Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P02749 (beta2-glycoprotein I)
 836 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Despite many studies on the pathophysiology of antiphospholipid antibodies (aPL), the mechanism by which aPL causes thrombosis has not been established. We have tried to elucidate the paradox between the prolongation of the clotting time of phospholipid-dependent coagulation tests in vitro and the occurrence of thrombosis in vivo. The effect on endothelial cell-mediated prothrombinase activity of 30 IgG fractions, of which 22 prolong the aPTT of normal plasma, was investigated. Only 4 of 22 fractions (18%) inhibited prothrombinase activity when tested on this more physiologic phospholipid surface, indicating that in most patients with aPL the prolongation of clotting tests is predominantly as in vitro phenomenon. It was recently reported that in detection methods for aPL, two plasma proteins, beta 2-glycoprotein I and prothrombin, enhance the binding of aPL to phospholipids. We have studied the specificity of the 4 IgG fractions that inhibit the prothrombinase activity and found that they were directed against a combination of phospholipids and prothrombin. However, the involvement of prothrombin in binding of aPL leading to impaired thrombin generation could still result in both a bleeding and a thrombotic tendency. Therefore, we proposed a new thrombogenic mechanism for aPL in which aPL bind to complexes of phospholipids and coagulation proteins, thereby interfering in different coagulation reactions. We tested this new hypothesis by investigating the effect of IgG from the same 30 patients on the activated protein C (APC)-mediated factor Va inactivation in the absence and presence of protein S. Three IgGs that inhibited APC-mediated factor Va inactivation independent of protein S and 4 additional IgGs that inhibited in the presence of protein S were found. Furthermore, we could specifically adsorb the inhibitory IgG with cardiolipin vesicles to which APC with or without protein S was bound. In conclusion, these results suggest that subpopulations of aPL exist that are directed to complexes of phospholipids and different plasma proteins. The identity of the plasma proteins involved in the binding of aPL might determine which pathogenic mechanism causes thrombosis.
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PMID:Antiphospholipid antibodies directed against a combination of phospholipids with prothrombin, protein C, or protein S: an explanation for their pathogenic mechanism? 811 Oct 59

Antiphospholipid antibodies, defined either by lupus anticoagulant (LA) activity or positive anticardiolipin immunoabsorbent assay (ACA) are associated with a predisposition to thromboses, recurrent fetal loss or thrombocytopenia. The mechanisms for these predispositions remain undefined. We have enriched immunoglobulin fractions from two patient plasmas to obtain antibodies with LA activity but no ACA, or conversely, with ACA positivity but no LA, in order to investigate in vitro characteristics which might explain a thrombotic propensity. beta 2-glycoprotein I (beta 2-GPI), the plasma cofactor required for ACA binding to negatively charged phospholipid, has previously been shown to inhibit prothrombinase generation in the presence of activated platelets (8). We now report that beta 2-GPI, at physiological concentrations, inhibits the generation of factor Xa in the presence of activated gel-filtered platelets. Further, ACA interferes with this inhibition, resulting in protracted, unopposed factor Xa generation. This interference with beta 2-GPI, a natural anticoagulant component of plasma, is potentially prothrombotic. LA immunoglobulins behave differently and inhibit factor Xa generation in a manner similar to beta 2-GPI. These findings provide the basis for a previously unsuspected mechanism for thrombosis in patients with aPL.
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PMID:Anticardiolipin antibodies block the inhibition by beta 2-glycoprotein I of the factor Xa generating activity of platelets. 805 75

