The pathogenesis of the antiphospholipid syndrome. N Engl J Med

Department of Infectious Diseases, Immunology, and Sexual Health, St. George Hospital, Kogarah, Sydney, NSW 2217, Australia.
New England Journal of Medicine (Impact Factor: 55.87). 03/2013; 368(11):1033-44. DOI: 10.1056/NEJMra1112830
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Available from: Steven Antony Krilis
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    • "The antiphospholipid syndrome (APS) is the most common acquired thrombophilia affecting both the arterial as well as the venous circulation. While there is broad consensus that the antiphospholipid antibodies (aPL) detected in these patients trigger the thrombotic events, the underlying mechanisms are still a matter of debate123456. This is related to the great heterogeneity of aPL. "
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    ABSTRACT: Background: There is general consensus that the antiphospholipid syndrome (APS) is caused by antiphospholipid antibodies (aPL) with antibodies against β2-glycoprotein-I being the most relevant. aPL which bind phospholipids in the absence of protein cofactors are generally considered pathogenetically irrelevant. We showed that cofactor independent human monoclonal aPL isolated from APS patients induce proinflammatory and procoagulant cellular responses by activating endosomal NADPH-oxidase-2 (NOX2). Similar aPL were detected in all IgG-fractions from APS patients analyzed. Objectives: We aimed to clarify if cofactor independent aPL can be thrombogenic in vivo and if so, whether these effects are mediated via activation of NOX2. Methods: Two cofactor independent human monoclonal aPL, HL5B and RR7F were tested in a mouse model of venous thrombosis. Genetically modified mice and in vitro assays were used to delineate the mechanisms underlying thrombus induction. Results: HL5B and RR7F dramatically accelerate thrombus formation in this mouse model. Thrombus formation depends on tissue factor activation. It cannot be induced in NOX2-deficient mice. Bone marrow chimeras of C57BL/6J mice reconstituted with NOX2 deficient bone marrow showed that leukocyte activation plays a major role in thrombus formation. Neither TLR4 signaling nor platelet activation by our aPL are required for venous thrombus formation. Conclusions: Cofactor independent aPL can induce thrombosis in vivo. This effect is mainly mediated by leukocyte activation which depends on the previously described signal transduction via endosomal NOX2. Since most APS patients have been shown to harbor aPL with similar activity, our data are of general relevance for the APS. This article is protected by copyright. All rights reserved.
    Full-text · Article · Jan 2016 · Journal of Thrombosis and Haemostasis
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    • "Antiphospholipid Syndrome (APS) is an autoimmune disorder characterized by ischemic vascular events both in arterial and venous compartment [1] Venous thromboembolism (VTE) and cerebral ischemia represent the most frequent complications of APS. Patients positive for anti-phospholipid antibodies have a low risk to develop thrombotic events (<1%/year), but after a first episode of venous thromboembolism, or after the interruption of anticoagulation the risk dramatically increases by 10e67% [2]. "
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    ABSTRACT: Background and aims: Antiphospholipid Syndrome (APS) is often complicated by ischemic vascular events. Vitamin K Antagonists (VKAs) reduce the risk of recurrent thrombosis. Quality of VKAs treatment, as assessed by the Time in Therapeutic Range (TTR), has never been investigated in APS patients. Methods: We performed a prospective observational study including 30 APS and 30 Atrial Fibrillation (AF) patients balanced by age and gender. All patients were treated with VKAs (INR target 2.5), and TTR was calculated. Results: Median TTR of APS was 53.5% vs. 68% of AF patients (p = 0.001). A multivariable linear regression analysis confirmed that the presence of APS (vs. AF) was independently associated with a worse TTR (B: -14.067, 95% Confidence Interval -25.868/-2.266, p = 0.020). The weekly dosage of VKAs was significantly higher in APS than AF patients. Conclusions: APS patients disclose a lower quality of anticoagulation compared to those with AF, requiring higher doses of VKAs. The efficacy of non-vitamin K oral anticoagulants in this high-risk patients should be tested.
    Full-text · Article · Oct 2015 · Atherosclerosis
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    • "Les mécanismes responsables sont multifactoriels et encore mal connus. Le processus inflammatoire intrinsèque, l'activation du complément, le stress oxydatif, l'inhibition de la production endothéliale d'oxyde nitrique, l'activation plaquettaire par les Ac anti-2-glycoprotéine 1, l'augmentation de l'expression du facteur tissulaire sont autant de mécanismes impliqués dans le SAPL [6] [7]. À côté des événements thrombotiques, existent des lésions vasculaires avec épaississement intimal, notamment impliquées dans la néphropathie associée au SAPL. "
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    ABSTRACT: Introduction: Antiphospholipid syndrome is an autoimmune disorder causing venous and arterial thrombosis. Acute coronary complications are rare but potentially dramatic. Case report: We report a 39-year-old woman who presented with an acute anterior myocardial infarction after intravenous corticosteroids as part of the treatment of lupus arthritis and revealing antiphospholipid syndrome. Emergency coronary angiography was performed with drug-eluting stent angioplasty despite the need for anticoagulation and dual antiplatelet therapy. Conclusion: Antiplatelet and anticoagulant therapy management is pivotal in patients with antiphospholipid syndrome and acute coronary syndrome to prevent thrombosis recurrence.
    Full-text · Article · Sep 2015 · La Revue de Médecine Interne
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