Thrombin-induced Platelet-fibrin Clot Strength Research Articles

New interest in fibrinogen as an ischemic risk factor.

Platelet-fibrin clot formation is a key process in acute arterial thrombosis. The relationship between thrombin-induced platelet-fibrin clot strength (P-FCS) and fibrinogen levels in patients with cardiovascular disease (CVD) and COVID-19 has not been studied. In thhe current study, the contribution of fibrinogen to P-FCS has been explored in healthy subjects (n=157), patients hospitalized with COVID-19 (n=116), and patients with CVD (n=93) using thrombelastography (TEG 6s) with citrate cartridge. We found that thrombin-induced P-FCS, fibrin clot strength (F-CS) and fibrinogen levels (FLEV) were higher among patients with CVD and COVID-19 compared to HS(p<0,05 for all) and highest among patients with COVID-19. P-FCS, an established risk factor for post-PCI ischemic event occurrences, was associated with both F-CS and FLEV (R2=0.67, p<0.001 for both comparisons.These data indicate that fibrinogen levels strongly influence the viscoelastic strength of the platelet-fibrin clot, fibrinogen may be an important driving factor for arterial thrombosis in the presence of potent platelet inhibition and may be as equally important a risk factor as high platelet reactivity. Since P-FCS is significantly associated with fibrinogen levels, the role of fibrinogen as a risk factor for arterial ischemic event occurrences should be further studied to improve antithrombotic therapy personalization.

Platelet-fibrin clot strength measured by thromboelastography could predict hypercoagulability and antiplatelet effects in patients after percutaneous coronary intervention.

It has been estimated that nearly one-fifth post-percutaneous coronary intervention (PCI) patients treated with clopidogrel continued to have recurrent thrombotic events, which implied the limitation of "one-size-fits all" strategy for antiplatelet therapy. From July 2017 to April 2019, patients with acute coronary syndrome [ACS, including unstable angina (UA), non-ST segment elevation myocardial infraction (NSTEMI), and ST segment elevation myocardial infraction (STEMI)] or old myocardial infarction (OMI), or patients without coronary heart disease (non-CAD) were retrospectively enrolled in this study. For CAD patients undergoing PCI, standard dual antiplatelet therapy (100 mg aspirin and 75 mg clopidogrel) was prescribed. After administration of dual antiplatelet agents for at least 5 days, whole blood samples were collected and platelet function was tested using thrombelastography (TEG). Thrombin-induced platelet-fibrin clot strength (MAthrombin) and ADPinduced platelet-fibrin clot strength (MAADP) were measured to assess the hypercoagulability and antiplatelet effects. A total of 571 patients, including 479 ACS patients, 21 OMI patients and 71 non-CAD patients were enrolled. Highest level of MAthrombin was detected in STEMI patients, while lowest MAthrombin level was observed in non-CAD patients (P1 <0.05 for OMI vs. non-CAD; P2 <0.001 for ACS vs. non-CAD; P3<0.05 among ACS). Higher MAADP was also observed in STEMI and NSTEMI patients compared with UA patients (P<0.001). When MAADP was divided into trisections (MAADP <31; 31-47; >47 mm), a considerable portion of 41.8% ACS patients were in the first trisection (MAADP <31 mm), containing 50.4% of UA patients, 35.7% of NSTEMI patients and 26.5% of STEMI patients, with significant difference being observed between UA patients and other ACS patients (P<0.05 for NSTEMI vs. UA; P<0.001 for STEMI vs. UA). Meanwhile, 27.6% of NSTEMI and 31.0% of STEMI patients were in the third trisection (MAADP >47 mm), which was significantly higher than that of UA patients (12.7%) (P<0.001 for NSTEMI or STEMI vs. UA). Considering various degrees of hypercoagulability and antiplatelet effects of clopidogrel among OMI and ACS patients post-PCI. More attention should be paid to personalized antiplatelet therapy according to individual's effects of P2Y12 receptor inhibitors.

