Enhanced monocyte expression of tissue factor by oxidative stress in patients with antiphospholipid antibodies: effect of antioxidant treatment

Abstract

Summary. In a first study, we performed a cross-sectional analysis of urinary excretion of isoprostanes, IPF 2a-III and VI , and monocyte tissue factor (TF) antigen and activity between 11 antiphospholipid (APL) antibody-positive patients and 13 APL negative subjects. In a second study, 11 APL positive patients were randomly supplemented either with (n ¼ 6) or without (n ¼ 5) antioxidants (vitamin E at 900 IU day À1 , vitamin C at 2000 mg day À1 ) for 6 weeks. In a third study, TF and superoxide anion were measured in human monocytes incubated with antib 2 glycoprotein 1 (b 2 GP 1 ) or control IgG, either with or without vitamin E. APL-positive patients had higher values of isoprostanes (P < 0.05) and monocyte TF antigen (P ¼ 0.001) and activity (P ¼ 0.0001) than APL-negative subjects. Only in APL positive patients did monocyte TF antigen correlate significantly with IPF 2a-III (rho 0.79; P < 0.003) and IPF 2a-VI (rho ¼ 0.87; P < 0.0001). In patients who received antioxidant supplementation, we found a significant decrease of isoprostanes (P < 0.05) and monocyte TF antigen (P < 0.01) and activity (P < 0.007). In vitro experiments demonstrated that anti-b 2 GP 1 antibodies dose-dependently enhanced the monocyte production of the superoxide anion and TF, which were significantly inhibited by vitamin E. This study demonstrates that in APL-positive patients, oxidative stress contributes to activate the clotting system via over-expression of monocyte TF. We suggest that anti-b 2 GP 1 antibodies could play a pivotal role by enhancing the monocyte production of oxygen free radicals.

Human antiphospholipid antibodies induce TNFα in monocytes via Toll-like receptor 8

“…It is well accepted that aPL promote thrombosis by interfering with normal cell surface haemostatic mechanisms and by inducing proinflammatory and procoagulant cellular phenotypes tissue factor by aPL in endothelial cells and monocytes (Ferro et al 2003;Giannakopoulos et al 2007). …”

“…The aPL are a very heterogeneous group of autoantibodies with an antigen specificity that still remains elusive, although their binding to different negatively charged phospholipids such as cardiolipin and phosphatidylserine and to protein binding cofactors like b-2-glycoprotein I (b2GPI) (Shoenfeld 2003) is well known. One of the mechanisms proposed for aPL is the stimulation of tissue factor (TF) expression in endothelial cells and monocytes (Roubey 2000;Ferro et al 2003;Kornberg et al 1994). TF as the main initiator of the coagulation cascade could therefore be one of the strongest triggers of thrombosis in the pathophysiology of APS (Lopez-Pedrera et al 2006).…”

Redox‐regulation of haemostasis in hypoxic exercising humans: a randomised double‐blind placebo‐controlled antioxidant study

“…Furthermore, studies in patients with antiphospholipid syndrome, which promotes a hypercoagulable state, have demonstrated that coagulation is activated by oxidative stress via overexpression of monocyte tissue factor (Ferro et al . ). Without the analysis of PF1+2 and T‐AT, these data would suggest increased coagulation activation and support the hypoxic findings of Wang and colleagues (2009).…”

Evaluation of the hypolipidemic activity of 6,7-dimethoxycoumarin on placental tissue factor mRNA expression in experimental anti-phospholipid syndrome

“…[21] It has been observed that enhanced TF expression on the monocytes in response to activated platelets during oxidative stress condition, followed by supplementation of antioxidants significantly decreased monocytes TF antigen and its activity. [22] 6,7-dimethoxycoumarin has already been proven that it has the capability of reducing superoxide anion-mediated TF expression and avert disseminated intravascular coagulation. [19] It is clear from our study that 6,7-dimethoxycoumarin significantly reduced aCL antibody-mediated TF overexpression in placenta, and increased the platelet count to be comparable with negative control mice (normal level).…”