Tissue factor in the antiphospholipid syndrome
ABSTRACT Antiphospholipid (aPL) antibodies are clinically important acquired risk factors for thrombosis and pregnancy loss and are thought to have a direct prothrombotic effect in vivo. Data suggest that a major mechanism by which aPL antibodies contribute to thrombophilia is the upregulation of tissue factor (TF) (CD142) on blood cells and vascular endothelium. TF is the physiological trigger of normal blood coagulation and thrombosis in many hypercoagulable conditions. This article reviews the physiology of TF, the molecular regulation of TF expression and the effects of aPL antibodies on intravascular TF regulation and expression. Inhibition of TF and the pathways by which aPL antibodies induce TF expression are potentially attractive therapeutic targets in the antiphospholipid syndrome.
- SourceAvailable from: Enrique García-Hernández
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- "The interaction of the anti-b 2 GPI/b 2 GPI/PL complex in genetically susceptible individuals disturbs the homeostatic reactions by the activation of the vascular endothelium and platelets    . In endothelial cells there is an increased expression of adhesion molecules such as ICAM-1, VCAM-1 and E-selectin  , in addition to allowing the expression of tissue factor  and the production of proinflammatory cytokines such as IL-1b, IL-6, IL-8, TNF-a and MCP-1 perpetuating activation and inducing a prothrombotic state  . "
ABSTRACT: Several studies have shown that conformational changes of β2-glycoprotein I (β2GPI) when bound to negatively charged components expose cryptic epitopes and subsequent binding of anti- β2GPI from patients with antiphospholipid syndrome (APS). However, the role of the carbohydrate chains of β2GPI in this anti- β2GPI reactivity is poorly understood. We therefore studied the reactivity and inhibition of anti- β2GPI antibodies from APS patients with native, partially glycosylated β2GPI (pdβ2GPI; without sialic acid) and completely deglycosylated β2GPI (cdβ2GPI). To determine the potential biologic importance of these glycoforms and their interaction with anti-β2GPI in vitro, stimulation assays were performed with the U937 cell line. Circular dichroism (CD) and fluorescence anaylsis of the three β2GPI forms were also studied. We found an increased reactivity of anti-β2GPI against pdβ2GPI and cdβ2GPI compared to native β2GPI. Both deglycosylated β2GPI isoforms showed higher inhibition of the anti- β2GPI reactivity than the native protein in soluble-phase. Likewise, the antibody/β2GPI/glycoform complexes increased the synthesis of IL-6, IFNγ and TNFα and the expression of HLA-DR, CD14 and CD11c in U937 cells. CD and fluorescence studies of the glycoforms yielded considerable changes in the fluorescence signals. Our work suggests that the partial or complete removal of the carbohydrate chains uncover cryptic epitopes present in β2GPI. The differentiation and increased synthesis of pro-inflammatory cytokines by U937 cells in vitro may have pathogenetic implications.Biochemical and Biophysical Research Communications 09/2014; 453(1). DOI:10.1016/j.bbrc.2014.09.064 · 2.28 Impact Factor
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ABSTRACT: The antiphospholipid syndrome is a relatively common acquired cause of venous thrombosis. Up to 20% of cases of deep vein thrombosis, with and without pulmonary embolism, may be associated with antiphospholipid antibodies. These antibodies are typically detected in lupus anticoagulant assays and tests for anticardiolipin antibodies. Most antiphospholipid antibodies are directed against several phospholipid-binding plasma proteins. The most common antigens are beta2-glycoprotein I and prothrombin. Immunoassays using these purified antigens are now available. In addition to being markers for thrombotic risk, antiphospholipid antibodies have been shown to directly contribute to hypercoagulability in animal models and in various in vitro studies. Prevention of recurrent venous thrombosis in patients with the antiphospholipid syndrome requires long-term anticoagulation. The optimal intensity of warfarin therapy is an ongoing issue, but most clinicians currently favor a target INR in the 2.0 to 3.0 range. In certain patients, antiphospholipid antibodies may interfere with determination of the INR, requiring other approaches to monitor and adjust the warfarin dose. Low-dose aspirin is typically recommended for primary prevention of thrombosis in asymptomatic patients with moderate to high levels of antiphospholipid antibodies, although strong supporting data are lacking.Arteriosclerosis Thrombosis and Vascular Biology 04/2009; 29(3):321-5. DOI:10.1161/ATVBAHA.108.182204 · 5.53 Impact Factor
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ABSTRACT: Antiphospholipid antibodies (aPL) are a family of autoantibodies directed against phospholipid-binding plasma proteins, most commonly beta(2)-glycoprotein-I. Primary thrombosis prevention in persistently aPL-positive individuals requires a risk-stratified approach; elimination of reversible thrombosis risk factors and aggressive prophylaxis during high-risk periods are crucial. The effectiveness of aspirin in persistently aPL-positive patients without vascular involvement is not supported by data from prospective, controlled studies. For the secondary prevention of thrombosis in persistently aPL-positive individuals, the current recommendation is life-long warfarin; however, determining the intensity and duration of warfarin treatment, as well as the role of alternative anticoagulants, requires further research. The effectiveness of high-intensity anticoagulation in patients with antiphospholipid syndrome (APS) and vascular involvement is not supported by data from prospective, controlled studies. Patients with catastrophic APS usually receive a combination of anticoagulants, corticosteroids, intravenous immunoglobulin and plasma exchange; however, despite this aggressive approach, the mortality rate remains high. Potential new approaches for the management of persistently aPL-positive patients include hydroxychloroquine, statins, rituximab, complement inhibition, and other targeted therapies that have been effective in experimental APS models.Nature Clinical Practice Rheumatology 04/2009; 5(3):160-70. DOI:10.1038/ncprheum1017 · 5.85 Impact Factor