Association between hypercoagulability and microvascular dysfunction in patients with acute myocardial infarction

Abstract Background Microvascular dysfunction (MVD) following percutaneous coronary intervention (PCI) can increase the risk of adverse clinical outcomes, which partly may be related with thromboembolic microvascular obstruction. This study was sought to determine whether hypercoagulability is linked with MVD post-PCI in patients with acute myocardial infarction (AMI). Methods Hypercoagulability was determined with thrombin-induced platelet-fibrin clot strength (maximal amplitude [MAthrombin] ≥68 mm evaluated by thromboelastography). Microvascular function was assessed by invasive physiological index after PCI (MVD: index of microcirculatory resistance [IMR] ≥40 U). Major adverse cardiovascular events (MACE) was defined as the incidence of death or rehospitalization for heart failure post-PCI. Results Among AMI patients (n=116), 46 patients (39.7%) met the criteria of hypercoagulability and 27 patients (23.3%) had a MVD. Level of IMR showed a significant correlation with MAthrombin value (r=0.313; p=0.001). Prevalence of MVD was increased proportionally according to the quartile scale of MAthrombin (3.6% vs. 21.9% vs. 25.9% vs. 41.4%; p for trend = 0.009). Hypercoagulability significantly increased the predictive value for MVD occurrence (odds ratio: 4.35; 95% confidence interval: 1.74 to 10.89; p=0.001). During the follow-up post-PCI of 40.9 months (IQR: 19.8 to 59.4 months), MVD and hypercoagulability were both associated with MACE (hazard ratio: 5.86 and 2.28 respectively). Patients with both MVD and hypercoagulability showed an increased risk for MACE compared with the others (18.2% vs. 5.3%; adjusted hazard ratio: 4.50; 95% confidence interval: 1.26 to 16.12; Log rank p=0.011) (Figure). Conclusion This is the first analysis to demonstrate that baseline hypercoagulability is an independent determinant of post-PCI MVD in AMI patients. Combining the measurements of hypercoagulability and MVD may enhance risk stratification and deserves further study. Long-term outcomes Funding Acknowledgement Type of funding source: None

Association Between Residual Platelet Reactivity on Clopidogrel Treatment and Severity of Coronary Atherosclerosis: Intrinsic Hypercoagulability as a Mediator.

High on-treatment residual platelet reactivity (HRPR) was associated with greater atherosclerosis burden. We examined whether intrinsic hypercoagulability (IHC) could be attributed to that association in patients treated by drug-eluting stents. This retrospective observation enrolled a total of 891 coronary artery disease (CAD) subjects. Platelet and coagulant reactivity was measured by thrombelastography. At least 24h after a 300-mg dose of clopidogrel, adenosine diphosphate (ADP)-induced maximum amplitude of clot strength (MAadp) > 47mm represented HRPR. Thrombin-induced platelet-fibrin clot strength (MAthrombin) and blood fibrinogen surrogated intrinsic coagulability. Using mediation analysis to evaluate the effect of IHC on the relationship between the number of narrowed coronaries and HRPR on clopidogrel. More HRPR on clopidogrel and higher intrinsic coagulability were observed in more severe coronary atherosclerosis, especially in the three-vessel disease. After adjustment for confounding factors, the number of narrowed coronaries (ORadj = 1.343, 95% CI 1.063-1.695, p = 0.013), MAthrombin (ORadj = 1.106, 95% CI 1.058-1.157, p < 0.001), and fibrinogen (ORadj = 1.003, 95% CI 1.001-1.005, p = 0.012) were all independent positive predictors for HRPR. MAthrombin and fibrinogen were meaningful mediators for the significant positive association of the number of narrowed vessels and HRPR on clopidogrel, which were enhanced by around 30% and 43%, respectively, for this effect. This is the first study to demonstrate that the positive correlation between the number of stenotic coronaries and HRPR on clopidogrel may be partly attributed to IHC, which may enhance the risk stratification, guide more precise coagulation in multi-vessel disease after drug-eluting stents, and therefore deserve further study.

Thrombogenicity and central pulse pressure to enhance prediction of ischemic event occurrence in patients with established coronary artery disease: The MAGMA-ischemia score

