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)

Oral tolerance was induced in BALB/c mice by feeding low dose beta2-glycoprotein I (beta2GPI). The beta2GPI-fed mice did not develop serologic and clinical markers of experimental antiphospholipid syndrome (APS) upon immunization with the autoantigen. The treated group was characterized by low titers of serum anti-beta2GPI and anticardiolipin Abs in the serum, lack of fetal resorptions, low incidence of thrombocytopenia, and normal aPTT (activated partial thromboplastin time) values. Beta2GPI given orally before priming with beta2GPI resulted in complete prevention of experimental APS development; beta2GPI given at an early stage of the disease reduced clinical manifestations. However, administration of beta2GPI 70 days postimmunization had a less significant effect on disease expression. Tolerized mice exhibited a diminished T lymphocyte proliferation response to beta2GPI in comparison with beta2GPI-immunized mice fed with OVA. When nontolerant beta2GPI-primed T lymphocytes were mixed with T lymphocytes derived from tolerized mice, a significant inhibition of proliferation upon exposure to beta2GPI was observed. The induction of suppression was beta2GPI specific and driven, as well as TGF-beta mediated. The beta2GPI-specific response of T lymphocytes from the beta2GPI-fed mice was reversed by anti-TGF-beta Abs. The tolerance was adoptively transferred by CD8+ T cells from the tolerized mice into naive mice. Those CD8+ cells were MHC class I restricted, found to secrete TGF-beta, and had no cytolytic activity. Oral administration of beta2GPI suppressed priming of CTLs in the recipient mice. In sum, beta2GPI-induced oral tolerance has an immunomodulatory effect in experimental APS, demonstrating the importance of beta2GPI in the pathogenesis of the disease.
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PMID:Oral tolerance to low dose beta 2-glycoprotein I: immunomodulation of experimental antiphospholipid syndrome. 982 May 3

Anticoagulant activity is present in non-immunoglobulin (IgG) fractions from plasma of patients with antiphospholipid syndrome (APS). Plasma from six patients with primary or secondary APS was passed through a protein A sepharose 4B column. Anticoagulant activity in IgG samples and non-IgG samples was determined by both dilute aPTT based clotting assay and by dilute PT based clotting assay. Thrombin generation was determined by prothrombinase complex assay in the presence of IgG sample or non-IgG sample. Anticoagulant activity was detected in the IgG samples with the dilute aPTT based clotting assay and in non-IgG samples with the dilute PT based clotting assay. The activity was not detected in IgG samples with the dilute PT clotting assay. Forty percent of total thrombin generation was inhibited in the presence of non-IgG samples although thrombin generation was not inhibited in the presence of IgG samples and beta2-glycoprotein I. The anticoagulant activity detected by dilute PT based clotting assay and prothrombinase complex assay was non-IgG, phospholipid-Ca++-dependent and beta2-glycoprotein I-independent. The role of non-IgG anticoagulants should be determined as well as the role of LA Igs antibodies in the mechanisms of thrombosis.
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PMID:Anticoagulant activity in non-immunoglobulin fraction from plasma of patients with antiphospholipid syndrome. 983 16

Prothrombin time (PT) is routinely used to monitor oral anticoagulant treatment in patients with the antiphospholipid antibody syndrome (APS). The fact that PT is a phospholipid (PL)-dependent coagulation test raises the possibility that lupus anticoagulant (LA) might interfere with this test, thus complicating the control of anticoagulant treatment. The effect of 6 affinity-purified preparations of anti- (a)beta2-glycoprotein I (GPI) antibodies with LA activity on the PT was tested. Instead of prolonging PT as expected, the abeta2-GPI antibodies reduced the PT of both normal plasma and anticoagulated plasma by a mean of 2.4 seconds and 5.6 seconds, respectively. This effect was also observed using other 5 commercially available preparations of thromboplastin. The abeta2-GPI-mediated reduction in PT was dose-dependent and was lost upon removal of beta2-GPI. The failure of abeta2-GPI antibodies to express LA activity in PT was found to depend on the fact that calcium ions were added together with PL at the beginning of the assay. In fact, modification of the standard diluted Russell viper venom time (dRVVT) test by adding calcium ions together with PL resulted in a loss of abeta2-GPI anticoagulant activity. The procoagulant effect was not as evident in an assay that used stimulated monocytes as a source of thromboplastin. These results show that abeta2-GPI antibodies exhibit an 'in vitro' procoagulant effect in PT and an anticoagulant effect in dRVVT only when the interaction with their antigen and PL occurs in the absence of calcium ions.
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PMID:Procoagulant effect of anti-beta2-glycoprotein I antibodies with lupus anticoagulant activity. 1057 96

