EC:3.4.21.69 - FACTA Search

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Query: EC:3.4.21.69 (APC)
16,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Autoantibodies to beta2-glycoprotein I (beta2GPI) are believed to be the primary cause of coagulation abnormalities in patients with antiphospholipid syndrome (APS). Clinical features include a range of life-threatening thrombotic events and microangiopathies affecting multiple organ systems. Current standard of care relies on long-term, high-intensity anticoagulation and is associated with a high risk for serious bleeding events. The relation between autoantibodies and the pathophysiology of APS is not clearly understood, but numerous in vitro studies have characterized the effects of antiphospholipid autoantibodies on various components of the coagulation cascade, including tissue factor and the protein C pathway. The fine specificity of autoantibodies to beta2GPI is a subject of considerable debate; however, a body of evidence may offer resolution by integrating concepts of antibody affinity and assay sensitivity with carefully designed molecular studies. An investigational new therapy for APS is based on the approach that pathogenic antibodies may be reduced via depletion of circulating autoantibodies and induction of immune tolerance at the B-cell level. Preliminary results from a phase I/II clinical trial with LJP 1082, a B-cell toleragen, indicate the drug was well tolerated and may warrant further development for reduction of thrombotic events in patients with APS.
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PMID:Therapeutic potential of toleragens in the management of antiphospholipid syndrome. 1537 72

Beta2-glycoprotein-I (beta2GPI) is a phospholipid-binding plasma protein that consists of five homologous domains. Domain V is distinguished from others by bearing a positively charged lysine cluster and hydrophobic extra C-terminal loop. Beta2GPI has been known as a natural anticoagulant regulator. Beta2GPI exerts anticoagulant activity by inhibition of phospholipid-dependent coagulation reactions such as prothrombinase, tenase, and factor XII activation. It also binds factor XI and inhibits its activation. On the other hand, beta2GPI inhibits anticoagulant activity of activated protein C. According to the data from knockout mice, beta2GPI may contribute to thrombin generation in vivo. Phospholipid-bound beta2GPI is one of the major target antigens for antiphospholipid antibodies present in patients with antiphospholipid syndrome (APS). Binding of pathogenic anti-beta2GPI antibodies increases the affinity of beta2GPI to the cell surface and disrupts the coagulation/fibrinolysis balance on the cell surface. These pathogenic antibodies activate endothelial cells via signal transduction events in the presence of beta2GPI. Impaired fibrinolysis has been reported in patients with APS. Using a newly developed chromogenic assay, we demonstrated lower activity of intrinsic fibrinolysis in euglobulin fractions from APS patients. Addition of monoclonal anti-beta2GPI antibodies with beta2GPI also decreased fibrinolytic activity in this assay system. beta2GPI is proteolytically cleaved by plasmin in domain V (nicked beta2GPI) and becomes unable to bind to phospholipids, reducing antigenicity against antiphospholipid antibodies. This cleavage occurs in patients with increased fibrinolysis turnover. Nicked beta2GPI binds to plasminogen and suppresses plasmin generation in the presence of fibrin, plasminogen, and tissue plasminogen activator (tPA). Thus, nicked beta2GPI plays a role in the extrinsic fibrinolysis via a negative feedback pathway loop.
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PMID:Beta2-glycoprotein I, anti-beta2-glycoprotein I, and fibrinolysis. 1550 79

