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)

The effect of sera and purified IgG isolated from plasma of 46 patients with systemic lupus erythematosus (SLE) and 9 healthy donors on the endothelial cell (EC) mediated protein C activation was investigated. Out of the 46 SLE sera used, 19 were antiphospholipid antibodies (aPL) positive. From 12 patients IgG was isolated, of which 6 contained aPL. EC were first incubated with IgG (7 mg/ml) or serum (1:1 diluted) for 1 h and then tested for their ability to promote protein C activation by thrombin, with the cells either in a monolayer or in a suspension. The normal range (mean of control values +/- 2 SD) of protein C activation was 80-120%. In contrast to others, we could not detect an inhibition of protein C activation by any of the patient IgG's or sera. The recently described cofactor for binding of antiphospholipid antibodies to phospholipids, beta 2-glycoprotein I, was purified and added to the purified IgG's. A combination of these two components did not inhibit the EC mediated protein C activation by thrombin. This study suggests that the inhibition of the protein C activation, mediated by EC, is not a general mechanism by which aPL related thrombosis can be explained.
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PMID:In vitro studies of antiphospholipid antibodies and its cofactor, beta 2-glycoprotein I, show negligible effects on endothelial cell mediated protein C activation. 179 12

Activated protein C (APC), an anticoagulant that acts by inactivating Factors Va and VIIIa, is dependent on a suitable surface for its action. In this study we examined the ability of human platelets to provide this surface and support APC-mediated anticoagulant effects. The activity of APC was examined in three systems: the Factor Xa recalcification time of Al(OH)3 adsorbed plasma, studies of thrombin generation in recalcified plasma, and assessment of the rate of inactivation of purified Factor Va. In comparison with phospholipid, intact platelets required significantly greater concentrations of APC to achieve a similar degree of anticoagulation. When washed platelet membranes were substituted for intact platelets, adequate support of APC was observed and the anticoagulant effect was similar to that obtained with phospholipid. Platelet releasate obtained by stimulation of platelets with thrombin and epinephrine contained an inhibitor that interfered with the ability of phospholipid and washed platelet membranes to catalyze the anticoagulant effects of APC. A noncompetitive inhibition was suggested by Dixon plot analysis of the interaction between platelet releasate and APC. The activity of the platelet APC inhibitor was immediate and was not enhanced by heparin, distinguishing it from the circulating protein C inhibitor. The presence of this inhibitor in the platelet and its release with platelet stimulation emphasizes the procoagulant role of this cell.
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PMID:Inhibition of activated protein C by platelets. 291 Sep 9

In the present paper the influence of beta 2-glycoprotein-I, also known as apolipoprotein H, upon the prothrombinase activity of platelets and phospholipid vesicles was investigated. The results can be summarized as follows. 1. The prothrombinase activity of resting, non-activated platelets, lysed platelets and vesicles composed of phosphatidylserine and phosphatidylcholine at different molar ratios is inhibited by beta 2-glycoprotein-I in a dose-dependent manner. The concentration of glycoprotein which produces marked inhibition is within the physiological plasma concentration range of beta 2-glycoprotein-I. 2. The time dependence of this inhibition is a relatively slow process, which is not fully expressed before 1 h of incubation. 3. The effect of the glycoprotein is not due to a direct interaction with the components of the prothrombinase complex, i.e. factors Xa, Va, Ca2+ or prothrombin, nor is the inhibitory action abolished by increasing concentrations of coagulation factors Xa and Va. This suggests that beta 2-glycoprotein-I causes a reduction of the prothrombinase binding sites of these coagulation factors to platelets or phospholipid vesicles. 4. The prothrombinase activity of platelets stimulated with ionophore A23187 or with collagen plus thrombin is also inhibited by beta 2-glycoprotein-I in a manner similar to that observed for phospholipid vesicles or for lysed platelets. These findings suggest a regulatory role for beta 2-glycoprotein-I in the pathway of blood coagulation.
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PMID:Prothrombinase activity of human platelets is inhibited by beta 2-glycoprotein-I. 376 9