Antiphospholipid antibodies (APAs) are considered risk factors in patients with thromboembolic diseases. Although the incidence of such acquired coagulation disturbances in adults are well described, only few data exist for children. Therefore, in a first step to collect new data we analyzed the presence of different APAs in 202 consecutive children and compared them with two groups of adults. The children screened for APA were exclusively those who did not have any thromboembolic complications or a tendency for thrombophilia due to other underlying diseases such as systemic lupus or malignancy in their past or present medical history. Consecutive blood samples were evaluated from routine laboratory specimens. The two groups of adults comprised 200 patients after deep vein thrombosis and 200 patients without thromboembolic events that served as controls. Four lupus anticoagulant (LA) screening tests were determined: the dilute Russell's viper venom test; a lupus anticoagulant-sensitive activated partial thromboplastin time reagent; a second lupus-sensitive activated partial thromboplastin time; and the Kaolin clotting time. Furthermore, three different antiphospholipid antibodies ELISA assays against cardiolipin (ACA), beta2-glycoprotein I, and phosphatidyl-serine, were determined. The children had a much higher prevalence for LA than did the adults. On the other hand, their values for ACA were significantly lower than in adults with a history of thromboembolism. Findings in children were similar to the normal adult group. This has to be taken into account when evaluating children with thromboembolic diseases.
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PMID:Antiphospholipid antibodies in children without and in adults with and without thrombophilia. 1129 Dec 89

We examined activated partial thromboplastin time, kaolin clotting time, mixing with normal plasma in kaolin clotting time, dilute Russell's viper venom time, dilute Russell's viper venom time at high lipid concentrations, anti-phospholipid antibodies, and anti-cardiolipin-beta2-glycoprotein I complex antibody in 135 patients with prolongation of activated partial thromboplastin time and diagnosed 86 patients positive for lupus anticoagulant. The sensitivity of activated partial thromboplastin time and dilute Russell's viper venom time/dilute Russell's viper venom time-high lipid concentrations ratio for lupus anticoagulant were markedly high, but the specificity of activated partial thromboplastin time for lupus anticoagulant was not markedly high. The specificity, but not the sensitivity, of kaolin clotting time-mixing with normal plasma in kaolin clotting time was markedly high. In summary, dilute Russell's viper venom time to dilute Russell's viper venom time-high lipid concentrations ratio gave high sensitivity as well as specificity, being the only assay to confirm this. Of the patients positive for lupus anticoagulant, 25% were positive for anti-phospholipid antibodies and 17% were positive for anti-cardiolipin-beta2-glycoprotein I complex antibody. Of the lupus anticoagulant-positive patients with thrombosis, 45% were positive for anti-phospholipid antibodies, 35% were positive for anti-cardiolipin-beta2-glycoprotein I complex antibody, 60% were positive for both anti-phospholipid antibodies and anti-cardiolipin-beta2-glycoprotein I complex antibody, and only 17% were negative for anti-phospholipid antibodies and anti-cardiolipin-beta2-glycoprotein I complex antibody. These findings suggest that lupus anticoagulant can be diagnosed by dilute Russell's viper venom time/dilute Russell's viper venom time-high lipid concentrations ratio, and that thrombosis in lupus anticoagulant-positive may be predictable from both anti-phospholipid antibodies and anti-cardiolipin-beta2-glycoprotein I complex antibody. Plasma tissue type plasminogen activator level in lupus anticoagulant patients was significantly increased, and plasma tissue type plasminogen activator and fibrin-D-dimer levels in lupus anticoagulant-positive patients with thrombosis were significantly higher than in those without thrombosis, suggesting that the diagnosis of thrombosis by hemostatic markers might be important in lupus anticoagulant.
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PMID:Coagulation tests and anti-phospholipid antibodies in patients positive for lupus anticoagulant. 1089 74

