thromboxane-a2 and Uremia

Topics: Anemia; Aspirin; Bleeding Time; Blood Platelets; Blood Transfusion; Cryoprotective Agents; Deamino Arginine Vasopressin; Erythrocyte Transfusion; Erythropoietin; Estrogens; Hemorrhage; Humans; Parathyroid Hormone; Platelet Adhesiveness; Platelet Aggregation; Thromboxane A2; Uremia; von Willebrand Factor

Topics: Animals; Arteriosclerosis; Cyclic AMP; Epoprostenol; Extracorporeal Circulation; Fibrinolytic Agents; Homeostasis; Humans; Platelet Adhesiveness; Platelet Aggregation; Prostaglandins; Prostaglandins E; Purpura, Thrombotic Thrombocytopenic; Rabbits; Thromboxane A2; Uremia

P-cresol is a well-known uremic toxin and environmental toxicant that may affect platelet functions. In this study, p-cresol (1-5 μM) inhibited the arachidonic acid (AA)-induced platelet aggregation, with 47% and 82% of inhibition at concentrations of 2 and 5 μM, respectively. Under similar experimental condition, p-cresol showed little effect on the U46619-induced platelet aggregation. p-cresol (<500 μM) revealed no discernable cytotoxicity to platelets as analyzed by quantification of lactate dehydrogenase release. Antiplatelet effect of p-cresol was related to inhibition of thromboxane A(2) (TXA(2)) and prostaglandin D(2) (PGD(2)) formation. P-cresol (2-100 μM) partly inhibited the AA-induced reactive oxygen species (ROS) production as well as the extracellular signal-regulated kinase (ERK1/2) and p38 phosphorylation in platelets. P-cresol further inhibited the AA-induced aggregation of rabbit platelet-rich plasma (PRP) with an IC50 of 2 μM and aggregation of human PRP (IC50 = 13.6 μM). Intravenous administration of p-cresol (250-1000 nmole) into mice effectively suppressed the ex vivo platelet aggregation, whereas showed little effect on the value of RBC, hemoglobin (HGB), hematocrit, MCV, MCH, MCHC, platelets and lymphocyte counts. These results indicate that in acute p-cresol-poisoning and long-term exposure to cresol as in severe uremic patients, p-cresol may potentially inhibit blood clot formation and lead to hemorrhagic disorders via inhibition of platelet aggregation, ROS production, ERK/p38 activation and TXA(2) production.

Topics: Animals; Blood Cell Count; Blood Platelets; Cresols; Dose-Response Relationship, Drug; Environmental Pollutants; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases; Humans; Male; Mice; Mice, Inbred ICR; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Prostaglandin D2; Rabbits; Reactive Oxygen Species; Signal Transduction; Thromboxane A2; Time Factors; Uremia

This study was designed to investigate the role of eicosanoids, thromboxane A2 (TXA2) and prostacyclin (PGI2) as well as their relationship with endothelin-1 (ET-1) in the pathogenesis of renal parenchymal hypertension. Uremic rats were prepared by renal mass ablation and compared with sham-operated controls. The stable metabolites of TXA2 (TXB2) and PGI2 (6-keto-PGF1alpha) and immunoreactive ET-1 concentrations were measured by specific RIAs in biological fluids and in vascular and renal tissues. To investigate the functional role of TXA2 in the progression of hypertension and renal failure, a group of uremic rats were treated with ridogrel (25 mg/kg/day), a TXA2 synthase inhibitor and receptor antagonist. Renal preproET-1 expression was assessed by Northern blot analysis. Systolic blood pressure (SBP), serum creatinine and proteinuria were found to be higher in uremic rats as compared to sham-operated controls (P < 0.01). TXB2 and ET-1 concentrations were increased in blood vessels, the renal cortex and in urine (P < 0.05). 6-keto-PGF1alpha concentrations were also increased in blood vessels and the renal cortex but decreased in urine (P < 0.05). Ridogrel significantly lowered SBP and proteinuria (P < 0.05) and blunted the increase of serum creatinine. Treatment with ridogrel resulted in a marked fall in vascular, renal and urine TXA2 concentrations, while ET-1 and 6-keto-PGF1alpha concentrations remained unchanged. The preproET-1 expression was higher in uremic rats than in the controls and was unaffected by ridogrel. These results suggest that TXA2 is involved in the pathogenesis of hypertension and renal failure progression in rats with subtotal 5/6 nephrectomy and that this effect is independent of the ET-1 system.

Topics: Animals; Blood Pressure; Disease Models, Animal; Disease Progression; Eicosanoids; Endothelin-1; Epoprostenol; Male; Rats; Rats, Wistar; Renal Insufficiency; Thromboxane A2; Time Factors; Uremia

The bleeding tendency associated with uremia is likely due to a qualitative platelet dysfunction. So far the data available on platelet aggregation are conflicting. Since platelet-activating factor (PAF) plays a role in primary hemostasis, we studied platelet aggregation in response to PAF in 40 patients with chronic uremia on regular hemodialysis and 12 control subjects. Our results showed that in 28 of 40 uremics, platelet aggregation response to PAF was normal, whereas in the remaining 12 it was defective in that no second wave of aggregation was elicited even if the PAF concentrations were increased by a factor of 10,000. This abnormal response was peculiar to PAF and only partially related to factor(s) of plasma origin. The number of platelet PAF receptors and their affinity for the agonist were comparable in controls and "PAF-unresponsive" patients. The defective platelet aggregation in response to PAF was associated with a statistically significant reduction (P less than 0.01) in thromboxane A2 (TxA2) generation in platelet-rich plasma (PRP) challenged with PAF (10 and 100 nmol/L). When PRPs from PAF-unresponsive patients were preincubated with a stable analogue of prostaglandin endoperoxides/TxA2 U-46619, an irreversible platelet aggregation in response to PAF was obtained. Thus in a subpopulation of uremics, platelet aggregation in response to PAF is selectively abnormal as a consequence of a reduced TxA2 generation.

