thromboxane-b2 and Stroke

Uncertainty remains regarding the impact of enteric-coated (EC) aspirin as it relates to the reduction of cardiovascular risk. We hypothesize that EC formulation based on a previous report may blunt aspirin response as evidenced by reduced Thromboxane A2 (TXA 2) levels in diabetic patients. Thus, it was imperative to ascertain and validate the effect of the EC formulation of Aspirin on the Thromboxane B2 (TXB2) level.. An open-label consecutive randomized interventional controlled trial. Patients with newly diagnosed ischemic stroke who are just about to start Aspirin were assessed for eligibility and inclusion in our trial. Consecutive patients (admitted to the stroke unit of Hamad General Hospital, Hamad Medical Corporation, Doha, Qatar) will be randomized to receive either EC aspirin or plain Aspirin. They will be required to continue taking them throughout the study (3 days). Demographics and laboratory records of the study participants will be abstracted from online records. Further study variables will be obtained manually in designated case record forms (CRF). The primary outcomes are the incidence of aspirin non-responders (level of residual serum TXB2 associated with elevated thrombotic risk (<99.0% inhibition or TXB2 >3.1 ng/mL) within 72 h after three daily aspirin doses). Whereas secondary outcomes are the incidence of GIT bleeding of various preparations of Aspirin. The study was approved by MRC and IRB of Hamad Medical Corporation (MRC number: 01-18-156).. This trial will determine potential differences in the efficacy of EC Aspirin and plain Aspirin on the Thromboxane B2 level. Additionally, it will ascertain the tolerability and safety of both formulations of Aspirin in patients with newly diagnosed ischemic stroke. These results will either support the current notion of no difference between the two formulations. However, if a difference is found, this will invite for future trials exploring clinical outcomes occurrence between various formulations.. Clinicaltrials.gov NCT04330872 registered on April 2, 2020.

Topics: Adolescent; Adult; Aged; Aspirin; Blood Platelets; Brain Ischemia; Female; Gastrointestinal Hemorrhage; Humans; Male; Middle Aged; Platelet Aggregation Inhibitors; Single-Blind Method; Socioeconomic Factors; Stroke; Tablets, Enteric-Coated; Thromboxane B2; Young Adult

Platelet-leukocyte aggregation is believed to contribute to acute thrombotic events. While the effect of aspirin on platelet-to-platelet aggregation is well established, the impact of the drug on pro-inflammatory platelet function remains equivocal. Thus we investigated the effect of aspirin on selected platelet-related inflammatory biomarkers in both acute ischaemic stroke patients and healthy volunteers.. Using five-colour flow cytometry the platelet surface expression of CD62P and CD40L and subpopulations of leukocyte-platelet aggregates were assessed in 63 acute stroke patients and 40 healthy volunteers at baseline and after a 10-day period of aspirin intake at a daily dose of 150 mg. Simultaneously the plasma levels of soluble CD62P and CD40L, serum level of TxB(2), and whole blood impedance platelet aggregation under arachidonic acid (AA) stimulation were investigated.. No differences in values of studied platelet-related inflammatory biomarkers in both resting platelets and those activated with TRAP after 10-day treatment with aspirin were confirmed in stroke subjects. In healthy individuals the resting platelet expression of CD62P, plasma level of soluble CD62P and percentage of circulating monocyte-platelet aggregates were lower after the aspirin intake period (P=0.009; P=0.04; P=0.004, respectively). In both studied groups serum level of TxB(2) and platelet aggregation under AA stimulation were lower than before treatment (P<0.001).. Despite effective inhibition of COX-1-dependent platelet aggregation, aspirin does not influence the platelet α-granule-derived inflammatory mediators and monocyte-platelet aggregation in acute stroke subjects, although it does in healthy individuals.

Topics: Aged; Aspirin; Biomarkers; Blood Platelets; Case-Control Studies; CD40 Ligand; Cyclooxygenase 1; Female; Flow Cytometry; Humans; Inflammation; Male; Middle Aged; Monocytes; P-Selectin; Platelet Adhesiveness; Platelet Aggregation Inhibitors; Stroke; Thromboxane B2

Aspirin-clopidogrel combination therapy inhibits platelet aggregation. The effect on platelet recruitment is unknown.. Thirty chronic ischemic stroke patients taking aspirin alone followed by aspirin-clopidogrel combined therapy had platelet reactivity tests performed over 3 months: ex vivo platelet aggregation, platelet recruitment and urinary 11-dehydro-thromboxane B(2) (11-dhTxB(2))excretion. Statistical analysis of variance compared platelet aggregation and recruitment between aspirin alone and aspirin-clopidogrel, and longitudinal regression analysis estimated platelet recruitment over time. Nonlinear mapping defined variable connections in each patient.. Statistically significant differences were found between aspirin alone and aspirin-clopidogrel for (1) adenosine-diphosphate- and collagen-induced platelet aggregation and maximum inhibition of platelet recruitment and (2) increasing inhibition of platelet recruitment over time. Urinary 11-dhTxB(2) excretion did not predict platelet aggregation response. Nonlinear mapping showed patient-unique variable interconnections.. Platelet inhibition with aspirin-clopidogrel may increase over time, and future studies should focus on this finding in the context of vascular complications.

