Tissue factor pathway inhibitor (TFPI) plays a critical role in the regulation of tissue factor-induced blood coagulation. This has been corroborated by gene knock-out experiments in mice and TFPI immunodepletion experiments in rabbits challenged with tissue factor. Numerous clinical studies, however, have been unable to establish an association between low TFPI levels and venous thrombosis.
Dahm and colleagues (page 4387) evaluated cases and controls from the Leiden Thrombophilia Study and found that low TFPI levels are a significant, albeit weak, risk factor for a first episode of deep venous thrombosis. The relationship was strongest for free TFPI but was also found for total TFPI antigen and activity. Measuring TFPI is a complex undertaking given that there are free and bound plasma pools of the inhibitor, as well as the presence of a large endothelial-associated pool, which may be the most important pool from a physiologic standpoint. The latter pool, however, is difficult to evaluate clinically, although it can be assessed following its release into the plasma by heparin.
A major confounding variable in studies of TFPI and thrombotic risk is use of exogenous estrogens, which is itself a known risk factor. Oral contraceptives and hormone replacement therapy lower TFPI levels substantially in women. This effect is taken into account in the analysis by Dahm and colleagues by excluding women using oral contraceptives at the time of blood sampling. The extent to which the lowering of TFPI levels by oral contraceptives contributes to the thrombotic risk associated with oral contraceptives is unknown.
The Leiden Thrombophilia Study has previously yielded positive associations between venous thrombotic risk and high levels of factor VIII, factor IX, factor XI, and thrombin-activatable fibrinolysis inhibitor (TAFI). The molecular basis for these abnormalities has not yet been elucidated. A low plasma level of free TFPI is another such risk factor.
