Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024141 (systemic lupus erythematosus)
 44,322 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Antiphospholipid antibodies (APA) are a family of immunoglobulins that react with anionic phospholipids, or anionic phospholipids-protein complexes. Recent evidence would support the latter definition. Lupus anticoagulants (LA) inhibit in vitro phospholipid dependent coagulation tests [e.g., activated partial thromboplastin time (APTT), prothrombin time (PT), and dilute Russell viper venom time (dRVVT)]. This inhibition appears to be specific for reagent phospholipids. The addition of freeze-thawed platelets or activated platelets will result in correction of the LA-induced abnormality. Anticardiolipin antibodies (ACA) are related to LA but appear to be distinct. ACA are detected by solid phase assays (ELISA, RIA) and require a plasma cofactor: beta 2 Glycoprotein-I (beta 2 GPI). ACA and LA activities can be separated in individual patient plasmas by affinity chromatography. In some instances they are of differing isotypes. Preliminary evaluation of beta 2 GPI in coagulation assays suggests it may function as a cofactor for LA activity. Recent work also suggests human prothrombin may represent a necessary cofactor for in vitro LA activity. Paradoxically, patients with LA/ACA may sustain thromboembolic events involving both venous and arterial sites. The prothrombotic properties of LA/ACA have not been satisfactorily characterized. A number of proposals have been reported, including inhibition of prostacyclin (PGI2) generation by endothelial cells, decreased activity of the protein C system, impaired fibrinolysis, and inhibition of beta 2GPI. Among these various hypotheses, down regulation of the protein C system appears most plausible. Also, LA/ACA may interfere with the phospholipase A2-phospholipid substrate complex involved in the generation of arachidonic acid from membrane phospholipids.
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PMID:Antiphospholipid antibodies: proposed mechanisms of action. 128 81

Most authors agree upon the causal association between antiphospholipid antibodies [lupus anticoagulant (LAC) and/or anticardiolipin antibodies] and adverse pregnancy outcome. Placental insufficiency, caused by thrombosis, infarction and maldevelopment, is thought to be the main cause of fetal loss in patients with LAC. Therapy given thus far to prevent fetal loss can be divided into (1) immunosuppression by corticosteroids, azathioprine, or intravenous gamma globulin (IVGG), (2) anti-aggregants to overcome imbalance of thromboxane/prostacycline production in patients with LAC, and (3) anticoagulants to neutralize the possible impairment of clotting inhibitor systems. Different therapeutic success rates have been reported by various authors who used the same combination of therapy. We report the results of different therapy regimens in 154 pregnancies in 31 women with LAC. These patients suffered from SLE with LAC or from APLA syndrome and experienced either recurrent miscarriages or thromboembolic phenomena in the past. With no therapy there were seven (6.8%) live births and 95 (93.2%) failures. Various combinations of corticosteroids, anti-aggregants and anticoagulants were used for treatment. Of 52 treated pregnancies, 27 (51.9%) were successful. Sixteen (69.1%) of 23 pregnancies treated by all three modalities ended in live births. Four of these successful pregnancies occurred after failure of treatment by prednisone and anti-aggregants only. In order to minimize osteoporosis caused by the combination of steroids and heparin, we have used warfarin in the second trimester and have lately substituted low molecular weight heparin for heparin. In the absence of a therapeutic schedule predicated on a large prospective study, therapy during pregnancy in patients having LAC should be individualized according to their obstetric and medical history.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Treatment of patients with antiphospholipid antibodies during pregnancy. 128 82

All pregnancy-associated tissues are capable of producing prostaglandins including PGI2 and TXA2. In normal pregnancy there is a dominance of PGI2 over TXA2 which may contribute to the maternal circulatory adaptation to pregnancy. Furthermore, both fetoplacental PGI2 and TXA2 production are important regulators of the fetal blood supply. It has been clearly established that in pre-eclampsia PGI2 production decreases in the fetoplacental tissues and quite probably also in the maternal tissues. The effect of this change may be further exaggerated by the simultaneous stimulation in pre-eclampsia of TXA2 production. The reason for PGI2 deficiency is not known. Other vasoactive agents, such as endothelin, may act in concert with prostaglandins. Relative PGI2 deficiency is likely to exist also in IUGR and lupus anticoagulant syndrome of pregnancy. In the latter, lupus anticoagulant may directly inhibit the synthesis of PGI2. One study suggests PGI2 deficiency also in early pregnancies of women with a history of repeated abortions. Prostaglandin production increases during full-term labour, and similar but smaller changes also occur in preterm labour. A silent bacterial infection may trigger the onset of preterm labour through cytokine-stimulated increase of prostaglandin production. No data were found on prostaglandin production in post-term pregnancies. That oligo-polyhydramnios is possibly prostaglandin mediated is suggested by the control of polyhydramnios by indomethacin treatment. Smoking decreases the production of PGI2 and possibly increases that of TXA2, which may lead to decreased blood flow and IUGR. Which constituent of cigarette smoke exerts this effect is not known. Ethanol consumption causes aberrations in prostaglandin metabolism which cannot be directly connected with fetal alcohol effects.
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PMID:The role of prostaglandins in obstetrical disorders. 147 99