Topics: Aspirin; Brain Ischemia; Clopidogrel; Cohort Studies; Drug Therapy, Combination; Humans; Platelet Aggregation; Platelet Aggregation Inhibitors; Stroke; Thromboxane B2; Ticlopidine

A large number of patients experience ischemic stroke despite treatment with aspirin (acetylsalicylic acid, ASA). It is not clear whether all of these patients with ischemic stroke respond normally to ASA or are hyporesponsive as assessed by inhibition of aggregation and thromboxane (TX) synthesis.. We studied the effect of ASA given orally and ASA in vitro on collagen- and arachidonic-acid-induced TX formation and aggregation in platelet-rich plasma of 90 patients with ischemic stroke and 25 healthy control subjects.. Thirty-seven patients were being treated with ASA at the time of stroke. Arachidonic-acid-induced TX formation was not depressed below a predefined threshold of 25 ng/ml in 9 patients. Eight of these however exhibited a normal platelet sensitivity to ASA in vitro, suggesting poor compliance or a pharmacokinetic mechanism of nonresponse. The addition of ASA in vitro did not inhibit arachidonic-acid-induced TX formation below the above threshold in 6 patients (11%) in the group of 53 stroke patients not receiving oral ASA, indicating an impaired response to ASA at the platelet level. Moreover, platelets from stroke patients showed an increased collagen-induced, TX-independent aggregation as compared with those of healthy individuals.. Different categories of ASA nonresponders can be distinguished in patients with ischemic stroke. These include patients with poor bioavailability or noncompliance, an impaired platelet response to ASA in vitro and an increased, TX-independent hyperreactivity to collagen.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Arachidonic Acid; Aspirin; Biological Availability; Blood Platelets; Brain Ischemia; Collagen; Cyclooxygenase Inhibitors; Dose-Response Relationship, Drug; Drug Resistance; Female; Humans; Male; Middle Aged; Patient Compliance; Platelet Aggregation; Platelet Aggregation Inhibitors; Stroke; Thromboxane B2; Treatment Outcome

There is still worldwide disagreement about the optimal lowest dose of aspirin to be used in patients after a transient ischemic attack (TIA) or nondisabling stroke. We measured the urinary 11-dehydro-thromboxane-B(2) (uTXB(2)) excretion to compare the degree of suppression of in vivo platelet activation by various low doses of aspirin.. 60 patients were randomly allocated to treatment with either 30, 50, 75 or 325 mg of aspirin. All patients received a 413-mg loading dose of carbasalate calcium (equivalent to 325 mg of aspirin) on day 0. The study population was stratified into a subgroup with acute ischemic stroke (AIS; n = 20; onset of symptoms <48 h) and a subgroup with a recent TIA or minor stroke (TIA/mS; n = 40) with onset of symptoms beyond 30 days, but less than a year previously. Urine samples were collected on day 0, 1, 5, 11 and 28 in patients with AIS, and on day 0, 11 and 28 in the patients with a TIA/mS.. On day 28, mean uTXB(2) levels were 241, 130, 217 and 187 pmol/mmol creatinine in the four treatment groups (ANOVA, p = 0.43). In the AIS subgroup, uTXB(2) remained suppressed on days 5 and 11 in all except the patients with the lowest dose (mean uTXB(2) on days 5 and 11: 475 and 392 pmol/mmol creatinine; log-transformed ANOVA, p = 0.05).. In patients with a TIA or nondisabling stroke, a daily dose of 30 mg of aspirin provides sufficient suppression of thromboxane synthesis. No indication of a dose-effect relationship was found. However, whether such a low dose adequately suppresses thromboxane synthesis in patients with acute stroke is uncertain.

Topics: Adult; Aged; Aspirin; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Ischemic Attack, Transient; Male; Middle Aged; Patient Compliance; Platelet Aggregation Inhibitors; Risk Factors; Stroke; Thromboxane B2; Thromboxanes; Treatment Outcome

The aim of the study was to evaluate the relationship between daily aspirin use and urinary excretion of a stable thromboxane metabolite, 11-dehydrothromboxane B(2) (11-DTB2), in African American stroke patients.. Subjects were a subgroup of those screened for the African American Antiplatelet Stroke Prevention Study. Subjects were within 4 months of noncardioembolic ischemic stroke and were not being treated with anticoagulants. Antithrombotic therapy at the time of urine collection varied according to the practice patterns of various attending physicians who treated the patients during their acute strokes. 11-DTB2 was measured by enzyme immunoassay in random urine samples 1 to 4 months after the stroke.. Eighty-seven of 92 patients enrolled were able to give a urine sample at the time of enrollment. There were 51 men and 36 women aged 36 to 87 (mean 62) years. On the basis of antithrombotic treatment before the sample collection, we divided patients into 4 groups: (1) 16 patients treated with no aspirin (no antithrombotic drugs [n=4] or ticlopidine [n=12]), (2) 21 patients treated with 81 to 325 mg aspirin per day (81 mg/d [n=2], 325 mg/d [n=19]), (3) 20 patients treated with 650 mg aspirin per day, and (4) 30 patients treated with 975 to 1300 mg aspirin per day (975 mg/d [n=2] and 1300 mg/d [n=28]). In patients taking daily aspirin at any dose, the median urinary 11-DTB2 was 783 pg/mg creatinine compared with 1386 pg/mg creatinine in patients not taking daily aspirin (P=0.01 by Wilcoxon rank sum test). In multivariate regression analysis, aspirin use remained significantly associated with lower urinary 11-DTB2 (P=0.008). There was no dose-response effect between the 3 aspirin dose groups and urinary 11-DTB2 (P=0.70).. In African American stroke patients, aspirin use is associated with significantly lower urinary 11-DTB2 independent of other vascular factors, and there does not appear to be a dose-response effect for aspirin doses of 325 to 1300 mg daily. The clinical significance of these finding remains to be determined.

