Role Of Platelet Reactivity Research Articles

Increased Platelet Reactivity and Proinflammatory Profile Are Associated with Intima-Media Thickness and Arterial Stiffness in Prediabetes.

Alterations of glucose homeostasis are associated with subclinical vascular damage; however, the role of platelet reactivity in this process has not been fully investigated. In this cross-sectional study, we evaluated the correlation between markers of platelet reactivity and inflammation and markers of vascular disease in subjects with prediabetes. Markers of platelet reactivity such as 11-dehydro-thromboxane B2 urinary levels (11-dh-TXB2) and mean platelet volume (MPV) and inflammatory indexes such as platelet-to-lymphocyte ratio (PLR) were evaluated in subjects with prediabetes (n = 48), new-onset type 2 diabetes (NODM, n = 60) and controls (n = 62). Furthermore, we assessed the cardiovascular risk profile of the study population with arterial stiffness and quality intima–media thickness (qIMT). Subjects with prediabetes and NODM exhibited higher 11-dh-TXB2 urinary levels and MPV and a proinflammatory profile with an increased PLR, high-sensitivity C-reactive protein, ferritin and fibrinogen. Furthermore, after multiple regression analyses, we found that urinary 11-dh-TXB2 was one of the major determinants of IMT and arterial stiffness parameters. In conclusion, subjects with prediabetes exhibit increased platelet reactivity as well as a proinflammatory profile. Furthermore, this condition is associated with early markers of cardiovascular disease.

Novel role of platelet reactivity in adverse left ventricular remodelling after ST-segment elevation myocardial infarction: The REMODELING Trial.

The role of platelet-leukocyte interaction in the infarct myocardium still remains unveiled. We aimed to determine the linkage of platelet activation to post-infarct left ventricular remodelling (LVR) process. REMODELING was a prospective, observational, cohort trial including patients (n = 150) with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention. Patients were given aspirin plus clopidogrel therapy (600 mg loading and 75 mg daily). Platelet reactivity (PRU: P2Y12 Reaction Units) was assessed with VerifyNow P2Y12 assay on admission. Transthoracic echocardiography was performed on admission and at one-month follow-up. The primary endpoint was the incidence of LVR according to PRU-based quartile distribution. LVR was defined as a relative ≥ 20 % increase in LV end-diastolic volume (LVEDV) between measurements. Adverse LVR was observed in 36 patients (24.0 %). According to PRU quartile, LVR rate was 10.8 % in the first, 23.1 % in the second, 27.0 % in the third, and 35.1 % in the fourth (p = 0.015): the optimal cut-off of PRU was ≥ 248 (area under curve: 0.643; 95 % confidence interval: 0.543 to 0.744; p = 0.010). LVR rate also increased proportionally according to the level of high sensitivity-C reactive protein (hs-CRP) (p = 0.012). In multivariate analysis, the combination of PRU (≥ 248) and hs-CRP (≥ 1.4 mg/l) significantly increased the predictive value for LVR occurrence by about 21-fold. In conclusion, enhanced levels of platelet activation and inflammation determined the incidence of adverse LVR after STEMI. Combining the measurements of these risk factors increased risk discrimination of LVR. The role of intensified antiplatelet or anti-inflammatory therapy in post-infarct LVR process deserves further study.

Platelet Reactivity Changes Significantly Throughout All Trimesters of Pregnancy Compared With the Nonpregnant State

