Summary
Tissue factor pathway inhibitor (TFPI) is a potent inhibitor of the extrinsic coagulation system. TFPI is increased several-fold in postheparin plasma and thereby thought to contribute significantly to the antithrombotic action of heparin. The present study was conducted to investigate how repeated (n = 8) and continuous (n = 6) administration of heparin affect plasma TFPI and the inhibition of tissue factor (TF)-induced coagulation ex vivo in humans. Free TFPI antigen (TFPI Ag) increased from 19.2 ± 4.0 ng/ml to 204.7 ± 31.7 ng/ml after intravenous injection of 5000IU of unfractionated heparin. Five repeated injections of 5000 IU of heparin at 4 h intervals caused a progressive decrease (−45 ± 8%, p <0.0001 for time effect) in heparin-releasable TFPI and a progressive shortening of the clotting time as determined in a dilute prothrombin time assay (dPT) (−8.7 ± 6.1 s, p <0.0001). The basal concentration of TFPI Ag in plasma collected immediately before each heparin injection was decreased by 29 ± 15% (p <0.0001), whereas the dPT was decreased by 6.9 ± 3.5 s (p <0.0001). During a 24 h continuous infusion of heparin TFPI Ag decreased from 161.5 ± 26.0 ng/ml to 35.6 ± 4.7 ng/ml (−77.3 ± 5.1%) (p <0.0001). The contribution of TFPI to the inhibition of TF-induced coagulation during heparin infusion was estimated to decrease from 60 ± 15% to 20 ± 10% (p <0.0001). The present data indicate partial depletion of intravascular pools of TFPI by repeated and continuous heparin administration and thereby attenuation of its contribution to the antithrombotic action of heparin.