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

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

We present functional and binding data relevant to the reported roles for prothrombin and beta 2-glycoprotein I (beta 2GPI) in the expression of lupus anticoagulant activity. In a purified system containing human prothrombin, Xa, Va, and a rate-limiting concentration of phosphatidylserine (PS)/phosphatidylcholine (PC) vesicles, the preliminary incubation of vesicles with protein A separated IgG preparations from 10 lupus anticoagulant plasmas, calcium, and prothrombin enhanced the inhibitory effect of all IgG preparations upon thrombin generation. Experiments in a purified factor X activation system provided supporting data that a similar preliminary incubation with prothrombin enhanced the inhibitory effect of many of the IgG preparations upon factor X activation. However, we could not obtain unequivocal evidence that prothrombin was an obligatory cofactor for lupus anticoagulant IgG to inhibit procoagulant phospholipid function, because lupus anticoagulant IgG separated by protein A chromatography contained traces of prothrombin. The binding of many IgG preparations to immobilized PS was enhanced by prothrombin when calcium ions were present. beta 2GPI enhanced binding of many of the IgG preparations to immobilized PS both in the presence and absence of calcium, yet beta 2GPI failed to enhance the ability of the IgG preparations to inhibit phospholipid function in purified prothrombin and factor X assays. Moreover, the IgG preparations prolonged the dilute Russell's viper venom time (dRVVT) of beta 2GPI-depleted normal plasma. Nine of 10 IgG preparations bound to prothrombin on Western blots in the absence of calcium and phospholipid, whereas no preparation bound to beta 2GPI. Passage of five citrated lupus anticoagulant plasmas through a prothrombin affinity column in the absence of added calcium and phospholipid removed most of the activity prolonging the dRVVT of normal plasma, and IgG in the pass-through plasma no longer bound to PS in the presence of prothrombin and calcium ions. IgG in prothrombin column eluates had strikingly enhanced specific lupus anticoagulant activity and also specific PS binding activity in the presence of prothrombin and calcium ions. Thus, lupus anticoagulant plasmas were shown to contain IgG binding to prothrombin, in the absence of calcium ions and phospholipid, which could also, in the presence of calcium ions and prothrombin, bind to PS and express lupus anticoagulant activity.
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PMID:Functional and binding studies of the roles of prothrombin and beta 2-glycoprotein I in the expression of lupus anticoagulant activity. 818 Mar 83

Antiphospholipid (aPL) antibodies are of major interest not only because the lupus anticoagulant (LA) causes an inhibition of in vitro blood coagulation, but also because the presence of aPL antibodies confers a risk of thrombosis. The inhibition of in vitro phospholipid-dependent coagulation (LA) is thought to be caused by the binding of LA to procoagulant phospholipid surfaces, thus impeding the clotting process. Another class of aPL antibodies are those originally described to be directed against negatively charged phospholipids, in particular cardiolipin (ACA). ACA are usually directed against a complex antigen consisting of negatively charged phospholipid and a plasma protein, beta 2-glycoprotein I (beta 2-GPI). Further, there is antibody heterogeneity even within individual patients so that ACA and LA are separable using physicochemical techniques such as ion exchange chromatography and chromatofocusing. Using such techniques we have enriched Ig fractions for LA and ACA from two patient plasmas. The majority of Ig with LA activity had a pI of 7.2 to 7.3 whereas ACA had a pI of 5.0 to 5.2. Using these enriched fractions labeled with [125I]-iodine we have shown that LA binds to platelets in a specific and saturable manner. Binding is dependent on thrombin activation. [125I]-ACA behaves differently. Like LA, binding is specific and dependent on thrombin activation but in this case requires the presence of beta 2-GPI. ACA, in the presence of beta 2-GPI, competes for binding with LA suggesting the same or contiguous site. There is no cross-reactivity of these antibodies with GPIIb/IIIa and the most likely binding site is phospholipid. In neither case does LA nor ACA have an effect on thrombin-induced release of serotonin or beta-thromboglobulin nor do they affect platelet aggregation induced by a number of agonists. This antibody binding may play an etiological role in thrombocytopenia associated with aPL, but does not explain thrombosis on the basis of hyperaggregability or increased platelet release.
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PMID:Beta 2-glycoprotein I is a requirement for anticardiolipin antibodies binding to activated platelets: differences with lupus anticoagulants. 844 87