Topics: Adult; Aged; Aspirin; Black People; Female; Fibrinolytic Agents; Humans; Male; Middle Aged; Stroke; Thromboxane B2

The aim of this study was to determine the extent of change in platelet and coagulation markers in the acute phase of ischemic stroke and to assess the utility of marker measurement in stroke subtype classification. Urinary 11-dehydro-thromboxane B(2) (11-dTXB2), a marker of in vivo platelet activation, and markers of coagulation activation, including prothrombin fragment 1+2 (F1+2), thrombin-antithrombin complex (TAT), and fibrinogen, were measured in 25 patients with ischemic stroke within 24 h of onset of symptoms. Marker levels in patients with ischemic stroke were compared with those in 19 age-matched controls who had not taken aspirin for at least 2 weeks before sampling and 25 healthy controls. Median marker levels were significantly increased in stroke over those in age-matched controls for fibrinogen (344 vs. 289 mg/dl; P=0.030), F1+2 (1.40 vs. 0.80 nmol/l; P=0.003), and TAT (6.65 vs. 2.20 microg/l; P<0.0001). Median marker levels for seven patients with cardioembolic stroke and 18 with non-cardioembolic stroke were not significantly different for any marker test. Eight patients taking aspirin at the time of the stroke had significantly lower 11-dTXB2 values than patients not taking aspirin (964 vs. 4,314 pg/mg of creatinine; P=0.007). Stroke patients not taking aspirin had significantly higher 11-dTXB2 concentration than age-matched controls (4,314 vs. 1,788 pg/mg of creatinine; P=0.006). Coagulation and platelet activation markers are increased in the acute phase of stroke regardless of the clinical mechanism. This finding suggests that the markers may not be useful for predicting clinical subtype of ischemic stroke in the acute phase.

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Aspirin; Biomarkers; Blood Coagulation; Brain Ischemia; Fibrinogen; Humans; Middle Aged; Platelet Aggregation Inhibitors; Prospective Studies; Stroke; Thromboxane B2

Heavy binge drinking may trigger the onset of embolic stroke and acute myocardial infarction, but the underlying mechanisms are unclear. The effects of binge drinking on the hemostatic system and its circadian variation have not been investigated. We investigated the effects of an acute intake of a large dose of alcohol (1.5 g/kg).. Twelve healthy, nonsmoking men participated in sessions where they were served ethanol in fruit juice or served fruit juice alone and, lying in a supine position, were followed up for 12 to 24 hours. The treatments were randomized and separated from each other by a 1-week washout period. Blood and urine were collected for hemostatic measurements.. The urinary excretion of the platelet thromboxane A(2) metabolite 2, 3-dinor-thromboxane B(2) was significantly (P<0.05) greater during the night after an evening intake of alcohol than during the control night. A smaller increase was observed during the daytime after an intake of alcohol in the morning. The effects on the endothelial prostacyclin metabolite 2,3-dinor-6-ketoprostaglandin F(1alpha) excretion were negligible. A 7-fold increase in plasminogen activator inhibitor 1 activity was observed after both morning (P<0. 05) and evening (P<0.01) intakes of alcohol.. This is the first study to suggest that acute ingestion of a relatively large but tolerable dose of alcohol transiently enhances thromboxane-mediated platelet activation. The observations also demonstrate alcohol-induced changes in the normal circadian periodicity of the hemostatic system in subjects not accustomed to consumption of alcohol.

Topics: 6-Ketoprostaglandin F1 alpha; Acute Disease; Adult; Alcoholic Intoxication; Biomarkers; Circadian Rhythm; Creatinine; Cross-Over Studies; Disease Susceptibility; Drug Administration Schedule; Ethanol; Fibrinolysis; Hemorheology; Hemostasis; Humans; Male; Myocardial Infarction; Plasminogen Activator Inhibitor 1; Platelet Activation; Platelet Aggregation; Stroke; Supine Position; Thromboxane B2

