thromboxane-a2 and Anemia--Sickle-Cell

Pregnancy increases the risk of morbidity and mortality in sickle cell disease. We previously showed pregnant women with sickle cell disease to have a relatively low plasma renin concentration in late pregnancy, associated with a lack of the expected plasma volume expansion. We hypothesized this to be due to increased systemic vascular resistance through an imbalance between the vasodilator prostacyclin and vasoconstrictor thromboxane, associated with decreased glomerular filtration rate (GFR).. To compare estimated prostacyclin, thromboxane and GFR in non-pregnant and pregnant women with hemoglobin SS (HbSS) and AA (HbAA).. Four groups of 20 normotensive, nulliparous women were studied in Lagos, Nigeria: pregnant HbSS or HbAA women at 36-40 weeks gestation; non-pregnant HbSS and HbAA controls. We measured stable metabolites of prostacyclin and thromboxane A2 by enzyme-linked immunosorbent assay; GFR using the Cockcroft-Gault equation. Data analysis was by independent (Student's) t-test or Mann-Whitney U test for comparisons between any two groups of continuous variables, univariate ANOVA for multiple groups and Pearson's correlation coefficient for degree of association between variables.. HbSS women had lower serum 6-keto-PGF1α concentrations than HbAA, whether pregnant or non-pregnant (P<0.001; P<0.004 respectively). Conversely, pregnant HbSS women had higher serum TxB2 (P<0.001); non-pregnant HbSS women had non-significantly higher TxB2 concentrations. The 6-keto-PGF1α:TxB2 ratio was markedly increased (pro-vasodilatory) in HbAA pregnancy (P<0.001) but reduced in HbSS pregnancy (P = 0.037). GFRs (mL/min) were higher in non-pregnant HbSS than HbAA (P<0.008) but only marginally raised in HbSS women in late pregnancy (P = 0.019) while markedly raised in HbAA pregnancy (P<0.001).. The lower ratio of prostacyclin-thromboxane metabolites in HbSS pregnancy may indicate endothelial damage and an increased tendency to vasoconstriction and clotting. If confirmed by subsequent longitudinal studies, interventions to increase prostacyclin and reduce thromboxane, such as low dose aspirin, may be potentially useful in their management.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Anemia, Sickle Cell; Blood Pressure; Creatinine; Cross-Sectional Studies; Eicosanoids; Epoprostenol; Female; Genotype; Glomerular Filtration Rate; Humans; Longitudinal Studies; Pregnancy; Pregnancy Outcome; Thromboxane A2; Thromboxane B2; Thromboxanes; Young Adult

The role of eicosanoids in the pathogenesis of acute or chronic lung syndrome in sickle cell disease is unknown. We investigated the synthesis of prostacyclin (PGI2), thromboxane (Tx) A2, and prostaglandin (PG) E2 by three groups of isolated rat lungs perfused with buffer (GPBS), normal (HbAA), and sickle (HbSS) erythrocyte suspensions. Isolated lungs were perfused at a constant pressure and flow rate (Q) of 40 ml x kg(-1) x min(-1) with GPBS or 7% erythrocyte suspensions for 15 min. Autologous platelet-rich plasma (PRP) was added, and perfusion was continued for 15 min and then at two times Q for another 15 min. Perfusate samples were assayed for the specific eicosanoids. Perfusate level of PGI2 in GPBS lungs was the least among the three groups. However, the PGI2 level in HbSS lungs was 90% higher than from HbAA lungs after 15 min of perfusion and was 180% higher on perfusion with PRP. Additionally, coperfusion of erythrocytes and PRP augmented perfusate levels of TxA2 and PGE2 over 1,000% more in HbSS than HbAAlungs. These data show that HbSS erythrocytes increased perfusate levels of the eicosanoids, suggesting increased synthesis, perhaps due to aberrant erythrocyte-endothelium interactions.

Topics: Acid-Base Equilibrium; Adult; Anemia, Sickle Cell; Animals; Dinoprostone; Epoprostenol; Erythrocytes; Humans; In Vitro Techniques; Lung; Perfusion; Rats; Thromboxane A2

Thrombosis represents an important cause of mortality in patients with sickle cell disease, in addition to the complications caused by the primary defect of inherited abnormal hemoglobin. To study the involvement of platelets in these complications, we assessed the biosynthesis of thromboxane A2 in samples from 49 patients with sickle cell disease and in 33 control subjects. The urinary excretion of the major arachidonic acid metabolite of platelet origin (11-dehydro-thromboxane B2) and of the vascular endothelial cell (2,3-dinor-6-ketoprostaglandin F1 alpha) were very significantly increased (p < 0.0002) in the patients. In a small group of patients (n = 14), we further investigated the ex vivo response of their platelets to U46619, a stable analogue of thromboxane A2. We observed decreased aggregation and [14C]serotonin release compared with control (p < 0.05); similarly, we found impaired p47 protein phosphorylation (p < 0.05). In contrast, platelets from these patients responded normally to thrombin (0.1 unit/mL). In vivo desensitization of platelets from these patients to thromboxane may constitute a form of regulation that may prevent the propagation of aggregation by this potent inducer, as has been hypothesized in in vitro studies. Our results may also provide a rationale for using antiplatelet drugs in the prophylaxis of thrombotic complications in sickle cell patients.

Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Adult; Anemia, Sickle Cell; Aspirin; Blood Platelets; Female; Humans; Male; Phosphorylation; Prostaglandin Endoperoxides, Synthetic; Thrombin; Thromboxane A2; Thromboxane B2