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)

Patients with antiphospholipid syndrome, whether primary or secondary to systemic lupus erythematosus, may have thrombocytopenia. Their antibodies to anionic phospholipids might bind to phospholipids on the platelet wall but anionic phospholipids are asymmetrically located in the inner leaflet. In addition, antibodies to anionic phospholipids may require beta 2 glycoprotein I (beta 2GPI) as a cofactor in order to bind to phospholipids. In turn, beta 2GPI has high affinity for anionic phospholipids. Loss of this asymmetry occurs upon platelet activation and could thus permit such antibody-beta 2GPI-platelet interaction. We studied this by flow cytometry using purified beta 2GPI-FITC labelled and similarly labelled affinity-purified polyclonal antibodies to cardiolipin or phosphatidylserine (aPL) obtained from sera of patients with primary antiphospholipid syndrome. Five percent of resting platelets were bound by aPL in the presence of beta 2GPI. Such binding increased when we activated platelets with various agonists, reaching 31% with the concurrent use of thrombin and the calcium ionophore A23187. Platelet activation resulted in the expression of GMP140 but this did not correlate with aPL binding. This probably reflects that the expression of GMP140, which depends on their secretion of alpha granules, has different agonist responses and occurs at different times than do microvesicle formation and expression of prothrombinase activity which coincide with the loss of phospholipid asymmetry on the platelet wall. When we studied the binding of purified beta 2GPI we also found that it binds preferentially to activated platelets and that it seems to be a prerequisite for the binding of aPL onto them. Our findings indicate that aPL from patients with antiphospholipid syndrome may bind to activated platelets through beta 2GPI.
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PMID:Exposure of anionic phospholipids upon platelet activation permits binding of beta 2 glycoprotein I and through it that of IgG antiphospholipid antibodies. Studies in platelets from patients with antiphospholipid syndrome and normal subjects. 791 7

Resistance to activated protein C (RAPC) has been described recently as a cause of trombophilia; this may justify up to 50% of thromboembolic disease without predisposing cause in patients under 45 years. A 29 years-old male with a previous deep venous thrombosis (DVT) in the lower left limb three years earlier, developed a DVT in the right lower limb after a trauma of the knee that required immobilization, was associated to pulmonary thromboembolism diagnosed by gammagraphic methods. The phlebographic study showed femoro-iliaco-caval venous thrombosis. The proband's father and a younger brother had a previous history of thrombotic episodes. The following tests, were performed in the proband and relatives: prothrombin time, aPTT, thrombin time, fibrinogen, (Von Clauss), antithrombin III (chromogenic), protein C and protein S (coagulometry and ELISA), plasminogen (chromogenic) and lupus anticoagulant (ITT, dRVVT, aCL). RAPC was evaluated in two different samples. The proband study was performed under oral anticoagulation treatment (OAT). Control groups were: 21 blood donors and 12 OAT patients. The results showed a decreased response to APC in the proband (ratio 1.5) and relatives: father (1.4), brothers (1.5 and 1.5), while the mother was within the normal range (> or = 2). In normal controls and OAT patients the ratio was over 2. No other abnormalities were detected in the assays performed. It is concluded that RAPC is the cause of this familial trombophilia. RAPC should be included in the evaluation study of trombophilia.
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PMID:[Familial thrombophilia due to resistance to activated protein C]. 798 58

Lupus anticoagulants, commonly found in the immunoglobulin fraction of patients with the antiphospholipid syndrome (APS), and the normal plasma protein beta 2-glycoprotein 1 (beta 2GP1) may both contribute to the in vitro impairment of prothrombin activation associated with the APS. We examined the effects upon prothrombin activation supported by phospholipid vesicles of plasma IgG preparations from APS patients in the presence and absence of beta 2GP1. Using a purified system for measurement of prothrombin activation to thrombin, we demonstrated significant phospholipid concentration-dependent inhibition of prothrombin activation in the absence of beta 2GP1 by 11 consecutive patient IgG preparations. The degree of inhibition of prothrombin activation by equivalent concentrations of patient IgG correlated well with the extent of prolongation of the plasma clotting time in lupus anticoagulant assays of whole patient plasma. Additional studies with eight patient IgG preparations indicated that the addition of beta 2GP1 to patient IgG-phospholipid vesicle mixtures resulted in either independently additive inhibition by the two protein species (six cases) or potential inhibition of beta 2GP1 of the IgG inhibitory activity demonstrable in the absence of beta 2 GP1 (two cases). In addition, beta 2GP1-independent inhibition of prothrombin activation also occurred with three patient IgG preparations obtained by affinity binding to cardiolipin.
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PMID:Inhibition of prothrombin activation by antiphospholipid antibodies and beta 2-glycoprotein 1. 799 95

