Download PDF
Thromb Haemost 1996; 76(05): 703-709
DOI: 10.1055/s-0038-1650647
Original Article
Schattauer GmbH Stuttgart

Depletion of Intravascular Pools of Tissue Factor Pathway Inhibitor (TFPI) during Repeated or Continuous Intravenous Infusion of Heparin in Man

John-Bjarne Hansen
1   The Department of Medicine, Institute of Clinical Medicine, Norway
,
Per Morten Sandset
2   Haematological Research Laboratory, Medical Clinic, Ullevaal University Hospital, Oslo, Norway
,
Kirsten Raanaas Huseby
1   The Department of Medicine, Institute of Clinical Medicine, Norway
,
Nils-Erik Huseby
3   Department of Clinical Chemistry, Institute of Medical Biology, University of Tromsø, Tromsø, Norway
,
Arne Nordøy
1   The Department of Medicine, Institute of Clinical Medicine, Norway
› Author Affiliations
Further Information

Publication History

Received 03 June 1996

Accepted after revision 01 August 1996

Publication Date:
11 July 2018 (online)

Also available at
  PDF Download  Permissions and Reprints

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.

 

  • References

  • 1 Rapaport SI, Rao LVM. The tissue factor pathway: How it has become a “prima ballerina”. Thromb Haemost 1995; 74: 7-17
    PubMedSearch in Google Scholar
  • 2 Osterud B, Rapaport SI. Activation of factor IX by the reaction product of tissue factor and factor VII: Additional pathway for initiating blood coagulation. Proc Natl Acad Sci USA 1977; 74: 5260-5264
    CrossrefPubMedSearch in Google Scholar
  • 3 Broze Jr GJ, Miletich JP. Characterizations of the inhibition of tissue factor in serum. Blood 1987; 69: 150-155
    PubMedSearch in Google Scholar
  • 4 Rao LVM, Rapaport SI. Studies of a mechanism inhibiting the initiation of the extrinsic pathway of coagulation. Blood 1987; 69: 645-651
    PubMedSearch in Google Scholar
  • 5 Girard TJ, Warren LA, Novotny WF, Likert KM, Brown SG, Miletich JP, Broze GJ. Functional significance of the Kunitz-type inhibitor domains of lipoprotein-associated coagulation inhibitor. Nature 1989; 338: 518-520
    CrossrefPubMedSearch in Google Scholar
  • 6 Abumiya T, Enjyoji K, Kokawa T, Kamikubo Y, Kato H. An anti-tissue factor pathway inhibitor (TFPI) monoclonal antibody recognized the third Kunitz domain (K3) of free-form TFPI but not lipoprotein-associated forms in plasma. J Biochem 1995; 118: 178-182
    CrossrefPubMedSearch in Google Scholar
  • 7 Norfang O, Bjpm SE, Valentin S, Nielsen LS, Wildgoose P, Beck TC, Hedner U. The C-terminus of tissue factor pathway inhibitor is essential to its anticoagulant activity. Biochemistry 1991; 30: 10371-10376
    CrossrefPubMedSearch in Google Scholar
  • 8 Wesselschmidt R, Likert KM, Girard TJ, Wun TC, Broze Jr GJ. Tissue factor pathway inhibitor: the carboxy-terminus is required for optimal inhibition of factor Xa. Blood 1992; 79: 2004-2010
    PubMedSearch in Google Scholar
  • 9 Bajaj MS, Kuppuswamy MN, Saito H, Spitzer SG, Bajaj SP. Cultured normal hepatocytes do not synthesize lipoprotein-associated coagulation inhibitor: evidence that endothelium is the principal site of its synthesis. Proc Natl Acad Sci USA 1990; 87: 8869-8873
    CrossrefPubMedSearch in Google Scholar
  • 10 Sandset PM, Abildgaard U. Extrinsic coagulation inhibitor: the key to feedback control of blood coagulation initiated by tissue thromboplastin. Haemostasis 1991; 21: 219-239
    PubMedSearch in Google Scholar
  • 11 Sandset PM, Abildgaard U, Larsen ML. Heparin induces release of extrinsic coagulation pathway inhibitor (EPI. Thromb Res 1988; 50: 803-813
    CrossrefPubMedSearch in Google Scholar
  • 12 Hansen JB, Huseby NE, Sandset PM, Svensson B, Lyngmo V, Nordpy A. Tissue factor pathway inhibitor and lipoproteins: evidence for association with and regulation by LDL in human plasma. Arterioscler Thromb 1994; 14: 223-229
    CrossrefPubMedSearch in Google Scholar
  • 13 Hull RD, Raskob GE, Hirsch J, Jay RM, Leclerc JR, Geerts WH, Rosen-bloom D, Sackett DL, Anderson C, Harrison L, Gent M. Continous intravenous heparin compared with intermittent subcutaneous heparin in the initial treatment of proximal-vein thrombosis. N Engl J Med 1986; 315: 1109-1114
    CrossrefPubMedSearch in Google Scholar