Activated protein C (APC) is a vitamin K dependent anticoagulant which catalyzes the inactivation of factor V a and VIII a, in a reaction modulated by phospholipid membrane surface, or blood platelets. APC prevents thrombin generation at a much lower concentration when added to recalcified plasma and phospholipid vesicles, than recalcified plasma and platelets. This observation was attributed to a platelet associated APC inhibitor. We have performed serial thrombin, factor V one stage and two stage assays and Western blotting of dilute recalcified plasma containing either phospholipid vesicles or platelets and APC. More thrombin was formed at a given APC concentration with platelets than phospholipid. One stage factor V values increased to higher levels with platelets and APC than phospholipid and APC. Two stage factor V values decreased substantially with platelets and 5 nM APC but remained unchanged with phospholipid and 5 nM APC. Western blotting of plasma factor V confirmed factor V activation in the presence of platelets and APC, but lack of factor V activation with phospholipid and APC. Inclusion of platelets or platelet membrane with phospholipid enhanced rather than inhibited APC catalyzed plasma factor V inactivation. Platelet activation further enhanced factor V activation and inactivation at any given APC concentration. Plasma thrombin generation in the presence of platelets and APC is related to ongoing factor V activation. No inhibition of APC inactivation of FVa occurs in the presence of platelets.
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PMID:Plasma factor V activation is prevented by activated protein C in the presence of phospholipid vesicles, not platelets. 845 24

beta 2-Glycoprotein I (beta 2-GPI), a phospholipid-binding plasma protein, is an absolute requirement (cofactor) for the binding of autoimmune-type anti-cardiolipin (aCL) antibodies to cardiolipin (CL). The nature of this cofactor activity and the specific regions of the molecule involved have not yet been determined. We have identified a preparation of beta 2-GPI that lacks aCL antibody cofactor activity. Analysis of the structural differences between the active and inactive forms enabled identification of the region of beta 2-GPI critically important for aCL cofactor activity. The active form of beta 2-GPI bound CL and displayed cofactor activity down to 1 microgram/ml. The inactive form failed to bind CL and possessed no cofactor activity even at concentrations up to 94 micrograms/ml, indicating that the ability of beta 2-GPI to bind lipids is an absolute requirement for aCL cofactor activity. Both forms possessed identical N-terminal sequences and were recognized as essentially immunoreactively identical by polyclonal antisera to beta 2-GPI. However, the inactive form has undergone proteolytic cleavage and exists primarily as a "clipped" molecule, the polypeptide chain being cleaved between Lys-317 and Thr-318 (a potential thrombin cleavage site), with the two cleaved segments linked as a disulfide-bonded complex. This indicates that the C-terminal region is critically important for beta 2-GPI to bind lipid and for aCL cofactor activity. The clipped form of beta 2-GPI would not be suitable for use as aCL cofactor and its use may have led some investigators to conclude incorrectly that beta 2-GPI does not interact with aCL antibodies.
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PMID:Identification of a region of beta 2-glycoprotein I critical for lipid binding and anti-cardiolipin antibody cofactor activity. 846 Jan 20

We investigated the role of alpha IIb beta 3 in microparticle generation by normal and thrombasthenic platelets stimulated with collagen plus thrombin. Microparticle generation by normal platelets was scarcely inhibited by monoclonal antibodies for glycoprotein Ib and glycoprotein IX. Although one monoclonal anti-alpha IIb beta 3 antibody (NNKY1-32) partly inhibited microparticle generation, 3 other monoclonal anti-alpha IIb beta 3 antibodies had little effect. However, the combination of 4 monoclonal anti-alpha IIb beta 3 antibodies or treatment with a polyclonal anti-alpha IIb beta 3 antibody significantly inhibited microparticle generation (p < 0.05). Microparticle generation by thrombasthenic platelets also occurred after stimulation with collagen plus thrombin, although at a significantly lower level compared with normal platelets. Monoclonal antibodies for resting alpha IIb beta 3, P-selectin, activated alpha IIb beta 3 and beta 2-glycoprotein I bound to microparticles from healthy platelets. In contrast, only a monoclonal antibody for beta2-glycoprotein I bound to thrombasthenic microparticles. These results suggest that microparticle generation by collagen plus thrombin occurs via two different mechanisms which are dependent and independent of alpha IIb beta 3, respectively. The alpha IIb beta 3-dependent mechanism appears to require activation of alpha IIb beta 3.
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PMID:Participation of alpha IIb beta 3 in platelet microparticle generation by collagen plus thrombin. 869 76


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