Intravascular release and urinary excretion of tissue factor pathway inhibitor during heparin treatment

Abstract

Tissue-factor-pathway inhibitor is the principal regulator of tissue factor-induced coagulation. Heparin treatment mobilizes TFPI into the circulation and contributes to the anticoagulant effects of heparins. Previous studies have demonstrated a selective depletion of intravascular TFPI by unfractionated heparin (UFH) but not by low-molecular-weight heparin (LMWH). In this study we sought to investigate the time- and dose-dependent relationships between release of TFPI and lipoprotein lipase (LPL) in respons to UFH and LMWH and to investigate whether the selective depletion of TFPI by UFH but not by LMWH is related to differential urinary excretion of TFPI. Eight healthy males participated in an open crossover study in which participants were assigned to receive (1) continuous infusion of unfractionated heparin (UFH, 450 IU/kg/24 hr); (2) subcutaneous dalteparin, 100 IU/kg given twice at a 12-hr interval; (3) subcutaneous dalteparin, 200 IU/kg given once; or (4) saline-solution infusion. Similar dose-dependent mobilization of TFPI and lipoprotein lipase (LPL), another glucosaminoglycan (GAG)-anchored protein of the endothelial membrane, was observed after both subcutaneous and intravenous administration of heparins. However, UFH induced a more efficient release of both TFPI and LPL into plasma than did LMWH at equivalent anti-Xa levels, indicating molecular-weight dependence of the release reactions. However, LPL reached peak levels faster and was more rapidly cleared from the circulation than was TFPI, regardless of the treatment modality. Only trace amounts of TFPI were detected in the urine in a native form (38 kD). UFH and LMWH treatment reduced renal clearance of TFPI compared with the control regimen. Our findings suggest that displacement of TFPI from the endothelial-surface GAG is the main mechanism for TFPI release during heparin treatment in vivo and that differential urinary excretion of TFPI is not the explanation for selective depletion of TFPI during UFH treatment.