Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.5 (thrombin)
 33,306 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect on thrombin-induced release of prostacyclin from human umbilical vein endothelial cells of preincubation with both serum and serum derived from platelet-poor plasma (PDS) from patients with systemic lupus erythematosus (SLE), systemic sclerosis, the antiphospholipid syndrome (APS) and normal controls was examined. Although no significant differences in thrombin-induced prostacyclin release were found in any of the patient groups, further analysis revealed that PDS from patients with SLE and APS that contained IgG anticardiolipin antibodies produced significant inhibition of prostacyclin release when compared with controls (P = 0.02). The effect was maximal with samples that contained both IgG and IgM anticardiolipin antibodies (P less than 0.01) and which had a significantly higher titre of IgG antibodies than samples which contained solely IgG antibodies (P less than 0.05). The absence of any corresponding inhibition of prostacyclin release by serum samples that contained anticardiolipin antibodies, possibly due to the release of masking stimulatory factors by platelets during coagulation, provides an explanation for the conflicting nature of previous reports.
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PMID:Serum masks the inhibition of thrombin-induced prostacyclin release produced by anticardiolipin antibodies. 154 Jul 86

Anticardiolipin antibodies (aCL) are induced both in the Antiphospholipid Syndrome (APS) and syphilis, but thrombosis, thrombocytopenia, and pregnancy loss occur only in the APS. Differences in specificity and function of aCL antibodies might explain clinical differences between APS and syphilis. This study compared the effects on platelet activation and aggregation of affinity purified IgG anticardiolipin antibodies from 6 patients with the APS (IgG-APS) and 5 patients with syphilis (IgG-syph). Platelet aggregation was studied by aggregometry and platelet activation by flow cytometry. In the presence of low concentrations of thrombin, ADP, or collagen, all 6 IgG-APS samples induced platelet aggregation and activation, but none of the IgG-syph samples had this effect. In the absence of platelet agonists, only 3 of 6 IgG-APS caused platelet aggregation and none caused platelet activation; IgG-syph had no effect. The IgG-APS samples but not IgG-syph bound phosphatidylserine by ELISA. We conclude that polyclonal antibodies specific for phosphatidylserine may induce platelet activation and aggregation in the presence of low concentrations of platelet agonists.
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PMID:Comparison of the effects of anticardiolipin antibodies from patients with the antiphospholipid syndrome and with syphilis on platelet activation and aggregation. 766 38

Patients with antiphospholipid syndrome, whether primary or secondary to systemic lupus erythematosus, may have thrombocytopenia. Their antibodies to anionic phospholipids might bind to phospholipids on the platelet wall but anionic phospholipids are asymmetrically located in the inner leaflet. In addition, antibodies to anionic phospholipids may require beta 2 glycoprotein I (beta 2GPI) as a cofactor in order to bind to phospholipids. In turn, beta 2GPI has high affinity for anionic phospholipids. Loss of this asymmetry occurs upon platelet activation and could thus permit such antibody-beta 2GPI-platelet interaction. We studied this by flow cytometry using purified beta 2GPI-FITC labelled and similarly labelled affinity-purified polyclonal antibodies to cardiolipin or phosphatidylserine (aPL) obtained from sera of patients with primary antiphospholipid syndrome. Five percent of resting platelets were bound by aPL in the presence of beta 2GPI. Such binding increased when we activated platelets with various agonists, reaching 31% with the concurrent use of thrombin and the calcium ionophore A23187. Platelet activation resulted in the expression of GMP140 but this did not correlate with aPL binding. This probably reflects that the expression of GMP140, which depends on their secretion of alpha granules, has different agonist responses and occurs at different times than do microvesicle formation and expression of prothrombinase activity which coincide with the loss of phospholipid asymmetry on the platelet wall. When we studied the binding of purified beta 2GPI we also found that it binds preferentially to activated platelets and that it seems to be a prerequisite for the binding of aPL onto them. Our findings indicate that aPL from patients with antiphospholipid syndrome may bind to activated platelets through beta 2GPI.
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PMID:Exposure of anionic phospholipids upon platelet activation permits binding of beta 2 glycoprotein I and through it that of IgG antiphospholipid antibodies. Studies in platelets from patients with antiphospholipid syndrome and normal subjects. 791 7

