Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.21.6 (thromboplastin)
13,278 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

Beta 2-glycoprotein I (beta 2-GPI) binds negatively charged substances and inhibits intrinsic blood coagulation in the presence of ellagic acid-phospholipid suspension. Beta 2-GPI is thought to be an important protein in the reaction between negatively charged phospholipids and anti-phospholipid antibodies which appear in patients with lupus anticoagulant/antiphospholipid antibody syndrome. We prepared a monoclonal antibody against beta 2-GPI purified from human plasma and obtained beta 2-GPI-depleted plasma using a monoclonal antibody-coupled column. Either partial thromboplastin time or the activation of prekallikrein induced by diluted ellagic acid-phospholipid suspension in beta 2-GPI-depleted plasma was not different from that in control plasma. Beta 2-GPI inhibited the intrinsic blood coagulation only when added to control or beta 2-GPI-depleted plasma in excess (more than physiological concentrations). The intrinsic fibrinolysis in beta 2-GPI-depleted plasma induced by dextran sulfate was not impaired and, again, beta 2-GPI inhibited the intrinsic fibrinolysis only when added to control or beta 2-GPI-depleted plasma in excess. These results indicate that both in vitro Actin-induced intrinsic coagulation and dextran sulfate-induced fibrinolytic activities are significantly inhibited by more than physiological concentrations of beta 2-GPI.
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PMID:Ellagic acid/phospholipid-induced coagulation and dextran sulfate-induced fibrinolytic activities in beta 2-glycoprotein I-depleted plasma. 786 69

Beta-2-GPI is a 50 kDa glycoprotein which is known to be a serum co-factor, with a role in determining the binding of pathogenic anticardiolipin antibodies to phospholipids. Immunization of naive mice with beta-2-GPI resulted in elevated levels of antibodies directed against negatively charged phospholipids (cardiolipin, phosphotidylserine, phosphatidylinositol). The presence of increased titres of antiphospholipid antibodies in the sera of the mice was later followed by prolonged activated partial thromboplastin time (APTT), thrombocytopenia, and when the mice were mated, by a high percentage of fetal resorptions in the uterus. These data point to the ability of beta-2-GPI to induce pathogenic anti-cardiolipin antibodies following active immunization.
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PMID:Immunization with anticardiolipin cofactor (beta-2-glycoprotein I) induces experimental antiphospholipid syndrome in naive mice. 798 Aug 47

Primary antiphospholipid syndrome (pAPS) can be experimentally induced in mice by immunization with anti-cardiolipin (aCL) antibodies (Abs). Recently, we have pointed to the pathogenic role of antiphosphatidylserine (aPS) Abs by inducing an experimental model of pAPS in naive mice following passive transfer of human aPS to the tail vein of ICR mice. The aim of the present study was to induce experimental pAPS in mice following active immunization with aPS. Mice were immunized with IgG and IgM aPS, purified from two patients with pAPS. The sera of the mice were examined for the presence of different antiphospholipid Abs, and the beta 2 GPI dependency of aPS, using an enzyme-linked immunosorbent assay (ELISA). Inhibition ELISA studies, with silica beads coated with phospholipids, were used to detect cross-reactivity of aPS or aCL to other phospholipids. The mice were also tested for the presence of thrombocytopenia, prolonged activated partial thromboplastin time (APTT), and the percentage of fetal resorptions. The purified IgG aPS but not IgM aPS had a strong lupus anticoagulant activity. Both IgG and IgM aPS were beta 2 GPI dependent and did not bind PS in the absence of the glycoprotein. The mice immunized with IgG aPS, but not IgM aPS, developed high titers of mouse aPS. The mice generated polyspecific Abs, cross-reacting with aCL and aPS, as well as individual aPS or aCL Abs. Only the mice immunized with IgG aPS developed clinical parameters of pAPS: prolonged APTT, thrombocytopenia, and an increased fetal resorption rate. In conclusion, active immunization with IgG, but not IgM, aPS induces experimental pAPS in naive mice, thus pointing to the participation of aPS in the idiotypic network.
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PMID:The pathogenic role of anti-phosphatidylserine antibodies: active immunization with the antibodies leads to the induction of antiphospholipid syndrome. 859 79

