Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.69 (APC)
 16,337 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

Presence of beta 2 Glycoprotein I (beta 2GPI), in addition to phospholipids, is an absolute requirement for binding APA. This binding is frequently observed with beta 2GPI coated alone, however many APA react only with beta 2GPI complexed to phospholipids, but not with phospholipids alone. We demonstrate that a subgroup of rabbit polyclonal antibodies to human beta 2GPI binds to this protein only when it is coated on a solid surface, but not if it is in solution. In addition, beta 2GPI present in goat serum is strongly fixed by the coated phospholipids and the complexes formed bind as well APA as the rabbit antibodies to beta 2GPI. The diluent used for testing APA, has a strong incidence on APA's reactivity as it can be a source of beta 2GPI. Antibody binding to beta 2GPI, Prothrombin, Protein S, and Annexin V, coated in the presence or in the absence of phospholipids, was tested in 55 patients with the antiphospholipid syndrome. The strongest binding of antibodies was observed in 39 plasma to a mixture of phospholipids and purified human beta 2GPI, however 17 samples also presented a significant reactivity to beta 2GPI alone. Nine plasmas contained antibodies to Prothrombin, 4 to Protein S, 3 to Annexin V, and 1 to Protein C. We conclude that most of the APA are directed to a complex of beta 2GPI and phospholipids although in some patients antibodies to beta 2GPI alone or to other phospholipid binding proteins are present.
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PMID:Standardization of immunoassays for antiphospholipid antibodies with beta 2GPI and role of other phospholipid cofactors. 752 66

Protein C, a vitamin K-dependent protein, is a blood coagulation inhibitor. Its deficiency causes systemic thrombosis. A 31-year-old woman developed cerebral infarction followed by late psychomotor seizures, and thrombosis in the inferior mesenteric vein and bilateral crural veins. Her parents were first cousins. Her mother died of cerebral thrombosis in her 30's. Her elder brother died of suspected purpura fulminans immediately after birth. Her protein C activity and protein C antigen level decreased markedly and were less than 5% of those of normal controls and 0.3 microgram/ml, respectively. Her father, a paternal aunt and a maternal uncle also showed a low protein C activity and protein C antigen level. This patient seems to have congenital protein C deficiency which produced thrombosis in the leg veins and the mesenteric vein, probably cerebral infarction.
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PMID:A case of protein C deficiency associated with cerebral infarction and obstruction of deep leg and inferior mesenteric veins. 820 99

The effects of annexin V on the anticoagulant activity of activated protein C (APC) and protein S were examined. Although annexin V did not influence the amidolytic potential of APC, it inhibited both APC and protein S function in a factor Va inactivation assay. Competition experiments demonstrated that annexin V inhibits protein S binding to phospholipid vesicles in a dose-dependent manner. These results demonstrate that annexin V effectively interferes with the anticoagulant arm of the hemostatic system.
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PMID:Effects of annexin V on the activity of the anticoagulant proteins C and S. 847 78

We have demonstrated the presence of a saturable, reversible, and Ca(2+)-dependent binding site for 125I-labeled factor X ([125I]factor X) on human platelets (16000 +/- 2000 sites per platelet, Kd = 320 +/- 40 nM, n = 12) activated with either thrombin or the thrombin receptor agonist peptide, SFLLRN-amide, but not with ADP. Bound [125I]factor X could be completely removed by the addition of a Ca2+ chelator or an excess of unlabeled factor X. Antibodies that inhibit binding of factor X to the MAC-1 integrin receptor of monocytes and those directed against human factor V, failed to disrupt [125I]factor X binding to platelets. Prothrombin, but neither factor VII, factor IX, protein C, nor protein S, was an effective competitor of [125I]factor X binding with a K1 approximately Kd. [125I]Prothrombin also binds to activated (but not unactivated) platelets in a saturable, reversible, and Ca(2+)-dependent manner (20500 +/- 1500 sites, Kd = 470 +/- 110 nM, n = 3). Annexin V potently inhibited the binding of both [125I]factor X and [125I]prothrombin (IC50 approximately 3 nM). Factor X, prothrombin, and prothrombin fragment 1 (residues 1-155) were equipotent inhibitors of [125I]prothrombin and [125I]factor X binding, whereas Gla-domain-less factor X was unable to compete with [125I]factor X for platelet binding sites. Thus, it is the Gla-domains of factor X and prothrombin that appear to contain the regions necessary for platelet binding. The results of studies utilizing artificial phospholipid surfaces have led to the hypothesis that the substrates (FX and prothrombin) for the intrinsic pathway FXase and prothrombinase complexes are bound to the phospholipid surface. The factor X/prothrombin binding site we have described on the surface of activated platelets permits the utilization of surface-bound substrates by these complexes when they are assembled on a physiologic surface.
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PMID:A binding site expressed on the surface of activated human platelets is shared by factor X and prothrombin. 868 25

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.
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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.
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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).
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PMID:Lupus anticoagulants/antiphospholipid-protein antibodies: the great imposters. 890 75

Antiphospholipid antibodies (aPL) are a heterogeneous family of antibodies, including those specific for a variety of phospholipid (PL)-binding proteins and also those reacting with PL molecules. The former seem to be associated with the antiphospholipid syndrome (APS). At present, the main proteins proposed as antigens are beta 2 glycoprotein I, prothrombin, protein C, protein S, kininogens and annexin V. Anionic PL might play a key role "in vivo" in the binding of aPL to PL-bound proteins. Different mechanisms may be involved in the pathogenesis of the APS, including effects of aPL on the protein C system and antithrombin III and also on platelets, endothelial cells and monocytes. Recent data on experimental animal models have provided support for a causative role of aPL in the clinical complications of the APS.
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PMID:Pathogenic role of antiprotein-phospholipid antibodies. 897 39


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