Anti‐tissue factor pathway inhibitor activity in patients with primary antiphospholipid syndrome

Abstract

Summary. The association between antiphospholipid antibodies and an increased risk of thrombosis in antiphospholipid syndrome (aPS) patients is probably caused by numerous mechanisms, including the effects of antibodies to phospholipid-binding proteins such as b 2 -glycoprotein I and prothrombin. In this study, we investigated the inhibition of tissue factor pathway inhibitor (TFPI) in 33 patients with primary antiphospholipid syndrome (PAPS). TFPI was measured in PAPS patients using an amidolytic assay, dependent on the generation of activated factor X (Fxa), and this was compared with 55 healthy subjects. Functional levels of TFPI (mean^SD) were significantly lower in PAPS patients (0´89^0´37 U/ml) than the control group (1´05^0´15 U/ml) (P 0´02). The difference was caused by a subset of five patients who had TFPI levels below the lower 99% confidence interval of the normal reference range, representing increased FXa generation in the assay system. IgG fractions were isolated from these five patients and five control subjects, then incorporated into normal plasma to measure FXa generation in the TFPI assay system. FXa generation was increased when polyclonal rabbit anti-human TFPI IgG (P , 0´0001) or PAPS IgG (P 0´0001) were added to normal plasma, demonstrating inhibition of TFPI. The apparent anti-TFPI activity demonstrated in the five subjects with PAPS in this study may represent a significant new mechanism for thrombosis in patients with aPS, as it implies that increased tissue factor FVIIa-mediated thrombin generation might occur.

Antigen Specificity and Clinical Relevance of Antiphospholipid Syndrome- Related Autoantibodies

“…Adams et al [124] have recently confirmed their previous data about the inhibitory effect of IgG fractions from APS against TFPI activity. The purified IgGs, however, demonstrated a variable ability to interfere with TF-induced in vitro thrombin generation.…”

Thrombin generation and factor X assays for the assessment of warfarin anticoagulation in thrombotic antiphospholipid syndrome

“…This could be attributed to the LA influence on the lag time, as the majority of APS patients were LA positive [18], or could reflect the effect of other aPL [18,35], particularly as prolonged lag times in the PNP mixing studies were limited to the 12 triple aPL positive APS patients. The presence of other antibodies found in APS patients, such as those directed against protein C, FX, FVII, tissue factor pathway inhibitor, that mainly have an effect on the initiation phase of coagulation, may also influence TG [34,[38][39][40]. Notably, TG testing highlighted a small subgroup of four APS patients (Fig.…”

Changes to fibrinolysis in patients with systemic lupus erythematosus are associated with endothelial cell damage and inflammation, but not antiphospholipid antibodies

“…APL antibodies have been demonstrated to induce a procoagulant state through endothelial cell, monocyte, and platelet activation, inhibition of antithrombotic proteins such as tissue factor pathway inhibitor and protein C, activation of complement, and inhibition of proteins of the fibrinolytic pathway, including plasminogen and tissue-type plasminogen activator (t-PA) [1,[10][11][12][13][14][15][16].…”