BACKGROUND: D-dimer is considered a marker of hypercoagulable state and of endogenous fibrinolysis, so increased d-dimer is detectable in patients affected by thrombosis. Yet, several studies showed that also infertility, in particular secondary infertility due to recurrent fetal losses, has been often related to thrombotic events, in particular in women carrying thrombotic risk factors such as inherited thrombophilia (MTHFRC677T, PTHRA20210G, Factor V Leiden polimorphisms and/or inhAfter this screening we selected 39erited protein C, protein S, AT III deficiency) or acquired thrombophilia (primary antiphospholipid syndrome, acquired protein C, protein S, AT III deficiency, drugs induced thrombophilia). However, because its high predictive negative value in case of suspected thrombosis, increased d-dimer has been often associated to subclinical thrombophilia. The aim of this study is to investigate the role of d-dimer as first marker of thrombophilia in women affected by unexplained infertility and subsequently to search the cause of increased d-dimer, such as inherited and/or acquired thrombophilia. PATIENTS AND METHODS: We selected 79 patients with unexplained primary or secondary infertility. We excluded 40 patients affected by hydrosalpinx, uterine fibroids, uterine malformations, endocrinological and immunological diseases, luteal insufficiency, cytogenetical alterations. All remaining 39 patients were tested for d-dimer and divided in two groups: the patients of group A (25 patients) showed increased plasma d-dimer, in group B were included 14 patients with normal plasma level of d-dimer. After this step all 39 patients were screened for MTHFRC677T, PTHRA20210G, Factor V Leiden polimorphisms, protein C, protein S, AT III, anticardiolipin IgM and IgG, lupus anticoagulant. In the control group were included 15 age matched women without sterility problems referred to our outpatient's section of vascular medicine for suspected deep venous thrombosis.Statistical analysis was based on chi2 test, differences were considered to be significant if p < 0.05. RESULTS: D-dimer was increased in 25/39 and 20/25 showed inherited/acquired thrombophilia while patients with normal d-dimer showed inherited/acquired thrombophilia in 7/14 (p: < 0.05, s). DISCUSSION: D-dimer is a well known marker of hypercoagulable state, in particular its high predictive negative value in case of suspected thrombosis has been recognised by several reports. Yet, increased d-dimer has been identified also for subclinical thrombophilia besides for vascular thrombosis. Our data, in fact, for the first time suggest an interesting role of d-dimer to identify women affected by unexplained primary or secondary infertility and thrombophilia. So, probably there is a role for d-dimer in these subjects for its predictive positive value. Of course, further data on large based population are needed to confirm our results, because these findings may speed up a diagnostic screening in these patients also for a good cost/effectiveness of this test.
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PMID:The role of d-dimer as first marker of thrombophilia in women affected by sterility: implications in pathophysiology and diagnosis of thrombophilia induced sterility. 1553 89

Antiphospholipid syndrome (APS) is characterized by arterial and/or venous thrombosis and pregnancy morbidity in the presence of antiphospholipid antibodies (aPL). Beta2-glycoprotein I (beta2-GPI) and prothrombin are representative autoantigens, the former more extensively investigated. Anti-beta2-GPI antibodies are not only markers of APS, but also are considered to be pathogenic. Possible roles of anti-beta2-GPI antibodies are, 1) enhancement the binding of beta2-GPI to anionic phospholipid and inhibition of protein C activation/activated protein C, 2) to form anti-beta2-GPI antibody-beta2-GPI-oxidized LDL complex and to promote uptake by sub-endothelial macrophage, resulting in atherosclerosis, 3) to dimerize beta2-GPI on the surface of platelets and to activate platelets via apoE receptor 2 and subsequent signal transduction, 4) stimulation of monocytes via p38 MAP kinase pathway and induction of tissue factor production. In pregnancy morbidity, activation of complement cascade plays an important role. These findings may provide a novel target in the management of APS.
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PMID:[Pathogenic roles of anti-beta2-GPI antibody in patients with antiphospholipid syndrome]. 1567 90

Thrombophilias may be inherited or acquired, continuing or transient, and may contribute strongly or weakly to thrombosis. They may predispose to venous thromboembolism alone or also to artery occlusion. Advice on management must recognize these variations. The presence of an inherited thrombophilia should not alter the intensity of anticoagulant therapy, given that antithrombin, protein C, or protein S deficiency, factor V Leiden, and the prothrombin G20210A mutation are not unusually anticoagulant resistant. However, they can increase the optimal treatment duration after a first thromboembolic event. Optimal duration depends on the balance between thrombosis risk off treatment and bleeding risk during extended anticoagulant therapy, and needs to be separately estimated for each individual with thrombosis and thrombophilia. The higher the thrombosis risk and the lower the bleeding risk, the longer the optimal treatment duration. This balance favors continued (but perhaps not indefinite) therapy in antithrombin, protein C, and protein S deficiency, and perhaps also in patients with the factor V Leiden or prothrombin mutations if their bleeding risk is low. Thrombosis that complicates active malignancy, the antiphospholipid syndrome, or heparin-induced thrombocytopenia needs special consideration: recent clinical trials suggest that low molecular weight heparins are more effective than warfarin in thrombosis with cancer, and that a more intense warfarin effect is not needed for patients with antiphospholipid syndrome and thrombosis. Debate continues about the place of screening for presymptomatic but affected relatives of patients with thrombosis and an inherited predisposition. It is essential that any family testing be done only with the informed consent of all concerned. Given consent, there is general support for family testing in antithrombin, protein C, or protein S deficiency and where the factor V Leiden or prothrombin mutation is strongly penetrant and expressed. There is, however, a strong argument that any testing in families in which clotting factor polymorphisms are weakly expressed should be restricted to young women when they consider hormonal contraception or pregnancy, given that these acquired factors multiply the risk.
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PMID:Management options for thrombophilias. 1570 84

