11-dehydro-TXB2 Research Articles

Statin therapy and inflammation in patients with diabetes treated with high dose aspirin

BackgroundStatin and aspirin form the therapeutic cornerstone in patients with coronary artery disease (CAD) and diabetes. Little is known about relationship of statins with blood thrombogenicity and inflammation in these patients. MethodsTwo hundred nine consecutive patients with diabetes and suspected CAD undergoing elective cardiac catheterization were divided in groups based on statin treatment in the Multi-Analyte, Thrombogenic, and Genetic Markers Atherosclerosis study. Urinary 11-dehydrothromboxane B2 (11-dh-TxB2), lipid profile and oxLDL/β2GPI were measured by AspirinWorks™ ELISA assay, vertical density gradient ultracentrifugation and immunoassay respectively. Thrombelastography, and ADP- and collagen-induced light transmittance aggregometry assessed thrombogenicity. CAD was classified as none/minor [<20% diameter stenosis (DS)], moderate (20–75% DS), or severe (>75% DS). ResultsSevere, moderate, and no CAD was observed in 66, 19, and 15% of patients respectively. Patients on statins had significantly lower 11-dh-TxB2, collagen-induced aggregation, total cholesterol, total LDL, LDL3, oxidized-LDL, Apo B100, and ApoB100/A1 ratio (p<0.01 for all). Statin therapy demonstrated a lower proportion of patients with high urinary 11-dh-TxB2 (>1500pg 11-dh-TxB2/mg creatinine) (25 vs. 57%, p=0.01). ConclusionStatins along with aspirin, confers additional anti-inflammatory and antithrombotic effect in diabetics with CAD. Urinary 11-dh-TxB2 may be a useful biomarker for personalizing statin therapy.

(677) - Elevated Levels of 11-dehydrothromboxane B2 in Urine Is Associated with an Increased Risk of Bleeding in Patients Supported with a Continuous Flow-Left Ventricular Assist Device

(677) - Elevated Levels of 11-dehydrothromboxane B2 in Urine Is Associated with an Increased Risk of Bleeding in Patients Supported with a Continuous Flow-Left Ventricular Assist Device

Cardiovascular events occur independently of high on-aspirin platelet reactivity and residual COX-1 activity in stable cardiovascular patients.

Several studies have indicated that approximately 25 % of patients treated with aspirin exhibit high on-treatment platelet reactivity (HTPR), which is potentially associated with cardiovascular events (CVEs). However, this association is still controversial, since the mechanisms by which HTPR contributes to CVEs remain unclear and a no standardised definition of HTPR has been established. To determine whether HTPR is associated with CVE recurrence and what type of assay would best predict CVE recurrence, we conducted a multicentre prospective cohort study of 592 stable cardiovascular outpatients treated with aspirin monotherapy for secondary prevention. Their HTPR was determined by arachidonic acid- or collagen-induced aggregation assays using two different agonist concentrations. Residual cyclooxygenase (COX)-1 activity was assessed by measuring serum thromboxane (TX)B2 or urinary 11-dehydro TXB2. Shear-induced platelet thrombus formation was also examined. We followed all patients for two years to evaluate how these seven indexes were related to the recurrence of CVEs (cerebral infarction, transient ischaemic attack, myocardial infarction, unstable angina, revascularisation, other arterial thrombosis, or cardiovascular death). Of 583 patients eligible for the analysis, CVEs occurred in 69 (11.8 %). A Cox regression model identified several classical risk factors associated with CVEs. However, neither HTPR nor high residual COX-1 activity was significantly associated with CVEs, even by applying cut-off values suggested in previous reports or a receiver-operating characteristic analysis. In conclusion, recurrence of CVEs occurred independently of HTPR and residual COX-1 activity. Thus, our findings do not support the use of platelet or COX-1 functional testing for predicting clinical outcomes in stable cardiovascular patients.

Oxidative stress and thromboxane-dependent platelet activation in inflammatory bowel disease: effects of anti-TNF-α treatment.