To evaluate the rate of thromboxane biosynthesis in patients with systemic lupus erythematosus (SLE), exploring the interplay between antiphospholipid antibodies (aPL) and 2 markers of endothelial perturbation: thrombin generation and platelet activation.. A comparison of 11-dehydrothromboxane B2 (TXB2) excretion, which is a marker of in vivo platelet activation, aPL, von Willebrand factor (vWF) and tissue plasminogen activator (tPA), which are 2 circulating markers of endothelial perturbation, and plasma levels of the prothrombin fragment F1+2, which is a marker of thrombin generation, was performed in 40 SLE patients and 40 healthy subjects. Thromboxane metabolite excretion was also measured in 8 SLE patients before and after treatment with low-dose aspirin.. SLE patients had significantly higher 11-dehydro-TXB2 excretion, plasma F1+2, vWF, and tPA levels than controls. A statistically significant correlation was found between plasma levels of vWF and tPA and excretion of thromboxane metabolite. Moreover, significantly higher 11-dehydro-TXB2 was found in patients with aPL positivity and endothelial perturbation. Low-dose aspirin suppressed 11-dehydro-TXB2 by 80%, suggesting a predominant platelet source of enhanced thromboxane biosynthesis. After a median followup of 48 months, all SLE patients who experienced major cardiovascular events had thromboxane metabolite excretion, aPL positivity, and signs of endothelial perturbation.. We have characterized a sensitive marker of platelet activation, which is abnormal in SLE patients who were positive for aPL and endothelial perturbation. This analytical approach may help identify those patients at increased risk of thrombosis as potential candidates for antiplatelet therapy.

Topics: Adult; Antibodies, Antiphospholipid; Antigens; Aspirin; Cross-Sectional Studies; Dose-Response Relationship, Drug; Female; Humans; Ischemia; Lupus Erythematosus, Systemic; Male; Middle Aged; Myocardial Infarction; Stroke; Thromboxane B2; Thromboxanes; Tissue Plasminogen Activator; Venous Thrombosis; von Willebrand Factor

Progressive ischemic stroke is a common cerebrovascular disease with high morbidity. This study aimed to investigate the relationship between changes of Thromboxane B2 (TXB2), 6-keto-prostaglandin Fla (6-k-PGFla), and blood glucose (BG) levels with progressive ischemic stroke.. A total of 106 patients with progressive ischemic stroke admitted to our hospital from December 2016 to December 2018 were recruited as the observation group, and 110 patients who received physical examination in our hospital during the same period were selected as the control group. The levels of TXB2, 6-k-PGFla, and BG in different groups were compared, the related risk factors affecting the prognosis of patients with progressive ischemic stroke were analyzed, and the receiver operating characteristic (ROC) curve was drawn to evaluate the predictive value of TXB2, 6-k-PGFla, and BG for the prognostic mortality of patients with progressive ischemic stroke.. The levels of TXB2, 6-k-PGFla, and BG in the observation group were significantly higher than those in the control group (P<0.05). The prognostic mortality of participants with abnormally increased expression of TXB2, 6-k-PGFla, and BG was significantly higher than that of patients with normal expression of TXB2, 6-k-PGFla, and BG (P<0.05). Hypertension, diabetes, collateral circulatory disorders, hyperlipidemia, TXB2 (abnormal increase), 6-k-PGFla (abnormal increase), and BG (abnormal increase) were risk factors affecting the prognosis of patients with progressive ischemic stroke (P<0.05). The area under the curve (AUC) of the ROC curve showed that TXB2, 6-k-PGFla, BG, and the combination of them were 0.846, 0.893, 0.835, and 0.971, respectively, showing that the AUC of the combination of them was the largest.. Hypertension, diabetes, collateral circulatory disorders, hyperlipidemia, TXB2 (abnormal increase), 6-k-PGFla (abnormal increase), and BG (abnormal increase) are risk factors affecting the prognosis of patients with progressive ischemic stroke. The combined detection of the 3 indicators showed high sensitivity and specificity in evaluating the prognostic mortality of patients with progressive ischemic stroke, indicating that clinicians might improve the early diagnosis rate of progressive ischemic stroke by combining the detection of TXB2, 6-k-PGFla, and BG to predict the prognosis of patients.

Topics: Blood Glucose; Brain Ischemia; Humans; Ischemic Stroke; Prostaglandins; Stroke; Thromboxane B2

Experimental studies demonstrated that glutathione peroxidase 3 (GPx3), an antioxidant enzyme that catabolizes hydrogen peroxide, protects against thrombosis. Little is known about its role in cardiovascular disease.. A prospective cohort study was conducted in 909 atrial fibrillation patients. Serum activities of GPx3, superoxide dismutase (SOD), and catalase were measured at baseline to assess the risk of cardiovascular events during a mean follow-up of 43.4 months (3291 person-years). Serum Nox2 and urinary excretion of 11-deydro-thromboxane B2 were also measured. During follow-up 160 cardiovascular events occurred (4.9%/year). Significantly lower values of GPx3 (P<0.001) and SOD (P=0.037) were detected in patients with, compared to those without, cardiovascular events. A lower survival rate was observed in patients with GPx3 (P<0.001) and SOD (P=0.010) activities below the median, as compared to those above. In a fully adjusted Cox regression model, GPx3 was the only antioxidant enzyme predictor of cardiovascular events (hazard ratio 0.647, 95% confidence interval 0.524-0.798, P<0.001). GPx3 was inversely associated with urinary 11-dehydro-thromboxane B2 (B -0.337, P<0.001) and serum Nox2 (B: -0.423, P<0.001). GPx3 activity progressively decreased with decades of age (P<0.001), with a progressive reduction in people aged ≥70 years.. This study provides evidence that a low antioxidant status, as depicted by reduced levels of GPx3, increases the risk of cardiovascular events in patients with atrial fibrillation. The age-related decline of GPx3 may represent a mechanism for the enhanced cardiovascular risk in the elderly population.