Catastrophic antiphospholipid syndrome (CAPS) is a severe and rare variant of antiphospholipid syndrome (APS) characterized by acute multiorgan failure due to small vessel thrombi in patients with positive antiphospholipid antibodies. We report a fatal case of catastrophic antiphospholipid syndrome in a young woman with a history of polymyositis and Hodgkin lymphoma. The patient was admitted to hospital because of severe foot pain following several weeks of skin ulcerations. Doppler ultrasonography showed evidence of arterial ischemia of the both lower extremities. Despite anticoagulation, immunosuppression, plasmapheresis and antibiotic therapy, she developed cutaneous gangrene, retroperitoneal hematoma, ileus, and acute respiratory and renal failure that resulted in death. Autopsy showed multifocal vascular injury and microthrombi with associated hemorrhages and infarcts in multiple organs. The patient had normal levels of functional protein C and protein S and a normal level of plasma homocysteine. Tests for common thromophilic gene mutations including prothrombin 20210, factor V Leiden 1691, and methylene tetrahydrofolate reductase 677 were negative. To our knowledge, this is the first CAPS patient with molecular studies for genetic prothrombotic mutations. Our report showed that there was no association between the development of CAPS and inherited thromophilia.
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PMID:Catastrophic antiphospholipid syndrome: a rare cause of disseminated microvascular thrombotic injury - a case report with pathological and molecular correlative studies. 1574 23

Making decisions about any modality of secondary prophylaxis in patients with venous thromobembolism (VTE) has to balance the risk of bleeding induced by anticoagulants against the benefit of reducing the risk of recurrent disease. It has to be kept in mind that the magnitude of risk is not only defined by the number of events per time period but also by the impact of the event on the fate of the patient. With standard intensity Vitamin K antagonists, the risk of bleeding is more closely related to comorbidities than to other factors, e.g. age. The risk of VTE recurrence differs largely between patient groups. The criterion of presence, or absence of a permanent or transient clinical trigger factor for the actual VTE episode has a greater impact than an abnormal result in thrombophilia testing. The standard period ofsecondary prophylaxis for proximal deep vein thrombosis and for pulmonary embolism is three to six months. The concept of prolonging this period for several months according to the risk of recurrence is seriously challanged by the observation that the prolongation period seems to delay recurrencies rather than truly avoiding them. For this reason, patients who clearly are threatened by recurrent episodes should receive indefinitive secondary prophylaxis. This is the case for cancer patients, patients with the antiphospholipid syndrome, and those who belong to families with severe and symptomatic protein C, protein S, or antithrombin deficiencies. Patients with recurrent VTE, with idiopathic VTE, or with combined thrombophilic conditions may only benefit from indefinitive secondary prophylaxis if the bleeding risk of the anticoagulant regimen under consideration is very low.
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PMID:Secondary prophylaxis of venous thromboembolism. 1578 31

Activated protein C (APC) anticoagulant activity and the ability to be inhibited by auto-antibodies associated with thrombosis are strongly augmented by the presence of phosphatidylethanolamine (PE) and phospholipid oxidation. beta(2)-glycoprotein I (beta(2)-GPI) is a major antigen for antiphospholipid antibodies present in patients with the antiphospholipid syndrome. We therefore investigated whether anti-beta(2)-GPI monoclonal antibodies (mAbs) could inhibit APC with similar membrane specificity. Five mouse mAbs that reacted with different epitopes on beta(2)-GPI were examined. Each inhibited the PE-, phospholipid oxidation-dependent enhancement of APC anticoagulant activity and required antibody divalency. A chimeric APC that retains anticoagulant activity but is relatively unaffected by protein S, PE, or oxidation was not inhibited by the antibodies. In purified systems, anti-beta(2)-GPI mAb inhibition of factor Va inactivation was greater in the presence of protein S and required beta(2)-GPI. Surprisingly, although the mAbs did increase beta(2)-GPI affinity for membranes, PE and oxidation had little influence on the affinity of the beta(2)-GPI antibody complex for the membrane vesicles. We conclude that antibodies to beta(2)-GPI inhibit APC function specifically and contribute to a hypercoaguable state by disrupting specific protein-protein interactions induced by oxidation of PE-containing membranes.
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PMID:Inhibition of APC anticoagulant activity on oxidized phospholipid by anti-{beta}2-glycoprotein I monoclonal antibodies. 1589 Jun 86

