11-dehydro-thromboxane-b2 and Diabetic-Angiopathies

The efficacy of low-dose aspirin in type 2 diabetes mellitus (T2DM) has been questioned. We tested if twice daily dosing of aspirin would be more effective in T2DM, possibly due to increased platelet turnover. A randomised cross-over study compared 75 mg aspirin OD, 75 mg BID and 320 mg OD (≥ 2 week treatment periods) in 25 patients with T2DM and micro- or macrovascular complications. Platelet responses were examined by impedance aggregometry (WBA) and the IMPACT-R aspirin test in whole blood, light transmittance aggregometry in platelet-rich plasma (LTA), and urinary 11-dehydro-thromboxane B2 (TxM). Aspirin 75 mg BID decreased arachidonic acid (AA)-induced WBA compared to 75 mg OD (9.7 ± 4.5 vs. 12.6 ± 3.5 ohm; p = 0.003) or to 320 mg OD (11.5 ± 4.2 Ohms; p = 0.049). WBA responses to collagen were similarly attenuated by BID or high dosing (by 12-14%; p = 0.02 for both). The IMPACT-R showed a better response to 75 mg BID compared to 75 mg OD (p = 0.049), but not to 320 mg OD. AA-induced aggregation by LTA was <6.5% on all occasions, with no differences between aspirin dosages. TxM was reduced after 320 mg OD (p = 0.002), but not 75 mg BID (p = 0.07). Reticulated platelets were highly correlated with mean platelet volume (MPV; r2 = 0.74, p<0.0001). Both markers for platelet turnover were correlated with AA-induced WBA, but neither identified patients who benefited from BID dosing dependably. In conclusion, twice daily dosing improved laboratory responses to aspirin in high risk T2DM patients. Studies of whether BID dosing of aspirin can improve clinical outcomes in such patients are of interest.

Topics: Aspirin; Blood Platelets; Cells, Cultured; Clinical Protocols; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Drug Dosage Calculations; Humans; Microvessels; Platelet Aggregation; Platelet Aggregation Inhibitors; Thromboxane B2

Recent studies indicate that not all diabetic subjects benefit from aspirin therapy. Our objective is to characterize diabetic subjects with aspirin resistance using urine thromboxane, and VerifyNow measures. Our results suggest that cardiovascular disease, microalbuminuria, poor diabetes control, and increased waist circumference help identify aspirin resistance in diabetes.

Topics: Albuminuria; Aspirin; Cohort Studies; Diabetic Angiopathies; Drug Resistance; Female; Glycated Hemoglobin; Humans; Insulin Resistance; Male; Middle Aged; Nephelometry and Turbidimetry; Platelet Aggregation; Platelet Aggregation Inhibitors; Thromboxane B2; Waist Circumference

To investigate the possible relevance of free radicals and prostanoids to the mode of initiation and/or evolution of microangiopathy in diabetes mellitus, we measured serum lipid peroxides (LPO), an accepted index of intravascular free radicals, and plasma 11-dehydrothromboxane B2 (11-dehydro-TXB2), a stable metabolite of vasoactive thromboxane A2 released from platelets, in 95 patients with normolipidemic type 2 (non-insulin-dependent) diabetes mellitus at different stages of the disease. In general, either LPO or 11-dehydro-TXB2 was significantly greater in the patients, as a group, than in the matched controls (3.82 vs. 2.65 nmol/ml, P < 0.01 for LPO; and 17.3 vs. 5.8 pg/ml, P < 0.01 for 11-dehydro-TXB2). In patients, both LPO and 11-dehydro-TXB2 increased according to the severity of their diabetic retinopathy. A highly significant positive correlation existed between the LPO values and 11-dehydro-TXB2 in the patients (r = 0.64, P < 0.0001), while there was no such relationship in the controls (r = 0.18, P = NS). No difference in serum levels of apolipoproteins A-I, A-II, B, C-II, C-III, or E was observed between the patients and controls. Short-term glycemic control (25 cal/kg of standardized body weight/day, for 8 weeks) resulted in a small but significant reduction in LPO (4.2 vs. 4.6 nmol/ml, control; P < 0.05) without alteration in 11-dehydro-TXB2. There was a tendency towards deterioration in LPO according to the improvement in glycemic control. These results appear consistent with the view that, in addition to LPO, the release of TXA2 from activated platelet in the human circulation could be an important factor for the initiation and/or evolution of microangiopathy in diabetic patients even when they are not apparently hyperlipidemic. Further, the results of the present study emphasize the notion that more tight control of serum lipids is worthy of serious consideration in preventing the advance of diabetic microangiopathy.

Topics: Aged; Apolipoproteins; Biomarkers; Blood Glucose; Cholesterol; Cholesterol, HDL; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Retinopathy; Female; Free Radicals; Glycated Hemoglobin; Humans; Lipid Peroxidation; Lipid Peroxides; Male; Middle Aged; Reference Values; Thromboxane B2; Triglycerides

It has been speculated that platelet activation may contribute to the evolution of vascular complications in patients with Type I diabetes mellitus. To address this hypothesis, we measured the plasma and urinary metabolites of thromboxane, presumably of platelet origin, and of prostacyclin, derived from endothelial cells, in addition to more conventional indexes of platelet function. Urinary excretion of the metabolites 2,3-dinor-thromboxane B2 and 2,3-dinor-6-keto-prostaglandin F1 alpha did not differ between diabetics with or without retinopathy and nondiabetic controls. Furthermore, measurement of platelet granule constituents, the aggregation responses to ADP or arachidonic acid, and levels of serum thromboxane B2 failed to discriminate between the groups. The institution of tight diabetic control with multiple daily injections of insulin failed to alter either urinary metabolite excretion or plasma levels of 11-dehydro-thromboxane B2. Conversely, insulin-induced hypoglycemia failed to alter the concentrations of plasma or urinary thromboxane metabolites in nondiabetic volunteers, despite a mean 60-fold increase in plasma epinephrine. These studies suggest that platelet activation does not precede the development of microvascular complications in patients with Type I diabetes who lack clinical evidence of macrovascular disease and have normal renal function. Furthermore, it is unlikely that platelet activation due to intermittent hypoglycemia contributes to the reportedly accelerated development of retinopathy in such patients, when they are subject to tight diabetic control.

Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Adult; Blood Platelets; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Epoprostenol; Humans; Insulin; Platelet Aggregation; Thromboxane B2; Thromboxanes