An abnormal increase in anti-beta2-glycoprotein I antibodies (abeta2GPI) is capable of producing thrombosis and the vasculopathy-simulating antiphospholipid antibody (aPL). However, it is rarely described in cerebral ischemia without an association with aPL. The authors report a middle-aged man who experienced recurrent cerebral ischemia and diffuse cerebral stenosis without the apparent traditional cardiovascular risk factor. He was free of antiphospholipid/cofactor syndrome (APCS) and systemic lupus erythematosus (SLE). An increase of blood abeta2GPI was detected in serial measurements. The aPL, Venereal Disease Research Laboratory (VDRL) test, Coombs' test, and antinuclear factor were negative. Activated partial thromboplastin time was normal. This patient is a reminder to consider abeta2GPI in an unexplained recurrent cerebral thrombosis and cerebral artery stenosis even when the typical clinical manifestation or laboratory data of APCS is absent.
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PMID:An unusual increase of blood anti-beta 2-glycoprotein-I antibody but not antiphospholipid antibody in cerebral ischemia--a case report. 1122 90

We investigated the mechanism by which anti-prothrombin antibodies cause lupus anticoagulant (LAC) activity. Addition of affinity-purified anti-prothrombin antibodies from LAC-positive plasma samples (alpha-FII-LAC+) to normal plasma induced LAC activity. Upon increasing the phospholipid concentration, LAC activity was neutralized. Addition of purified alpha-FII-LAC+ to normal plasma strongly inhibited factor Xa formation. No inhibition was measured when alpha-FII-LAC+ were added to prothrombin-deficient plasma or when purified anti-prothrombin antibodies from LAC-negative plasma samples (alpha-FII-LAC-) were added. When a combination of prothrombin and alpha-FII-LAC+ was added to the purified clotting complex, a strong inhibition of factor Xa and IIa formation was seen. The alpha-FII-LAC+ alone or a combination of prothrombin and alpha-FII-LAC- did not show inhibition. Ellipsometry studies showed that, in the presence of alpha-FII-LAC+, the affinity of prothrombin for a phospholipid surface increased dramatically, whereas a much lower increase was observed with alpha-FII-LAC-. Our results show that complexes of prothrombin and anti-prothrombin antibodies with LAC activity inhibit both prothrombinase and tenase. The antibodies increase the affinity of prothrombin for the phospholipid surface, thereby competing with clotting factors for the available catalytic phospholipid surface, a mechanism similar to that of anti-beta2-glycoprotein I antibodies.
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PMID:Complexes of anti-prothrombin antibodies and prothrombin cause lupus anticoagulant activity by competing with the binding of clotting factors for catalytic phospholipid surfaces. 1138 Apr 47