Antiphospholipid syndrome is characterized by the presence of high titers of anti-beta(2)-glycoprotein I (beta(2)GPI) antibodies, lupus anticoagulant associated with thromboembolic phenomena, thrombocytopenia and recurrent fetal loss. Single-chain Fv (scFv) were prepared from four anti-beta(2)GPI mAb, CAM, CAL, CAR and 2C4C2, and one anti-ssDNA. All five scFv showed the same antigen binding properties as the original mAb. Replacement of the pathogenic CAM V(H) domain with the non-pathogenic CAL V(H) or anti-ssDNA V(H) decreased the binding affinity of the scFv to beta(2)GPI and completely abrogated the anticoagulant activity. Exchanging the CAM V(H) with anti-DNA V(H) resulted in a shift from anti-beta(2)GPI to anti-ssDNA binding of the scFv. Replacement of the CAM V(L) with CAL V(L) did not affect the binding and activity. BALB/c mice were immunized with the anti-beta(2)GPI scFv, and the scFv resulting from the substitution of the heavy (H) and light (L) chains. The mice which were immunized with CAM, 2C4C2 and CAR scFv developed clinical manifestations of experimental anti-phospholipid syndrome. Elevated titers of mouse anti-cardiolipin (aCL), anti-beta(2)GPI, associated with lupus anticoagulant activity, thrombocytopenia, prolonged activated partial thromboplastin time and a high percentage of fetal resorptions were detected, in the CAM scFv group and in the scFv composed of CAM V(H) groups. High titers of aCL, anti-beta(2)GPI, anti-ss/dsDNA and anti-histone associated with lupus findings were observed in the sera of the 2C4C2 scFv-immunized mice. Immunization with CAL scFv did not lead to any clinical findings. The current study shows that scFv of pathogenic antibodies are capable of inducing the same clinical manifestations as the whole antibody molecule upon active immunization. Replacement of H/L chains point to the importance of the V(H) domains in the pathogenic potential of anti-beta(2)GPI.
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PMID:Characteristics and pathogenic role of anti-beta2-glycoprotein I single-chain Fv domains: induction of experimental antiphospholipid syndrome. 1059 Feb 57

beta(2)-Glycoprotein I (beta(2)GPI) is a major antigen for antiphospholipid antibodies, and its multiple in vitro functions have been reported. This glycoprotein not only down-regulates thrombin formation by inhibiting contact activation or prothrombinase activity, but also up-regulates coagulation by reducing protein C anticoagulant activity. However, the in vivo roles of beta(2)GPI remain obscure. Coagulation and fibrinolytic characteristics were investigated in individuals with beta(2)GPI deficiency. An apparently healthy woman and her brother are homozygotes for beta(2)GPI deficiency. In these patients, Russell viper venom time was shortened (40.4 seconds; normal range, 47.8 +/- 4.95 seconds), but all markers of thrombin generation and fibrin turnover were within normal ranges. Exogenous activated protein C adequately prolonged the clotting time of the beta(2)GPI-deficient plasma, and euglobulin lysis time was also normal. Thus, elevated thrombin generation, enhancement of activated protein C response, and an altered fibrinolytic system were not found in congenitally beta(2)GPI-deficient plasma. (Blood. 2000;96:1594-1595)
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PMID:Coagulation and fibrinolytic activities in 2 siblings with beta(2)-glycoprotein I deficiency. 1094 13

Transmittance waveforms are generated during clot formation on photo-optical coagulation analyzers. We previously showed that 61.5% of patients with antiphospholipid antibodies (APLA) exhibited a negative deflection in the pre-coagulation phase of the prothrombin time (PT slope 1). The current studies investigated the 'molecular basis' of this abnormal parameter. We found that the negative PT slope 1 is IgG-mediated and is not dependent on the presence of fibrinogen or thrombin activity. We also found that IgG from most of the patients required a specific thromboplastin and the presence of prothrombin or beta(2)-glycoprotein I beta(2) GPI) to produce an abnormal IgG wave-form assay. In addition, the abnormal IgG waveform required cofactor binding to phospholipids when beta(2) GPI was the cofactor, and annexin V could partially block this interaction. In conclusion, these results showed that the interactions of IgG with phospholipids via beta(2) GPI or prothrombin constitute the core mechanisms of the abnormal waveforms.
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PMID:Prothrombin and beta 2-glycoprotein I frequently contribute to antiphospholipid antibody interactions with phospholipids and the generation of abnormal waveform profiles in coagulation assays. 1288 68