Background and aimsConventional cardiovascular risk estimators based on clinical demographics have limited prediction of coronary events. Markers for thrombogenicity and vascular function have not been explored in risk estimation of high-risk patients with coronary artery disease. We aimed to develop a clinical and biomarker score to predict 3-year adverse cardiovascular events. MethodsFour hundred eleven patients, with ejection fraction ≥40% undergoing coronary angiography, and found to have a luminal diameter stenosis ≥50%, were included in the analysis. Thrombelastography indices and central pulse pressure (CPP) were determined at the time of catheterization. ResultsWe identified predictors of death, myocardial infarction (MI) or stroke and developed a numerical ischemia risk score. The primary endpoint of cardiovascular death, MI or stroke occurred in 22 patients (5.4%). The factors associated with events were age, prior PCI or CABG, diabetes, CPP, and thrombin-induced platelet-fibrin clot strength, and were included in the MAGMA-ischemia score. The MAGMA-ischemia score showed a c-statistic of 0.85 (95% Confidence Interval [CI] 0.80–0.87; p<0.001) for the primary endpoint. In the subset of patients who underwent revascularization, the c-statistic was 0.90 (p<0.001). Patients with MAGMA-ischemia score greater than 5 had highest risk to develop clinical events, hazard ratio for the primary endpoint: 13.9 (95% CI 5.8–33.1, p<0.001) and for the secondary endpoint: 4.8 (95% CI 2.3–9.6, p<0.001). When compared to previous models, the MAGMA-ischemia score yielded a higher discrimination. ConclusionsInclusion of CPP and assessment of thrombogenicity in a novel score for patients with documented CAD enhanced the prediction of events.

Thrombin induced platelet-fibrin clot strength in relation to platelet volume indices and inflammatory markers in patients with coronary artery disease.

Platelet aggregation and inflammation are both implicated in coronary artery disease (CAD). Thrombin induced platelet-fibrin clot strength (MAThrombin) measured by thrombelastography (TEG) has been proved to be a novel marker of platelet aggregation. The aim of this study was to investigate the correlation of MAThrombin to platelet volume indices (PVIs) or to inflammatory markers in different types of CAD. 206 patients with different types of CAD were enrolled. MAThrombin, PVIs, including mean platelet volume (MPV), platelet distribution width (PDW), and platelet-large cell ratio (P-LCR) as well as inflammatory markers, including high-sensitivity C-reactive protein (hs-CRP) and fibrinogen (Fbg) were measured. Multiple linear regression models were used to analyze the association between MAThrombin, PVIs, and inflammatory markers. MAThrombin and inflammatory markers both varied with CAD types (P<0.001). MAThrombin was correlated to PVIs in NSTEMI individuals (MPV, r=0.393, P=0.007; PDW, r=0.334, P=0.023; P-LCR, r=0.382, P=0.008), but had inner-link with inflammatory markers in STEMI cases (hs-CRP, r=0.499, P<0.001; Fbg, r=0.500, P<0.001). These findings may suggest different mechanisms of platelet aggregation in different types of CAD. Moreover, MAThrombin may be used as a potential parameter to evaluate platelet aggregation and inflammation together.

Central aortic pulse pressure, thrombogenicity and cardiovascular risk.

High central aortic pulse pressure (CPP) and thrombin-induced platelet-fibrin clot strength (TIP-FCS) have been associated with ischemic outcomes in patients with coronary artery disease in separate studies. But, the ischemic risk associated with these factors has never been analyzed in a single study and their interrelation is unknown. The primary aim of the study was to establish cut points for CPP and TIP-FCS measured at the time of catheterization associated with long term major adverse cardiovascular events. We enrolled 334 consecutive patients undergoing cardiac catheterization and assessed thrombogenicity by thrombelastography. Patients were followed up to 3 years. The primary endpoint was a composite of cardiovascular death, myocardial infarction, and ischemic stroke and the secondary endpoint was occurrence of the primary endpoint or recurrent ischemic events requiring hospitalization. Patients with primary and secondary endpoint occurrence had higher CPP (83 ± 20 vs. 60 ± 18mmHg, p < 0.0001; 70 ± 21 vs. 59 ± 18mmHg, p < 0.0001, respectively) and TIP-FCS (68.5 ± 5.8 vs. 65.5 ± 5.0mm, p = 0.008; 67.4 ± 5.9 vs. 65.2 ± 4.8mm, p = 0.001, respectively). CPP >60mmHg and TIP-FCS >69mm were both independent predictors of primary endpoint occurrence (p = 0.0001 and p = 0.02, respectively). ROC analysis for CPP and TIP-FCS showed a C-statistic of 0.81 (p < 0.0001) and 0.68 (p = 0.007) for the primary endpoint, respectively. Patients with CPP >60mmHg had higher TIP-FCS (66.8 ± 5.1 vs. 64.8 ± 5.0mm, p < 0.001) and primary and secondary endpoint occurrence (13 vs. 1.1%, p < 0.0001 and 31.8 vs. 14.4%, p = 0.0002, respectively). CPP >60mmHg + TIP-FCS > 69mm was associated with a markedly increased risk of primary endpoint occurrence [HR (95% CI) 5.4(2.3-12.5), p = 0.0001]. High CPP and thrombogenicity are interrelated; each are independently associated with increased cardiovascular risk; and simultaneous presence markedly enhances risk. The mechanistic link between CPP and thrombogenicity deserves further study.