Intra-uterine growth retardation, intra-uterine fetal death and pre-eclampsia have common abnormalities: A reduction of uteroplacental perfusion, lack of vasodilation of spiral arteries and subsequent thrombosis. These physiological processes have been explained by an imbalance between prostacyclin and thromboxane A2 production. Many studies have suggested that treatment with low-dose aspirin and steroids is effective in preventing pregnancy loss or pre-eclampsia, but the mechanism has not been established. We evaluated the effectiveness of these therapies in patients at risk for pregnancy loss with the aspect of intracellular ionized calcium mobilization. Low-dose aspirin directs the prostacyclin/thromboxane A2 balance to the dominance of prostacyclin and steroids suppress the activities of lupus anticoagulant or antiphospholipid antibodies. The intracellular ionized calcium concentration in platelets is decreased significantly after these therapies. Concerning the pathological examination of placenta, there were deposits of fibrin in only 2 out of 8 cases and there were no abnormal findings in the other 6 cases. These data show that the aggregation of platelets is suppressed in microvascular circulations. These therapies do not cause any adverse effect on the mother or fetus. It is concluded that low-dose aspirin therapy with steroids is useful for patients with a poor obstetrical history.
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PMID:[A trial of low-dose aspirin therapy in high-risk pregnancy]. 150 Aug 6

The effect on thrombin-induced release of prostacyclin from human umbilical vein endothelial cells of preincubation with both serum and serum derived from platelet-poor plasma (PDS) from patients with systemic lupus erythematosus (SLE), systemic sclerosis, the antiphospholipid syndrome (APS) and normal controls was examined. Although no significant differences in thrombin-induced prostacyclin release were found in any of the patient groups, further analysis revealed that PDS from patients with SLE and APS that contained IgG anticardiolipin antibodies produced significant inhibition of prostacyclin release when compared with controls (P = 0.02). The effect was maximal with samples that contained both IgG and IgM anticardiolipin antibodies (P less than 0.01) and which had a significantly higher titre of IgG antibodies than samples which contained solely IgG antibodies (P less than 0.05). The absence of any corresponding inhibition of prostacyclin release by serum samples that contained anticardiolipin antibodies, possibly due to the release of masking stimulatory factors by platelets during coagulation, provides an explanation for the conflicting nature of previous reports.
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PMID:Serum masks the inhibition of thrombin-induced prostacyclin release produced by anticardiolipin antibodies. 154 Jul 86

The hypothesis has been made that inhibition of prostacyclin (PG12) production may play a role in the pathogenesis of thrombosis in patients with the lupus anticoagulant (LA), but so far no evidence of reduced PG12 levels in vivo has been produced. We have tested the plasma levels of PG12 and thromboxane A2 (TXA2) and the platelet sensitivity to PG12 in 14 patients with and without LA and in 14 healthy controls. No significant difference in the prostanoid basal levels was detected among the groups; however, in some patients PG12 increments seemed to parallel the clinical course of the disease. Platelet sensitivity to exogenous PG12 was significantly enhanced in the LA + patients and correlated with PG12 values. We suggest that in these subjects additional factors, other than reduced PG12, may predispose to thrombosis.
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PMID:Lupus anticoagulant: interference with in vivo prostaglandin production and with platelet sensitivity to prostacyclin. 160 49

The in vivo production of thromboxane A2 and prostacyclin was assessed in 31 samples from 25 patients with lupus anticoagulant and in 32 controls. The urinary excretion of 11-dehydro-thromboxane B2 (a major thromboxane metabolite of platelet origin) was very significantly increased (p less than 0.0003) in the patients contrasting with a lesser increase of urinary 2,3-dinor-6-keto-prostaglandin F1 alpha reflecting the vascular production of prostacyclin (p less than 0.02). Our study shows that in patients with lupus anticoagulant, platelet activation may occur without a compensatory increment in the vascular biosynthesis of prostacyclin suggesting an increased risk for thrombosis.
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PMID:Increased production of platelet-derived thromboxane in patients with lupus anticoagulant. 163