Objective Platelets play an important role in the pathophysiology of uteroplacental disease and platelet reactivity may be an important marker of uteroplacental disease activity. However, platelet reactivity has not been evaluated comprehensively in normal pregnancy. We sought to evaluate platelet reactivity using a number of agonists at defined time points in pregnancy using a novel platelet assay and compare these with a nonpregnant cohort. Design Prospective longitudinal study. Setting Outpatient department of a large tertiary referral centre. Sample Eighty participants with 30 nonpregnant women and 50 pregnant women assessed longitudinally. Methods This was a prospective cohort study performed longitudinally throughout uncomplicated singleton pregnancies with participants recruited before 15 weeks of gestation. They were controlled for a number of factors known to affect platelet reactivity. Blood samples were obtained in each trimester. Thirty nonpregnant healthy female volunteers also had a platelet assay performed. A modification of standard light transmission aggregometry was used to assess platelet function, with light absorbance measured following the addition of five different agonists at submaximal concentrations. Dose–response curves were plotted for each agonist for the nonpregnant cohort and in each trimester for the pregnant cohort. Main outcome measures Dose–response curves and median effective concentration. Results When compared with the nonpregnant controls a significant reduction was demonstrated in platelet reactivity to collagen during the first trimester of pregnancy (P < 0.0001). Platelet aggregation increased significantly from the first to third trimesters in response to collagen and arachidonic acid. Conclusion Platelet reactivity varies according to pregnancy state, gestational age and agonist. The finding that platelet reactivity is reduced in the first trimester of pregnancy may be useful for the interpretation of further studies examining the role of platelet reactivity in the first trimester of pregnancies that develop uteroplacental disease.

High On-Treatment Platelet Reactivity Predicts Cardiac Events in Patients with Drug-Eluting Stents

The role of platelet reactivity (PR) tests in the prediction of long-term events in Latin-American patients treated with drug-eluting stents (DES) has not been established. To assess the role of PR tests in the prediction of events after DES implantation. From May 2006 through January 2008, 209 Brazilian patients who underwent elective treatment with DES were included. PR was assessed 12 to 18h after the procedure by light transmittance aggregometry with 5µM of ADP. Patients were prospectively followed for up to 4.8 years. Seventeen (8%) individuals were lost to follow-up and the final cohort comprised 192 patients. Receiver operating curve (ROC) was used to determine the best 5µM of ADP cutoff to predict events. The primary endpoint was a combination of cardiovascular death, acute myocardial infarction, definite stent thrombosis, and target-artery revascularization. Cox proportional hazard models were used to determine the variables independently associated with the time to the first event. The best ADP 5µM cutoff was 33%. One hundred and seven (55.7%) patients had ADP 5µM >33%. Event-free survival rate at 1,800 days was 55% vs. 70% for individuals with ADP5 above and below such cutoff, respectively (p=0.001). Independent predictors of time to first event were current smoking (HR 3.49; 95% CI 1.76-6.9; p=0.0003), ADP 5µM >33% (HR 1.95; 95% CI 1.09-3.51; p=0.025) and age (HR 1.03; 95% CI 1.0-1.06; p=0.041). In this study, 55.7% of the patients had high on-treatment platelet reactivity. ADP 5µM >33% was an independent predictor of long-term events.

The Role of Platelet Reactivity and Genotype Testing in the Prevention of Atherothrombotic Cardiovascular Events Remains Unproven

Clopidogrel is the second-leading drug sold worldwide, yet 13 years and millions of patients treated later, we are just beginning to understand the complexity of its metabolism and antiplatelet effects. There is a high degree of clopidogrel response variability in terms of pharmacokinetic and pharmacodynamic effects related to genetic and nongenetic factors.1–4 Several recent studies have shown that both high on-clopidogrel platelet reactivity5–8 and the cytochrome ( CY ) P2C19 reduced-function genotype9–11 are associated with an increased risk of cardiovascular events, including stent thrombosis (ST). Given the central role of clopidogrel in the management of acute coronary syndrome (ACS) and percutaneous coronary intervention (PCI), physicians and regulatory bodies are tackling how best to integrate these data to guide patient care. These efforts are fueled by the motivation to identify people at risk of developing adverse outcomes on clopidogrel, to develop more precise estimates about prognosis, and to fine-tune treatment selection, thereby approaching a form of tailored or personalized medicine. Response by Gurbel and Tantry on p 1303 On March 12, 2010, the US Food and Drug Administration (FDA) called attention to this issue via a boxed warning about the diminished effectiveness of the drug in patients with impaired ability to convert the drug into its active form as a result of genetic polymorphism in CYP2C19 , one of the principal enzymes responsible for metabolic conversion of clopidogrel into its active form.12 In response to this boxed warning, the American College of Cardiology Foundation (ACCF)/American Heart Association released a clinical expert consensus document13 stating “the evidence base is insufficient to recommend either genetic testing or platelet function testing at the present time.” Since that statement, additional studies have been published that question the value of platelet function and genetic testing.14– …