Thrombin-Induced Platelet-Fibrin Clot Strength Identified by Thrombelastography: A Novel Prothrombotic Marker of Coronary Artery Stent Restenosis.

In-stent restenosis (ISR) is a limitation of percutaneous coronary intervention and has been linked to specific clinical and angiographic variables. We aimed to simultaneously assess thrombosis biomarkers and lipid levels in patients with and without ISR. Consecutive patients (n = 170) with a history of coronary stenting undergoing elective angiography were studied. Blood samples for thrombelastography, light transmittance aggregometry, and lipid levels were obtained prior to cardiac catheterization. Sixty-nine patients (41%) had ISR (>50% luminal diameter stenosis). Among patients with ISR, 40 (58%) had ISR in more than one stent bed. Patients with ISR were more often female (37.7% vs. 21.8%, P = 0.04), had higher thrombin-induced platelet-fibrin clot strength (TIP-FCS) (69.9 mm vs. 65.6 mm, P < 0.001), and a higher ApoB/A1 ratio (0.65 vs. 0.59, P = 0.03). In patients on dual antiplatelet therapy (n = 86), there were no differences in ADP-, arachidonic acid-, and collagen-induced platelet aggregation between groups. The frequency of patients with ISR increased with TIP-FCS quartiles and by ROC analysis, TIP-FCS = 67.0 mm was the cutpoint for identification of ISR (AUC = 0.80 (95%CI 0.73-0.87, P < 0.0001). By multivariate analysis, TIP-FCS ≥67.0 mm strongly associated with ISR (OR = 7.3, P = 0.004). Patients with ISR identified at the time of cardiac catheterization have a prothrombotic phenotype indicated by high TIP-FCS, a novel marker. Studies to confirm the prognostic utility of high TIP-FCS for the development of ISR are ongoing.

Relation of Fish Oil Supplementation to Markers of Atherothrombotic Risk in Patients With Cardiovascular Disease Not Receiving Lipid-Lowering Therapy

Fish oil supplementation (FOS) is known to have cardiovascular benefits. However, the effects of FOS on thrombosis are incompletely understood. We sought to determine if the use of FOS is associated with lower indices of atherothrombotic risk in patients with suspected coronary artery disease (sCAD). This is a subgroup analysis of consecutive patients with sCAD (n=600) enrolled in the Multi-Analyte, Thrombogenic, and Genetic Markers of Atherosclerosis study. Patients on FOS were compared with patients not on FOS. Lipid profile was determined by vertical density gradient ultracentrifugation (n=520), eicosapentaenoic acid+docosahexaenoic acid was measured by gas chromatography (n=437), and AtherOx testing was performed by immunoassay (n=343). Thromboelastography (n=419), ADP- and collagen-induced platelet aggregation (n=137), and urinary 11-dehydrothromboxane B2 levels (n=259) were performed immediately before elective coronary angiography. In the total population, FOS was associated with higher eicosapentaenoic acid+docosahexaenoic acid content (p<0.001), lower triglycerides (p=0.04), total very low-density lipoprotein cholesterol (p=0.002), intermediate-density lipoprotein cholesterol (p=0.02), and AtherOx levels (p=0.02) but not in patients on lipid-lowering therapy. Patients not on lipid-lowering therapy taking FOS had lower very low-density lipoprotein cholesterol, intermediate-density lipoprotein cholesterol, remnant lipoproteins, triglycerides, low-density lipoprotein cholesterol, AtherOx levels, collagen-induced platelet aggregation, thrombin-induced platelet-fibrin clot strength, and shear elasticity (p<0.03 for all). In clopidogrel-treated patients, there was no difference in ADP-induced aggregation between FOS groups. Patients on FOS had lower urinary 11-dehydrothromboxane B2 levels regardless of lipid-lowering therapy (p<0.04). In conclusion, the findings of this study support the potential benefit of FOS for atherothrombotic risk reduction in sCAD with the greatest benefit in patients not receiving lipid-lowering therapy. Future prospective studies to compare FOS with lipid-lowering therapy and to assess the independent effects of FOS on thrombogenicity are needed.