Patients with inflammatory bowel disease (IBD) are at higher risk of venous thromboembolism and coronary artery disease despite having a lower burden of traditional risk factors. Platelets from IBD patients release more soluble CD40 ligand (CD40L), and this has been implicated in IBD platelet hyper-activation. We here measured the urinary F2-isoprostane 8-iso-prostaglandin (PG)2α (8-iso-PGF2α), urinary 11-dehydro-thromboxane (TX) B2 (11-dehydro-TXB2) and plasma CD40L in IBD patients, and explored the in vitro action of anti-tumour necrosis factor (TNF)-α antibody infliximab on IBD differentiating megakaryocytes. Urinary and blood samples were collected from 124 IBD patients and 37 healthy subjects. Thirteen IBD patients were also evaluated before and after 6-week infliximab treatment. The in vitro effect of infliximab on patient-derived megakaryocytes was evaluated by immunoflorescence microscopy and by flow cytometry. IBD patients had significantly (p<0.0001) higher urinary 8-iso-PGF2α and 11-dehydro-TXB2 as well as plasma CD40L levels than controls, with active IBD patients displaying higher urinary and plasma values when compared to inactive patients in remission. A 6-week treatment with infliximab was associated with a significant reduction of the urinary excretion of 8-iso-PGF2α and 11-dehydro-TXB2 (p=0.008) and plasma CD40L (p=0.001). Infliximab induced significantly rescued pro-platelet formation by megakaryocytes derived from IBD patients but not from healthy controls. Our findings provide evidence for enhanced in vivo TX-dependent platelet activation and lipid peroxidation in IBD patients. Anti-TNF-α therapy with infliximab down-regulates in vivo isoprostane generation and TX biosynthesis in responder IBD patients. Further studies are needed to clarify the implication of infliximab induced-proplatelet formation from IBD megakaryocytes.

Comparison between urinary 11-dehydrothromboxane B2 detection and platelet Light Transmission Aggregometry (LTA) assays for evaluating aspirin response in elderly patients with coronary artery disease

Aspirin is widely used in the primary and secondary prevention of cardiovascular diseases. The aim of our study was to compare between two established methods of aspirin response, urinary 11-dehydrothromboxane B2 (11dhTXB2) and platelet Light Transmission Aggregometry (LTA) assays in elderly Chinese patients with coronary artery disease (CAD), and to investigate the clinical significance of both methods in predicting cardiovascular events. Urinary 11dhTxB2 assay and arachidonic acid-induced (AA, 0.5mg/ml) platelet aggregation by Light Transmission Aggregometry (LTAAA) assay were measured to evaluate aspirin responses. High-on aspirin platelet reactivity (HAPR) was defined as urinary 11dhTxB2>1500pg/mg or AA-induced platelet aggregation≥15.22%—the upper quartile of our enrolled population. The two tests showed a poor correlation for aspirin inhibition (r=0.063) and a poor agreement in classifying HAPR (kappa=0.053). With a mean follow-up time of 12months, cardiovascular events occurred more frequently in HAPR patients who were diagnosed by LTA assay as compared with no-HAPR patients (22.5% versus 10.6%, P=0.039, OR=2.45, 95% CI=1.06–5.63). However, the HAPR status, as determined by urinary 11dTXB2 measurement, did not show a significant correlation with outcomes.

Overcoming aspirin resistance with loading clopidogrel earlier in elective percutaneous coronary intervention.

We aimed to analyze the clinical effect of clopidogrel loading time on adverse cardiovascular events among patients with aspirin resistance. Recurrent adverse events may still occur despite dual antiplatelet therapy after coronary stenting. Aspirin resistance is one of the possible reasons of this trouble. Optimal antiplatelet strategy for coronary stenting is unknown among patients with aspirin resistance. A total of 980 patients scheduled for elective coronary stenting were enrolled and allocated into two groups according to the loading time of clopidogrel more or less than 6 hours before coronary intervention (early- or late-loaded groups, respectively). Aspirin resistance was determined according to the urinary levels of 11-dehydrothromboxane B2. Overall 240 patients who were allocated to early- and late-loaded groups were identified as aspirin resistant according to the urinary levels of 11-dehydrothromboxane B2. After a follow-up period of 12 months major adverse cardiac events were observed among 16 patients (13.9%) in the early-loaded group and 30 patients (25.8%) in the late-loaded group (p = 0.02). Early loading of clopidogrel was an independent predictor of lower rate of cardiac events (hazard ratio = 0.46 [0.32-0.76, 95% confidence interval], p = 0.001). The rates of bleeding events and periprocedural myocardial infarction were similar in early- and late-loaded groups. The current study demonstrated that loading of clopidogrel earlier than 6 hours before elective coronary stenting among aspirin-resistant patients was associated with increased benefits for ischemic events with similar bleeding rates.

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.