Immunoglobulin G (IgG) isolated from the blood plasma of a patient with secondary antiphospholipid syndrome (APS) expresses fibrinogen-clotting and amidolytic activity (the thrombin activity in 20 micromole IgG is equivalent to approximately 5 nmole pure thrombin), and activates factor XIII. Hirudin (1 microM) decreases the intrinsic thrombin activity of the APS IgG by only 25%, whereas it inhibits completely pure thrombin with equivalent activity. Under conditions, when antithrombin inactivates 60% of the thrombin activity in the presence of normal IgG, the APS IgG protects almost completely the added thrombin against inactivation by antithrombin. Heparin, however, partially relieves this protective effect and at the same time it facilitates the inhibition of the intrinsic thrombin activity by antithrombin. The APS IgG reduces the thrombin activity in protein C activation assay by 50% compared to the activity in the presence of normal IgG. All described properties are related to the Fab fragment of the antibody. The IgG preserving the fibrin-generating activity of thrombin with concomitant protection against inhibitors unravels a new aspect of the thrombotic mechanism in APS. This condition is probably rare: only one out of 23 examined patients with primary or secondary APS expresses IgG with the described properties.
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PMID:Impaired inactivation by antithrombin and hirudin and preserved fibrinogen-clotting activity of thrombin in complex with anti-thrombin antibody from a patient with antiphospholipid syndrome. 1611 88

Antiphospholipid syndrome (APS) is characterized by recurrent thrombosis or pregnancy morbidity associated with antiphospholipid antibodies (aPL). Impaired fibrinolysis is a contributing factor for the development of thrombosis, and the effect of aPL in the fibrinolytic system has been investigated. Impaired release of tPA and enhanced release of PAI-1 after endothelial activation is reported in patients with APS. Elevated Lipoprotein (a) levels have been found in APS, which results in inhibition of fibrinolytic activity. Phospholipid-bound beta(2)-glycoprotein I (beta(2)GPI) is a major autoantigen for aPLs. beta(2)GPI exerts both anti-coagulant and pro-coagulant properties mainly by interacting with other phospholipid-binding proteins such as coagulation factors and protein C. Dramatic increase in the affinity of beta(2)GPI to the cell surface is induced by binding of pathogenic anti-beta(2)GPI antibodies, which may modify the physiological function of beta(2)GPI and may affect the coagulation/fibrinolysis balance on the cell surface. Using chromogenic assays for measuring fibrinolytic activity, we demonstrated that addition of monoclonal anticardiolipin antibody (aCL) decreases the activity of extrinsic/intrinsic fibrinolysis. Significantly lower activity of intrinsic fibrinolysis was also demonstrated in the euglobulin fractions from APS patients. Endothelial cells and monocytes are activated by aPLs in vitro, resulting in production of tissue factor (TF), a major initiator of the coagulation system. Recently, aPLs are reported to induce thrombocytes to produce thromboxane. The importance of apoE receptor 2 on platelets for the binding of artificially dimerized beta(2)GPI was suggested. By investigating aPL-inducible genes in peripheral blood mononuclear cells, we found that the mitogen-activated protein kinase (MAPK) pathway was up-regulated. Using a monocyte cell line, phosphorylation of p38 MAPK, NF-kappaB translocation to the nuclear fraction, and up-regulated TF mRNA expression were demonstrated after treatment with monoclonal aCL. These phenomena were observed only in the presence of beta(2)GPI. Moreover, a specific p38 MAPK inihibitor SB203580 decreased aCL/beta(2)GPI-induced TF mRNA expression. Thus, aCL/beta(2)GPI plays dual roles in the pathogenesis of APS, firstly by deranging the fibrinolytic system and secondly by activating monocytes, endothelial cells and thrombocytes to produce TF or thromboxane.
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PMID:Pathogenesis of antiphospholipid antibodies: impairment of fibrinolysis and monocyte activation via the p38 mitogen-activated protein kinase pathway. 1632 97

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