11-dehydro-thromboxane-b2 and Chronic-Disease

It has been suggested that daily intake of aspirin is associated with a reduction of cognitive decline, both in normal and in demented subjects, but the mechanism is unclear. We have therefore studied the relationship between thromboxane (TX) A(2) biosynthesis, as reflected by the urinary excretion of 11-dehydro-TXB(2), and the presence of dementia in patients after acute stroke.. Patients from the Rotterdam Stroke Databank were screened for dementia between 3 and 9 months after stroke. Patients had a full neurological examination, neuropsychological screening, and, if indicated, extensive neuropsychological examination. Criteria used for the diagnosis of dementia were from the Diagnostic and Statistical Manual of Mental Disorders, Third Edition (Revised). Urine samples were taken at the time of screening. Urinary 11-dehydro-TXB(2) was measured by means of a previously validated radioimmunoassay.. Dementia was diagnosed in 71 patients, and urine samples were available for 62. Median value (range) of 11-dehydro-TXB(2) was 399 (89 to 2105) pmol/mmol creatinine for demented patients versus 273 (80 to 1957) for 69 controls with stroke but without dementia (P=0.013). No difference was found between 44 patients with vascular dementia, 404 (89 to 2105) pmol/mmol creatinine, and 18 patients with Alzheimer's disease plus cerebrovascular disease, 399 (96 to 1467) pmol/mmol creatinine (P=0.68). In a stepwise logistic regression analysis, in which possible confounders such as use of antiplatelet medication, cardiovascular risk factors, and type of stroke were taken into account, increased urinary excretion of 11-dehydro-TXB(2) remained independently related to the presence of dementia (OR 1.12, 95% CI 1.03 to 1.22 per 100 pmol/mmol creatinine). The difference in metabolite excretion rates between demented and nondemented patients was most prominent within the subgroup of ischemic stroke patients who received aspirin (P<0.01).. Increased thromboxane biosynthesis in the chronic phase after stroke is associated with the presence of but not the type of poststroke dementia. It is particularly apparent in patients on aspirin, thereby suggesting the involvement of extraplatelet sources of TXA(2) production in this setting.

Topics: Aged; Aspirin; Biomarkers; Blood Platelets; Brain Ischemia; Cerebral Hemorrhage; Chronic Disease; Cognition; Creatinine; Dementia, Vascular; Female; Humans; Male; Platelet Aggregation Inhibitors; Prognosis; Prospective Studies; Radioimmunoassay; Thromboxane A2; Thromboxane B2

Platelet activation is involved in acute coronary syndromes (ACS). Incomplete suppression by low-dose aspirin treatment of thromboxane (TX) metabolite excretion (urinary 11-dehydro-TXB2) is predictive of vascular events in high-risk patients. Myeloid-related protein (MRP)-8/14 is a heterodimer secreted on activation of platelets, monocytes, and neutrophils, regulating inflammation and predicting cardiovascular events. Among platelet transcripts, MRP-14 has emerged as a powerful predictor of ACS.. We enrolled 68 stable ischemic heart disease (IHD) and 63 ACS patients, undergoing coronary angiography, to evaluate whether MRP-8/14 release in the circulation is related to TX-dependent platelet activation in ACS and IHD patients and to residual TX biosynthesis in low-dose aspirin-treated ACS patients. In ACS patients, plasma MRP-8/14 and urinary 11-dehydro-TXB2 levels were linearly correlated (r=0.651, P<0.001) but significantly higher than those in IHD patients (P=0.012, P=0.044) only among subjects not receiving aspirin. In aspirin-treated ACS patients, MRP-8/14 and 11-dehydro-TXB2 were lower versus those not receiving aspirin (P<0.001) and still significantly correlated (r=0.528, P<0.001). Higher 11-dehydro-TXB2 significantly predicted higher MRP-8/14 in both all ACS patients and ACS receiving aspirin (P<0.001, adj R(2)=0.463 and adj R(2)=0.497) after multivariable adjustment. Conversely, plasma MRP-8/14 (P<0.001) and higher urinary 8-iso-prostaglandin F2α (P=0.050) levels were significant predictors of residual, on-aspirin, TX biosynthesis in ACS (adjusted R(2)=0.384).. Circulating MRP-8/14 is associated with TX-dependent platelet activation in ACS, even during low-dose aspirin treatment, suggesting a contribution of residual TX to MRP-8/14 shedding, which may further amplify platelet activation. Circulating MRP-8/14 may be a target to test different antiplatelet strategies in ACS.