Topics: Aged; Aged, 80 and over; Aging; Atrial Fibrillation; Cardiovascular Diseases; Catalase; Cohort Studies; Female; Follow-Up Studies; Glutathione Peroxidase; Humans; Ischemic Attack, Transient; Male; Middle Aged; Myocardial Infarction; Myocardial Revascularization; NADPH Oxidase 2; Prognosis; Proportional Hazards Models; Prospective Studies; Stroke; Superoxide Dismutase; Thromboxane B2

Aspirin resistance has an incidence of 5%-65% in patients with ischemic stroke, who receive the standard dose of aspirin, but the platelet function is inadequately inhibited, thereby leading to thrombotic events. Numerous evidence shows that thromboxane A. A total of 283 ischemic stroke patients receiving 100 mg aspirin for 7 d were genotyped for polymorphisms in MDR1 C3435T, TBXA2R (rs1131882), PLA2G7 (rs1051931, rs7756935), and PEAR1 (rs12566888, rs12041331). The platelet aggregation response was measured using an automatic platelet aggregation analyzer and a commercially available TXB. Thirty-three patients (11.66%) were insensitive to aspirin treatment. MDR1 3435TT genotype carriers, whose arachidonic acid (AA) or adenosine diphosphate (ADP)-induced platelet aggregation was lower than that of CC+CT genotype carriers, were less likely to suffer from aspirin resistance (odds ratio=0.421, 95% CI: 0.233-0.759). The TBXA2R rs1131882 CC genotype, which was found more frequently in the aspirin-insensitive group (81.8% vs 62.4%) than in the sensitive group, was identified as a risk factor for aspirin resistance (odds ratio=2.712, 95% CI: 1.080-6.810) with a higher level of AA-induced platelet aggregation. Due to the combined effects of PLA2G7 rs1051931 and rs7756935, carriers of the AA-CC haplotype had a higher level of ADP-induced platelet aggregation, and were at considerably higher risk of aspirin resistance than noncarriers (odds ratio=8.233, 95% CI: 1.590-42.638).. A considerable portion (11.66%) of Chinese ischemic stroke patients are insensitive to aspirin treatment, which may be correlated with the MDR1 C3435T, TBXA2R (rs1131882), and PLA2G7 (rs1051931-rs7756935) polymorphisms.

Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Aged; Asian People; Aspirin; ATP Binding Cassette Transporter, Subfamily B; Blood Platelets; Brain Ischemia; Female; Gene Frequency; Genetic Association Studies; Humans; Linkage Disequilibrium; Male; Middle Aged; Platelet Aggregation Inhibitors; Polymorphism, Single Nucleotide; Receptors, Cell Surface; Receptors, Thromboxane A2, Prostaglandin H2; Stroke; Thromboxane B2; Treatment Failure

Elucidating action mechanisms of Chinese medicines has remained a challenging task due to the chemical and biological complexity that needs to be resolved. In this study we applied a gene expression data and connectivity map (CMAP) based approach to study action mechanisms of a Chinese medicine Xuesaitong injection (XST) on preventing cerebral ischemia-reperfusion injury. XST is a standardized patent Chinese medicine of Panax notoginseng roots and it has long been used for the effective prevention and treatment of stroke in China. However, more research is needed to understand the mechanisms underlying its effects against ischemic stroke. We first evaluated the effect of XST against ischemic stroke in an ischemia-reperfusion rat animal model and dissected its mechanisms based on gene expression data of injured brain. The results showed that treatment with XST significantly attenuated infarct area and histological damage. Based upon pathway analysis and the CMAP query of microarray data, anti-inflammatory response and anti-platelet coagulation were found as the major mechanisms of XST against stroke, which were further validated in vitro and with pharmacological assays of serum. We demonstrated the feasibility of applying the combination of the microarray with the CMAP in identifying mechanisms of Chinese medicine.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Anti-Inflammatory Agents; Brain; Cerebral Infarction; Drugs, Chinese Herbal; Gene Expression Profiling; Infarction, Middle Cerebral Artery; Macrophages; Male; Mice; Nerve Net; Nitric Oxide; Oligonucleotide Array Sequence Analysis; Platelet Aggregation; Rats, Sprague-Dawley; RAW 264.7 Cells; Real-Time Polymerase Chain Reaction; Reproducibility of Results; Saponins; Stroke; Thromboxane B2

Patients with nonvalvular atrial fibrillation (AF) show high residual cardiovascular (CV) risk despite oral anticoagulants. Urinary 11-dehydro-thromboxane B2 (TxB2) is associated with an increased risk of CV events (CVEs), but its predictive value in patients with anticoagulated AF is unknown.. A prospective single-center cohort study, including 837 patients with AF, was conducted. Mean time of follow-up was 30.0 months, yielding 2,062 person-years of observation. Urinary 11-dehydro-TxB2 was measured at baseline. The primary end point was the occurrence of a CVE including fatal/nonfatal myocardial infarction and ischemic stroke, transient ischemic attack, cardiac revascularization, and CV death.. Mean age of patients was 73.1 years, and 43.6% were women. Median 11-dehydro-TxB2 levels were 100 (interquartile range 50-187) ng/mg of urinary creatinine. Overall, the anticoagulation control was adequate (63.9% of mean time in therapeutic range). A CVE occurred in 99 (11.8%) patients, and 55 were CV deaths. At baseline, 11-dehydro-TxB2 levels were higher in patients with a CVE compared with those without (186 [107-400] vs 98 [52-170], P < .001). An increased rate of CVEs (log-rank test, P < .001) and CV deaths (P < .001) was observed across tertiles of 11-dehydro-TxB2. Cardiovascular events were associated with age (hazard ratios [HR] 1.72 per 1 SD, 95% CI 1.33-2.21, P < .001), diabetes mellitus (HR 1.89, 95% CI 1.20-2.96, P = .005), heart failure (HR 1.60, 95% CI 1.01-2.54, P = .044), history of stroke/transient ischemic attack (HR 1.96, 95% CI 1.25-3.06, P = .003), and 11-dehydro-TxB2 (HR 1.64 per 1 SD, 95% CI 1.42-1.89, P < .001).. Urinary 11-dehydro-TxB2 levels are associated with a residual risk of CVEs and CV mortality in patients with AF despite anticoagulant treatment.