Abstract 18848: Weight Gain is Not a Significant Predictor of Coronary Artery Disease Severity

Background: Obesity, along with hypertension and diabetes, is a known risk factor for coronary artery disease (CAD). Recent studies have proposed that obese individuals may actually experience less adverse cardiovascular outcomes and mortality compared to non-obese individuals, a phenomenon known as the “obesity paradox”. We sought to determine if weight gain is associated with overall CAD severity measured by coronary angiography. Methods: Suspected CAD patients (n=418) were enrolled in the Multi-Analyte, Thrombogenic, and Genetic Markers of Atherosclerosis (MAGMA) study prior to elective cardiac catheterization. Demographics and weight information were obtained, and maximum weight gain (MWG) was defined as the percent increase in weight from year of high school graduation to year of heaviest weight. Subjects were divided into the following quartiles based on MWG: none (≤30%), minor (31%-47%), major (48%-69%), and extreme (≥70%). Detailed lipid profiling was determined by vertical density gradient ultracentrifugation, thrombin-induced platelet fibrin clot strength (TIP-FCS) by thromboelastography, and urinary 11-dehydrothromboxane B2 (11-dhTxB2) by ELISA. Severity of CAD was defined as none/minimal (&lt;20%), moderate (20-75%), and severe (75%) luminal diameter obstruction of any major coronary vessel. Results: The average MWG in the study population was 53 ± 33%. Patients in the extreme MWG group had the highest incidence of DM (47.5%), hypertension (80.8%), and depression (25.3%), and were most often female (59.6%). There was an inverse relationship between MWG and CAD severity (p=0.005)(figure). TIP-FCS increased in a stepwise fashion with MWG (p=0.001). 11-dTxB2 and triglyceride levels were significantly higher in the extreme MWG group, regardless of cholesterol lowering therapy (p&lt;0.05 for all). Conclusion: Our data suggest that weight gain is associated with heightened thrombotic risk but not an increased risk for CAD.

Statin therapy and thromboxane generation in patients with coronary artery disease treated with high-dose aspirin

Aspirin and statin therapy are mainstay treatments in patients with coronary artery disease (CAD). The relation between statin therapy, <i>in vivo</i> thromboxane (Tx) generation; a marker of inflammation, and blood thrombogenicity has never been explored. Urinary 11-dehydro (dh) TxB₂ was determined in patients with suspected CAD on 325 mg daily aspirin therapy prior to undergoing cardiac catheterisation (n=281). Thrombogenicity was estimated by thrombelastographic measurement of thrombin-induced platelet-fibrin clot strength (TIP-FCS) and lipids/lipoproteins were determined by vertical density gradient ultracentrifugation/ELISA. The influence of statin therapy and dose was analysed by the atorvastatin equivalent dose (5–10 mg, 20–40 mg, or 80 mg daily). Statin therapy (n=186) was associated with a dose-dependent reduction in urinary 11-dh TxB₂ (p=0.046) that was independent of LDL and apo B100 levels but was strongly related to TIP-FCS (p=0.006). By multivariate analysis, no statin therapy (n=95) and female gender were independently associated with high urinary 11-dh TxB₂ [OR=2.95 (0.1.57–5.50, p=0.0007); OR=2.25 (1.24–4.05, p=0.007)], respectively. In aspirin-treated patients, statin therapy was independently and inversely associated with inflammation in a dose-dependent manner. Elevated 11-dh TxB₂ was associated with a prothrombotic state indicated by high TIP-FCS. Our data suggest that measurement of urinary 11-dTxB₂ may be a useful method to optimise statin dosing in order to reduce thrombotic risk.

