thromboxane-a2 and Nephrotic-Syndrome

Nephrotic syndrome characterized by hypoalbuminemia and hyperlipidemia is associated with an increased incidence of thromboembolism and increased platelet hyperaggregability. Although plasma coagulation proteins are also abnormal, changes are too inconsistent to attribute thromboembolic complications to the coagulation cascade alone. Antithrombin III (ATIII) has been shown to be deficient in nephrotic syndrome. There is, however, an increase in alpha 2 macroglobulin. It is clear that platelet to platelet interactions require exposure of platelet fibrinogen receptors, the binding of fibrinogen to these receptors, platelet crossbridging, and subsequent platelet aggregation. Fibrinogen is consistently elevated in nephrotic syndrome. Hyperlipidemia and hypoalbuminemia in nephrotic syndrome increases the availability of thromboxane A2 (TxA2) by increasing the availability of TxA2 precursors and the removal of TxA2 inhibitors. Thromboxane A2 is a known inducer of platelet aggregation probably through the exposure of platelet fibrinogen receptors. Recently, fibronectins a group of adhesive proteins, were implicated in platelet to platelet interactions. Since thrombin increases the expression of platelet surface fibronectin, fibronectin may be involved in thrombus formation in nephrotic syndrome. Thromboembolic formation in nephrotic syndrome is a composite mechanism involving the coagulation cascade, platelet-platelet interactions, and platelet-surface interactions.

Topics: beta-Thromboglobulin; Blood Platelets; Epoprostenol; Fibrinogen; Fibronectins; Humans; Nephrotic Syndrome; Platelet Aggregation; Platelet Factor 4; Thromboembolism; Thromboxane A2

In order to examine the intracellular thromboxane A2 (TXA2) signal transduction system in platelets of patients with nephrotic syndrome, we measured the levels of TXA2 metabolites in urine and blood and platelet calcium ion level as a result of STA2, an analog of STA2 (9,11-dimethylmethano-11,12-methano-TXA2) stimulation, and obtained the following results: (1) In pediatric patients with nephrotic syndrome, urinary thromboxane B2 (TXB2) and 11-dehydro-TXB2 excretion were signficantly higher in the onset and relapse groups compared to the remission and control groups. (2) The blood 11-dehydro-TXB2 level in the onset group was significantly higher than those in the remission and control groups. (3) Platelet calcium concentrations due to STA2 stimulation were significantly increased in the onset, relapse and remission groups compared to the control group. These findings suggest activation of the TXA2 signal transduction system in platelets of pediatric patients with nephrotic syndrome.

Topics: Blood Platelets; Calcium; Child; Child, Preschool; Female; Humans; Male; Nephrotic Syndrome; Thromboxane A2; Thromboxane B2

For the purpose of clarifying the changes occurring in thromboxane (TX)A2 metabolism in the platelet of nephrosis patients, we investigated the changes in platelet sensitivity to TXA2 and the changes in TXA2 production in pediatric patients with nephrotic syndrome (N.S.) using STA2 which is an analogue of TXA2 and ONO 3708 which is a TXA2 receptor antagonist. The subjects investigated in the present study consisted of 11 cases with initial onset of N.S. (onset group), 15 relapse patients (relapse group) and 15 children with N.S. without any recurrence in the past 6 months (remission group) as well as 25 normal children (control group). The results were as follows: (1) Platelet aggregation attributable to STA2 stimulation was enhanced at the onset and relapse of N.S. (2) Sensitivity to TXA2 was enhanced in the platelets of patients in the relapse group. (3) Though some demonstrated enhanced platelet sensitivity to TXA2, while others in the onset group did not, enhanced sensitivity was observed in all the patients along with an improvement in hypoalbuminemia. (4) The amount of daily urinary excretion of TXB2 and 11-dehydro-TXB2 in the onset group and relapse group was increased in comparison with the status in the remission group and control group. The above results demonstrated enhanced platelet sensitivity to TXA2 and increased biological production of TXA2 in patients with N.S., suggesting that TXA2 metabolism in the platelet is deeply involved in the pathophysiology of N.S.

