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)

Antiphospholipid antibodies are well recognized as associated with serious clinical complications such as arterial and venous thrombosis and recurrent spontaneous abortion. These complications are collectively called antiphospholipid syndrome(APS). The mechanisms responsible for the thrombosis are unclear. We reported three mechanisms. beta 2-glycoprotein I(beta 2GPI) inhibited activated protein C(APC) activity and, furthermore, APC activity decreased by the addition of monoclonal aCL and beta 2GPI. Monoclonal anticardiolipin antibodies(aCL) seemed to enhance the inhibition of APC procoagulant activity caused by beta 2GPI. Monoclonal aCL in the presence of beta 2GPI also increased the activity of plasminogen activator inhibitor(PAI)-1 in the mixture of tissue-plasminogen activator(t-PA) and PAI-1 by inhibiting the function of beta 2GPI, which increased the remaining t-PA activity in the mixture. The formation of thrombin-antithrombin complexes(TAT) in APS was impaired. The level of TAT in APS did not increase, however the level of prothrombin fragment 1 + 2 (F1 + 2) increased. Therefore, free thrombin present in patients' blood may contribute to thrombosis in APS. These reports indicate that thrombosis in APS may be caused by several thrombogenic factors that stimulate aCL.
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PMID:[Antiphospholipid antibodies and thrombosis: the putative mechanisms of hypercoagulable state in patients with anticardiolipin antibody]. 1081 Aug 73

The clinically relevant antiphospholipid antibodies (APA) include anticardiolipin antibodies and lupus anticoagulant. Most autoimmune APA require the presence of a cofactor for phospholipid binding, and the growing list of candidate cofactors has prompted redefinition of APA to 'antiphospholipid protein antibodies'. Current evidence favours beta2-glycoprotein I (beta2GPI) and prothrombin as the primary antigens for anticardiolipin antibodies and lupus anticoagulant respectively. Patients with APA show a predisposition for venous and arterial thromboembolism, recurrent fetal loss, thrombocytopenia and a number of neurological syndromes and miscellaneous conditions. The association between APA and thrombosis has been well documented, but a definite mechanism remains to be clarified. Proposed mechanisms have included disruption of endothelial regulatory processes, impairment of fibrinolysis, augmented platelet activation and/or adhesion, inhibition of antithrombin activity and negation of the anticoagulant effects of beta2GPI and annexin V. In this review we describe recent insights into the role of beta2GPI as a natural anticoagulant, the procoagulant effects of APA on the Protein C system, the interactions between APA and prothrombin resulting in augmentation of thrombin generation, and cellular expression of Tissue Factor in patients with APA. Cellular immunity to beta2GPI is also discussed. Elucidation of these pathophysiological mechanisms may shed further light on the association between APA and thrombosis.
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PMID:Recent insights into antiphospholipid antibody-mediated thrombosis. 1085 78

We have investigated beta2-glycoprotein I (beta2GPI) binding to platelet-derived microparticles (PMP) and its effect on GPIIb/IIIa. PMP were isolated from washed human platelets after stimulation with A23187, and analyzed by surface plasmon resonance spectroscopy. Beta2GPI as well as activated protein C (APC) or annexin V bound to PMP-coated sensorchips, demonstrating exposure of anionic phospholipids on immobilized PMP. Beta2GPI binding was impaired by calcium and occurred in a concentration-dependent manner with apparent k(on) = 2.6 x 10(4) M(-1) s(-1) and k(off) = 4.4 x 10(-3) s(-1), corresponding to a KD value of 1.7 x 10(-7) M. When analyzed by flow cytometry, the binding of certain mAbs specific for GPIIb and/or GPIIIa was reduced in the presence of beta2GPI but not of APC or annexin V, whereas the binding of anti-GPIb or anti-P-selectin mAbs, or of soluble fibrinogen remained unchanged. These results suggest a broad but specific influence of beta2GPI on GPIIb/IIIa immunoreactivity, and indicate that beta2GPI may act as a modulator of GPIIb/IIIa-dependent functions of PMP.
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PMID:Beta2-glycoprotein I binding to platelet microparticle membrane specifically reduces immunoreactivity of glycoproteins IIb/IIIa. 1124 54

Congenital and acquired thrombophilia are associated with an increased risk of pregnancy-associated venous thrombosis and fetal loss. Two hundred eighty-nine patients with a history of recurrent spontaneous abortion were subjected to screening examinations for the etiology of these abortions. Endocrine abnormality (28.0%), uterine abnormality (10.4%), autoimmune diseases (1.4%), antiphospholipid antibody syndrome (4.5%), and balanced type chromosome translocation (4.2%) were found as underlying causes of recurrent abortions, and the remaining 55.0% of the 289 patients were classified as having an unexplained etiology. Congenital thrombophilia such as protein C (PC) deficiency, protein S (PS) deficiency, antithrombin deficiency, and factor V Leiden mutation was not frequently detected; only one patient had PS deficiency. A reduced factor XII activity was found at a frequency of 4.2%. The frequency of methylene tetrahydrofolate reductase gene C677T mutation in recurrent aborters (0.38) was the same as that found in a fertile control group. Although the prevalence of anti-beta2-glycoprotein I antibody (abeta2-GPI) syndrome was very low (1.7%), patients with a high titer of immunoglobulin G (IgG) class abeta2-GPI, despite anticoagulation therapy, experienced severe fetomaternal complications in subsequent pregnancies. The rate (13.8%) of positive tests for serum IgA class abeta2-GPI in patients with unexplained etiology was higher than that in the controls (0%) (P < .05). We conclude that congenital thrombophilia is rare in Japanese patients who had experienced consecutive spontaneous abortions.
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PMID:Recurrent pregnancy loss: etiology of thrombophilia. 1137 65