Thrombin induced platelet–fibrin clot strength measured by thrombelastography is a novel marker of platelet activation in acute myocardial infarction

After disruption of coronary arteriosclerotic plaques, platelet activation plays a causal role in the subsequent thrombus formation, leading to acute myocardial infarction (AMI) [ [1] Trip M.D. Cats V.K. van Capelle F.J.L. et al. Platelet hyperreactivity and prognosis in survivors of myocardial infarction. N Engl J Med. 1990; 322: 1549-1554 Crossref PubMed Scopus (536) Google Scholar ]. Although many attempts have been made to monitor platelet activity to detect atherothrombotic process, thus far an easy, useful and specific assay has not been discovered. As a point-of-care testing, thrombelastography (TEG) specifically evaluates the contribution of platelet to thrombosis. Of the TEG parameters, thrombin-induced platelet–fibrin clot strength (MAthrombin) has been shown to reflect the maximal potential platelet reactivity [ [2] Gurbel P.A. Bliden K.P. Guyer K. et al. Adenosine diphosphate-induced platelet-fibrin clot strength: a new thrombelastographic indicator of long-term poststenting ischemic events. Am Heart J. 2010; 160: 346-354 Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar ]. Interestingly, it has been demonstrated that MAthrombin exhibited significant correlation with other prothrombotic markers and with C-reactive protein and were increased in patients with angina as compared to asymptomatic patients [ [3] Tantry U.S. Bliden K.P. Suarez T.A. et al. Hypercoagulability, platelet function, inflammation and coronary artery disease acuity: results of the Thrombotic RIsk Progression (TRIP) study. Platelets. 2010; 21: 360-367 Crossref PubMed Scopus (61) Google Scholar ]. Taken together, these findings suggest the potential of MAthrombin for diagnostic evaluation of pathophysiological state of hypercoagulability in AMI patients. However, the association between MAthrombin and AMI has not yet been clarified. In the present study, we investigated the level of MAthrombin in patients with AMI and other forms of coronary atherosclerosis disease (CAD) and found that there is a dynamic elevation of MAthrombin after the onset of myocardial infarction.

Thrombin-induced platelet-fibrin clot strength: Relation to high on-clopidogrel platelet reactivity, genotype, and post-percutaneous coronary intervention outcomes

The relationship between thrombin-induced platelet-fibrin clot strength (MATHROMBIN), genotype and high on-treatment platelet reactivity (HPR) is unknown. The aim of this study is to assess the influence of MATHROMBIN measured by thrombelastography on HPR and long-term major adverse cardiovascular events (MACE) in percutaneous coronary intervention (PCI)-treated patients during aspirin and clopidogrel therapy. MATHROMBIN, platelet aggregation, genotype, and two-year MACE were assessed in 197 PCI-treated patients. HPR was defined as 5 µM ADP-induced PR ≥ 46% measured by conventional aggregometry. Both high MATHROMBIN(≥ 68 mm) and CYP2C19*2 allele carriage were independently associated with ADP-induced platelet aggregation (β coefficient: 8.3% and 12.0%, respectively). The combination of CYP2C19*2 allele carriage and high MATHROMBIN increased the predictive value for the risk of HPR (odds ratio: 13.89; 95% confidence interval: 3.41 to 55.56; p < 0.001). MACE occurred in 25 patients (12.7%). HPR and high MATHROMBIN were both associated with MACE (hazard ratio: 3.09 and 2.24, respectively), and patients with both HPR and high MATHROMBIN showed an increased risk for MACE (adjusted hazard ratio: 5.56; 95% confidence interval: 1.85 to 16.67; p = 0.002). In conclusion, this is the first study to demonstrate that high platelet-fibrin clot strength is an independent determinant of HPR in PCI-treated patients. Combining the measurements of platelet aggregation and platelet-fibrin clot strength may enhance post-PCI risk stratification and deserves further study.

Statin therapy and thromboxane generation in patients with coronary artery disease treated with high-dose aspirin.

