Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0409974 (lupus)
 22,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This review has stressed the common hereditary and acquired blood protein defects associated with thrombosis. The most common of the hereditary defects appear to be antithrombin, protein C, and protein S deficiency, and the most common acquired defects are anticardiolipin antibodies and the lupus anticoagulant. Therefore, these are the defects which should first be searched for in an individual with unexplained thrombosis. If these more common defects are not found, the rarer defects, including HC-II, plasminogen, or TPA deficiency, dysfibrinogenemia, elevated PAI-1, or heterozygous homocystinemia should be looked for. The incidence of activated protein C co-factor deficiency (APC resistance) is not yet clear but may also represent a common defect. PAI-1 defects may, with time, be shown to be common. Finding these defects has important implications for therapy for the individual patient and for the institution of family studies to identify, inform, and possibly treat others at risk. It is expected that as knowledge of hemostasis expands, more hereditary and acquired defects, such as elevated lipoprotein(a) or defects of extrinsic (tissue factor) pathway inhibitor (EPI, TFPI), may be associated with enhanced risks for thrombosis.
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PMID:Blood protein defects associated with thrombosis. Laboratory assessment. 778 Dec 75

Some researchers claim that lupus anticoagulant-positive plasma may cause a false-positive reaction in the test for activated protein C (APC) resistance, a hereditary thrombophilic state characterized by abnormal factor V, which frequently causes venous thrombosis. We investigated whether anti-beta 2-glycoprotein I antibody (aGPI), which has recently come to be regarded as an anti-cardiolipin antibody (aCL) itself, might have an effect on the APC resistance test.
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PMID:Resistance to activated protein C activity of an anti-beta 2-glycoprotein I antibody in the presence of beta 2-glycoprotein I. 778 85

The mouse model described in this study offers a unique method of determining the characteristics and mechanism(s) of action of aCL antibodies in thrombosis in vivo. In addition, this animal model enables the study of the kinetics of formation and dissolution of thrombus, as well as clot area, to be studied in a dynamic fashion. Other models for evaluation of thrombus formation rely on measurements of thrombus size and weight in ligated vessel segments where flow may be interrupted artificially. In addition, two important findings can be extracted from the study. (1) The size of the thrombi were significantly larger in mice that were passively immunized with IgG-APS (four patient samples examined) and with IgM-APS (two patient samples examined) compared with mice injected with saline or with immunoglobulin from control patients. (2) The clot persisted significantly for longer periods of time (total time) in animals injected with IgG-APS or IgM-APS when compared with control animals. Based on in vitro experiments, it is possible that these antibodies may inhibit protein C activation, neutralize the inhibitory activity action of beta 2 glycoprotein I (beta 2GPI), or activate platelets at the site of the femoral vein injury. Because this model enables to study the dynamics of thrombus formation, it is possible that these hypotheses and other mechanisms by which aPL antibodies are thrombogenic be investigated. Future studies will also include the effects of different levels of antibodies, as well as effects of affinity purified and monoclonal aPL antibodies on thrombus formation.
Lupus 1994 Aug
PMID:Antiphospholipid antibodies in an in vivo thrombosis model in mice. 780 10

Phosphatidylethanolamine (PE) is an important membrane component for supporting activated protein C anticoagulant activity but has little influence on prothrombin activation. This difference constitutes a potential mechanism for selective inhibition of the protein C anticoagulant pathway by lupus anticoagulants and/or antiphospholipid antibodies. In this study, we demonstrate that the presence of PE augments lupus anticoagulant activity. In the plasma of some patients with lupus anticoagulants, activated protein C anticoagulant activity is more potently inhibited than prothrombin activation. As a result, in the presence of activated protein C and PE, these patient plasmas clot faster than normal plasma. Patients with minimal lupus anticoagulant activity are identified whose plasma potently inhibits activated protein C anticoagulant activity. This process is also PE dependent. In three patient plasmas, these phenomena are shown to be due to immunoglobulins. The PE requirement in the expression of activated protein C anticoagulant activity and the PE dependence of some antiphospholipid antibodies provide a mechanistic basis for the selective inhibition of the protein C pathway. Inhibition of activated protein C function may be a common mechanism contributing to increased thrombotic risk in certain patients with antiphospholipid antibodies.
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PMID:On the role of phosphatidylethanolamine in the inhibition of activated protein C activity by antiphospholipid antibodies. 781 31

