Irene A. Navickas

Race and sex differences in thrombogenicity : risk of ischemic events following coronary stenting

Race and sex affect thrombogenicity. We have demonstrated that platelet–fibrin clot characteristics can be used to stratify patients for risk of ischemic events following percutaneous coronary intervention. We investigated race and sex differences in thrombogenicty and the relation to ischemic risk in 252 consecutive African–American and Caucasian men and women undergoing elective percutaneous coronary intervention. Platelet–fibrin clot characteristics were measured using the Thrombelastograph Hemostasis System. The incidence of adverse ischemic events was assessed over a 6-month follow-up period. Overall, 40 ischemic events (15.9%) occurred. Adverse events were higher in African–Americans than Caucasians (P = 0.14), and in women than men (P = 0.004). The incidence was highest in African–American women (37.5%) and lowest in African–American men (6.5%). Measured Thrombelastograph parameters were significantly different between ischemic and nonischemic patients (P < 0.05). African–American women in the ischemic group exhibited higher thrombogenicity than the other race and sex groups (P < 0.05). Multivariate logistic regression identified platelet–fibrin mediated clot strength (relative risk 2.52, P = 0.017) and sex (relative risk 2.56, P = 0.009) as significant independent predictors of ischemic events 6 months postpercutaneous coronary intervention. Thrombogenicity is a novel measurable cardiovascular risk factor that varies by race and sex, is highest in African–American women, and independently predicts the frequency of ischemic events following percutaneous coronary intervention. Point-of-service measurements of platelet–fibrin clot characteristics may lead to more intensified antithrombotic therapy and reduced mortality in selected patients.

Post-coronary intervention recurrent ischemia in the presence of adequate platelet inhibition by dual antiplatelet therapy: what are we overlooking?

Recurrent ischemia following percutaneous coronary intervention (PCI) despite therapy with aspirin and clopidogrel may be due to: (i) insufficient inhibition of P2Y12 or COX-1; or (ii) platelet activation and aggregation stimulated by agonists other than ADP and thromboxane A2, or hypercoagulability resulting from thrombin generation [1]. A key element in providing optimal antithrombotic therapy is the ability to diagnose all of the potential causes of pathological thrombus formation so that each can be therapeutically addressed to the appropriate degree. Results from the Platelet REactivity in Patients And Recurrent Events (PREPARE POST-STENTING) study demonstrated that rapid plateletfibrin clot generation (an indirect measure of the rate of thrombin generation), high thrombin-induced maximum platelet-fibrin clot strength, and high platelet reactivity to ADP were risk factors for post-PCI ischemic events. In this subanalysis of the PREPARE POST-STENTING study, we examined platelet-fibrin clot strength and the kinetics of platelet-fibrin clot formation in patients responsive to clopidogrel and aspirin who experienced ischemic events. We hypothesized that the recurrence of ischemic events in clopidogrel and aspirin responsive patients was secondary to a hypercoagulable state characterized by rapid plateletfibrin clot formation, and high thrombin-induced plateletfibrin clot strength function as measured by the TEG hemostatic analyzer (Haemoscope Corp., Niles, IL, USA). One hundred and ninety-two consecutive patients undergoing elective coronary stenting were prospectively studied. The study was conducted at the Sinai Center for Thrombosis Research. Patient recruitment, data acquisition and statistical analysis were performed at the Sinai Center for Thrombosis Research. The manufacturer had no role in these activities. Platelet fibrin-clot strength, time to platelet-fibrin clot generation and ADPand arachidonic acid-induced platelet aggregation were studied before treatment using the Platelet Mapping Assay as previously described [2]. Adequate platelet inhibition was defined as >75% inhibition of ADPand arachidonic acid-induced platelet aggregation as measured by the Platelet Mapping Assay. Patient demographics and recurrent ischemic events have been described previously. Thirty-six patients experienced recurrent ischemic events and were subdivided into two groups based on the presence or absence of adequate platelet inhibition (Table 1). Comparisons between the groups were performed using the ANOVA method using SAS software (Cary, NC, USA). Among the 36 patients, only seven (19%) demonstrated >75% platelet inhibition by both aspirin and clopidogrel treatment as compared with <75% inhibition in the remaining patients with ischemia (P < 0.05). Patients with ischemic events and adequate platelet inhibition (Group A) had a more rapid time platelet-fibrin clot generation and a greater thrombininduced clot strength compared with patients without ischemic events (P £ 0.001 for both). This is the first study to demonstrate the existence of a subset of patients whose platelets were markedly inhibited by aspirin and clopidogrel therapy and yet experienced the recurrence of an ischemic event within 6 months of elective PCI. Examination of these patients by thrombelastography revealed a hypercoagulable state that may explain the occurrence of ischemic events after stenting in the presence of adequate platelet inhibition. These results would indicate that the achievement of an adequate level of protection against a recurrent thrombotic event might require conventional antiplatelet therapywith aspirin and a P2Y 12 blocker together with long-term anticoagulant therapy in selected patients who can be identified by TEG. PAR-1 receptor blockers may also have benefits in these patients. Correspondence: Paul A. Gurbel, Sinai Center for Thrombosis Research, Hoffberger Building, Suite 56, 2401W. Belvedere Avenue, Baltimore, MD 21215, USA. Tel.: +410 601 9600; fax: +1 410 601 9601; e-mail: pgurbel@ lifebridgehealth.org