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)

Phospholipids bearing a proportion of anionic species such as phosphatidylserine are necessary to promote the anticoagulant potential of the protein C pathway. Factor Xa (200 or 350 pM) was found to activate protein C in a thrombomodulin-independent reaction requiring only phospholipids in Al(OH)3,-adsorbed plasma resupplemented with physiological concentrations of protein C (70 nM) and protein S (130 nM). All experiments were performed in the presence of an excess of hirudin. The activity of activated protein C was assessed by the survival of factor Va. The optimal phospholipid concentration range was 5 to 25 microM with a proportion of phosphatidylserine of 50% (mol/mol) resulting in a half-life of factor Va of 7.5 min in the absence of protein S and 4.2 min in its presence. Dns-EGR-Xa, an inactive derivative of factor Xa, behaved as an apparent protector of factor Va. When replacing factor Xa, thrombin at 10 nM was not an efficient protein C activator in the absence of purified human placenta thrombomodulin. In the presence of 100 pM activated protein C, factor Va half-life was 2 min in the absence of protein S and 1.1 min in its presence in the above optimal phospholipid concentration range. The presence of protein S allowed reduction of phospholipid requirements. Annexin-V (placental anticoagulant protein-I), a potent phospholipid antagonist, fully protected factor Va from degradation by phospholipid-dependent mechanisms. Factor Va was partially protected in the plasma of a patient having experienced thrombosis associated with lupus-like anticoagulant and anti-phospholipid auto-antibodies.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The catalytic role of anionic phospholipids in the activation of protein C by factor Xa and expression of its anticoagulant function in human plasma. 179 56

Two classes of antiphospholipid antibodies (APA) are associated with adverse pregnancy outcomes. Those APA identified by immunoassays using phospholipid-coated surfaces (e.g., anticardiolipin antibodies) seem to bind to the 57 kD anticoagulant protein, beta 2-glycoprotein-I, when complexed with anionic phospholipid bilayers. Such APA may or may not prolong phospholipid-dependent clotting assays. A second class of APA are identified by their interference with phospholipid-dependent clotting assays (i.e., lupus anticoagulants). The latter bind to phospholipids present in a unique hexagonal phase either alone or complexed with prothrombin or beta 2-glycoprotein-I. There is evidence that both classes of APA are directly responsible for adverse pregnancy outcomes including spontaneous abortions, stillbirths, fetal growth retardation, thrombosis, thrombocytopenia, and preeclampsia. Putative APA-mediated pathogenic mechanisms include intervillous thrombosis, intravillous infarctions and decidual vasculopathy. The thrombogenicity of APA may result from their interference with endothelial phospholipids required for antithrombin III and protein C and S anticoagulant activity and prostacyclin synthesis and/or increased endothelial expression of the procoagulants: tissue factor, von Willebrand factor, platelet-activating factor, and plasminogen activator inhibitor type-1. Other prothrombotic properties seem to include: increased platelet aggregation, and reduced beta 2-glycoprotein-1 and annexin V anticoagulant activity. Rigorous diagnostic criteria must be applied to the detection of both classes of APA because the prevention of adverse pregnancy outcomes requires potentially hazardous anticoagulant therapy.
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PMID:The immunobiology and obstetrical consequences of antiphospholipid antibodies. 752 11

Anti-annexin V (anti-ANXV) IgG and lupus anticoagulant (LAC) were both shown to be capable of inducing apoptosis in umbilical vein endothelial cells [Nakamura et al.: Biochem Biophys Res Commun 205:1488-1493, 1994]. In the present study, we have demonstrated that anti-ANXV IgG prolongs the activated partial thromboplastin time and has an affinity for phospholipids in enzyme-linked immunosorbent assay. This indicates overlapping of anti-ANXV and LAC activities, suggesting that ANXV may be involved in the autoimmune mechanism for LAC production.
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PMID:Antibody to annexin V has anti-phospholipid and lupus anticoagulant properties. 763 81