Topics: Aged; Atrial Fibrillation; Biomarkers; Death, Sudden, Cardiac; Enzyme-Linked Immunosorbent Assay; Female; Follow-Up Studies; Humans; Incidence; Italy; Male; Myocardial Infarction; Prospective Studies; Risk Assessment; Stroke; Survival Rate; Thromboxane B2; Time Factors

A genetic variant (rs20417) of the PTGS2 gene, encoding for COX-2, has been associated with decreased COX-2 activity and a decreased risk of cardiovascular disease (CVD). However, this genetic association and the role of COX-2 in CVD remain controversial.. The association of rs20417 with CVD was prospectively explored in 49 232 subjects (ACTIVE-A, CURE, epiDREAM/DREAM, ONTARGET, RE-LY, and WGHS) and the effect of potentially modifiable risk factors on the genetic association was further explored in 9363 INTERHEART participants. The effect of rs20417 on urinary thromboxane and prostacyclin metabolite concentrations was measured in 117 healthy individuals. Carriage of the rs20417 minor allele was associated with a decreased risk of major CVD outcomes (OR = 0.78, 95% CI: 0.70-0.87; P = 1.2 × 10(-5)). The genetic effect was significantly stronger in aspirin users (OR: 0.74, 95% CI: 0.64-0.84; P = 1.20 × 10(-5)) than non-users (OR: 0.87, 95% CI: 0.72-1.06; P = 0.16) (interaction P-value: 0.0041). Among patients with previous coronary artery disease (CAD), rs20417 carriers had a stronger protective effect on risk of major adverse events when compared with individuals without previous CAD (interaction P-value: 0.015). Carriers had significantly lower urinary levels of thromboxane (P = 0.01) and prostacyclin (P = 0.01) metabolites when compared with non-carriers.. The rs20417 polymorphism is associated with a reduced risk of major cardiovascular events and lower levels of thromboxane and prostacyclin. Our results suggest that a genetic decrease in COX-2 activity may be beneficial with respect to CVD risk, especially, in higher risk patients on aspirin.

Topics: 6-Ketoprostaglandin F1 alpha; Aged; Aspirin; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Female; Heterozygote; Humans; Male; Multicenter Studies as Topic; Myocardial Infarction; Polymorphism, Genetic; Prospective Studies; Randomized Controlled Trials as Topic; Stroke; Thromboxane B2

From previous studies, the prevalence of aspirin nonresponders is 5.5-45% in patients with various cardiovascular diseases. Those who have aspirin nonresponders have a greater risk of clinically cardiovascular events. The purpose of the study was to look for the prevalence, associated factors and the outcomes of aspirin nonresponders among patients with ischaemic stroke. Patients with ischaemic stroke who were treated during January 2011-August 2011 were included. Urine 11-dehydro-thromboxane B2 (dTXB2) was measured to determine the response to aspirin in patients. The demographics and vascular risk factors were compared between patients who were classified as aspirin responders or aspirin nonresponders. The outcomes of the study were favourable outcome, cardiovascular events and mortality. There were 182 patients included during the study period: 128 patients with an acute ischaemic stroke and 54 patients with a stable ischaemic stroke. Ninety patients (49.5%) were found to be aspirin nonresponders. Multivariate analysis revealed that stroke presentation (acute stroke) was the only factor associated with aspirin nonresponders [odds ratio (OR) 2.38, 95% confidence interval (CI) 1.193-4.746, P = 0.014]. With a mean follow-up time of 16 months, aspirin nonresponders had a less favourable outcome (54 vs. 83%, OR 0.24; 95% CI 0.11-0.51, P < 0.001), marginally higher cardiovascular events (11 vs. 2%, OR 4.48; 95% CI 0.92-21.37, P = 0.045) and higher mortality (12 vs. 1%, OR 10.52; 95% CI 1.3-85.28, P = 0.007). The prevalence of aspirin nonresponders was rather high in Thai patients with ischaemic stroke. Aspirin nonresponders had a less favourable outcome, higher cardiovascular events and death rate.