ASSA14-03-38 Comparison of Urinary11-DehydrothromboxaneB2 detection and Plasma LTA Assay for evaluating aspirin response in the Aged Patients with Coronary Artery Disease

Aims Aspirin is widely used in the primary and secondary prevention of cardiovascular diseases. Nevertheless, the responses to aspirin administration vary from one patient to another, and there is a lack of efficient and platelet-specific method correlated well with clinical outcomes. The aim of our study was to make comparisons between 2 established methods of aspirin response evaluation)—measurement of urinary 11-dehydrothromboxane B2 (11dhTxB2) and plasma Light Transmission Aggregometry (LTA) assay—in aged patients with coronary artery disease (CAD), and examinethe relationship between AR and clinical outcomes. Methods A total of 145 aged patients with CAD on low-dose aspirin (100 mg/d) therapy were enrolled in this study. All patients were measuredby urinary11dhTxB2 and platelet aggregation. Aspirin response was assessed via urinary 11dhTxB2 measurement and plasma LTAassay. AspirinResistance (AR) was defined as urinary11dhTxB2 >1500 pg/mg or 0.5 mg/ml AA-induced platelet aggregation ≥ 15.07%. The Spearman correlation coefficients andkappa statistics were calculated to assess correlation and agreement between the2 tests. The measured clinical outcome was defined as the occurrence of cardiovascular events and death. Results Prevalence of aspirin non-responders was 32.1% and 13.2%, according to urinary 11dhTxB2 measurement and LTA assay, respectively. Poor correlation in the results between the 2 tests was observed (r = 0.135, p = 0.151). Besides, the correlation between the 2 methods and AR was weak (kappa = 0.113, p = 0.113). With a mean follow-up time of 12 months, the clinical outcomes occurred more frequently in AR patients based on urinary 11dhTxB2 measurement as compared with normal aspirin response patients (18% vs 2%, OR: 8.8, 95% CI: 1.18~65.4, p = 0.037). Conclusions Our research observed poor correlation and lack of agreement between the 2 tests. Urinary 11dhTxB2 measurement might be a better predictor in the risk of cardiovascular events and death as compared to LTA assay. Nevertheless, development of efficient and inexpensive platelet function tests, which should also have a good correlation with clinical outcomes was necessary.

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.

Hydroxychloroquine's Efficacy as an Antiplatelet Agent Study in Healthy Volunteers: A Proof of Concept Study.

With the inflammatory model of atherosclerosis taking center stage, anti-inflammatory drugs hold a promising place in the therapy of cardiovascular disease (CVD). Recent studies showed that hydroxychloroquine (HCQ) was protective against thrombovascular events in lupus erythematosus and traditional cardiovascular risk factors in patients with rheumatoid arthritis. Some preliminary experimental data have shown that it may prevent platelet activation too. To evaluate the antiplatelet activity of HCQ when given alone and in combination with aspirin (ASA) and compare it with ASA alone and ASA plus clopidogrel (CLOP) in healthy human volunteers. In part 1 of the study, 8 volunteers were given HCQ for 7 days. In part 2, 12 volunteers were randomly assigned in a 1:1:1 ratio to the 3 groups in which 2 of the 3 treatments, ASA, ASA plus CLOP, and ASA plus HCQ, were given in the 2 treatment periods separated by a 14-day washout period using the incomplete block design. Inhibition of platelet aggregation (IPA) was measured by light transmission aggregometry. When arachidonic acid (AA) was used as agonist, HCQ given alone showed a significant reduction in platelet aggregation (11.0% ± 4.2%, P = .03). The IPA was significantly increased when ASA plus HCQ was compared with ASA alone (31.2% ± 8.1%, P = .002). This synergistic effect was not seen with adenosine diphosphate and collagen as agonists. Levels of serum 11-dehydrothromboxane B2, a stable marker of thromboxane A2 production, were not significantly different between the groups. There was also a significant decrease in fibrinogen and erythrocyte sedimentation rate values when HCQ was used alone or in combination with ASA. This study suggests that HCQ has antiplatelet properties possibly through the AA pathway (downstream to thromboxane A2 production). With possible additional beneficial effects over the traditional CVD risk factors, larger studies in the future might explore HCQ's potential as an antiplatelet agent.

Increased platelet expression of glycoprotein IIIa following aspirin treatment in aspirin-resistant but not aspirin-sensitive subjects.