Topics: Adult; Aged; Blood Platelets; Female; Humans; Male; Middle Aged; Platelet Activating Factor; Platelet Aggregation; Protein Binding; Radioimmunoassay; Thromboxane A2; Thromboxane B2; Uremia

A recently described method to evaluate the primary haemostatic mechanism under in vivo conditions was utilised to investigate thromboxane A2 (TXA2) and prostacyclin (PGI2) production by platelets and vascular endothelial cells, respectively, in patients with severe chronic renal failure. Unlike some previous studies, a decrease in TXA2 production by uraemic platelets could not be demonstrated. PGI2--produced by microvascular endothelial cells after a standardised injury--was, however, 59% higher in patients than controls (P less than 0.05). An increased local level of this potent platelet inhibitory eicosanoid could play an important role in the bleeding tendency exhibited in chronic renal failure.

Topics: 6-Ketoprostaglandin F1 alpha; Bleeding Time; Blood Platelets; Epoprostenol; Female; Humans; Kidney Failure, Chronic; Male; Microcirculation; Thromboxane A2; Uremia

Overall 14 patients with chronic renal failure treated by hemodialysis were examined. The content of the key metabolites of the arachidonic cascade thromboxane B2, 6-keto-prostaglandin F1 alpha and 12-hydroxyeicosatetraene acid (12-HETE) in blood plasma was reduced in the patients as compared to donors. By the end of hemodialysis, part of the patients showed a tendency towards its normalization, however, no complete recovery was practically recorded. Derangement of the formation of thromboxane A2, prostacyclin and 12-HETE in uremia is likely to be related to reverse inhibition of the function of platelet cyclooxygenase and lipoxygenase by plasma inhibitor. The recovery of the function can be attained after adequate hemodialysis.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; 6-Ketoprostaglandin F1 alpha; Adult; Epoprostenol; Humans; Hydroxyeicosatetraenoic Acids; Kidney Failure, Chronic; Middle Aged; Renal Dialysis; Thromboxane A2; Thromboxane B2; Uremia

We reported that aspirin (ASA) abnormally prolongs bleeding time (BT) in uremia. The present study was designed to investigate whether the abnormally prolonged post-ASA BT in uremia is due to different ASA pharmacokinetics and bioavailability that might be a consequence of uremic condition, platelet cyclooxygenase is peculiarly sensitive to ASA in uremia, and ASA affects primary hemostasis in uremia by a mechanism independent of cyclooxygenase inhibition. Our results showed that in patients with uremia, but not in normal subjects, ASA markedly prolongs the BT. This effect is transient and depends on the presence of ASA in the blood. The observed differences in ASA kinetic parameters are not an explanation of the exaggerated effect of ASA on primary hemostasis in uremia. The sensitivity of platelet cyclooxygenase to ASA inhibition is comparable in uremics and in normal subjects. The temporal dissociation between ASA-induced prolongation of BT and the effect on platelet thromboxane A2 generation suggests that ASA inhibits platelet function in uremia by a mechanism distinct from cyclooxygenase blocking. This possibility is strengthened by the observation that ibuprofen at a dose that fully inhibits platelet cyclooxygenase activity does not significantly prolong BT.

Topics: Acetylation; Adult; Aged; Aspirin; Bleeding Time; Blood Platelets; Cyclooxygenase Inhibitors; Female; Hemorrhagic Disorders; Humans; Ibuprofen; Kinetics; Male; Middle Aged; Platelet Function Tests; Thromboxane A2; Uremia

To study the effects of uremia and hemodialysis on the production rates of antiaggregatory prostacyclin (PGI2) and proaggregatory thromboxane A2 (TxA2), we collected serial plasma samples from eight patients with chronic uremia before, during and after hemodialysis and assayed them for 6-keto-PGF1 alpha and TxB2, the stable metabolites of PGI2 and TxA2, respectively. In addition, the capacity of the platelets to produce TxB2 during spontaneous clotting was studied by measuring the TxB2 levels in serum incubated at +37 degrees C for 60 minutes. The PGI2 production of the uremia patients before hemodialysis was less (P less than 0.001) than that of healthy volunteers. It rose significantly following heparinization and remained elevated during hemodialysis. TxB2 generation by platelets during clotting was diminished in uremia. Plasma TxB2 levels were normal before, but increased during hemodialysis. Thus, profound changes in the PGI2/TxA2-system seem to be associated with uremia and hemodialysis.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Blood Platelets; Epoprostenol; Female; Glomerulonephritis; Heparin; Humans; Kidney Failure, Chronic; Male; Middle Aged; Prostaglandins; Pyelonephritis; Renal Dialysis; Thromboxane A2; Thromboxane B2; Thromboxanes; Uremia

Topics: Epoprostenol; Female; Humans; Pre-Eclampsia; Pregnancy; Prostaglandins; Purpura, Thrombotic Thrombocytopenic; Thromboxane A2; Uremia