The role of tissue factor pathway inhibitor in the mediation of the antithrombotic actions of heparin and low-molecular-weight heparin.

It is widely accepted that antithrombin III (ATIII) mediated anti-Xa and anti-IIa effects are the sole determinant of the antithrombotic actions of unfractionated heparin (UFH) and low-molecular-weight heparins (LMWHs). However, there are several unexpected observations such as the greater than 100% bioavailability of subcutaneously administered LMWH as measured by a chromogenic based anti-Xa method. The authors have proposed that, besides ATIII mediated antiprotease actions, additional endogenous factors may be responsible for the observed therapeutic and prophylactic actions of heparins. With the identification of tissue factor pathway inhibitor (TFPI) some of the unexpected effects of heparins can now be clarified. To investigate the role of heparin-releasable TFPI on LMWHs the anti-Xa and TFPI antigen levels after prophylactic and therapeutic administration of UFH and LMWHs have been studied in defined clinical trials. Regardless of the dosage designation (mg/kg or units/kg) each LMWH followed a distinct TFPI release profile. Similarly, in the intravenous studies these LMWHs produced an instantaneous increase in the TFPI antigen level. The anti-Xa effects did not always follow the same pattern as the TFPI antigen levels. These data suggest that the anti-Xa potency of a given LMWH is not the sole determinant of the antithrombotic actions of heparin and LMWH. In addition to pharmacologic agents, the effect of sequential compression devices (SCD) on the release of TFPI was also studied. A two-fold increase in TFPI antigen levels was observed in normal volunteers undergoing long leg compression for 1 h.(ABSTRACT TRUNCATED AT 250 WORDS)