Topics: Acute Coronary Syndrome; Aged; Aspirin; Calgranulin A; Calgranulin B; Chronic Disease; Dinoprost; Female; Humans; Male; Middle Aged; Myocardial Ischemia; Platelet Activation; Platelet Aggregation Inhibitors; Thromboxane B2

Enhanced thromboxane (TX) biosynthesis has previously been reported in the acute phase after ischemic stroke. We investigated whether enhanced urinary excretion of 11-dehydro-TXB2, a noninvasive index of platelet activation, was present in the chronic phase after a transient ischemic attack (TIA) or stroke, including intracerebral hemorrhage.. We obtained a single urinary sample from 92 patients between 3 and 9 months after onset of stroke or TIA. The urinary excretion of the major enzymatic metabolite of TXA2, 11-dehydro-TXB2, was measured by a previously validated radioimmunoassay. The excretion rates were compared with those of 20 control patients with nonvascular neurological diseases.. Urinary 11-dehydro-TXB2 averaged 294+/-139, 413+/-419, and 557+/-432 pmol/mmol creatinine for patients with TIA, ischemic stroke, and intracerebral hemorrhage, respectively; the values were higher in all subgroups (P<0.01) than that in control patients (119+/-66 pmol/mmol). Increased 11-dehydro-TXB2 excretion was present in 59% of all patients, in 60% (P<0.001) of patients with TIA, in 56% (P<0.001) of patients with ischemic stroke, and in 73% (P<0.001) of patients with intracerebral hemorrhage. Atrial fibrillation, no aspirin use, and severity of symptoms at follow-up contributed independently to the level of 11-dehydro-TXB2 excretion in a multiple linear regression analysis.. Platelet activation is often present in patients in the chronic phase after stroke, including those with intracerebral hemorrhage. Persistent platelet activation, which is associated with atrial fibrillation and poor stroke outcome, can be substantially suppressed by aspirin treatment.

Topics: Brain Ischemia; Cerebral Hemorrhage; Chronic Disease; Follow-Up Studies; Humans; Platelet Activation; Thromboxane B2

Prostacyclin (PGI2) and thromboxane A2 (TXA2) play an important role in the pathophysiology of various cardiovascular diseases. The balance between PGI2 and TXA2 regulates the interaction between platelets and the vessel wall in vivo. In this study we measured PGI2 and TXA2 synthesis by analysing their urinary index metabolites 2,3-dinor-6-keto-PGF1 alpha and 11-dehydro-TXB2, respectively, in acute (10 patients) and chronic (10 patients) lower limb ischaemia. Both PGI2 and TXA2 synthesis were increased about two-fold in patients with acute lower limb ischaemia compared to chronic lower limb ischaemia. However, the PGI2/TXA2 ratio was more or less the same in acute and chronic lower limb ischaemia. In patients with acute lower limb ischaemia caused by thrombotic occlusion, PGI2 and TXA2 formation were about two times higher than in patients with acute lower limb ischaemia caused by embolic occlusion. Elevation of PGI2 and TXA2 synthesis in acute lower limb ischaemia may reflect increased platelet-vascular wall interactions without changing the PGI2/TXA2 ratio.

Topics: 6-Ketoprostaglandin F1 alpha; Aged; Aged, 80 and over; Chronic Disease; Creatinine; Epoprostenol; Extremities; Female; Humans; Ischemia; Male; Middle Aged; Thrombosis; Thromboxane A2; Thromboxane B2