The GAIT (Genetic Analysis of Idiopathic Thrombophilia) Project is a family-based study dedicated to elucidating the genetic basis of hemostasis-related phenotypes and thrombosis risk. In this paper, we have examined several lesser-studied hemostasis-related phenotypes in the 21 GAIT families: levels of vitamin B 12, serum folate, whole blood folate, alpha2-antiplasmin, prekallikrein, beta2-glycoprotein I, soluble P-selectin, factor XIII A and B subunits and a new coagulation measurement based on thromboplastin time in the presence or absence of thrombomodulin. Using the variance component method, we estimated the relative contributions of genetic and environmental influences on these phenotypes. In addition, we calculated the genetic correlations between thrombosis risk and each of these phenotypes. All 12 phenotypes showed significant genetic contributions with genes accounting for 22% to 78% of the variance after correction for covariate effects. Four phenotypes (three traits involving thromboplastin-thrombomodulin mediated coagulation time and serum folate) exhibited significant genetic correlations with thrombosis. Thus, some of the genes that influence quantitative variation in these physiological phenotypes also influence the risk of thrombosis. The high heritabilities and significant genetic correlations between thrombosis and some risk factors suggest that joint consideration of correlated quantitative phenotypes will aid in identifying susceptibility genes.
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PMID:Thromboplastin-thrombomodulin-mediated time and serum folate levels are genetically correlated with the risk of thromboembolic disease: results from the GAIT project. 1184 58

Nodular regenerative hyperplasia (NRH) of the liver is a local hyperplastic response of hepatocytes, probably due to vascular abnormalities. Since it was shown in a few case reports that NRH may be associated with antiphospholipid antibodies (APA) we wanted to analyze the relevance of APA in patients with this disease. Sera from 13 patients with histologically defined NRH were tested for APA by an in-house ELISA using as antigens cardiolipin (CL), beta2-glycoprotein I (beta2-gp I), phosphatidylserine (PS), and thromboplastin (TP), a mixture of different phospholipids and phospholipid-binding proteins. As controls, sera from patients with serologically and histologically defined autoimmune liver diseases (primary biliary cirrhosis n = 14; autoimmune hepatitis n = 14) without histological evidence for NRH as well as from 14 healthy blood donors were analyzed. 77% of the NRH patients had APA. In 46% they were directed against CL. In contrast, only 14% of the patients with autoimmune liver diseases and 14% of the healthy controls had anti-CL antibodies (p < 0,05). Antibodies to beta2-gp I and TP did not discriminate between NRH and autoimmune liver diseases. Anti-PS antibodies were not observed. These data indicate that determination of anti-CL antibodies in NRH may help to identify a subgroup of patients in whom an 'organ-specific antiphosholipid syndrome' of the liver may be involved in the pathogenesis.
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PMID:Nodular regenerative hyperplasia (NRH) of the liver--a manifestation of 'organ-specific antiphospholipid syndrome'? 1263 4

Autoantibodies to prothrombin are common in patients with systemic lupus erythematosus. Although their presence is a risk factor for thrombosis, neither their origin nor their precise role in inducing the procoagulant state is known. We have developed a phage-display antibody library from patients with systemic lupus erythematosus with antiprothrombin antibodies, and we have selected two single-chain Fv antibody fragments (ScFvs) by panning on a prothrombin-coated surface. In prothrombin activation assays using purified components, these antibodies promoted prothrombin activation. These ScFvs, termed AN78 and AN129, bound to immobilized prothrombin in a concentration-dependent specific manner but not to other anionic phospholipid binding proteins such as beta2-glycoprotein I or annexin V. Phosphatidylserine-bound prothrombin, but not soluble prothrombin, inhibited the binding suggesting that the epitope is available only on immobilized prothrombin. To localize the epitope, prothrombin was treated with thrombin or factor Xa and various prothrombin activation fragments were subsequently isolated and tested in ELISA with the ScFvs. Both AN78 and AN129 bound to prethrombin I (the fragment lacking the Gla domain and the first kringle domain), to fragment 1.2 (containing Gla and the two kringle domains only) and to fragment 2 but not to thrombin, thus localizing the cognate epitope to the kringle 2 domain in prothrombin. Analysis of the cDNA sequences of these antibodies show clustered mutational patterns in the complementarity determining region, suggesting that variable domains are the products of antigen-driven B cell clonal maturation.
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PMID:Lupus-derived antiprothrombin autoantibodies from a V gene phage display library are specific for the kringle 2 domain of prothrombin. 1504 12


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