Genotyping, Clopidogrel Metabolism, and the Search for the Therapeutic Window of Thienopyridines

It is somewhat remarkable to note that not until recently, nearly 12 years and tens of millions of treated patients after its initial approval, has the metabolism of clopidogrel, an inactive prodrug, begun to be more fully understood. Although this lack of knowledge may not be unique among common cardiovascular drugs, there are 4 characteristics of clopidogrel therapy that make this gap in understanding disconcerting: The potential for life-threatening complications (bleeding or thrombosis) at both ends of its therapeutic spectrum; the fact that 1 dose is supposed to fit all; the lack of a measureable, proven end point (such as blood pressure for antihypertensive drugs) that allows for titration to a target response; and the nearly mandatory need by many patients for clopidogrel, with no acceptable alternative until recently. Article see p 512 Historically, understanding the metabolism of a drug has been critical in identifying those patients most likely to benefit from and, more important, potentially be harmed by that drug. This is especially true for drugs with relatively narrow therapeutic windows, such as phenytoin, warfarin, and others. Although it seems safe to assume, on the basis of our extensive clinical experience, that the therapeutic window of clopidogrel is unlikely to be narrow, this certainly does not represent the depth of knowledge we would hope for after so much clinical experience and research. What we do know is that P2Y12 inhibition with thienopyridines is beneficial in preventing arterial thrombotic events, presumably requiring the achievement of some minimal level of receptor inhibition that may or may not vary on the basis of the patient and clinical scenario. We also know that it is associated with a significant increase in serious bleeding events, with higher levels of inhibition associated with greater bleeding. In the present and future practice environment, with a growing …

Coated–platelets in Ischemic Stroke

While platelets are acknowledged as critical components of ischemic stroke pathophysiology, little is known about the role of platelet reactivity or platelet subclasses in stroke. Coated-platelets are a pro-thrombotic subclass of platelets, levels of which can vary substantially among individuals. Recently, coated-platelets were observed to be elevated in cortical stroke patients and decreased in lacunar stroke patients, thereby providing for the first time a biochemical marker distinguishing these two stroke subtypes. This article reviews the primary observation as well as the clinical and epidemiological implications of this finding.

Increased platelet aggregability associated with platelet GPIIIa PlA2 polymorphism: the Framingham Offspring Study.

The platelet glycoprotein IIb/IIIa (GP IIb/IIIa) plays a pivotal role in platelet aggregation. Recent data suggest that the PlA2 polymorphism of GPIIIa may be associated with an increased risk for cardiovascular disease. However, it is unknown if there is any association between this polymorphism and platelet reactivity. We determined GP IIIa genotype and platelet reactivity phenotype data in 1422 subjects from the Framingham Offspring Study. Genotyping was performed using PCR-based restriction fragment length polymorphism analysis. Platelet aggregability was evaluated by the Born method. The threshold concentrations of epinephrine and ADP were determined. Allele frequencies of PlA1 and PlA2 were 0.84 and 0.16, respectively. The presence of 1 or 2 PlA2 alleles was associated with increased platelet aggregability as indicated by incrementally lower threshold concentrations for epinephrine and ADP. For epinephrine, the mean concentrations were 0.9 micromol/L (0.9 to 1.0) for homozygous PlA1, 0.7 mmol/L (0.7 to 0.9) for the heterozygous PlA1/PlA2, and 0.6 micromol/L (0.4 to 1.0) for homozygous PlA2 individuals, P=0.009. The increase in aggregability induced by epinephrine remained highly significant (P=0.007) after adjustment for covariates. For ADP-induced aggregation, the respective mean concentrations were 3.1 micromol/L (3.0 to 3.2), 3.0 micromol/L (2.9 to 3.2), and 2.8 micromol/L (2.4 to 3.3); P=0.19 after adjustment for covariates. Our findings indicate that molecular variants of the gene encoding GP IIIa play a role in platelet reactivity in vitro. Our observations are compatible with and provide an explanation for the reported association of the PlA2 allotype with increased risk for cardiovascular disease.