Topics: Aspirin; Brain Ischemia; Female; Humans; Male; Middle Aged; Multivariate Analysis; Platelet Aggregation Inhibitors; Risk Factors; Stroke; Survival Analysis; Thromboxane B2; Treatment Outcome

Aspirin achieves its antithrombotic effect through inactivation of cyclo-oxygenase (COX)-1, thereby preventing generation of thromboxane (TX)A2 from arachidonic acid (AA). The reported prevalence of aspirin "resistance" varies significantly and is usually based on platelet function tests (PFTs) that use AA-induced platelet reactivity as a surrogate measure of the effect of aspirin, rather than specific assessment of its effect on its therapeutic target (ie, COX-1 inhibition). The reported rates are not only assay specific but also condition specific, with particularly high rates (up to 70%) previously reported in the stroke population. We investigated whether pharmacological responses to aspirin can be reliably determined from a functional test of AA-induced whole-blood clotting.. A prospective study included 35 patients admitted with ischemic stroke and commenced on 300 mg aspirin. AA-induced whole-blood clotting was measured using short thrombelastography, a previously extensively validated near-patient PFT. Serum TXB2 and inflammatory biomarkers were also measured. The prevalence of apparent aspirin resistance measured using AA was high (range from 49% to 67%). However, serum [TXB2] was consistently low, thereby confirming adequate inhibition of COX-1 by aspirin. Mean inflammatory biomarker levels were elevated throughout.. This study demonstrates that although COX-1 activity is adequately and consistently suppressed by aspirin in stroke patients, this effect is not reliably indicated by whole-blood clotting in response to AA. These data help to explain why the reported prevalence of aspirin resistance in stroke from studies employing AA-induced platelet reactivity is high and cast doubt on the veracity of such reports.

Topics: Aged; Aged, 80 and over; Aspirin; Biomarkers; Brain Ischemia; Cytokines; Drug Resistance; Female; Humans; Male; Middle Aged; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Prospective Studies; Stroke; Thrombelastography; Thromboxane B2

Among patients with stroke, the phenomenon of resistance to treatment with low-dose aspirin acetylsalicylic acid (ASA) is quite common. The study included 133 patients hospitalized with acute ischemic stroke. Impedance platelet aggregometry (IPA) and levels of vWF and thromboxane (TXB2) were assessed - with the efficacy of aspirin in daily clinical investigation. Responses to treatment with doses of 150 and 300 mg/day were measured. In addition, we analyzed the response of proinflammatory factors [fibrinogen, C-reactive protein (CRP), white blood corpuscles (WBC)], lipids and hemoglobin A1c, which may alter platelet aggregation response to treatment. After a week of treatment at 150 mg/day, ASA patients were classified as laboratory resistant (42%) or sensitive (58%). Values of IPA in the resistant group were significantly higher (472 ± 150 vs. 222 ± 59 AUC, P < 0.0001). In resistant patients were also found higher levels of fibrinogen (3.90 ± 0.89 vs. 3.46 ± 0.74 g/l, P = 0.0046), CRP (6.97 ± 5.66 vs. 4.17 ± 4.03 mg/l, P = 0.0011), WBC (9.2 ± 2.4 vs. 8.3 ± 2.2 × 10/l, P = 0.0207) and lower HDL cholesterol (46 ± 12 vs. 52 ± 15 mg/dl, P = 0.016). This research shows that aspirin resistance assessment by IPA well reflects the clinical status of patients and should be used routinely. Resistance generally fails to 'break' at higher doses, hence our suggestion that patients resistant to low doses of the drug immediately switch to a thienopyridine class antiplatelet agent, for example, clopidogrel.

Topics: Adult; Aged; Aspirin; Blood Platelets; Brain Ischemia; C-Reactive Protein; Cholesterol, HDL; Clopidogrel; Electric Impedance; Female; Fibrinogen; Glycated Hemoglobin; Humans; Leukocyte Count; Leukocytes; Male; Middle Aged; Pilot Projects; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Stroke; Thromboxane B2; Ticlopidine; von Willebrand Factor

Aspirin resistance (AR) is common in Chinese stroke patients taking antiplatelet medications; however, few studies have documented the role of cyclooxygenase (COX)-1 C50T and COX-2 G765C polymorphisms in AR. The aim of this study was to investigate the prevalence of AR in Chinese stroke patients and the relationships between AR and COX-1 C50T and COX-2 G765C polymorphisms, and to evaluate the effect of these polymorphisms on platelet response to aspirin.. We prospectively enrolled 634 Chinese stroke patients. Platelet aggregation testing was performed before and after aspirin administration. The pre- and post-aspirin levels of 11-dehydrothromboxane B(2) (11-dTxB(2)) were determined in urine samples. COX-1 C50T and COX-2 G765C genotypes were determined by a polymerase chain reaction-allelic restriction assay.. AR was detected in 129 patients (20.4%), aspirin semi-resistance (ASR) was detected in 28 patients (4.4%), and aspirin sensitivity (AS) was detected in 477 patients (75.2%). There was no association between COX-1 C50T or COX-2 G765C polymorphisms and ASR+AR. Aspirin could efficiently reduce 11-dTxB(2) production by approximately 75%. In addition, platelet aggregation, both in response to arachidonic acid (AA) and adenosine 5'-diphosphate (ADP), was inhibited by more than 80% and 40%, respectively; however, the percentage reduction in platelet aggregation and 11-dTxB(2) levels was not significantly different between the COX-1 C50T and COX-2 G765C genotypes (p＞0.05).. There was no association between COX-1 C50T and COX-2 G765C polymorphisms and AR in Chinese stroke patients. In addition, COX-1 C50T and COX-2 G765C polymorphisms had no effect on the platelet response to aspirin.

