- Elevated platelet count, platelet activation and platelet hyperreactivity (defined as residual platelet activity despite antiplatelet drug therapy) may be associated with adverse cardiovascular events in patients with acute coronary syndromes (ACS).
- Certain platelet reactivity tests can help predict the risk of adverse outcomes related to blood clots in patients receiving dual anti-platelet therapy following percutaneous coronary interventions (PCI). Thus testing response to anti-platelet therapy has a role in high risk patients undergoing complex PCI procedures.
- Patients showing a high degree of platelet reactivity despite being treated with a clopidogrel/aspirin combination would be suitable for treatment with new antiplatelet agents like prasugrel or ticagrelor.
1. The clinical dilemma
Platelet activation is one of the essential mechanisms in the genesis and propagation of atherothrombotic complications.
Anti-platelet therapy is widely used in clinical practice. As percutaneous coronary interventions (PCI) increase in number and complexity, more and more patients receive anti-platelet therapy for treating or preventing cardiovascular disease where arterial thrombosis plays a major role.
Coronary heart disease is a common cardiovascular disease, affecting millions of patients wold-wide. Anti-platelet therapy is first-line medical treatment for these patients, and can be increased double or three-fold in cases of interventional coronary procedures such as stent implantation.
Although anticoagulation monitoring is standard practice, monitoring antiplatelet therapy has not yet been widely adopted as a means of assessing antithrombotic response.
2. Platelet function tests
Response to antiplatelet therapy varies from one patient to another. A variety of platelet function tests have been developed to monitor the effects of antiplatelet drugs in cardiovascular diseases, in an attempt to tailor the type and dosing of antiplatelet therapy to achieve optimal prevention or treatment of thrombosis while minimising bleeding complications. A number of these methods are briefly outlined.
Platelet count: low platelet count is one of the most common causes of bleeding. It is not a functional assay.
Bleeding time: developed in 1900s. It has many disadvantages, it is therefore not useful.
Platelet aggregometry: measures aggregation between platelets in a glycoprotein IIb/IIIa-dependent manner measured in platelet-rich plasma by turbidometry. It is a time-consuming expensive assay and requires a skilled technician.
Platelet Function Analyser (PFA-100): is a global platelet function assay that measures multiple platelet functions, including platelet adhesion and aggregation. Platelets adhere to several membranes and then activate, aggregate and occlude a hole in the centre of each membrane, yielding a measurable closure time. Its utility lies on its ability to detect aspirin-induced platelet dysfunction or intrinsic platelet functional disorders.
Whole blood platelet aggregation (VerifyNow®): offers a point-of-care assessment of platelet function. It has a small size and operates measuring the rate and extent of change in light transmittance in response to the introduction of agonists specific to various antiplatelet medications. It measures the aspirin -or thienopyridine-induced defects in platelet function. Three assays are currently available: IIb/IIIa, aspirin and P2Y12.
PlateletworksTM: is another whole-blood assay with minimal sample preparation which compares platelet counts in a control tube with platelet counts in a citrate tube after aggregation with either ADP or collagen.
Measurement of VASP phosphorylation: vasodilator-stimulated phosphoprotein (VASP) is an intracellular platelet protein that is nonphosphorilated in basal state. Its phosphorylation depends on the level of activation of the P2Y12 receptor, a target of thienopyridine drugs. Thus, measuring VASP phosphorylation by flow cytometry using citrated whole blood can be a highly specific indicator of the action and efficacy of thienopyridine drugs.
Impact: after automated staining, platelet adhesion to a standardised cup is evaluated by image analysis software. It has been used to monitor GP IIb/IIIa antagonists, aspirin and thienopyridines.
In the POPULAR study, 1069 patients were analysed with + 6 platelet reactivity tests.
Three of theses tests (VerifyNow-P2Y12®, Light Transmittance Aggregometry –LTA- and PlateletworksTM) predicted a risk of adverse events in patients receiving two antiplatelet drugs following angioplasty (PCI) plus stenting at one year. Of these three predictive tests,
- LTA is labour-intensive and cannot be performed at bedside.
- PlateletworksTM must be done within 10 minutes of drawing blood.
- VerifyNow does not have the above written limitations.
The other three tests tested didn’t show predictive value (Impact R with and without ADP stimulation; PFA-100 system and Innovance PFA P2Y).