Resistance to Activated Protein C (APC) was evaluated using 3 different methods: two of them were based on the prolongation of the Activated Partial Thromboplastin Time (APTT) using 2 different APTT reagents in the presence of APC, whereas the third method was based on the prolongation of prothrombin time when APC is added. The three methods were significantly correlated. APTT-based assays were sensitive to factor XII deficiency, whereas thromboplastin-based assay was sensitive to factor VII deficiency (< 0.5 UI/ml), which surestimates the response to APC. In contrast, an increase in factor VIII (F. VIII) level is associated with a decreased response to APC, when APTT-based assays are used, whereas thromboplastin-based assay is unmodified. During pregnancy, a decreased response to APC is observed, which is not only due to the increase in F. VIII, since thromboplastin-based assay is also modified. In Protein S (PS) immuno-depleted plasma, the low response to APC is corrected by addition of free PS: the thromboplastin-based assay was the most sensitive one to PS deficiency. However, in patients with congenital PS deficiency, there was no correlation between APC-resistance and free PS level. In patients with lupus anticoagulant, discrepancies were observed between the 3 methods, but with a high frequency of low response to APC. For the 3 assays, there was a good differentiation and correlation between normal and pathological results, the thromboplastin-based assay being perhaps the most discriminating. However, 3 unrelated thrombophilic patients showed normal results using thromboplastin-based assay, although they were APC-resistant using APTT-based assays. For 2 patients, this discrepancy can be explained by high levels of F. VIII. For the last patient, an abnormal F. VIII, resistant to APC can be suspected.
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PMID:Resistance to activated protein C: evaluation of three functional assays. 781 60

Lupus anticoagulants (LAs) are acquired antiphospholipid antibodies, and the occurrence of LA is associated with an increased risk of developing thrombosis. In a population of 46 patients with LA with or without LA-associated thrombophilia, it was analyzed whether the concentration of LA could be correlated to the individual thrombotic risk in patients with LA. No significant difference was found in the concentrations of LA measured by routinely used functional and immunologic assays in patients with LA with thrombophilia when compared with patients with LA without thrombophilia. Inhibition of thrombomodulin (TM) activity by LA has been postulated to be one of the major pathogenic mechanisms causing thrombophilia in LA. Therefore the inhibition of endothelial cell-dependent TM activity by LA was analyzed by using a protein C (PC) activation assay. Reduced rates of PC activation were found in only 2 out of the 46 cases, ruling out that inhibition of TM activity is a common phenomenon in patients with LA. However, anionic phospholipids are necessary to ascertain the anticoagulant activity of activated PC (APC). To prove the hypothesis that the anticoagulant activity of APC is inhibited by LA, the anticoagulant response of purified APC added to LA-containing plasma was measured through the amount of factor VIII inactivation. Thirteen out of 14 patients with recurrent thrombotic events and 10 out of 19 patients with one single episode of thrombosis showed an APC response outside the mean--2 SD range of normal human controls. In contrast, among 13 patients with LA without symptoms, only one showed an abnormal APC response. From these data it is concluded that LA inhibits the APC anticoagulant activity and that this type of acquired APC dysfunction may contribute to the pathogenesis of LA-associated thrombophilia. Moreover, the APC anticoagulant response assay may prove to be a useful marker to identify patients with LA with a high thrombotic risk.
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PMID:Acquired protein C dysfunction but not decreased activity of thrombomodulin is a possible marker of thrombophilia in patients with lupus anticoagulant. 782 42

Antiphospholipid antibodies are a diverse group of immunoglobulins initially thought to have specificity to phospholipid epitopes. It is apparent that autoimmune anticardiolipin antibodies require a serum cofactor beta-2-glycoprotein I (beta 2GPI) for their binding to phospholipids. Lupus anticoagulant also may bind to phospholipids by beta 2GPI or by prothrombin. The description of binding to protein-phospholipid epitopes may explain several perplexing features of these antibodies both in vitro and in vivo. Antiphospholipid antibodies have a well-established association with clinical disease--in particular thrombosis, thrombocytopenia and recurrent fetal loss. The mechanism of the predisposition to thrombosis seen with these antibodies is poorly understood. It has been suggested that they may cause endothelial dysfunction by causing increased tissue factor expression, by inhibiting prostacyclin secretion or by inhibiting fibrinolysis. Various platelet-activating activities have also been described. The evidence that antiphospholipid antibodies promote thrombosis by effects on endothelium or platelets is inconclusive. Inhibition of protein C activation, or of activated protein C action, has been demonstrated in vitro. A poor correlation between thrombosis in vivo and these inhibitory effects has been found. Beta-2-glycoprotein I has been identified as a cofactor for binding to phospholipid by thrombogenic anticardiolipin antibodies. That beta 2GPI may be a natural anticoagulant of importance remains to be proved. Inhibition by antiphospholipid antibodies of this anticoagulant function could explain the propensity to thrombosis seen in association with these antibodies.
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PMID:Antiphospholipid antibodies and thrombosis. 784

