title: Depletion of intravascular pools of tissue factor pathway inhibitor (TFPI) during repeated or continuous intravenous infusion of heparin in man.
abstract: 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 5000 IU 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.
authors.affiliation: Department of Medicine, University of Tromsø, Norway.
authors.forename: J B
authors.initials: JB
authors.lastname: Hansen
authors.forename: P M
authors.initials: PM
authors.lastname: Sandset
authors.forename: K R
authors.initials: KR
authors.lastname: Huseby
authors.forename: N E
authors.initials: NE
authors.lastname: Huseby
authors.forename: A
authors.initials: A
authors.lastname: Nordøy
mesh_terms: D000328:Adult; D000925:Anticoagulants / Q000008:administration & dosage / Q000494:pharmacology*; D002352:Carrier Proteins / Q000097:blood; D004334:Drug Administration Schedule; D006493:Heparin / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D008074:Lipoproteins / Q000032:analysis* / Q000172:deficiency; D008297:Male; D010314:Partial Thromboplastin Time
chemical_list: D000925:Anticoagulants; D002352:Carrier Proteins; D008074:Lipoproteins; C051928:lipoprotein-associated coagulation inhibitor; D006493:Heparin