Activated protein C (APC)-protein C inhibitor (PCI) complex and APC-alpha 1antitrypsin (alpha 1AT) complex levels were measured in 29 patients positive for lupus anticoagulant (LA). LA was considered positive if two of the following three criteria were fulfilled: (1) prolongation of the activated partial thromboplastin time, (2) prolongation of the kaolin clotting time (KCT) and KCT mixing test, and (3) prolongation of the dilute Russell's viper venom time (DRVVT) and DRVVT/DRVVT with high lipid concentration. Plasma thrombin-antithrombin III (AT-III) complex and plasmin-alpha 2-antiplasmin inhibitor complex levels in patients positive for LA were increased slightly, but not significantly, and FDP-D-dimer and t-PA levels were not markedly increased. Plasma PAI-1 level in the LA-positive patients was significantly increased compared with normal volunteers. AT-III activity, protein C antigen, PCI antigen, and protein S antigen levels in the LA-positive patients were virtually normal, while protein C activity was slightly, but not significantly, decreased. APC-PCI complex level was increased in all LA-positive patients, and was not detectable in patients with systemic lupus erythematosus and normal volunteers. APC-alpha 1AT complex was increased slightly, in only two LA-positive patients; it was not detectable in the other patients or in the normal volunteers. These findings suggest that patients positive for LA are in a hypercoagulable state and that protein C activity in such patients is decreased, due to the activation of this protein.
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PMID:Increased activated protein C-protein C inhibitor complex level in patients positive for lupus anticoagulant. 805 49

Anticardiolipin antibodies are produced both in patients with the antiphospholipid syndrome (APS) and in patients with syphilis, but lupus anticoagulant activity has been reported only for the former group. To understand these differences, affinity-purified immunoglobulin G anticardiolipin antibodies from APS (n = 11) and syphilis (n = 5) patients were compared. Only the antibodies from the APS group inhibited prothrombin conversion to thrombin and cross-reacted with phosphatidylserine. These findings may enable better definition of the phospholipid epitopes involved in the hemostatic abnormalities of APS.
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PMID:Differences in functional activity of anticardiolipin antibodies from patients with syphilis and those with antiphospholipid syndrome. 806 29

Snake venoms contain a rich variety of factors affecting the haemostatic mechanism which can be broadly classified as possessing coagulatant, anticoagulant and haemorrhagic activity. Coagulant enzymes include activators of blood coagulation factors II (prothrombin), V and X; anticoagulants include protein C activators, inhibitors of prothrombin complex formation and fibrinogenases which can be further classified according to their specificity for the alpha-, beta- and gamma-chains of fibrinogen. Intermediate between true coagulants and true anticoagulants are the thrombin-like enzymes which bring about clotting in vitro but defibrination (anticoagulation) in vivo. Snake venoms also affect platelets either by inducing or inhibiting platelet aggregation and cause haemorrhage via an action on platelets or via proteolysis of the blood vessel wall. Haemorrhagins also include inter alia, the alpha-fibrinogenases. This rich diversity of snake venom components affecting haemostasis has enabled a range of practical applications to be established including therapeutic anticogulation with thrombin-like enzymes (Ancrod and Defibrase) and laboratory tests for individual haemostatic factors (protein C, prothrombin, factor X and lupus anticoagulant). This broad spectrum of materials in snake venoms suggests some evolutionary advantage to the venom producer, not only for dispatching prey but as agents which 'spread' the venom toxins throughout the body and initiate digestion.
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PMID:Snake venoms affecting the haemostatic mechanism--a consideration of their mechanisms, practical applications and biological significance. 807 11

Lupus anticoagulants are antibodies that inhibit phospholipid dependent coagulation reactions in vitro. These antibodies are of clinical interest because of their association with a variety of clinical manifestations characterized by microvascular thrombosis. Although these antibodies were originally thought to be directed at negatively charged phospholipid, recent studies have suggested that they may be directed at phospholipid-protein complexes. The effect of antibodies directed against beta 2-glycoprotein I (beta 2-GP I, apolipoprotein H) on phospholipid-dependent coagulation reactions has been studied. Polyclonal and monoclonal antibodies to beta 2-GP I were found to inhibit thrombin generation in a dose dependent manner. Inhibition of thrombin formation was due to specific interaction with beta 2-GP I. There was no evidence that inhibition was due to crossreactivity with other proteins involved in the prothrombinase complex. These findings document that antibodies directed against beta 2-GP I can have anticoagulant activity analogous to lupus anticoagulant activity and are consistent with the recent observation of such activity in lupus anticoagulant patient samples.
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PMID:Antibodies to beta 2-glycoprotein I inhibit phospholipid dependent coagulation reactions. 811 86

