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

The association between antiphospholipid antibodies and an increased risk o f thrombosis in antiphospholipid syndrome (aPS) patients is probably caused by numerous mechanisms, including the effects of antibodies to phospholipi d-binding proteins such as beta (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 (PA-PS). TFPI w as measured in PAPS patients using an amidolytic assay, dependent on the ge neration 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 +/- 0.1 5 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 r eference range, representing increased FXa generation in the assay system. IgG fractions were isolated from these five patients and five control subje cts, 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 d emonstrated in the five subjects with PAPS in this study may represent a si gnificant new mechanism for thrombosis in patients with aPS, as it implies that increased tissue factor FVIIa-mediated thrombin generation might occur .