3. Clinical applications
Oral antiplatelet therapy could be tailored depending on platelet reactivity tests in some clinical scenarios: (i) to optimize the dose of aspirin for long-term therapy; (ii) to select the dose of thienopyridines, especially in percutaneous coronary interventions, acutely and during long-term therapy; and (iii) to evaluate the level of platelet inhibition before coronary artery bypass grafting or other major surgery.
3.1. Acute coronary syndromes
The formation of blood clots within a stent (stent thrombosis) is an important concern after PCI with coronary stenting placement to open narrowed coronary arteries.
Recent trials have demonstrated that high levels of platelet reactivity, measured by the VerifyNow assay, are associated with an increase 12-month risk of ischemic events in patients who undergo stenting for acute coronary syndromes, with a cut-off value of platelet reactivity units (PRU) = 240, with hazard ratios up to 2,73 for nonfatal MI and 2,38 for cardiovascular death.
These authors calculated the predictive accuracy of VerifyNow with this cut-off value in this setting, showing a sensitivity of 61%, specificity of 70%; negative predictive value up to 96% and positive predictive value of 12%.
In a recent study, tailored dose of clopidogrel based on VASP phosphorylation analysis demonstrated a significant reduction of blood clots in stents and MACE one month after the implantation of stents after ACS (basal clopidogrel dose of 600 mg and titrated up to 2800 mg in low responders) (0,5% vs. 4,2% and 0,5% vs 8,9%, respectively).
Before platelet reactivity assays can be implemented in daily practice, it still remains to be seen whether tailoring antithrombotic therapy leads to a reduction in adverse events. Ongoing trials, GRAVITAS (Gauging Responsiveness with A VerifyNow assay-Impact on Thrombosis And Safety) and DANTE (Dual Antiplatelet Therapy tailored on the Extent of platelet inhibition) are expected to answer this question. In addition, other forms of platelet hyperreactivity are being studied in diabetics, obesity and advanced age.
The next step will be to study specific genetic polymorphisms in order to anticipate patient response to aspirin/clopidogrel associated with a reduced metabolism of the drug. These genetic studies are unlikely to be available in clinical setting in patients treated for acute coronary syndromes.
3.2. Presurgical screening and implications for cardiac and noncardiac surgical procedures
Bleeding is a common complication of cardiac surgery, accounting for a significant proportion of the total transfusions performed in the United States and Europe. This may be due in part to surgical factors and to the fibrinolysis and platelet activation induced by cardiopulmonary bypass (CPB), especially in elderly patients. Furthermore, CPB is associated with hemodilution, platelet sequestration, adhesion and destruction.
The increasing frequency with which antiplatelet medications are used to prevent thrombosis in cardiac surgical patients with cardiovascular disease also elevates the risk of postoperative bleeding. The resulting coagulopathy and need for transfusions may increase morbidity and mortality risk in cardiac surgical patients, depending on the specific antiplatelet drug used, as well as patient factors.
Platelet function testing can be useful in the clinical setting for patients undergoing cardiac and noncardiac surgical procedures in order to assess the aggregability state of the patient and avoid excessive risk. Platelet testing may have a role in the following clinical settings:
- Emergency cardiac and noncardiac surgery in patients receiving antiplatelet therapy
- Patients with bleeding complications after surgery before platelet transfusion
3.3. Antiplatelet resistance
Figure 1 illustrates how to manage antiplatelet therapy in patients undergoing percutaneous coronary interventions.
Up to 8% of patients receiving 81 mg-dose of aspirin have significantly less platelet inhibition than those receiving higher dose. Nevertheless, patients taking 100 mg-dose aspirin may improve their response.
In those patients showing high platelet reactivity despite 100 mg-dose aspirin, 325 mg-dose should be considered. Other drugs with similar antiplatelet effects such as triflusal may be an option for these patients.
4. Thienopiridine resistance
Patients with low clopidogrel response are at high risk of thromboembolic complications, especially in the setting of ACS and stent implantation. There are no practice guidelines recommending platelet functional tests in order to adjust antiplatelet therapy with thienopiridine.
Several options have been proposed. Firstly, to increase loading and maintenance doses up to 600 mg and 75-mg twice daily. A comparison study showed no increased bleeding risk. A second option would be to change from clopidogrel to ticlopidine (with different hepatic metabolism), although the safety profile of this agent is not as good as that of clopidogrel. Recent development of new antiplatelet drugs such as prasugrel or ticagrelor adds new therapeutic options for these patients, and will soon become part of daily practice.
Figure 1. Antiplatelet therapy in patients undergoing percutaneous coronary interventions and receiving dual antiplatelet therapy.