Topics: Adolescent; Blood Platelets; Child; Child, Preschool; Female; Humans; Male; Nephrotic Syndrome; Platelet Aggregation; Recurrence; Serum Albumin; Thromboxane A2; Thromboxane B2

We have characterized the thromboxane (TX) A2/prostaglandin (PG) H2 receptor in glomeruli isolated from the rat using the agonist radioligand [125I]-BOP. Binding of [125I]-BOP was highly specific, stereoselective, and to a single class of high affinity binding sites (Kd = 1.16 +/- 0.22 nM and Bmax = 348 +/- 32 fmol/mg protein; n = 6). Binding of [125I]-BOP was competed for by the agonist ONO11113 (Kd = 50.8 +/- 8.0 nM; n = 4) and the antagonists SQ29548 (Kd = 15.8 +/- 1.0 nM; n = 3), L657925 (Kd = 12.1 +/- 2.2 nM; n = 3) and L657926 (Kd = 1642 +/- 135 nM; n = 3). I-BOP also produced a TXA2/PGH2 receptor-mediated rise in [Ca2+]i in isolated glomeruli In adriamycin-induced nephrotic syndrome in the rat, the development of proteinuria is reported to be dependent on increased renal TXA2 production. We therefore examined whether or not changes in glomerular TXA2/PGH2 receptors occur between control and nephrotic rats. No changes in expression or affinity of either glomerular or platelet TXA2/PGH2 receptors were observed. Kd and Bmax values for isolated glomeruli were 1.45 +/- 0.24 nM and 406 +/- 72 fmol/mg for controls and 1.22 +/- 0.25 nM and 321 +/- 62 fmol/mg for nephrotic rats (n = 6).

Topics: Animals; Binding, Competitive; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Doxorubicin; Fatty Acids, Unsaturated; Kidney Glomerulus; Kinetics; Male; Nephrotic Syndrome; Rats; Rats, Sprague-Dawley; Receptors, Prostaglandin; Receptors, Thromboxane; Receptors, Thromboxane A2, Prostaglandin H2; Thromboxane A2

Intraplatelet serotonin (5-HT), beta-thromboglobulin (beta-TG), and histamine content as well as platelet total thromboxane A2 (TXA2) synthesizing capacity were measured in 53 patients with chronic renal disease: nephrotic syndrome (n = 18); end-stage renal failure (ESRF; n = 13); continuous ambulatory peritoneal dialysis (CAPD; n = 9); hemodialysis (HD; n = 13). These indices of platelet function were correlated with plasma total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG) concentrations. When compared with controls, intraplatelet 5-HT was significantly reduced in all patient groups studied and beta-TG was diminished in all patient groups except CAPD. Total platelet TXA2 synthesizing capacity was increased in ESRF and HD groups. Intraplatelet histamine content was not altered in any of the patient groups studied. There was a significant inverse correlation between intraplatelet 5-HT content on the one hand and plasma TC, LDL-C, and TG on the other. The depletion of intraplatelet 5-HT and beta-TG and the increase in total TXA2 synthesizing capacity are consistent with platelet activation in chronic renal disease. The correlation between these indices of platelet activation and TC, LDL-C, HDL-C, and TG suggests that changes in the concentrations of these lipids may contribute to the activation of platelets in these conditions.

Topics: Adolescent; Adult; beta-Thromboglobulin; Blood Platelets; Female; Histamine; Humans; Kidney Diseases; Kidney Failure, Chronic; Male; Middle Aged; Nephrotic Syndrome; Peritoneal Dialysis; Renal Dialysis; Serotonin; Thromboxane A2

Topics: Animals; Indoles; Male; Nephrotic Syndrome; Piperazines; Platelet Activating Factor; Proteinuria; Puromycin Aminonucleoside; Rats; Rats, Inbred Strains; Thromboxane A2