clopidogrel platelet reactivity was measured with VerifyNow P2Y12 and vasodilator-stimulated phosphoprotein (VASP) phosphorylation assay. The mean P2Y12 reaction units (PRU) was higher (246.8 ± 75.9 vs 200.0 ± 82.7, P = .001) in STh patients compared with controls. The optimal cutoff for STh was 222 PRU or higher (area under the curve 0.69, P < .0001) in a receiver operating characteristics (ROC) analysis. The cutoff level resulted in 70.2% sensitivity and 67.3% specificity. There was no significant difference in mean PRU but a higher device-reported percent inhibition (45.1 ± 23.8 vs 32.1 ± 23.2, P = .04) in patients with MI compared with controls. Results with the VASP phosphorylation assay were not related to the occurrence of STh or MI. STh was associated with high on-clopidogrel platelet reactivity measured with VerifyNow (cutoff level of PRU ≥222) but spontaneous MI in stented patients on clopidogrel treatment was not. There was, however, a substantial overlap in on-clopidogrel platelet reactivity between patients with and without on-treatment STh questioning the clinical use of platelet function testing to identify patients at high risk for STh.

Routine Platelet Testing Should Not Be Performed on All Patients Undergoing Percutaneous Coronary Intervention

We all know that clopidogrel reduces thrombotic complications during and after a percutaneous coronary intervention (PCI) procedure. Because clopidogrel is a prodrug and only ≈2% of ingested clopidogrel is ultimately bound to platelets, it is entirely possible, even likely, that small differences in metabolism that lead to a reduction in the formation of the active metabolite could potentially have an enormous clinical impact.1 So, it would seem entirely logical to measure individual patient's response to clopidogrel and to alter their therapy in an individualized manner. After all, are we not moving as a profession with great enthusiasm to the practice of “personalized medicine?” And should we not? Does it make sense that patients young or old, tall or short, lightweight or obese, and so on would all require the same dose of clopidogrel and respond to it to the same degree? No, it does not. Response by Price on p 288 Having said that, the truth is that there are scant data to date that the routine use of platelet function testing for all patients to whom clopidogrel is administered would improve clinical outcomes. In fact, the currently available data suggest the opposite. How can we make such a statement in view of all the studies that at first glance might seem to suggest the opposite? The issues suggesting that routine platelet function testing of all patients on clopidogrel ought not yet be routinely used to guide clinical practice can perhaps be most clearly understood by examining the following basic yet fundamental concerns: Clopidogrel resistance, or to use the more appropriate and preferred term, hyporesponsiveness to …

Review: Platelet Function Testing and Implications for Clinical Practice

Platelets are key mediators in the pathophysiology of atherothrombotic disease. Inappropriate platelet activation can lead to thrombosis and ischemic events. Platelet function testing has been used to monitor patient response to antiplatelet therapy. Variability in response to antiplatelet therapy may be due in part to incomplete inhibition of targeted pathways (thromboxane A(2) and adenosine diphosphate [ADP]) by currently available agents (aspirin and P2Y(12) ADP receptor antagonists). Low responsiveness to antiplatelet therapy (as measured in various platelet function assays) correlates with a high rate of ischemic events. However, tailoring treatment based on platelet response remains to be definitively proven in clinical trials, correlations between assays are modest, and concordance in defining suboptimal response is poor. Additional studies are needed to determine whether changes in therapy based on results of platelet function testing improve clinical outcomes, and thus will determine whether broader use of platelet function testing in clinical practice is warranted.

Monitoring Antiplatelet Therapy with Point-of-Care Platelet Function Assays: A Review of the Evidence

Multiple studies have demonstrated that subgroups of patients receiving combination therapy with aspirin and clopidogrel fail to produce the anticipated antiplatelet effect, and various terms such as 'aspirin resistance', 'clopidogrel resistance', 'heightened post-treatment platelet reactivity' and 'residual platelet reactivity' have been introduced in the medical literature. Light transmittance aggregometry is generally considered to be the gold standard for determining platelet function, but its relevance to in vivo platelet function is questionable and the logistical demands of the method make it impossible to use in daily practice. The introduction of several point-of-care platelet function assays may be the key to the widespread clinical use of platelet function testing and may identify patients who are at risk for the occurrence of adverse cardiac events. In the present paper, we discuss the current commercially available methods of assaying platelet function, including their advantages and limitations and whether they have been shown to correlate with clinical outcomes.

Heritability, Platelet Function, and Aspirin

Platelets play a critical role in the pathophysiology of atherothrombotic disease. A pivotal event contributing to the understanding of platelet-dependent clot formation was the development of the platelet aggregometer in 1962.1 An aggregometer specifically measures the ability of platelets to adhere via glycoprotein IIb/IIIa (integrin αIIbβ3), and thousands of articles using this technique have been published, characterizing platelet function; however, the usefulness of these measurements remains unclear. Whereas the aggregometer and related techniques that measure platelet aggregation or glycoprotein expression have led to large amounts of data characterizing platelet function in various settings, the clinical importance of measurable differences in platelet function is still debated.2 The use of platelet function testing is established in rarer platelet abnormalities, such as the autosomal recessive bleeding disorder Glanzmann thrombasthenia,3 but no clear consensus has been reached on its usefulness for highly prevalent diseases caused by platelet-dependent thrombosis, such as myocardial infarction. A major factor for this discrepancy is that many of the platelet function defects that lead to bleeding are known to be caused by a single defect, whereas thrombosis in the setting of cardiovascular disease is presumed to be multifactorial. Article p 2490 The evolution of platelet function studies in various clinical settings has led to the realization that wide interindividual variability exists in the platelet activation response.4,5 What accounts for this variability? Only a few studies have systematically examined this question. Platelet function has been established as markedly dependent on the type of agonist used, the agonist concentration, and the concomitant use of antiplatelet therapy.6 In addition, in the large population-based Framingham Heart Study, O’Donnell and colleagues7 have demonstrated that heritable factors play a major role in determining platelet aggregation, as opposed to measured covariates. Less clear from the current literature is the direct …