Aspirin is widely used as an anti-platelet agent for cardiovascular prophylaxis. Despite aspirin treatment, many patients experience recurrent thrombotic events, and aspirin resistance may contribute to this. We examined the prevalence of aspirin resistance in a healthy population, and investigated whether the platelet proteome differed in aspirin-resistant subjects. Ninety-three healthy subjects received aspirin 300 mg daily for 28 days. Before and at the end of treatment, urine was taken to determine 11-dehydrothromboxane B2 , and blood was taken to measure arachidonic acid (AA)-induced aggregation of platelet-rich plasma and to interrogate the platelet proteome by mass spectrometric analysis with further confirmation of findings using Western blotting. In two of the 93 subjects, neither AA-induced aggregation nor urinary 11-dehydrothromboxane B2 was effectively suppressed by aspirin, despite measurable plasma salicylate concentrations, suggesting the presence of true aspirin resistance. Despite no detectable differences in the platelet proteome at baseline, following aspirin a marked increase was seen in platelet glycoprotein IIIa expression in the aspirin-resistant but not aspirin-sensitive subjects. An increase in platelet glycoprotein IIIa expression with aspirin resistance was confirmed in a separate cohort of 17 patients with stable coronary artery disease on long term aspirin treatment, four of whom exhibited aspirin resistance. In a healthy population, true aspirin resistance is uncommon but exists. Resistance is associated with an increase in platelet glycoprotein IIIa expression in response to aspirin. These data shed new light on the mechanism of aspirin resistance, and provide the potential to identify aspirin-resistant subjects using a novel biomarker.

Opposing roles of prostaglandin D2 receptors in ulcerative colitis.

Proresolution functions were reported for PGD2 in colitis, but the role of its two receptors, D-type prostanoid (DP) and, in particular, chemoattractant receptor homologous molecule expressed on Th2 cells (CRTH2), is less well defined. We investigated DP and CRTH2 expression and function during human and murine ulcerative colitis (UC). Expression of receptors was measured by flow cytometry on peripheral blood leukocytes and by immunohistochemistry and immunoblotting in colon biopsies of patients with active UC and healthy individuals. Receptor involvement in UC was evaluated in a mouse model of dextran sulfate sodium colitis. DP and CRTH2 expression changed in leukocytes of patients with active UC in a differential manner. In UC patients, DP showed higher expression in neutrophils but lower in monocytes as compared with control subjects. In contrast, CRTH2 was decreased in eosinophils, NK, and CD3(+) T cells but not in monocytes and CD3(+)/CD4(+) T cells. The decrease of CRTH2 on blood eosinophils clearly correlated with disease activity. DP correlated positively with disease activity in eosinophils but inversely in neutrophils. CRTH2 internalized upon treatment with PGD2 and 11-dehydro TXB2 in eosinophils of controls. Biopsies of UC patients revealed an increase of CRTH2-positive cells in the colonic mucosa and high CRTH2 protein content. The CRTH2 antagonist CAY10595 improved, whereas the DP antagonist MK0524 worsened inflammation in murine colitis. DP and CRTH2 play differential roles in UC. Although expression of CRTH2 on blood leukocytes is downregulated in UC, CRTH2 is present in colon tissue, where it may contribute to inflammation, whereas DP most likely promotes anti-inflammatory actions.

Age-related differences in urinary 11-dehydroxythromboxane B2 between infants, children, and adolescents: another example of developmental hemostasis?

Our study was developed to ascertain reference ranges of 11-dehydrothromboxane B2 (11-dhTXB2) in the urine of healthy pediatric subjects. Urine samples were analyzed using the AspirinWorks™ assay that measures levels of 11-dehydrothromboxane B2. 128 individuals (2 months to 18 years) were identified as healthy and not receiving aspirin. When adjusted as picograms/milligrams urine creatinine, there was a negative correlation between age and level of 11-dehydrothromboxane B2 (P = 0.0001). This study confirms a negative correlation between age and level of urinary 11-dehydrothromboxane B2 and provides a set of age-specific reference ranges.

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.

Acetylsalicylic acid therapy: Influence of metformin use and other variables on urinary 11-dehydrothromboxane B2 levels

