thromboxane-b2 and Autoimmune-Diseases

Early pregnancies in women with a history of recurrent spontaneous abortion (RSA) are accompanied by a deficiency in vasodilatory and anti-aggregatory prostacyclin (PGI2) and/or overproduction of its endogenous antagonist thromboxane A2 (TXA2). We evaluated the effect of a low-dose aspirin (LDA) on PGI2 and TXA2 production and on pregnancy outcome in RSA women with and without detectable anticardiolipin antibodies (ACA). Of 82 RSA women studied, 66 became pregnant, and of them, 33 (six with elevated and 27 with normal ACA concentrations) were randomized to receive LDA (50 mg/day) and 33 (six with elevated and 27 with normal ACA concentrations) to receive placebo (PLA) from a mean of 6.6 days after the missed period to delivery. Treatment with LDA inhibited platelet TXA2 production similarly in RSA women with and without detectable ACA and with continuing pregnancies (7.0 +/- 0.7 ng/ml, LDA group versus 254.5 +/- 37.8 ng/ml, PLA group, mean +/- SEM, P < 0.0001) or miscarrying pregnancies (13.8 +/- 3.8 ng/ml compared with 233.6 +/- 59.8 ng/ml, P < 0.0001 respectively). Furthermore, LDA decreased urinary excretion of the TXA2 metabolite (2,3-dinor-TXB2) both in pregnancies which went to term (6.1 +/- 0.6 ng/mmol creatinine, LDA group versus 19.3 +/- 3.0 ng/mmol creatinine, PLA group, P < 0.0001) or again ended in miscarriage (4.7 +/- 0.8 ng/mmol creatinine versus 17.3 +/- 4.4 ng/mmol creatinine, P < 0.0001 respectively), but did not affect the excretion of the prostacyclin metabolite (2,3-dinor-6-keto-PGF1alpha). Early pregnancy ultrasound examination revealed a living fetus in 58 women. Of these, seven in the LDA group (23.3%, four with elevated and three with normal ACA concentrations) and five in the PLA group (17.9%, two with elevated and three with normal ACA concentrations; not significant) experienced a miscarriage. All infants were healthy, and the frequency of growth retardation was similar in both groups (13.0%). One woman in the LDA group (4.3%) and three women receiving PLA (13.0%) developed pre-eclampsia (not significant). Therefore, although treatment with LDA caused a desirable biochemical effect, it did not improve pregnancy outcome in RSA women with or without detectable ACA.

Topics: Abortion, Habitual; Adult; Aspirin; Autoimmune Diseases; Blood Platelets; Epoprostenol; Female; Humans; Pregnancy; Thromboxane A2; Thromboxane B2

Antiphospholipid antibodies (aPL) reactive with anionic phospholipids and beta2-glycoprotein I (beta2-GPI) are found in the sera of patients with autoimmune diseases. Clinically, aPL/beta2-GPI complexes are associated with arterial and venous thrombosis, fetal loss, and thrombocytopenia, i.e., the antiphospholipid syndrome (APS). The mechanism of thrombosis is not known. We hypothesized that aPL/beta2-GPI complexes could perturb the platelet membrane and increase production of thromboxane A2 (TXA2, a proaggregatory prostanoid).. We isolated an IgG fraction containing anticardiolipin antibody (aCL) and the plasma cofactor, beta2-GPI, from a patient with a high titer of aCL and thrombotic cerebrovascular disease. We then examined the effect of aCL, beta2-GPI, and the aCL/beta2-GPI complex on platelet TXB2 (a stable metabolite of TXA2) biosynthesis in vitro from 7 healthy controls. We also measured in vitro platelet TXB2 biosynthesis in 7 patients with APS and in 8 controls.. We found: (1) significantly increased in vitro TXB2 production by platelets from controls after incubation with aCL/beta2-GPI complexes; (2) moderately increased TXB2 production by aCL alone; (3) no increase in TXB2 production by beta2-GPI alone; and (4) significantly increased 11-dehydro-TXB2, a metabolite of TXB2 production in vivo, in the urine of patients with APS compared with controls.. These data suggest that aCL/beta2-GPI complexes play a role in activating platelets to produce TXA2, which could contribute to the prothrombotic state found in patients with APS.

Topics: Adult; Aged; Antibodies, Anticardiolipin; Antibodies, Antiphospholipid; Antiphospholipid Syndrome; Autoimmune Diseases; beta 2-Glycoprotein I; Binding Sites; Blood Platelets; Female; Glycoproteins; Humans; Immunoglobulin Fab Fragments; Male; Middle Aged; Phospholipids; Thromboxane A2; Thromboxane B2

