Thromboxane biosynthesis and future events in diabetes: the ASCEND trial.

BACKGROUND AND AIMS: Thromboxane (TX) A2, released by activated platelets, plays an important role in atherothrombosis. Urinary 11-dehydro-TXB2 (U-TXM), a stable metabolite reflecting the whole-body TXA2 biosynthesis, is reduced by ∼70% by daily low-dose aspirin. The U-TXM represents a non-invasive biomarker of in vivo platelet activation and is enhanced in patients with diabetes. This study assessed whether U-TXM is associated with the risk of future serious vascular events or revascularizations (SVE-R), major bleeding, or cancer in patients with diabetes. METHODS: The U-TXM was measured pre-randomization to aspirin or placebo in 5948 people with type 1 or 2 diabetes and no cardiovascular disease, in the ASCEND trial. Associations between log U-TXM and SVE-R (n = 618), major bleed (n = 206), and cancer (n = 700) during 6.6 years of follow-up were investigated by Cox regression; comparisons of these associations with the effects of randomization to aspirin were made. RESULTS: Higher U-TXM was associated with older age, female sex, current smoking, type 2 diabetes, higher body size, urinary albumin/creatinine ratio of ≥3 mg/mmol, and higher estimated glomerular filtration rate. After adjustment for these, U-TXM was marginally statistically significantly associated with SVE-R and major bleed but not cancer [hazard ratios per 1 SD higher log U-TXM (95% confidence interval): 1.09 (1.00-1.18), 1.16 (1.01-1.34), and 1.06 (0.98-1.14)]. The hazard ratio was similar to that implied by the clinical effects of randomization to aspirin for SVE-R but not for major bleed. CONCLUSIONS: The U-TXM was log-linearly independently associated with SVE-R in diabetes. This is consistent with the involvement of platelet TXA2 in diabetic atherothrombosis.

An Ex Vivo Study to Evaluate the Effect of Tegaserod on Platelet Activation and Aggregation.

INTRODUCTION: Tegaserod, an orally active, potent 5-hydroxytryptamine-4 serotonin receptor agonist, was previously indicated for irritable bowel syndrome but was voluntarily withdrawn due to potential cardiovascular side effects. In vitro studies suggested that tegaserod increased platelet aggregation, but these results were not reproduced or were inconclusive. We sought to assess ex vivo effects of tegaserod on platelet aggregation. METHODS: In this double-blind, placebo-controlled, crossover study, we randomized a majority of healthy patients with no history of cardiovascular risk factors (n = 21) to receive tegaserod or matching placebo for 7 + 2 days followed by a 7- to 10-day washout period, and then patients were crossed over to the other study drug for the next 7 + 2 days. Unstimulated and agonist-stimulated platelet aggregation; P-selectin expression; serum thromboxane (Tx)B2 and urinary 11-dehydro (11-dh) TxB2; and tegaserod and M29.0 concentrations were serially assessed. RESULTS: There was no significant difference in percentage change in unstimulated or adenosine diphosphate (ADP)- and ADP + serotonin-, collagen- and thrombin receptor activating peptide-induced maximum platelet aggregation and in platelet P-selectin expression in the presence of tegaserod at any time point when compared to placebo. Similarly, there was no significant difference in percentage change in serum TxB2 or urinary 11-dhTxB2 levels between placebo and tegaserod. No new or unexpected findings were observed in evaluations of safety or pharmacokinetic parameters. CONCLUSION: This comprehensive pharmacodynamic study, by employing established markers used in prior investigations, which have been considered by the Food and Drug Administration to indicate drug-related platelet effects, does not demonstrate any influence of tegaserod treatment on platelet function.

First Experience Addressing the Prognostic Utility of Novel Urinary Biomarkers in Patients With COVID-19.

Urine 11-dehydro-thromboxane B2 (u11-dh-TxB2), 8-hydroxy-2'-deoxyguanosine (8-OHdG), and liver-type fatty acid binding protein levels (L-FABP) at the time of hospitalization were higher in coronavirus disease 2019 (COVID-19) patients with adverse events vs without events. Higher u11-dh-TxB2 and L-FABP levels were associated with longer hospitalization, more thrombotic events, and greater mortality, providing evidence for potential utility as early prognostic biomarkers for COVID-19.

Correlation of carotid intima-media thickness with platelet parameters and markers of platelet activation in patients with type 2 diabetes mellitus / 实用医学杂志

Objective To observe the correlation between platelet parameters , platelet activation marker and carotid intima-media thickness (CIMT) in patients with type 2 diabetes mellitus. Methods One hundred and ninety-five type 2 diabetic patients were enrolled in this study. The patients were divided into the normal control group, the CIMT increased group and the clot group according to the carotid intima-media thickness. Levels of platelet count (PLT), mean platelet volume (MPV), platelet distribution width (PDW), platelet hematocrit(PCT), urinary 11-dehydro-thromboxane B2 (11-DH-TXB2) and other clinical, biochemical characteristics were measured. Results (1) Levels of serum LDL-C, MPV, PDW, urinary 11-DH-TXB2 and clinical course in the clot group were higher than those in the CIMT increased group and the normal control group (P < 0.05). (2) Compared with the normal control group, the clinical course, serum LDL-C, MPV, PDW and urinary 11-DH-TXB2 were higher in the CIMT increased group (P < 0.05). (3) By using with spearman rank correlation test, carotid intima-media thickness was positively associated with age , course , BMI , GLU , GHbA1C , LDL-C , MPV , PDW and urinary 11-DH-TXB2, whereas carotid intima-media thickness was negative associated with HDL-C, PLT (both P < 0.05). (4) MPV, PDW and urinary11-DH-TXB2 were shown as the independent risk factors for CIMT. Conclusions Platelet activation marker and platelet parameters are associated with carotid intima-media thickness in patients with type 2 diabetes mellitus.