BackgroundThe effect of acetylsalicylic acid (ASA) may be measured through the analysis of urinary concentrations of 11-dehydrothromboxane B2 (11-dhTXB2), a metabolite of thromboxane A2, which is a potent platelet aggregant agent. It has been suggested that metformin (an oral antidiabetic drug) could improve oxidative stress and control platelet activation in type 2 diabetic patients, potentially reducing cardiovascular risk. We determined the concentrations of urinary 11-dhTXB2 in type 2 diabetic patients taking ASA and its concentrations with metformin use and several other clinical variables (hypertension, age, gender, smoking, body mass index, insulin and statin use), considering a reduction of at least 75% in the concentrations of this marker as a target, compared to results before ASA intake. MethodsUrinary concentrations of 11-dhTXB2 of 81 type 2 diabetic patients were measured before and at 15days taking 100mg of aspirin daily. ResultsMost patients who presented a reduction of 11-dhTXB2 above 75% were under metformin use. This reduction was achieved in 51.5% of patients taking this drug, against 20.0% in the patients who were not (p=0.027). The analysis of the other variables did not show a significant difference. The use of metformin appears to play a role in the reduction of 11-dhTXB2 concentrations in type 2 diabetic patients. ConclusionAccording to previous reports, hyperglycemia control seems to be a determinant factor for the success of ASA therapy, given the influence of metformin in the reduction of 11-dhTXB2 concentrations.

Comparison of Aspirin Response Measured by Urinary 11-Dehydrothromboxane B2 and VerifyNow Aspirin Assay in Patients with Ischemic Stroke

We looked for the prevalence of aspirin nonresponders, compared theresults of 2 tests assessing aspirin responses-measurement of urinary 11-dehydrothromboxane B2 (dTXB2) and VerifyNow Aspirin assay-in patients with ischemic stroke, and examined the relationship of aspirin nonresponse and the outcomes of the patients. One hundred one patients with ischemic stroke were prospectively included. Aspirin response was assessed by urinary dTXB2 measurement and VerifyNow Aspirin assay. The Spearman correlation coefficients and kappa statistics were calculated to assess correlation and agreement between the 2tests. The measured outcome was the occurrence of cardiovascular events and death. Prevalence of aspirin nonresponders was 40% and 6%, if they were measured by urinary dTXB2 and VerifyNow Aspirin assay, respectively. Poor correlation in the results between the 2 tests was found (r=.135, P=.190). The degree of agreement between the 2 tests in relation to resistance status was weak (kappa=.032, P=.590). With a mean follow-up time of 17months, the outcomes occurred significantly higher in aspirin nonresponders who were diagnosed by urinary dTXB2 measurement as compared with patients with aspirin response (18% versus 2%, odds ratio 8.8, 95% confidence interval 1.18-65.4, P=.037). Our research confirmed poor correlation and lack of agreement between the 2 tests. Only aspirin nonresponders who were diagnosed by dTXB2 measurement were related to having cardiovascular events and death. Further research is still needed to identify the best method of diagnosis of aspirin nonresponders.

Comparison of aspirin response measured by urinary 11-dehydrothromboxane B2 and VerifyNow Aspirin assay in patients with ischemic stroke

Comparison of aspirin response measured by urinary 11-dehydrothromboxane B2 and VerifyNow Aspirin assay in patients with ischemic stroke

Predictors of high platelet reactivity during aspirin treatment in patients with type 2 diabetes

Diabetes mellitus type 2 (DM2) is associated with high platelet reactivity both in patients who do not receive antiplatelet drugs and in those treated with acetylsalicylic acid (ASA). The pathomechanism of this phenomenon has not been fully understood. 1. To evaluate variability of platelet reactivity in patients with DM2 treated with oral antidiabetic drugs and receiving chronic ASA therapy. 2. To identify independent predictors of high platelet reactivity during ASA therapy in patients with DM2. We studied 171 patients with DM2 treated with oral antidiabetic drugs and receiving long-term treatment with 75 mg of ASA daily, selected among the participants of the prospective AVOCADO study. Platelet function was simultaneously evaluated using 4 methods: 1. measurement of serum thromboxane B2 (TXB2) concentration; 2. measurement of urinary 11-dehydrothromboxane B2 (11-dhTXB2) concentration; 3. VerifyNow® automated analyser; 4. PFA-100® automated analyser.High platelet reactivity was defined as at least 3 of the following criteria: 1. serum TXB2 concentration in the upper quartile;2. urinary 11-dhTXB2 concentration in the upper quartile; 3. value ≥ 550 aspirin reaction units (ARU) by VerifyNow®;4. collagen-epinephrine closure time (CEPI-CT) below median of readings other than 300 s by PFA-100®. In all patients, DM2 control was evaluated, insulin resistance was measured using HOMA-IR, and routine laboratory tests were performed, including full blood count, renal function parameters, and inflammation markers. Mean patient age was 67.8 years, and median duration of DM2 was 5 years. We found poor agreement between different tests of platelet function. ARU ≥ 550 (VerifyNow®) was found in 14.0% of patients, and CEPI-CT below median of readings other than 300 s (PFA-100®) was found in 32.8% of patients. Our criteria of high platelet reactivity were met by 9.9% of patients. In multivariate logistic regression analysis, independent predictors of high platelet reactivity despite ASA therapy included chronic heart failure, current smoking, and higher leukocyte count. 1. Patients with DM2 are characterised by large variability of platelet reactivity, with little agreement between various methods. 2. Smoking, chronic heart failure, and subclinical inflammation may be associated with high platelet reactivity in patients with DM2 treated with ASA.