The presence of lupus anticoagulants (LAC) in plasma is a major risk factor for thrombosis. An attractive hypothesis to explain a LAC-mediated thrombotic tendency is that LAC interfere with activation of protein C, a natural antithrombotic in plasma. We investigated the relationship between LAC and protein C activation in vivo. We selected 20 patients with systemic lupus erythematosus (SLE) with LAC (and not using oral anticoagulants), 36 patients with SLE without LAC and 25 healthy volunteers. In these, we measured circulating levels of activated protein C (APC), prothrombin (FII), free protein S, C4BP, protein C, and antibodies to protein C, protein S, FII and beta2-glycoprotein I (beta2GPI). In SLE patients (n = 56), mean levels of APC, FII and free protein S were significantly (P < 0.001) lower than those in healthy volunteers (respectively 13%, 17% and 14%). Mean protein C levels and C4BP levels were similar for SLE patients and healthy volunteers. In contrast to the above hypothesis, the decreased levels of APC could not be attributed to the presence of LAC. Levels of APC were correlated with both FII levels and protein C levels. Decreased levels of APC, FII, protein C and free protein S were related to the presence of anti-FII antibodies. None of the patients had antibodies against protein C or protein S. In conclusion, although the mean levels of APC, FII and free protein S were significantly decreased in SLE patients, no correlation with LAC was found. However, anti-FII antibodies were related to decreased levels of APC, FII, protein C, free protein S and C4BP. As FII levels, and not protein C levels, were decreased in SLE patients and correlated with APC levels, we conclude that the decreased FII levels are responsible for the low levels of APC.
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PMID:Low levels of activated protein C in patients with systemic lupus erythematosus do not relate to lupus anticoagulants but to low levels of factor II. 1202 41

Venous thromboembolism (VTE) is one of the common manifestations in the anti-phospholipid (aPL) syndrome. We examined the levels of IgG antibodies (Abs) to beta2-glycoprotein I (beta2-GP I) and prothrombin, lupus anticoagulant (LA) activity, activated protein C resistance (APC-R), and factor V Leiden in 96 patients with systemic lupus erythematosus (SLE); 19 with VTE and 77 without VTE. Acquired APC-R, which was not found in any patient with the factor V Leiden mutation, was present in 33 (34.4%) out of the 96 patients with SLE. The presence of acquired APC-R was a strong risk factor for VTE. The SLE patients were divided into four groups according to the results of enzyme-linked immunosorbent assay (ELISA) and LA activity for each aPL Abs: ELISA+, LA+; ELISA+, LA-; ELISA-, LA+; and ELISA-, LA-. A significant association was observed between APC-R and the co-existence of anti-beta2-GP I Abs and LA activity or of anti-prothrombin Abs and LA activity. There was no association between APC-R and the presence of anti-beta2-GP I Abs, anti-prothrombin Abs, or LA activity alone. However, when multivariate logistical regression analysis was performed, it was clear that only the co-existence of anti-prothrombin and LA activity was a significant risk factor for APC-R. These findings indicate that the co-existence of anti-prothrombin Abs and LA activity may be an important factor in the pathogenesis of acquired APC-R in patients with SLE.
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PMID:Acquired activated protein C resistance is associated with the co-existence of anti-prothrombin antibodies and lupus anticoagulant activity in patients with systemic lupus erythematosus. 1271 80

Anti-phospholipid (aPL) antibodies (Abs) are well known to be associated with thromboembolic events in patients with systemic lupus erythematosus (SLE). However, the clinical relevance of a PL Abs in patients without SLE (non-SLE) who have venous thromboembolism remains unclear. We evaluated 143 non-SLE patients with a first episode of clinically suspected deep vein thrombosis (DVT) by using objective tests for diagnosing DVT and laboratory tests including the activated protein C resistance (APC-R) test, the factor V Leiden test, and various aPL Abs. The prevalence of acquired APC-R, in which case there was no factor V Leiden mutation, was significantly higher in patients with DVT (15/58 cases, 25.9%, p < 0.0001) than in those without DVT (3/80 cases, 3.7%), and confirmed that acquired APC-R was a strong risk factor for DVT (odds ratio [OR], 8.95; 95% confidence intervals [CI], 2.45-32.7; p < 0.001). Multivariate logistic analysis revealed that the presence of LA, aCL, anti-beta2-glycoprotein I, anti-prothrombin and anti-protein C Abs was not reliable as a risk factor for DVT in non-SLE patients, and that the presence of anti-protein S Abs was the most significant risk factor for DVT (OR, 5.88; 95% CI, 1.96-17.7; p < 0.002). Furthermore, the presence of anti-protein S Abs was strongly associated with acquired APC-R (OR, 57.8; 95% CI, 8.53-391; p < 0.0001). These results suggest that acquired APC-R may reflect functional interference by anti-protein S Abs of the protein C pathway, which action may represent an important mechanism for the development DVT in non-SLE patients.
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PMID:Acquired activated protein C resistance associated with anti-protein S antibody as a strong risk factor for DVT in non-SLE patients. 1242 83