Lupus anticoagulants, commonly found in the immunoglobulin fraction of patients with the antiphospholipid syndrome (APS), and the normal plasma protein beta 2-glycoprotein 1 (beta 2GP1) may both contribute to the in vitro impairment of prothrombin activation associated with the APS. We examined the effects upon prothrombin activation supported by phospholipid vesicles of plasma IgG preparations from APS patients in the presence and absence of beta 2GP1. Using a purified system for measurement of prothrombin activation to thrombin, we demonstrated significant phospholipid concentration-dependent inhibition of prothrombin activation in the absence of beta 2GP1 by 11 consecutive patient IgG preparations. The degree of inhibition of prothrombin activation by equivalent concentrations of patient IgG correlated well with the extent of prolongation of the plasma clotting time in lupus anticoagulant assays of whole patient plasma. Additional studies with eight patient IgG preparations indicated that the addition of beta 2GP1 to patient IgG-phospholipid vesicle mixtures resulted in either independently additive inhibition by the two protein species (six cases) or potential inhibition of beta 2GP1 of the IgG inhibitory activity demonstrable in the absence of beta 2 GP1 (two cases). In addition, beta 2GP1-independent inhibition of prothrombin activation also occurred with three patient IgG preparations obtained by affinity binding to cardiolipin.
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PMID:Inhibition of prothrombin activation by antiphospholipid antibodies and beta 2-glycoprotein 1. 799 95

The mechanisms underlying clinical abnormalities associated with the antiphospholipid antibody syndrome (APAS) have not been elucidated. We measured plasma levels of lipoprotein(a) [Lp(a)], the active form of plasminogen activator inhibitor (active PAI), thrombin-antithrombin III complex (TAT) and soluble thrombomodulin (TM), to investigate the relationship of these factors to thrombotic events in APAS. Mean plasma levels of Lp(a), TAT, active PAI and TM were all significantly higher in patients with aPL than in a control group of subjects. Plasma levels of Lp(a) and active PAI were significantly higher in patients with aPL and arterial thromboses than in patients with aPL but only venous thromboses. There was a significant correlation between plasma levels of Lp(a) and active PAI in patients with aPL. These findings suggest that patients with aPL are in hypercoagulable state. High levels of Lp(a) in plasma may impair the fibrinolytic system resulting in thromboses, especially in the arterial system.
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PMID:Plasma levels of lipoprotein(a) are elevated in patients with the antiphospholipid antibody syndrome. 858 28

Anticardiolipin antibodies are produced both in patients with the antiphospholipid syndrome (APS) and in patients with syphilis, but lupus anticoagulant activity has been reported only for the former group. To understand these differences, affinity-purified immunoglobulin G anticardiolipin antibodies from APS (n = 11) and syphilis (n = 5) patients were compared. Only the antibodies from the APS group inhibited prothrombin conversion to thrombin and cross-reacted with phosphatidylserine. These findings may enable better definition of the phospholipid epitopes involved in the hemostatic abnormalities of APS.
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PMID:Differences in functional activity of anticardiolipin antibodies from patients with syphilis and those with antiphospholipid syndrome. 806 29