Topics: Aged; Aspirin; Base Sequence; Blood Platelets; China; Cyclooxygenase 1; Cyclooxygenase 2; DNA Primers; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Middle Aged; Platelet Aggregation; Polymerase Chain Reaction; Prospective Studies; Stroke; Thromboxane B2

Cyclooxygenase-derived prostaglandins modulate cardiovascular disease risk. We genotyped 2212 Atherosclerosis Risk in Communities study participants (1,023 incident coronary heart disease (CHD) cases; 270 incident ischemic stroke cases; 919 non-cases) with available DNA for polymorphisms in PTGS1 and PTGS2. Using a case-cohort design, associations between genotype and CHD or stroke risk were evaluated using proportional hazards regression. In Caucasians, the reduced function PTGS1 -1006A variant allele was significantly more common among stroke cases compared to non-cases (18.2 versus 10.6%, P=0.027). In African Americans, the reduced function PTGS2 -765C variant allele was significantly more common in stroke cases (61.4 versus 49.4%, P=0.032). No significant relationships with CHD risk were observed. However, aspirin utilization appeared to modify the relationship between the PTGS2 G-765C polymorphism and CHD risk (interaction P=0.072). These findings suggest that genetic variation in PTGS1 and PTGS2 may be important risk factors for the development of cardiovascular disease events. Confirmation in independent populations is necessary.

Topics: Aspirin; Atherosclerosis; Biomarkers; Black or African American; Case-Control Studies; Coronary Disease; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Female; Gene Frequency; Genetic Predisposition to Disease; Genotype; Humans; Longitudinal Studies; Male; Middle Aged; Odds Ratio; Phenotype; Polymorphism, Single Nucleotide; Proportional Hazards Models; Prospective Studies; Risk Assessment; Risk Factors; Stroke; Thromboxane B2; United States; White People

We encountered a 10-year-old girl with fluctuating sensorineural hearing loss, episodic headache, and white matter stroke. Strenuous exercise, febrile illness, and general anesthesia all temporarily worsened hearing. Audiologic findings were asymmetric: left-sided retrocochlear dysfunction consistent with auditory neuropathy contrasted with cochlear hearing loss in the right ear. Platelets obtained during a headache-free period showed excessive responsiveness to collagen in vitro, while episodic elevations of thromboxane B(2) and thrombin-antithrombin III complex were noted in blood sampled during headache. Treatment of hyperaggregability of platelets with aspirin and antioxidant vitamins relieved headache, while adenosine triphosphate administration improved hearing thresholds. In this patient, hearing impairment and white matter strokes appeared to respectively related to impaired blood flow to the cochlea and white matter caused by platelet dysfunction triggered by physiologic stresses.

Topics: Adenosine Triphosphate; Antithrombin III; Audiometry; Blood Platelets; Child; Collagen; Evoked Potentials, Auditory, Brain Stem; Female; Functional Laterality; Headache; Hearing Loss, Sensorineural; Humans; Magnetic Resonance Imaging; Peptide Hydrolases; Platelet Aggregation; Stroke; Thromboxane B2

We studied whether aspirin resistance, defined as failure of suppression of thromboxane generation, increases the risk of cardiovascular events in a high-risk population.. Baseline urine samples were obtained from 5529 Canadian patients enrolled in the Heart Outcomes Prevention Evaluation (HOPE) Study. Using a nested case-control design, we measured urinary 11-dehydro thromboxane B2 levels, a marker of in vivo thromboxane generation, in 488 cases treated with aspirin who had myocardial infarction, stroke, or cardiovascular death during 5 years of follow-up and in 488 sex- and age-matched control subjects also receiving aspirin who did not have an event. After adjustment for baseline differences, the odds for the composite outcome of myocardial infarction, stroke, or cardiovascular death increased with each increasing quartile of 11-dehydro thromboxane B2, with patients in the upper quartile having a 1.8-times-higher risk than those in the lower quartile (OR, 1.8; 95% CI, 1.2 to 2.7; P=0.009). Those in the upper quartile had a 2-times-higher risk of myocardial infarction (OR, 2.0; 95% CI, 1.2 to 3.4; P=0.006) and a 3.5-times-higher risk of cardiovascular death (OR, 3.5; 95% CI, 1.7 to 7.4; P<0.001) than those in the lower quartile.. In aspirin-treated patients, urinary concentrations of 11-dehydro thromboxane B2 predict the future risk of myocardial infarction or cardiovascular death. These findings raise the possibility that elevated urinary 11-dehydro thromboxane B2 levels identify patients who are relatively resistant to aspirin and who may benefit from additional antiplatelet therapies or treatments that more effectively block in vivo thromboxane production or activity.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Aspirin; Canada; Cardiovascular Diseases; Case-Control Studies; Cohort Studies; Comorbidity; Cyclooxygenase Inhibitors; Death, Sudden, Cardiac; Demography; Female; Follow-Up Studies; Humans; Male; Myocardial Infarction; Odds Ratio; Randomized Controlled Trials as Topic; Risk Assessment; Risk Factors; Secondary Prevention; Stroke; Thromboxane B2; Thromboxanes; Vitamin E