The role of platelet reactivity in thrombogenesis (II)

Platelet aggregation is an important phenomenon in the first step of thrombogenesis. When platelets aggregate, ADP and other platelet aggregating and vasoactive substances may release. We reported that an injection of ADP caused pulmonary thromboembolism in rats associated with transient effects including thrombocytopenia, apnea, arrhythmia, rise in central venous pressure and fall in arterial blood pressure, while these changes were less severe in SHRs. In this study, platelet aggregability and thrombogenic tendency in response to ADP were analysed in SHRs in comparison with those in the control rats. 30 Wistar rats (control) and 30 SHRs (20-30 weeks old) were used. Blood samples were taken from carotid artery cannula for an analysis of platelet count, platelet volume and platelet aggregation by ADP. ADP (1mg/kg) was injected rapidly into the jugular vein of anesthetized rats. After ADP injection, blood samples were taken at 30sec, 3, 10, 20 and 30min. ECG and respiration were recorded continuously. Before ADP injection, platelet count (control; 53.1, SHR; 53.0×104/μl), the mode related platelet volume (control; 2.6, SHR; 2.7μ3) and platelet ADP content (control; 2.4, SHR; 2.7μmoles/1011pl.) were not different between the two groups. Maximum intensity of ADP (10μM) aggregation was significantly lower in SHR (39.4±4.8%) than in the control (50.3±5.1%) (p<0.05). After the injection, platelet count decreased to 59.7% of preinjection level at 30sec (p<0.01) and returned to 93.8% at 3min in the control; 90.5% at 30sec (p<0.01) and 74.9% at 3min in SHR. Platelet ADP content decreased to 61% at 10min in the control, while little change in SHR. Arrhythmia and apnea observed after ADP injection were significantly longer continued in the control (p<0.01). Histological study revealed that pulmonary microvasculature was frequently filled with platelet thrombi in the control and seldom in SHR. The lower incidence in pulmonary microthromboembolism in SHR might be related to its in vitro hypoaggregability of platelet due to the insufficient release reaction. The lower response of platelet might be explained by exhaustion under hypertensive stress, though further investigation is required.

The role of platelet reactivity in thrombogenesis

Platelet aggregation is an important phenomenon in the first step of thrombogenesis. When platelets aggregate, ADP and other platelet aggregating and vasoactive substances may release. We reported that an injection of ADP caused pulmonary thromboembolism in rats associated with transient effects including thrombocytopenia, apnea, arrhythmia, rise in central venous pressure and fall in arterial blood pressure, while these changes were less severe in SHRs. In this study, platelet aggregability and thrombogenic tendency in response to ADP were analysed in SHRs in comparison with those in the control rats. 30 Wistar rats (control) and 30 SHRs (20-30 weeks old) were used. Blood samples were taken from carotid artery cannula for an analysis of platelet count, platelet volume and platelet aggregation by ADP. ADP (1mg/kg) was injected rapidly into the jugular vein of anesthetized rats. After ADP injection, blood samples were taken at 30sec, 3, 10, 20 and 30min. ECG and respiration were recorded continuously. Before ADP injection, platelet count (control; 53.1, SHR; 53.0×104/μl), the mode related platelet volume (control; 2.6, SHR; 2.7μ3) and platelet ADP content (control; 2.4, SHR; 2.7μmoles/1011pl.) were not different between the two groups. Maximum intensity of ADP (10μM) aggregation was significantly lower in SHR (39.4±4.8%) than in the control (50.3±5.1%) (p<0.05). After the injection, platelet count decreased to 59.7% of preinjection level at 30sec (p<0.01) and returned to 93.8% at 3min in the control; 90.5% at 30sec (p<0.01) and 74.9% at 3min in SHR. Platelet ADP content decreased to 61% at 10min in the control, while little change in SHR. Arrhythmia and apnea observed after ADP injection were significantly longer continued in the control (p<0.01). Histological study revealed that pulmonary microvasculature was frequently filled with platelet thrombi in the control and seldom in SHR. The lower incidence in pulmonary microthromboembolism in SHR might be related to its in vitro hypoaggregability of platelet due to the insufficient release reaction. The lower response of platelet might be explained by exhaustion under hypertensive stress, though further investigation is required.