To elucidate the mechanism of vascular thrombosis in patients with systemic lupus erythematosus and the lupus anticoagulant changes in factors associated with haemostasis were investigated. The lupus anticoagulant was associated with an increased incidence of thrombosis, particularly cerebral thrombosis. Concentrations of fibrinopeptide A and fibrinopeptide B beta 15-42 were significantly raised in the plasma of patients with systemic lupus erythematosus and the anticoagulant compared with concentrations in patients without the lupus anticoagulant. The tendency towards formation of thrombosis was not found in all lupus patients with the anticoagulant, however. Concentrations of thromboxane B2 were remarkably raised in the plasma of the two patients with the lupus anticoagulant who had recently had thrombosis. Concentrations of 6-keto-prostaglandin F1 alpha, protein C, antithrombin III, and plasminogen were similar in both groups. No significant decrease in serum stimulatory activity on prostacyclin production by cultured aortic endothelial cells was noted in lupus patients with the anticoagulant, but inhibition was present in the two patients with recent thrombosis. These results indicate that although patients with the lupus anticoagulant are not always in a hypercoagulable state, haemostatic abnormalities found in some patients with the anticoagulant may be predictive of thrombotic events.
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PMID:Haemostatic factors associated with vascular thrombosis in patients with systemic lupus erythematosus and the lupus anticoagulant. 190 17

Vascular injury and microvascular thrombosis are prominent features of systemic lupus erythematosus, as are circulating DNA-binding antibodies (DNAb). Experimental glomerulonephritis can be induced by anti-endothelial cell antibodies, and polyreactive DNAb might be pathogenetic by binding to endothelial cells, perhaps influencing their non-thrombogenic nature. To test this hypothesis, eight monoclonal antibodies (mAb) that bind to DNA derived from (NZB x NZW)F1 or MRL/Mp-lpr/lpr mice, were tested for their ability to bind to human umbilical vein endothelial cells (HUVEC). Binding was assessed using flow cytometry, fluorescence microscopy and cellular ELISA. Three of the eight mAb, at concentrations employed in this study, bound to HUVEC and dermal fibroblasts. Of these three mAb, one bound also to platelets. Two of the three demonstrated strong binding to (1) freshly isolated, collagenase-digested HUVEC, (2) 2nd passage HUVEC in suspension after trypsinization and, (3) 2nd passage HUVEC growing on plastic plates. To determine whether DNA itself acted as a ligand in this binding, prior treatment with DNAase was studied. Treatment of the endothelial cells with DNAase had no effect on the binding of one mAb, but DNAase treatment of this monoclonal itself resulted in a 60% reduction in binding to HUVEC, suggesting that the binding might be mediated through DNA in the form of a DNA/anti-DNA immune complex. In contrast, DNAase digestion of the endothelial cells caused a 40% reduction in the binding of the other two monoclonal antibodies. Furthermore, one of the two mAb bound 30% more to HUVEC after themselves being subjected to DNAase treatment. These two monoclonals may therefore be binding directly to HUVEC, possibly to DNA associated with the membrane. Prior DNAase digestion of dermal fibroblasts had a more profound effect on the binding of all three autoantibodies compared to HUVEC after similar treatment. Therefore, DNA can bind independently to either antibody or cell, thus supporting build up of complexes and capture of preformed complexes. Functionally, the binding of mAb to HUVEC did not influence thrombin-induced prostacyclin synthesis, in contrast to a control monoclonal anti-endothelial cell antibody EN4, which did.
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PMID:A role for DNA in anti-DNA antibodies binding to endothelial cells. 191 Apr 25

The mechanism involved in the association between antiphospholipid antibodies and thrombosis or fetal loss remains unclear. We assessed the biosynthesis of thromboxane A2 and prostacyclin in 31 samples from 25 patients with lupus anticoagulant and in 32 controls. The urinary excretion of the major thromboxane metabolite of platelet origin (11-dehydrothromboxane B2) was very significantly increased (P less than .0003) in the patients. In contrast, the urinary metabolite reflecting the vascular production of prostacyclin (2,3-dinor-6-keto-prostaglandin F1 alpha) was much less increased (P less than .02). We found no correlation between the levels of anticardiolipin antibodies and the urinary excretion of 11-dehydro-thromboxane B2. Six patients with elevated urinary 11-dehydrothromboxane B2 were treated with low-dose aspirin (20 mg/d during 7 days). In these patients, there was a close relationship between the extent of inhibition of the thromboxane urinary metabolite (72%) and serum thromboxane B2 (79%). In contrast, the urinary excretion of 2,3-dinor-6-ketoprostaglandin F1 alpha was nearly unchanged (13% reduction). In addition, the F(ab')2 fragments isolated from six patients presenting increased urinary 11-dehydro-thromboxane B2 enhanced the generation of thromboxane B2 (P = .04) and the release of 14C serotonin (P = .009) by normal washed platelets, as compared with F(ab')2 from controls. In summary, our study shows that in patients with lupus anticoagulant, platelet activation may occur without a compensatory increment in the vascular biosynthesis of prostacyclin. This observation may be crucial to cause or reflect an increased risk for thrombosis. In addition, our results may suggest a rationale for antiplatelet agents for the prophylaxis of thrombosis in many patients with the antiphospholipid syndrome.
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PMID:Imbalance of thromboxane/prostacyclin biosynthesis in patients with lupus anticoagulant. 195 77


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