We have recently described the in vitro mechanism of action of anticardiolipin (aCL) and lupus anticoagulant (LA) antibodies in patients with the antiphospholipid syndrome. LA antibodies inhibit coagulation reactions in plasma because they appear to recognize the complex of lipid-bound (human) prothrombin, whereas aCL antibodies require beta 2-glycoprotein I (beta 2-GPI) for binding to anionic phospholipids. aCL antibodies can be divided into two subgroups, according to their behaviour in lipid-dependent coagulation reactions: aCL-type A enhances the anti-coagulant effect of beta 2-GPI, whereas aCL-type B does not. In the present study we investigated the effect of purified aCL-type A and B and of LA antibodies on the procoagulant activity of both Ca-ionophore activated platelets and platelet-derived microvesicles, using an assay system with highly purified bovine coagulation factors Xa, Va, and prothrombin from human and bovine origin. In the absence of beta 2-GPI neither type of aCL was able to inhibit the prothrombinase activity of platelets or microvesicles. However, a strong and dose-dependent inhibition of the prothrombinase activity of both platelets and platelet-derived microvesicles was observed within a few minutes, when aCL-type A antibodies were added in combination with beta 2-GPI. This inhibitory effect was dependent also on the concentration of beta 2-GPI. Conversely, no inhibitory effect of aCL-type B antibodies on platelet- (or microvesicle) prothrombinase activity in the presence of beta 2-GPI could be observed. LA antibodies were able to inhibit in a dose-dependent way the procoagulant activity of activated platelets and platelet-derived microvesicles. With two LA preparations this inhibition was only apparent when human prothrombin was used as substrate, while a third preparation exhibited its inhibitory effect both in the presence of human and bovine prothrombin. The data indicate that, in the presence of their respective cofactors beta 2-GPI and prothrombin, aCL and LA antibodies interact with the membrane of activated platelets and platelet-derived microvesicles in a very similar way as previously observed for their interaction with anionic phospholipid surfaces.
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PMID:Effect of antiphospholipid antibodies on procoagulant activity of activated platelets and platelet-derived microvesicles. 813 94

The objective of this study was to determine whether beta 2-glycoprotein I (beta 2GPI) has procoagulant activity by inhibiting the anticoagulant activity of activated protein C (APC). beta 2GPI inhibited significantly the APC-catalyzed inactivation of factor Va in an assay using factor V-deficient plasma and physiological levels of protein S and factor Va. This inhibitory effect was diminished by the addition of increasing concentrations of phospholipids, suggesting that beta 2GPI competitively inhibits the binding of APC to the phospholipid surface. beta 2GPI inhibited weakly factor Va- and phospholipid-dependent prothrombinase activity at concentrations similar to those to inhibit APC activity. The depletion of beta 2GPI from plasma led to only a slight shortening of the diluted Russell's viper venom-dependent clotting time, but to a strong and significant potentiation of the anticoagulant activity of APC. These results suggest that under certain physiological conditions beta 2GPI has procoagulant property by inhibiting the phospholipid-dependent APC anticoagulant activity.
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PMID:beta 2-Glycoprotein I modulates the anticoagulant activity of activated protein C on the phospholipid surface. 871 79

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

In order to elucidate the mechanism of binding of beta 2-glycoprotein I (beta 2-GPI) to cardiolipin (CL), we constructed a high-level expression system for the C-terminal domain (Domain V) of beta 2-GPI using Pichia pastoris and studied its conformation and liposome-binding activity. Purified Domain V was found to have the native disulfide bonds. It had a compactly folded conformation, judging from the circular dichroism spectrum, and exhibited a cooperative unfolding transition induced by pH or urea. Also, it bound liposomes containing CL. Commercially available human beta 2-GPI is known to be selectively cleaved between Lys 317 and Thr 318. We found that bovine factor Xa weakly but specifically cleaves the corresponding site of recombinant Domain V, i.e., the peptide bond between Lys 77 and Thr 78. The conformation of the "nicked" Domain V, which was cleaved at this site, was examined by circular dichroism and fluorescence measurements, and concluded to be similar to that of the intact protein. The stability of the nicked Domain V to urea was slightly lower than that of the intact protein. Although both Domains V bound to liposomes containing CL, the affinity of the nicked Domain V was greatly reduced in comparison with the intact protein, indicating that the cleavage of the peptide bond between Lys 77 and Thr 78 controls the binding to CL. In addition, analysis of the fluorescence spectra in the presence and absence of CL liposomes indicated that Trp 76 is involved in the binding site. These results suggest that the region including Trp 76, Lys 77, and Thr 78 has a critical role in binding to CL.
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PMID:Structure and function of the recombinant fifth domain of human beta 2-glycoprotein I: effects of specific cleavage between Lys77 and Thr78. 905 3