The antiphospholipid (aPL) syndrome is an autoimmune condition that is marked by recurrent pregnancy losses and/or systemic vascular thrombosis in patients who have antibodies against phospholipid/co-factor complexes. The mechanism(s) for pregnancy losses and thrombosis in this condition is (are) not known. Annexin A5 is a potent anticoagulant protein, expressed by placental trophoblasts and endothelial cells, that crystallizes over anionic phospholipids, shielding them from availability for coagulation reactions. We previously presented data supporting the hypothesis that aPL antibody-mediated disruption of the anticoagulant annexin A5 shield could be a thrombogenic mechanism in the aPL syndrome. However, this has remained a subject of controversy. We therefore used atomic force microscopy, a method previously used to study the crystallization of annexin A5, to image the effects of monoclonal human aPL antibodies on the crystal structure of the protein over phospholipid bilayers. In the presence of the aPL monoclonal antibodies (mAbs) and beta(2)-GPI, the major aPL co-factor, structures presumed to be aPL mAb-antigen complexes were associated with varying degrees of disruption to the annexin A5 crystallization pattern over the bilayer. In addition, measurements of prothrombinase activity on the phospholipid bilayers showed that the aPL mAbs reduced the anti-coagulant effect of annexin A5 and promoted thrombin generation. These data provide morphological evidence that support the hypothesis that aPL antibodies can disrupt annexin A5 binding to phospholipid membranes and permit increased generation of thrombin. The aPL antibody-mediated disruption of the annexin A5 anticoagulant shield may be an important prothrombotic mechanism in the aPL syndrome.
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PMID:Human monoclonal antiphospholipid antibodies disrupt the annexin A5 anticoagulant crystal shield on phospholipid bilayers: evidence from atomic force microscopy and functional assay. 1293 61

Rejected pig-to-primate organ xenografts almost invariably exhibit significant microvascular thrombosis, believed to be due in part to several molecular incompatibilities affecting the regulation of coagulation. In this study, we tested one such proposed incompatibility: whether there is, at least in part, a functional incompatibility in pig tissue factor pathway inhibitor (TFPI) that impedes binding of human factor Xa and regulation of human tissue factor-initiated coagulation. TFPIalpha cDNA was cloned from pig aortic endothelial cells and found to encode a 279-residue mature protein with 79% overall identity to human TFPIalpha, increasing to 88 to 90% in the functional Kunitz-1 and Kunitz-2 domains. Transfected primate cells expressing equivalent levels of GPI-linked pig or human TFPIalpha were assayed for binding of human factor Xa and inhibition of the human factor VIIa/tissue factor complex. The activity of the expressed pig anticoagulant was equivalent to that of the human protein in both measures of TFPI function in these systems. These data indicate that there are no apparent incompatibilities between recombinant pig TFPI and the human tissue factor pathway. Other factors must account for the thromboregulatory failure of pig endothelium and aberrant tissue factor activity in xenograft rejection.
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PMID:Recombinant pig TFPI efficiently regulates human tissue factor pathways. 1861 Dec 27

The antiphospholipid syndrome is characterized by the occurrence of vascular thrombosis combined with the presence of antiphospholipid antibodies in plasma of patients. It has been published that antibeta2-glycoprotein I (beta2-GPI) antibodies, with lupus anticoagulant activity (LAC), highly correlate with thrombosis. Resistance related to antiphospholipid antibodies against activated protein C (APC) is one of the proposed mechanisms responsible for thrombosis. We investigated a possible correlation between a beta2-GPI-dependent LAC (titration of cardiolipin into an activated partial thromboplastin time-based assay) and increased APC resistance in a population of 22 plasma samples with LAC activity. Eleven plasma samples that displayed a beta2-GPI-dependent LAC also showed increased APC resistance. In contrast, only one of the 11 plasma samples with a beta2-GPI-independent LAC displayed increased APC resistance. In addition, a monoclonal antibeta2-GPI antibody and patient-purified immunoglobulin G (both with LAC activity) were diluted in plasma with/without protein C. Both antibodies only displayed a beta2-GPI-dependent LAC in plasma in the presence of protein C. This indicates that the principle of the beta2-GPI LAC-assay was based on increased resistance against protein C. Surface plasmon resonance analysis was used to investigate binding between APC and beta2-GPI. We observed that beta2-GPI was able to bind APC directly, especially in the presence of a monoclonal antibeta2-GPI antibody. In conclusion, our observations show a direct correlation between a major clinical symptom of antiphospholipid syndrome (thrombosis), a diagnostic assay (beta2-GPI-dependent LAC) and a potential mechanism responsible for thrombosis in the antiphospholipid syndrome (increased APC resistance).
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PMID:Correlation between the potency of a beta2-glycoprotein I-dependent lupus anticoagulant and the level of resistance to activated protein C. 1900 41


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