The effect of doubling the dose of acetylsalicylic acid (ASA) on platelet function parameters in patients with type 2 diabetes and platelet hyperreactivity during treatment with 75 mg of ASA: a subanalysis of the AVOCADO study

Individuals with diabetes are at 2- to 4-fold higher risk of cardiovascular disease than those without diabetes. High platelet reactivity (HPR) plays a pivotal role in atherothrombotic complications of diabetes. Polish and American diabetes associations recommend treating high-risk diabetic patients with low doses of acetylsalicylic acid (ASA) in primary and secondary prevention of cardiovascular events. Unfortunately, some patients show HPR despite treatment with ASA. To determine the effect of doubling the dose of ASA on platelet reactivity in patients with type 2 diabetes and HPR despite treatment of with 75 mg of ASA. 304 type 2 diabetes patients treated with 75 mg of ASA were enrolled into the prospective, randomised, open-label Aspirin Versus/Or Clopidogrel in Aspirin-resistant Diabetics inflammation Outcomes (AVOCADO) study. Platelet reactivity was assessed by Platelet Function Analyser (PFA)-100®, VerifyNow® Aspirin Assay, and serum thromboxane B2 (sTXB2) and urinary 11-dehydrothromboxane B2 (u11dhTXB2) level measurements. Patients with HPR determined by collagen/epinephrine-induced closure time (CEPI-CT) measured by PFA-100® were randomised in a 2:3 ratio to receive 150 mg of ASA (Group 1) or 75 mg of clopidogrel (Group 2), respectively. Platelet reactivity was assessed at baseline and after 8 weeks of treatment. Complete clinical data and blood samples were ultimately available for 260 of 304 patients initially enrolled to the study. Subsequently, six patients were excluded from the analysis based on suspected ASA non-compliance (sTXB2 level > 7200 pg/mL). Among 254 patients finally included into analysis, HPR was found in 90 (35.4%) patients of whom 38 patients were randomised to Group 1 and 52 patients to Group 2. Doubling the dose of ASA resulted in a significant CEPI-CT prolongation (Delta 111 s, p < 0.001) and reduction of sTXB2 level (Delta -101.3 pg/mL, p = 0.001) but did not significantly affect results of other platelet function tests. Doubling the dose of ASA improved platelet reactivity in patients with type 2 diabetes and HPR.

Polymorphisms and high on-aspirin platelet reactivity after off-pump coronary artery bypass grafting

Objectives. High on-aspirin residual platelet reactivity (RPR) after coronary artery bypass grafting (CABG) is a transient phenomenon with important implications for graft patency. This study was designed to determine the role of polymorphisms [TBXA2R (T924C), GPIIIa (PlA1/A2), P2Y1 (A1622G), and GP1Bα (C1018T)] on RPR in Chinese patients undergoing off-pump CABG (OPCAB). Methods. Of 420 patients recruited to this study, 210 patients underwent primary OPCAB and 210 controls with ischemic heart disease received optimal medical therapy. Arachidonic acid-induced platelet aggregation and urinary 11-dehydro thromboxane B2 were measured at baseline and following aspirin administration on days 1, 4, 10, and on 6th month. Four polymorphisms were identified [TBXA2R (T924C), P2Y1 (A1622G), PlA1/A2 and GP1Bα (C1018T)]. Results. On the first post-operative day, 62 patients (29.5%) were with high RPR and 148 (70.5%) were with low RPR. Of the former, 33 (15.7%), 10 (4.6%), and 0 (0%) patients remained with high RPR on days 4, 10, and on 6 month, respectively. No individuals with high RPR was found in controls. Logistic regression identified TBXA2R-924TT (OR = 4.5; 95% CI, 1.8–11.1) and body mass index > 27 kg/m2 (OR = 2.73; 95% CI, 1.1–7.0) as independent risk factors for high on-aspirin RPR. Conclusions. High on-aspirin RPR after OPCAB is associated with genetic polymorphism TBXA2R-924TT and obesity.