Tissue factor pathway inhibitor release induced by defibrotide and heparins

We evaluated the release of tissue factor pathway inhibitor (TFPI) induced by defibrotide (DF), a single-stranded, negatively charged polydeoxyribonuc leotide extracted from mammalian organ. Ten normal volunteers were injected with an intravenous bolus of 400 mg DF and 2,000 IU unfractionated heparin (UFH). In addition, three volunteers were also injected with an intravenou s bolus of 2,000 anti-Xa U of two low-molecular-weight heparins (LMWHs), en oxaparin and nadroparin. UFH caused a 4-fold increase in plasma TFPI at 5 m inutes, with a decrease that was parallel to the heparin level measured by the anti-Xa assay. However, at 80 minutes, although the plasma anti-Xa acti vity of UFH was almost undetectable, the level of TFPI remained 2-fold base line. DF induced an increase of TFPI that was 2-fold higher than the baseli ne level, with a steady state achieved between 5 and 20 minutes. At 40 minu tes, the TFPI levels returned to basal level. This pattern was not coincide nt with the clearance of DF and at 40 minutes, the concentration of DF was still one third of the levels at 5 minutes (25.4 +/-4.04 mug/mL). Both of t he LMWHs induced a similar TFPI peak level at 5 minutes (1.5-fold increase) and at 40 minutes the TFPI levels returned to the initial levels. At 5 min utes, both LMWHs showed a higher plasma anti-Xa activity than UFH, which wa s detectable even at 80 minutes. The current study demonstrated that one of the mechanisms of the antithrombotic activity of DF is mediated via TFPI. Furthermore, the release of TFPI by heparin is mediated by non-antithrombin III binding fragments. Thus, polyanionic electrolytes are capable of relea sing TFPI irrespective of their antithrombin III effect.