Aspirin and statin therapy are mainstay treatments in patients with coronary artery disease (CAD). The relation between statin therapy, in vivo thromboxane (Tx) generation; a marker of inflammation, and blood thrombogenicity has never been explored. Urinary 11-dehydro (dh) TxB2 was determined in patients with suspected CAD on 325 mg daily aspirin therapy prior to undergoing cardiac catheterisation (n=281). Thrombogenicity was estimated by thrombelastographic measurement of thrombin-induced platelet-fibrin clot strength (TIP-FCS) and lipids/lipoproteins were determined by vertical density gradient ultracentrifugation/ELISA. The influence of statin therapy and dose was analysed by the atorvastatin equivalent dose (5-10 mg, 20-40 mg, or 80 mg daily). Statin therapy (n=186) was associated with a dose-dependent reduction in urinary 11-dh TxB2 (p=0.046) that was independent of LDL and apo B100 levels but was strongly related to TIP-FCS (p=0.006). By multivariate analysis, no statin therapy (n=95) and female gender were independently associated with high urinary 11-dh TxB2 [OR=2.95 (0.1.57-5.50, p=0.0007); OR=2.25 (1.24-4.05, p=0.007)], respectively. In aspirin-treated patients, statin therapy was independently and inversely associated with inflammation in a dose-dependent manner. Elevated 11-dh TxB2 was associated with a prothrombotic state indicated by high TIP-FCS. Our data suggest that measurement of urinary 11-dTxB2 may be a useful method to optimise statin dosing in order to reduce thrombotic risk.

PREDICTORS OF HIGH THROMBIN-INDUCED PLATELET-FIBRIN CLOT STRENGTH IN PATIENTS TREATED WITH PCI

High thrombin-induced platelet-fibrin clot strength (MATHROMBIN) measured by thrombelastography is associated with the risk of adverse clinical event occurrence. However, predictors and correlation with “HPR to ADP” of high MATHROMBIN are not undetermined. Among PCI patients (n=197), we

Abstract 19348: The Impact of Hypothyroidism on Platelet-Fibrin Clot Characteristics in Patients Undergoing Cardiac Catheterization

Hypothyroidism and accompanying hypercholesterolemia are associated with accelerated atherosclerosis. Hypothyroidism has been associated with inflammation, endothelial dysfunction, and platelet function abnormalities. However, impact of hypothyroidism on the physical characteristics of the platelet-fibrin clot is unknown. We sought to determine the impact of hypothyroidism on platelet-fibrin clot characteristics in patients undergoing cardiac catheterization. Methods: Patients on 325 mg daily aspirin with (n=41) and without (n=286) a history of hypothyroidism undergoing cardiac catheterization were studied. Hypothyroidism was defined as treatment with thyroid hormone replacement. Blood samples were collected immediately prior to coronary angiography to determine clotting characteristics by thrombelastography (TEG). Urinary 11-dehydrothromboxane B 2 was performed by immunoassay method. Results: Baseline demographics and cardiac risk factors were similar between groups. Thyroid stimulating hormone levels were within the normal range with no significant difference between groups. Patients with a history of hypothyroidism had significantly higher thrombin-induced platelet fibrin clot strength(67.9±5.3 mm vs.66.1±5.8 mm, p=0.04) , faster time to initial thrombin formation (6.9±1.9 vs. 7.8±2.1, p=0.02) , and higher clotting index(0.7±2.4 vs. -0.4±2.0, p=0.005). There were no differences in urinary 11-dehydrothromboxane B 2 between groups. Conclusion: This is the first report that a history of hypothyroidism is associated with altered physical characteristics of the platelet-fibrin clot; an increase in the tensile strength of the clot. Further studies are needed to confirm this association and its relation to ischemic outcomes.

TCT-715 First Demonstration of dose Dependent Effect of Statin Therapy on Urinary 11-dehydrothromboxane B2 levels in Patients Undergoing Coronary Angiography

Background: Aspirin and statin therapy are primary treatment strategies in patients with cardiovascular disease. Heightened urinary 11-dehydrothromboxane B2(11-dTxB2) levels have been associated with an increased risk of adverse cardiovascular events. The aim of the study was to determine the effect of statin therapy on 11-dTxB2 levels in patients undergoing coronary angiography on 325 mg aspirin. Methods: Urinary 11-dTxB2 was measured in patients prior to coronary angiography with (n 155) and without (n 95) statin therapy. Lipoproteins by vertical density gradient ultracentrifugation technique and thrombin-induced platelet-fibrin clot strength(TIP-FCS), a marker for cardiovascular events by thrombelastography, were also measured. The dose dependent effect of statin therapy was analyzed according to atorvastatin equivalent dose, categorized as: 5-10mg, 20-40mg, 80mg. Results: Baseline demographics and cardiac risk factors were similar between groups. Statins significantly reduced urinary 11-dTxB2 levels in a dose dependent manner (Figure). There was a significant relation between quartiles of 11-dTxB2 and TIPFCS,(p 0.05 for ANOVA). Patients on statin therapy had significantly lower levels of LDL, triglycerides, VLDL, atherox and apo B100 (p 0.005 for all). However, Urinary 11-dTxB2 did not correlate with lipids and lipoproteins measurements. Conclusions: This is the first study to demonstrate the dose dependent response of statin therapy on urinary 11-dTxB2 levels, independent of lipid lowering effects.Clinical outcome studies are required to determine the utility of this novel marker for optimizing statin therapy. TCT-716