Clinical and serological features in SLE patients with arterial or venous thrombosis were studied. The subjects consisted of 140 patients with SLE who met the revised criteria for the classification of SLE by the American Rheumatism Association. Forty patients (29%) had arterial or venous thrombosis. Arterial thrombosis such as stroke was found in 30 patients, and venous thrombosis such as deep vein thrombosis was seen in 24 patients. Average age at the disease onset was 34.5 +/- 12.5 years old. Renal disorder was found as a clinical feature, and IgG anticardiolipin antibodies (aCL), IgG phospholipid-dependent anti-beta 2-glycoprotein I (beta 2-GPI) antibodies and IgG anti-Annexin V antibodies were identified as serological features in SLE patients with thrombosis. These patients were diagnosed as having antiphospholipid syndrome. It was necessary to perform primary prevention therapy as well as secondary prevention therapy. Multiple thrombotic events in the past history and sustained positive reactions of IgG aCL were suggested as predictors of recurrent thrombosis. These data indicated the clinical and serological characteristics in SLE patients with arterial or venous thrombosis.
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PMID:[Thrombosis in patients with SLE and antiphospholipid syndrome]. 778 37

The effects of lupus anticoagulant (LAC) on cultured human umbilical vein endothelial cells were studied. All five monoclonal antibodies from a patient with systemic lupus erythematosus (SLE), as well as plasma samples with LAC activity from six SLE patients, induced apoptosis. Anti-annexin V IgG also induced apoptosis. Since monoclonal antibodies and plasma from SLE patients had an affinity for annexin V, an endothelial apoptosis pathway mediated by annexin V was suggested as the molecular pathogenesis of the hemostatic derangement associated with LAC.
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PMID:Lupus anticoagulant autoantibody induces apoptosis in umbilical vein endothelial cells: involvement of annexin V. 780 85

We investigated anti-annexin V antibody (aANX) in patients with systemic lupus erythematosus (SLE), and correlated to positivity with lupus anticoagulant (LA)/anticardiolipin antibody (aCL). aANX was positive in 12/47 SLE patients (26%), including 7 with beta 2-glycoprotein 1 (GPI)-dependent aANX. The positivity of aANX was higher in patients with aCL (19%) and LA/aCL (50%) than in those without LA/aCL (10%). From these results, it is concluded that aANX is an autoantibody closely related to LA/aCL, and can be a possible new risk marker for thrombosis.
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PMID:Anti-annexin V antibody in systemic lupus erythematosus patients with lupus anticoagulant and/or anticardiolipin antibody. 766 34

The restriction of phosphatidylserine (PtdSer) to the inner surface of the plasma membrane bilayer is lost early during apoptosis. Since PtdSer is a potent surface procoagulant, and since there is an increased incidence of coagulation events in patients with systemic lupus erythematosus (SLE) who have anti-phospholipid antibodies, we addressed whether apoptotic cells are procoagulant and whether anti-phospholipid antibodies influence this. Apoptotic HeLa cells, human endothelial cells, and a murine pre-B-cell line were markedly procoagulant in a modified Russell viper venom assay. This procoagulant effect was entirely abolished by addition of the PtdSer-binding protein, annexin V, confirming that it was PtdSer-dependent. The procoagulant effect was also abolished by addition of IgG purified from the plasma of three patients with anti-phospholipid antibody syndrome, but not IgG from normal controls. Confocal microscopy of apoptotic cells stained with fluorescein-isothiocyanate-conjugated-annexin V demonstrated (Ca2+)-dependent binding to the surface of membrane blebs o apoptotic cells, but not to intracellular membranes. Recent data indicate that the surface blebs of apoptotic cells constitute an important immunogenic particle in SLE. We propose that the PtdSer exposed on the outside of these blebs can induce the production of anti-phospholipid antibodies, which might also enhance the immunogenicity of the bleb contents. When apoptosis occurs in a microenvironment in direct contact with circulating plasma, the unique procoagulant consequences of the apoptotic surface may additionally be expressed. This might explain the increased incidence of pathological intravascular coagulation events that occur in some lupus patients who have anti-phospholipid antibodies.
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PMID:Surface blebs on apoptotic cells are sites of enhanced procoagulant activity: implications for coagulation events and antigenic spread in systemic lupus erythematosus. 864 81