Antiphospholipid antibodies (aPL) may induce acquired activated protein C resistance (acquired APCR). The role of acquired APCR in patients with systemic lupus erythematosus (SLE) is not well known. To evaluate the prevalence of acquired APCR and its association with clinical manifestations we studied 103 consecutive SLE patients and 103 matched controls. APCR in the undiluted test and after dilution in factor V deficient plasma, factor V Leiden, protein C and S, lupus anticoagulant, and anti-cardiolipin, anti-beta2-glycoprotein I and anti-prothrombin antibodies were determined. Factor V Leiden was found in 4% in both patients and controls. The prevalence of acquired APCR was 22% for the undiluted assay and 17% in the diluted test. In SLE patients, acquired APCR was associated with aPL (39 vs 13% in undiluted assay, P = 0.007; and 33 vs 7% in the diluted test, P = 0.001). Arterial thromboses were found in 24% of patients with acquired APCR and in 6% of patients without (P = 0.04). However, no relationship was found with venous thrombosis. Acquired APCR was also associated with pregnancy losses: miscarriages in 70% of women with acquired APCR vs 32% in those without (P=0.03). Thus, in SLE patients acquired APCR seems to be associated with increased prevalence of arterial thrombosis and pregnancy losses.
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PMID:Clinical significance of acquired activated protein C resistance in patients with systemic lupus erythematosus. 1247 3

A number of previous studies have shown that anti-phospholipid(aPL) antibodies(Abs) do not bind primarily to the negatively-charged phospholipid itself but rather to complexes of the phospholipid and plasma proteins, and that the most common antigenic targets are beta 2-glycoprotein I recognized by anticardiolipin Abs and prothrombin recognized by most lupus anticoagulants. However, resent studies suggest that other phospholipid-binding proteins, particularly protein C, protein S, and annexin V, may be important targets as well. To clarify the association between the various types of aPL Abs and thrombotic complications in patients with systemic lupus erythematosus(SLE), we examined the prevalence of aPL Abs to various phospholipid-binding proteins(beta 2-glycoprotein I, prothrombin, protein C, protein S, and annexin V). We found that anti-beta 2-glycoprotein I Abs may be associated primarily with cerebral infarction and femoral artery thrombosis, and that anti-protein S Abs may be associated primarily with venous thromboembolism and renal thrombotic microangiopathy. Furthermore, anti-annexin V Abs might be closely related to fetal loss. These findings suggest that thrombotic complications in SLE depend on the antigenic specificities of aPL Abs, alone or in combination.
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PMID:[Association between anti-phospholipid antibodies and thrombotic complications in systemic lupus erythematosus]. 1270 97

Antiphospholipid syndrome is considered to be a cause of an acquired hypercoagulable state leading to stroke and transient ischemic attack. Antiphospholipid antibodies (aPL) comprise a heterogeneous group of autoantibodies. Among them, lupus anticoagulant (LA) and beta 2-glycoprotein I dependent anticardiolipin antibody (beta 2-GPI aCL) are important and commonly measured. Recently, LA has been considered to be closely related to phosphatidylserine anti-prothrombin antibody. APL is an independent risk factor for first-ever ischemic stroke and a prognostic marker of recurrent stroke. The precipitating factors for the occurrence of stroke are the presence of beta 2-GPI-dependent aCL, a GPL aCL level of more than 40, and the simultaneous presence of lupus anticoagulant. Several mechanisms are believed to be involved in the thrombotic process in patients with antiphospholipid antibodies. Human activated protein C functions as a potent anticoagulant in human plasma by inhibiting the activity of coagulation cofactors Va and VIIIa. Activation of protein C is impaired in patients with aPL. Recently, the presence of aPL has been considered to be contributory factor for the development of atherosclerotic lesions. Transgenic mouse lacking the LDL receptor develop accelerated arteriosclerosis upon immunization with beta 2-GPL Several therapeutic options are available for the prevention of ischemic stroke in patients with aPL, such as antiplatelet, anticoagulant, and immunosuppressive therapy. The rate of recurrence in patients undergoing antiplatelet and anticoagulation combination therapy was found to be lower than that in patients receiving other forms of therapy. The WARSS-APASS collaborative study showed that there was no difference in the recurrence rate between aPL patients receiving antiplatelet or anticoagulation therapy alone. APL has been investigated in other neurological disorders such as multiple sclerosis, chorea, migraine and convulsion. The association of aPL with multiple sclerosis remains debatable. APL could be a contributory factor for the development of convulsion, but not for migraine.
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PMID:[Neurological aspects in antiphospholipid syndrome]. 1515 54


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