Resistance to activated protein C (RAPC) has been described recently as a cause of trombophilia; this may justify up to 50% of thromboembolic disease without predisposing cause in patients under 45 years. A 29 years-old male with a previous deep venous thrombosis (DVT) in the lower left limb three years earlier, developed a DVT in the right lower limb after a trauma of the knee that required immobilization, was associated to pulmonary thromboembolism diagnosed by gammagraphic methods. The phlebographic study showed femoro-iliaco-caval venous thrombosis. The proband's father and a younger brother had a previous history of thrombotic episodes. The following tests, were performed in the proband and relatives: prothrombin time, aPTT, thrombin time, fibrinogen, (Von Clauss), antithrombin III (chromogenic), protein C and protein S (coagulometry and ELISA), plasminogen (chromogenic) and lupus anticoagulant (ITT, dRVVT, aCL). RAPC was evaluated in two different samples. The proband study was performed under oral anticoagulation treatment (OAT). Control groups were: 21 blood donors and 12 OAT patients. The results showed a decreased response to APC in the proband (ratio 1.5) and relatives: father (1.4), brothers (1.5 and 1.5), while the mother was within the normal range (> or = 2). In normal controls and OAT patients the ratio was over 2. No other abnormalities were detected in the assays performed. It is concluded that RAPC is the cause of this familial trombophilia. RAPC should be included in the evaluation study of trombophilia.
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PMID:[Familial thrombophilia due to resistance to activated protein C]. 798 58

The authors define pro-thrombotic states as conditions associated with a high frequency of thrombosis; this association is based on pathogenetic or simply clinical and epidemiological relationships. Thrombophilic states have well-defined, specific causes: antithrombin III, protein C and S and similar deficiencies for inherited thrombophilias, and lupus anticoagulant, antiphospholipid antibodies for the acquired forms. Another identifiable group is made up of several conditions predisposing to thrombosis (CPT) characterized by less specific and multiple mechanisms (e.g. malignancy, inflammatory bowel disease, nephrotic syndrome, diabetes, obesity, etc.). These conditions may induce thrombosis by themselves or contribute to its clinical onset in patients with true thrombophilic states. This is especially the case for patients who are taking contraceptive drugs, are pregnant, have undergone surgery or trauma. The term hypercoagulability states is by no means equivalent to either thrombophilia or CPT. In fact, hypercoagulability may be defined as "activation of blood coagulation" in the presence of specific markers such as fibrinopeptide A and prothrombin fragment F1 + 2. Hypercoagulability is therefore a laboratory rather than a clinical condition and can be a transient feature appearing during certain phases of thrombophilia or CPT. Lastly, conditions involving the presence of hemostatic risk factors for atherothrombosis are simply terms used to describe a statistical-epidemiological relationship between certain hemostatic variables (fibrinogen, factor VII, PAI, etc.) involving the risk of cardiovascular morbidity and mortality but not necessarily indicating a hypercoagulability state.
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PMID:Pro-thrombotic states and their diagnosis. 800 87

The intraglomerular presence of thrombomodulin (TM) was examined in 19 patients with lupus glomerulonephritis (GN). TM is a cell surface glycoprotein found on endothelial cells and plays a key role in the protein C anticoagulant pathway. Renal biopsy specimens of patients with lupus GN and several kinds of renal disease other than lupus GN, i.e., membranous GN, IgA GN, minimal change nephrotic syndrome (MCNS) and hemolytic uremic syndrome (HUS) were examined by indirect immunofluorescence, using three kinds of monoclonal antibodies against human TM: KA-2, KA-3 and KA-4. It has been reported that KA-3 and KA-4 bind to enzyme-digested TM as well as intact TM, while KA-2 recognizes intact TM only. In the glomeruli from both normal subjects and patients with MCNS, only very weak staining of TM was found. Patients with HUS showed negative TM staining in the glomeruli. In contrast, positive to strongly positive staining of KA-2 as well as of KA-3 and KA-4 was observed mainly along the capillary wall of glomeruli from patients with lupus GN. Some patients with non-lupus GN showed positive staining of these monoclonal antibodies, but the staining was far more intense in most patients with lupus GN than in the patients with non-lupus GN. Staining of albumin and transferrin by the indirect method was negative in all cases of lupus GN that showed positive staining of TM. There was no relationship between the intensity of TM staining and the degree of proteinuria, creatinine clearance or histologic types of lupus GN.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Enhanced presence of thrombomodulin in the glomeruli of lupus glomerulonephritis. 802 12


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