Hypercoagulability, platelet function, inflammation and coronary artery disease acuity: Results of the Thrombotic RIsk Progression (TRIP) Study

The objective of the study was to determine the relation of platelet reactivity, hypercoagulability and inflammation in various stages of coronary artery disease acuity (CAD). Thrombin-induced platelet-fibrin clot strength (MA), time to initial platelet-fibrin clot formation (R), C-reactive protein (CRP), prothrombotic factors, activated GPIIb/IIIa receptor expression and other biomarkers were studied in patients with asymptomatic stable CAD (AS), in patients undergoing PCI for stable (SA) and unstable angina (UA). MA and R were measured by thrombelastography, GPIIb/IIIa expression by flow cytometry and all other markers by fluorokine multianalyte profiling assays. An overall increase in all measurements from a clinically stable to an unstable disease state was observed. There was a distinct stepwise increment in MA [AS vs. SA (p = 0.02), SA vs. UA (p = 0.02) and AS vs. UA (p < 0.001)]. MA exhibited the strongest correlation with other prothrombotic markers (p ≤ 0.02), with CRP (p < 0.001) at all levels of CAD acuity. A distinct pathophysiological state of heightened platelet function, hypercoagulability and inflammation marks the presence of unstable cardiovascular disease requiring intervention. Further studies are required to investigate the primary mechanisms linking the above processes associated with a prothrombotic state resulting in clinical destabilization of the disease.

Bivalirudin and Clopidogrel With and Without Eptifibatide for Elective Stenting: Effects on Platelet Function, Thrombelastographic Indexes, and Their Relation to Periprocedural Infarction: Results of the CLEAR PLATELETS-2 (Clopidogrel With Eptifibatide to Arrest the Reactivity of Platelets) Study

The primary objective of this study was to compare the effect of therapy with bivalirudin alone versus bivalirudin plus eptifibatide on platelet reactivity measured by turbidometric aggregometry and thrombin-induced platelet-fibrin clot strength (TIP-FCS) measured by thrombelastography in percutaneous coronary intervention (PCI) patients. The secondary aim was to study the relation of platelet aggregation and TIP-FCS to the occurrence of periprocedural infarction. Bivalirudin is commonly administered alone to clopidogrel naïve (CN) patients and to patients on maintenance clopidogrel therapy (MT) undergoing elective stenting. The effect of adding eptifibatide to bivalirudin on platelet reactivity (PR) and TIP-FCS, and their relation to periprocedural infarction in these patients are unknown. Patients (n = 200) stratified to clopidogrel treatment status were randomly treated with bivalirudin (n = 102) or bivalirudin plus eptifibatide (n = 98). One hundred twenty-eight CN patients were loaded with 600 mg clopidogrel immediately after stenting, and 72 MT patients were not loaded. The PR, TIP-FCS, and myonecrosis markers were serially determined. In CN and MT patients, bivalirudin plus eptifibatide was associated with markedly lower PR at all times (5- and 20-microM adenosine diphosphate-induced, and 15- and 25-microM thrombin receptor activator peptide-induced aggregation; p < 0.001 for all) and reduced mean TIP-FCS (p < 0.05). Patients who had a periprocedural infarction had higher mean 18-h PR (p < 0.0001) and TIP-FCS (p = 0.002). For elective stenting, the addition of eptifibatide to bivalirudin lowered PR to multiple agonists and the tensile strength of the TIP-FCS, 2 measurements strongly associated with periprocedural myonecrosis. Future studies of PR and TIP-FCS for elective stenting may facilitate personalized antiplatelet therapy and enhance the selection of patients for glycoprotein IIb/IIIa blockade. (Peri-Procedural Myocardial Infarction, Platelet Reactivity, Thrombin Generation, and Clot Strength: Differential Effects of Eptifibatide + Bivalirudin Versus Bivalirudin [CLEAR PLATELETS-2]; NCT00370045.