IgG from 18 patients with SLE, eight with the primary antiphospholipid syndrome and 19 controls was examined for its effect on thrombin-induced prostacyclin (PGI2) release from human umbilical vein endothelial cells in relation to both the titre of anticardiolipin (ACA) and antiendothelial activity (AEA) and clinical thrombotic events. Although no significant inhibition of PGI2 release was found overall, examination of subgroups revealed that IgG from patients with ACA produced significant inhibition of PGI2 release (mean stimulation index IgGM, 0.74 +/- 0.12, P = 0.02) when compared with patients without ACA (1.18 +/- 0.12). Further analysis revealed a significant positive correlation between ACA and AEA (r = 0.52, P = 0.006) in the total patient group which was reflected in significant negative correlations between inhibition of PGI2 release and increasing titre of both ACA (r = -0.42, P = 0.032) and AEA (r = -0.57, P = 0.002). However, only increasing titre of AEA showed a significant negative correlation with inhibition of PGI2 release when patients with (r = -0.74, P = 0.0005) and without (r = 0.23, N.S.) thromboses were compared. The titre of ACA failed to show any significant correlation with inhibition of PGI2 release in either patients with (r = -0.42, N.S.) or without (r = -0.16, N.S.) thromboses. These findings suggest that previous, sometimes conflicting, reports of an association between inhibition of PGI2 release and ACA may be explained by the co-incidence of AEA with ACA.
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PMID:Inhibition of prostacyclin release by endothelial binding anticardiolipin antibodies in thrombosis-prone patients with systemic lupus erythematosus and the antiphospholipid syndrome. 816 51

The antiphospholipid antibody syndrome (APS) is characteristically associated with thrombosis. Heparan sulfate (HS) is a physiologic endothelial cell surface modulator of normal anticoagulation, containing a specific oligosaccharide sequence that binds antithrombin III with high affinity and also is present in heparin, a related glycosaminoglycan. We hypothesized that a subset of antiphospholipid antibodies with high affinity for heparan sulfate/heparin epitopes may inhibit the function of HS, promoting a procoagulant state. Purified IgG from all seven patients with APS studied were reactive with heparin by enzyme-linked immunosorbent assay, whereas none of five controls had antiheparin reactivity. IgG antiheparin antibodies were purified from two APS patients by affinity chromatography on heparin-Sepharose. Specificity studies showed that low-affinity electrostatic interactions clearly did not account for the observed reactivity with heparin, and that APS IgG antiheparin antibodies were specifically reactive with a disaccharide present in the heparin pentasaccharide that binds antithrombin III. Furthermore, APS IgG antiheparin antibodies inhibited heparin-accelerated formation of antithrombin III-thrombin complexes. We conclude that antiheparan sulfate/heparin antibodies may be a cause of autoimmune vascular thrombosis in the antiphospholipid antibody syndrome.
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PMID:Autoantibodies to heparin from patients with antiphospholipid antibody syndrome inhibit formation of antithrombin III-thrombin complexes. 816 28

The antiphospholipid antibody syndrome is characterized by circulating antiphospholipid antibodies against cardiolipin (CL) and phosphatidylserine (PS) and clinically associated with a high risk of spontaneous thrombosis. Three monoclonal antibodies that differentiate between CL or PS were tested against resting and thrombin-activated platelets by flow cytometry. Each antibody reacted differently with CL and PS; 3SB9b reacted with PS, D11A4 reacted with CL, and BA3B5C4 reacted with both CL and PS. Activated platelets bound BA3B5C4 and 3SB9b, but not D11A4. The BA3B5C4-reactive epitope appeared earlier during activation than the epitope reactive with 3SB9b. These data suggest that antibodies against PS are reactive with activated platelets and that two immunoreactive forms of PS are sequentially expressed on platelets during activation.
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PMID:Immunologic detection of phosphatidylserine externalization during thrombin-induced platelet activation. 843 44

Two girls, 22 months and 12 years of age, presented with repeated cerebral infarctions in association with primary antiphospholipid syndrome. The younger patient also suffered from protein C deficiency, while the other one had protein S and complement C4 deficiencies. All other causes of cerebral infarction were excluded; however, vasculitis remains a possibility in one patient. Both girls developed spastic tetraparesis as a sequela of the previous infarctions. The two patients were treated with aspirin and prednisone, with remission of the infarctions during the next 8 months of observation. A primary deficiency of protein C or S is proposed which would produce cerebral thrombosis with exposure of phospholipids; this thrombosis then, like antigens, would generate antibodies acting on the thrombin-thrombomodulin complex, exacerbating the thrombotic process. The association of complement C4 deficiency is an additional risk factor.
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PMID:Childhood stroke associated with protein C or S deficiency and primary antiphospholipid syndrome. 845 4


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