Platelet Function Testing: Quality Assurance

Platelet function tests are widely used for the diagnosis of platelet disorders. In recent years there has been increasing interest in the use of platelet function tests to monitor antiplatelet drug therapy. Quality assurance is important to optimize the performance of laboratory assays but it has not been widely applied to platelet function tests. This deficiency likely reflects the need to use freshly collected blood samples for platelet function tests, and the complex, time-consuming nature of some assays such as aggregation studies. Platelet function testing lacks guidelines, is poorly standardized between laboratories, and rarely is evaluated by internal and external quality assurance exercises. The sensitivity, specificity, and diagnostic utility of some newer, simplified assays of platelet function have been evaluated in a range of clinical settings but corresponding quality assurance data for many established as well as emerging platelet function assays are lacking. Quality assurance issues relevant to testing platelet function are reviewed in this article, with a focus on their application to established and to new and emerging tests.

Current Options in Platelet Function Testing

The variable response to antiplatelet therapy has led to the use of platelet function tests to monitor the effects of antiplatelet drugs in cardiovascular diseases. The goal is to guide antiplatelet therapy to the optimal dose for the prevention or treatment of thrombosis while minimizing hemorrhagic side effects. The bleeding time is no longer recommended for use because of its nonspecificity and lack of clinical correlations. The current de facto "gold standard" test of platelet function is turbidometric platelet aggregometry. Although this method has been successful in measuring the aggregation of platelets in a glycoprotein (GP) IIb/IIIa (integrin alpha(IIb)beta(3))-dependent manner, it has several limitations, including poor reproducibility, high sample volume, requirement for sample preparation, length of assay time, requirement for a skilled technician, and cost. Therefore, new options for platelet function testing have been developed to address these disadvantages and to meet the need for point-of-care testing that can be performed at or near a patient's bedside without requiring a high degree of technical expertise. The new tests include VerifyNow (Accumetrics, San Diego, CA); Plateletworks (Helena Laboratories, Beaumont, TX); Thrombelastograph PlateletMapping System (Haemoscope Corporation, Niles, IL); Impact cone and plate(let) analyzer (DiaMed, Cressier, Switzerland); and Platelet Function Analyzer 100 (PFA-100; Dade Behring, Newark, DE). In patients treated with antiplatelet drugs, the degree of platelet inhibition, as determined by several of these new platelet function assays, has been shown to predict major adverse cardiac events.

The assessment of platelet function

SUMMARYPlatelet activation is involved in physiological hemostasis and in a variety of thromboembolic events leading to stroke, myocardial ischemia, and other organ dysfunction. Apart from congenital platelet dysfunction, acquired platelet defects are increasingly common in patients due to the widespread use of antiplatelet agents. Newer antiplatelet agents targeting platelet glycoprotein IIb–IIIa and adenosine‐5′‐diphosphate receptors inhibit platelet activation, and therefore assessing platelet inhibition may be important to prevent major bleeding, especially before a surgical intervention. In the past decade, the knowledge from genotypic analyses and prospective outcome studies suggested inter‐patient variability in the therapeutic response to antiplatelet therapies, which further stresses the need for individual platelet testing. In managing bleeding patients, platelet transfusion may be better guided by the use of platelet function tests because transfusion therapy is costly and potentially harmful if administered inappropriately. Basic understanding of the hemostatic roles of platelets, etiologies of platelet defects, and characteristics of current platelet assessment methods should help physicians who manage complex coagulation issues in critically ill patients.

Small peptide GP IIb/IIIa receptor inhibitors as upstream therapy in non-ST-segment elevation acute coronary syndromes: results of the PURSUIT, PRISM, PRISM-PLUS, TACTICS, and PARAGON trials.

The primary pathophysiologic mechanism underlying all non-ST-segment elevation acute coronary syndromes (NSTE ACS) is the formation of platelet-rich coronary thrombi in response to spontaneous or intervention-induced endothelial damage with exposure of subendothelial substrates. Antagonists of the glycoprotein (GP) IIb/IIIa receptor ameliorate this process by blocking the final common pathway for platelet aggregation. Based upon collective data in over 24,000 patients, clinical trials have demonstrated that treatment of NSTE ACS patients with GP IIb/IIIa agents results in an approximate 12% relative risk reduction in the incidence of death or myocardial infarction at 30 days. The magnitude of this clinical benefit is increased in patients who are troponin-positive and who are referred for early percutaneous intervention. Potential benefits of GP IIb/IIIa inhibitor use must be weighed against an increased risk of bleeding. Ongoing controversies exist concerning the relative efficacy of different GP IIb/IIIa antagonists, the accurate use of platelet function tests to define safe and efficacious drug dosing, the adjunctive use of additional anti-thrombotic agents, and the optimal timing of upstream therapy before diagnostic cardiac catheterization and revascularization.