A 33-year-old man presented malar rash in April, 1992. The rash had gradually developed and he was admitted to our hospital in February, 1994. Laboratory findings showed proteinuria of 0.5-0.8 g/ day, thrombocytopenia (4.8 x 10(4)/mm3), false positive serologic test for syphilis, anti-nuclear antibody with a speckled type at a titer of 1 : 80. Activated partial thromboplastin time was prolonged (41.3 s), and anti-beta 2-GPI antibody was strongly positive (56.6 U/ml on enzyme linked immunosorbent assay). The diagnosis of systemic lupus erythematosus with antiphospholipid syndrome was made and prednisolone 60 mg/day improved his manifestations. He could be discharged in July, 1994. Nine months after the discharge he developed dyspnea, and he was admitted to our hospital again. On admission the blood pressure was 212/170 mmHg, Levine III/VI systolic murmur was noted at the apex of heart. Significant laboratory findings showed as follows: WBC 15, 110/mm3 (Neu 73%, Lym 18%), RBC 380 x 10(4)/mm3, Hb 10.2 g/dl, Plt 20.0 x 10(4)/mm3, GOT 23 IU/l, GPT 21.
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PMID:[Acute cardiac failure due to dilated cardiomyopathy in systemic lupus erythematosus with antiphospholipid antibody]. 912 25

We report a 40-year-old Japanese woman with antiphospholipid antibody syndrome (APS) associated with myasthenia gravis (MG). She had a history of miscarriage at the age of 27 followed by pulmonary embolism 3 weeks later. At the age of 40, she developed diplopia, bilateral ptosis and easy fatigability. Serum anti-acetylcholine receptor antibody and tensilon test were positive. She was diagnosed as having MG. The laboratory test revealed mild thrombocytopenia, prolonged activated partial thromboplastin time (aPTT) and positive findings for both beta 2-glycoprotein I-dependent anticardiolipin antibody and lupus anticoagulant. She fulfilled the diagnostic criteria of APS, but did not the criteria proposed by American Rheumatism Association for SLE. An extended total thymectomy was performed after administration of oral prednisolone and low-dose aspirin. This is a patient who had APS associated with MGs: both are known to result from autoimmune abnormality. The clinical and laboratory manifestations of APS were ameliorated after removal of the thymus, suggesting that thymectomy alleviates APS symptoms.
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PMID:[A case of antiphospholipid syndrome associated with myasthenia gravis]. 939 64

The beta2-glycoprotein I (beta2-GPI) is known for its procoagulant as well as anticoagulant properties. The influence of beta2-GPI on tissue factor (TF) activity was investigated by chromogenic assays for both factor Xa generation and factor VIIa activity. When 1.36 mg/mL beta2-GPI was added to phospholipids prior to the addition of TF and factor VIIa, the TF activity was moderately inhibited by beta2-GPI in a concentration-dependent manner. Inhibition of TF activity by beta2-GPI required incubation for at least 20 min. When beta2-GPI was added to the mixture of phospholipids and TF followed by the addition of factor VIIa, the TF activity was little affected by the addition of beta2-GPI. The TF activity was inhibited when beta2-GPI was added after forming a complex with TF and factor VIIa. The results suggest that beta2-GPI inhibits both the reconstitution of TF with phospholipids and factor Xa generation by the TF factor-VIIa complex but does not affect the formation of a TF factor-VIIa complex.
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PMID:The influence of beta2-glycoprotein I on tissue factor activity. 970 50

The antiphospholipid syndrome is a thrombophilic condition marked by antibodies that recognize anionic phospholipid-protein cofactor complexes. We recently reported that exposure to IgG fractions from antiphospholipid patients reduces the level of annexin-V, a phospholipid-binding anticoagulant protein, on cultured trophoblasts and endothelial cells and accelerates coagulation of plasma exposed to these cells. Therefore, we asked whether antiphospholipid antibodies might directly reduce annexin-V binding to noncellular phospholipid substrates. Using ellipsometry, we found that antiphospholipid IgGs reduce the quantity of annexin-V bound to phospholipid bilayers; this reduction is dependent on the presence of beta2-glycoprotein I. Also, exposure to plasmas containing antiphospholipid antibodies reduces annexin-V binding to phosphatidyl serine-coated microtiter plates, frozen thawed washed platelets, activated partial thromboplastin time (aPTT) reagent and prothrombin time reagent and reduces the anticoagulant effect of the protein. These studies show that antiphospholipid antibodies interfere with the binding of annexin-V to anionic phospholipid and with its anticoagulant activity. This acceleration of coagulation, due to reduced binding of annexin V, stands in marked contrast to the "lupus anticoagulant effect" previously described in these patients. These results are the first direct demonstration of the displacement of annexin-V and the consequent acceleration of coagulation on noncellular phospholipid surfaces by antiphospholipid antibodies.
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PMID:Antiphospholipid antibodies accelerate plasma coagulation by inhibiting annexin-V binding to phospholipids: a "lupus procoagulant" phenomenon. 971 93


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