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 a nd anti-IIa effects are the sole determinant of the antithrombotic act ions of unfractionated heparin (UFH) and low-molecular-weight heparins (LMWHs). However, there are several unexpected observations such as t he greater than 100% bioavailability of subcutaneously administered LM WH as measured by a chromogenic based anti-Xa method. The authors have proposed that, besides ATIII mediated antiprotease actions, additiona l endogenous factors may be responsible for the observed therapeutic a nd prophylactic actions of heparins. With the identification of tissue factor pathway inhibitor (TFPI) some of the unexpected effects of hep arins can now be clarified. To investigate the role of heparin-releasa ble TFPI on LMWHs the anti-Xa and TFPI antigen levels after prophylact ic and therapeutic administration of UFH and LMWHs have been studied i n defined clinical trials. Regardless of the dosage designation (mg/kg or units/kg) each LMWH followed a distinct TFPI release profile. Simi larly, in the intravenous studies these LMWHs produced an instantaneou s increase in the TFPI antigen level. The anti-Xa effects did not alwa ys follow the same pattern as the TFPI antigen levels. These data sugg est that the anti-Xa potency of a given LMWH is not the sole determina nt of the antithrombotic actions of heparin and LMWH. In addition to p harmacologic 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. These data suggest that, in addition to LMWH and heparin, manipulation of the vascular endothelium by SCD results in th e release of TFPI.