The 'lupus anticoagulant' phenomenon is the best documented functional effect of antiphospholipid (aPL) antibodies, occurring either by inhibition of the prothrombinase and/or Factor X activation reactions. Understanding the mechanism by which aPL antibodies inhibit phospholipid dependent coagulation reactions may yield important clues about their 'thrombogenic effects' in vivo. We conducted a series of studies to determine the specificity, diversity, and mechanism by which aPL antibodies inhibit phospholipid dependent reactions. Results showed that purified immunoglobulins with lupus anticoagulant and anti-cardiolipin activities were absorbed by negatively charged phospholipids and both activities were recovered from the phospholipid-antibody precipitate. Purified aPL antibodies inhibited the prothrombinase reaction in a plasma free system in which beta 2-glycoprotein 1 (beta 2-GP1) was absent. Affinity purified aPL antibodies had 25-50 times the inhibitory activity of immunoglobulin preparations. The phospholipid binding proteins, beta 2-GPI and placental anticoagulant protein I (PAP I), independently inhibited the prothrombinase reaction, and when these proteins were combined with aPL, inhibition of the prothrombinase reaction was additive. Antibodies of syphilis had no inhibitory effect, partially accounted for by lack of specificity for phosphotidylserine (PS). Although aPL antibodies inhibited the protein C activation reaction, there was no correlation of these activities with inhibition of the prothrombinase reaction. Together, these results show that aPL exert their effects by interaction with negatively charged phospholipids, in particular phosphotidylserine, but lack of correlation between inhibition of the prothrombinase and protein C activation reactions, suggests that the nature of the coagulation protein is also important.
Lupus 1996 Oct
PMID:Functional effects of anticardiolipin antibodies. 890 63

The Antiphospholipid Syndrome is defined by the association between peculiar clinical manifestations, namely arterial and/or venous thrombosis, recurrent abortions and thrombocytopenia, and the antiphospholipid antibodies. These antibodies are directed to plasma proteins bound to anionic phospholipids or other anionic surfaces: so far, beta 2-glycoprotein I is the best known and characterized antiphospholipid 'cofactor' (this issue is specifically treated in other parts of this journal). In recent years, such a role has been reported also for prothrombin, activated Protein C, Protein S, Annexin V, Thrombomodulin, high- and low-molecular weight kininogens. Anti-prothrombin antibodies are detected in approximately 50% of the antiphospholipid-positive patients; conversely, limited data are available regarding the prevalence the other antibodies. 'Cofactors' are necessary for the expression of both the immunological and the functional properties of their respective antiphospholipid antibodies. In particular, the recognition of the calcium-mediated prothrombin/lipid complex by anti-prothrombin antibodies hampers prothrombin activation, thus causing the prolongation of the phospholipid-dependent coagulation reactions. The interaction between antiphospholipid antibodies and natural inhibitors of coagulation such as activated Protein C, its non-enzymatic accessory protein Protein S or Thrombomodulin might increase the risk to develop thromboembolic events. Similarly, the presence of antibodies to surface-bound Annexin V has been hypothesized to play a role in recurrent abortions and fetal deaths. However, to clearly establish whether and which antiphospholipid antibodies represent risk factors for the thromboembolic events of the antiphospholipid syndrome, further studies of their behaviour and properties as well as the identification and characterization of (possibly) other antibodies are required.
Lupus 1996 Oct
PMID:Non beta 2-glycoprotein I cofactors for antiphospholipid antibodies. 890 67

Antiphospholipid-protein antibodies (APA) represent a family of immunoglobulins which recognize protein-phospholipid complexes. A variety of proteins have been implicated including: prothrombin, annexin V, beta 2-Glycoprotein I, and protein S. APA are detected utilizing either coagulation-based tests to identify lupus anticoagulants (LA) or solid phase ELISA assays to identify anticardiolipin antibodies (ACA). APA may be seen in a variety of different clinical settings including convalescence from infections, resulting from exposure to certain drugs, or in association with autoimmune diseases. Autoimmune APA have been linked to a variety of thromboembolic complications involving both arterial and venous sites. In addition, recurrent fetal loss has been linked to a APA. The underlying pathophysiology of the thromboembolic events remains controversial. Given the diversity of anatomic sites, more than one thromboembolic mechanism(s) is likely. Abnormalities of the protein C system most likely account for the venous thromboembolic events. Because of the spectrum of clinical complications, virtually any clinician may encounter patients with the APA syndrome (thrombosis, thrombocytopenia, recurrent fetal loss coupled with positive LA or ACA testing).
Lupus 1996 Oct
PMID:Lupus anticoagulants/antiphospholipid-protein antibodies: the great imposters. 890 75


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