The anticoagulant effect of recombinant hirudin (rHir) and Hirulog has been monitored in patients with the activated partial thromboplastin time. Accurate monitoring with this test cannot be achieved if plasmas contain heparin, lupus anticoagulants, low concentrations of fibrinogen or other factors, or elevated fibrinogen-fibrin degradation products (FDP). We have therefore developed a simple, rapid, sensitive clot-based method, the quantitative thrombin time (QTT), to measure levels of rHir and Hirulog in patient plasma (or whole blood). The QTT is performed by mixing a 1:10 dilution of patient plasma (50 microliters) with human fibrinogen (50 microliters, 128 mg/dl) at 37 degrees C; the clotting time is initiated by adding human thrombin (50 microliters, 5-7.5 U/ml). The concentration of Hirulog or rHir in plasma can be determined by comparing the QTT in patient plasma with a standard curve that is generated by adding different concentrations of anticoagulant to pooled normal plasma. Studies with whole blood using the same procedure yield similar results. In the absence of Hirulog or rHir, the baseline QTT is the same in normal and abnormal plasmas (fibrinogen < 150 mg/dl and FDP as high as 1024 micrograms/ml, elevated FDP alone, lupus anticoagulant, or heparin < 0.9 U/ml). When known concentrations of either rHir or Hirulog are added to abnormal plasmas, the mean observed concentrations as determined by the QTT deviate from the expected values by less than 10% (range 0-19%). The data indicate that the QTT is a simple, rapid, and accurate test for the determination of levels of rHir and Hirulog in plasma or whole blood.
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PMID:A quantitative thrombin time for determining levels of hirudin and Hirulog. 811 87

In a group of 6 patients with lupus anticoagulant (LA) and antiphospholipid (aPL) antibodies detected by ELISA overnight urine and blood were simultaneously collected. A significantly increased urinary excretion of the platelet-derived thromboxane (TX) metabolite 11-dehydro-TXB2 was found in this group, as compared to 12 healthy individuals. In contrast, a small but significant reduction of the vascular prostacyclin (PGI2) metabolite 2,3-dinor-6-keto-prostaglandin F1 alpha was observed. To further elucidate the effect of these antibodies on platelet activation we isolated the F(ab')2 fragments from IgG of the 6 patients and 5 controls, and we evaluated the effect of these fragments on the responses of isolated normal platelets to thrombin. Patients' F(ab')2 increased platelet aggregation and serotonin release of platelets stimulated by low dose thrombin (0.01 U/ml). At threshold thrombin concentration (0.05 U/ml) an enhanced TXB2 production was also observed. In summary, our results show, in addition to the altered TXA2/PGI2 balance observed in vivo, a direct stimulatory effect of aPL antibodies on platelet activation in vitro. This effect is related to recognition of phospholipid epitopes on platelets as shown by its neutralization upon preincubation with phospholipids. This phenomenon may be relevant for the thrombotic tendency of these patients.
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PMID:Antiphospholipid antibodies enhance thrombin-induced platelet activation and thromboxane formation. 811 93

Monocyte stimulation may be induced by various agents. Monocytes generate procoagulant activity (PCA) in response to stimulation; they widely interact with the hemostatic system and participate in thrombin formation. Extensive placental thrombotic infarction has been implicated in fetal death in polyabortive patients with lupus anticoagulant (LA). We investigated 38 polyabortive women: 17 LA negative (LA-) and 18 LA positive (LA+). We compared the results with 25 clinically normal women. After four hours of incubation, the mean value of monocyte PCA in the LA+ women was significantly higher than in either the LA- or the control group (p < 0.0001). The monocyte PCA was out of the range of the controls in 9 of the 18 LA+ women. No correlation was observed between the levels of LA and monocyte PCA (r = 0.02; p = 0.94). No differences were found in monocyte PCA increase when induced by LA-, LA+ or control plasma; in all cases the increase was about five-six fold. Our results indicate that an increased monocyte PCA is present in some LA+ polyabortive women, thus suggesting that monocyte activation might be involved in the formation of thrombotic placental infarction and the consequent fetal loss in some patients. It might also suggest that these patients, in particular, could benefit from corticosteroid treatment, which is known to inhibit the formation of monocyte PCA.
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PMID:Lupus anticoagulant and monocyte procoagulant activity in polyabortive women. 813 58


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