Oral administration of CGS-13080 [imidazo (1, 5-alpha) pyridine-5-hexanoic acid], a thromboxane synthetase inhibitor, has been reported to cause a marked reduction in serum thromboxane B2 concentration in humans and animals. Since thromboxane metabolites play an important role in ocular inflammation, the effect of oral CGS-13080 in the development of experimental autoimmune uveoretinitis in Lewis rats has been investigated. Females were immunized with bovine S-antigen (S-Ag). Treatment was started on day 0 of immunization. Animals were divided into three groups. The control group was fed a standard pellet diet, while the treated groups were fed the standard diet supplemented with either a low dose (0.8 g per 10 kg pellet) or a high dose (1.6 g per 10 kg pellet) of CGS 13080. From day 10 after immunization, the eyes of these rats were examined daily for clinical evidence of experimental autoimmune uveoretinitis. On day 14, the eyes were collected for histologic study. The cellular immune responses were evaluated on the draining inguinal lymph nodes. Blood samples were also collected for the measurement of anti-S-Ag antibody production, thromboxane B2 and prostaglandin A2 levels. Clinical disease developed in 73.3% of the control rat group, 30.0% of the low-dose treated group and 17.6% of the high-dose group. The average histologic grade was 1.9 in the control group, 0.65 in low-dose group and 0.32 in high-dose group. Lymphocyte proliferation to S-Ag paralleled the clinical disease scores. Average stimulation indices were 10.9 in the controls, 7.5 in the low-dose group and 2.2 in the high-dose group.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Antigens; Arrestin; Autoantigens; Autoimmune Diseases; Chorioretinitis; Choroid; Dinoprostone; Eye Proteins; Female; Imidazoles; Immunoglobulin G; Lymphocyte Activation; Pyridines; Rats; Rats, Inbred Lew; Retina; Thromboxane B2; Thromboxane-A Synthase

Willebrand-factor antigen level and structure analysis, ristomycin-cofactor assay, beta-thromboglobulin and thromboxane metabolite estimations were performed in 22 patients with mixed connective tissue disease to evaluate the incidence and the possible role of haemostatic alterations in the complications occurring during the course of the disease. High levels of Willebrand-factor antigen and ristomycin-cofactor activity were detected in patients with thrombocytopenia, previous thrombotic event, pulmonary vascular lesions and usually in the presence of circulating anti-endothelial antibodies. Increased platelet activation could have been found in antibody positive cases and in patients with thrombocytopenia as well. The documented alterations of endothelial and platelet functions may play important role in the vascular complications of mixed connective tissue disease.

Topics: Adult; Autoantibodies; Autoimmune Diseases; beta-Thromboglobulin; Blood Coagulation Disorders; Blood Platelets; Endothelium, Vascular; Female; Hemostasis; Humans; Incidence; Male; Mixed Connective Tissue Disease; Thromboxane B2; von Willebrand Factor

We found a novel platelet aggregating factor in a patient with steroid-responsive immune thrombocytopenic purpura that is associated with defective collagen-induced platelet functions. The aggregating factor and platelet functions were analyzed. The patient, a 58-year-old female, had purpura and prolonged bleeding time despite adequate platelet counts (greater than 140,000/microL) after steroid therapy. The patient's platelets responded normally to all agonists except collagen. Platelet adhesion to collagen fibrils was decreased. The patient's plasma induced irreversible aggregation and ATP release in normal platelet-rich plasma (PRP). This platelet aggregating factor was found in F(ab')2 fragments of the patient's IgG, which caused thromboxane B2 synthesis, elevation of cytoplasmic Ca2+ levels, and phosphorylation of 40 kDa protein in normal platelets. Platelet aggregation by the patient's IgG was inhibited by prostacyclin, dibutyryl cAMP, diltiazem, disodium ethylenediaminetetraacetate, and antimycin A plus iodoacetate, but ADP scavengers, cyclo-oxygenase inhibitors, and heparin had little or no effect. The aggregating activity of the patient's IgG absorbed to and eluted from normal platelets. The patient's Fab fragments did not induce platelet aggregation in eight of ten normal PRP but specifically inhibited aggregation induced by collagen and by the patient's IgG. The major component of an immunoprecipitate made with the patient's IgG from radiolabeled membrane proteins of normal platelet extract had a 62 kDa mol wt, while no such precipitate appeared in extracts of the patient's platelets. These results indicated that platelet aggregation by the patient's IgG was induced by the reaction of an antibody with a specific antigen on the normal platelet membrane through stimulus-response coupling. This antigen may be a collagen receptor on the platelet, most likely a polypeptide of 62 kDa under reducing condition. The defect of collagen-induced aggregation of the patient's platelets seemed to be due to alteration of the membrane protein related to this putative collagen receptor.

Topics: Autoimmune Diseases; Blood Coagulation Factors; Blood Platelet Disorders; Collagen; Female; Humans; Immunoglobulin G; Middle Aged; Platelet Activating Factor; Platelet Aggregation; Purpura, Thrombocytopenic; Thrombocytopenia; Thromboxane B2

Synthesis of both prostaglandin E2 and thromboxane B2 in liver and kidney tissue of NZB/W F1 hybrid mice was found to increase with advancing age. The rise in prostanoid generation coincided with the appearance and progression of the spontaneous systemic lupus erythematosus (SLE)-like disorders seen in these mice. Substitution of a diet supplemented with histidine (50 g kg-1 dry weight) and/or zinc (160 mg kg-1 dry weight) suppressed the autoimmune disease associated increase in prostanoid generation. The parent NZB and NZW strains also revealed an age-dependent increase in prostanoid synthesis whereas no age-related changes of tissue prostanoid generation were seen in healthy DBA-2 and C57-BL/6 control mice. In a previous study [Schwerdtfeger et al. 1980] a protective effect of histidine and/or zinc on the course of SLE-like disease in NZB/W F1 mice was reported. The current work suggests that this effect may in part have been mediated by the modulation of cellular arachidonic acid metabolism. The proposal that prostanoids are involved in the pathogenesis of autoimmune disease in NZB/W F1 mice is supported by these results.

Topics: Administration, Oral; Age Factors; Animals; Arachidonic Acids; Autoimmune Diseases; Diet; Dinoprostone; Female; Histidine; Kidney; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Prostaglandins E; Thromboxane B2; Zinc