  • 14 Neri Serneri GG, Gensini GF, Poggesi L, Trotta F, Modesti PA, Boddi M, Ieri A, Margheri M, Casolo GC, Bini M, Rostagno C, Carnovali M, Abbate R. Effect of heparin, aspirin, or alteplase in reduction of myocardial ischemia in refractory unstable angina. Lancet 1990; 335: 615-618
    CrossrefPubMedSearch in Google Scholar
  • 15 Bourin MC, Lindahl U. Glycosaminoglycans and the regulation of blood coagulation. Biochem J 1993; 289: 313-330
    CrossrefPubMedSearch in Google Scholar
  • 16 Tollefsen DM. Insight into the mechanism of action of heparin cofactor II. Thromb Haemost 1995; 74: 1209-1214
    Thieme ConnectPubMedSearch in Google Scholar
  • 17 Nordpy A. Difference in the heparin-neutralizing effect of protamine and polybrene as tested by thrombotest. Scand J Clin Lab Invest 1963; 15: 205-210
    CrossrefPubMedSearch in Google Scholar
  • 18 Lindahl AK, Abildgaard U, Larsen ML, Staalesen R, Hammer AKG, Sandset PM, Norfang O, Beck TC. Extrinsic pathway inhibitor (EPI) released to the blood by heparin is a more powerful coagulation inhibitor than is recombinant EPI. Thromb Res 1991; 62: 607-614
    CrossrefPubMedSearch in Google Scholar
  • 19 Hansen JB, Huseby KR, Huseby NE, Sandset PM, Hansen TA, Nordpy A. Effect of cholesterol lowering on intravascular pools of TFPI and its anticoagulant potential in type II hyperlipoproteinemia. Arterioscler Thromb Vase Biol 1995; 15: 879-885
    CrossrefPubMedSearch in Google Scholar
  • 20 Novotny WF, Palmier M, Wun TC, Broze GJ, Miletich JP. Purification and properties of heparin releasable lipoprotein-associated coagulation inhibitor. Blood 1991; 78: 394-400
    PubMedSearch in Google Scholar
  • 21 Lindahl AK, Abildgaard U, Staalesen R. The anticoagulant effect in hepari-nized blood and plasma resulting from interactions with extrinsic pathway inhibitor. Thromb Res 1991; 64: 155-168
    CrossrefPubMedSearch in Google Scholar
  • 22 Harenberg J, Siegele M, Dempfle CE, Stehle G, Heene DL. Protamine neutralization of the release of tissue factor pathway inhibitor activity by hepa-rins. Thromb Haemost 1993; 70: 942-945
    Thieme ConnectPubMedSearch in Google Scholar
  • 23 Lindahl AK, Sandset PM, Abildgaard U. The present status of tissue factor pathway inhibitor. Blood Coagul Fibrinolysis 1992; 3: 439-449
    CrossrefPubMedSearch in Google Scholar
  • 24 Huseby KR, Hansen JB, Huseby NE, Nordpy A. The anticoagulant potential of tissue factor pathway inhibitor (TFPI) is restricted to its free form in human plasma. Thromb Haemost 1995; 73: 1260 (abstract)
    PubMedSearch in Google Scholar
  • 25 Valentin S, Ostergaard P, Kristensen H, Norfang O. Synergism between full length TFPI and heparin: evidence for TFPI as and important factor for the antithrombotic activity of heparin. Blood Coagul Fibrinolysis 1992; 3: 221-222
    CrossrefPubMedSearch in Google Scholar
  • 26 Anderson S, Cohen AT, Melissari E, Scully MS, Kakkar VV. Loss of hep-arin-releasable tissue factor pathway inhibitor in patients undergoing PTCA. Thromb Haemost 1995; 73: 328-329
    Thieme ConnectPubMedSearch in Google Scholar
  • 27 Erhardsen E, Ezban E, Madsen MT, Diness V, Glazer S, Hedner U, Norfang O. Blocking of tissue factor pathway inhibitor (TFPI) shortens the bleeding time in rabbits with antibody induced haemophilia A. Blood Coagul Fibrinolysis 1995; 5: 388-395
    PubMedSearch in Google Scholar
  • 28 Kasper CK, Aledort ML, Counts RB, Edson JR, Fratantoni J, Green D, Hampton JW, Hilgartner MW, Lazerson J, Levine PH, McMillan CW, Pool JG, Shapiro SS, Shulman NR, van Eys J. A more uniform measurement of factor VIII inhibitors. Thrombos Diathes haemorrh 1975; 34: 869-872
    PubMedSearch in Google Scholar
  • 29 Hjort PF. Intermediate reactions in the coagulation of blood with tissue thromboplastin. Scand J Clin Lab Invest 1957; 9 (Suppl. 27) 1-173
    CrossrefPubMedSearch in Google Scholar
  • 30 Sandset PM, Larsen ML, Abildgaard U, Lindahl AK, Odegaard OR. Chro-mogenic substrate assay of extrinsic pathway inhibitor (EPI): levels in the normal population and relation to cholesterol. Blood Coagul Fibrinolysis 1991; 2: 425-433
    CrossrefPubMedSearch in Google Scholar
  • 31 SAS Institute Inc, SAS/STAT Guide for personal computers, version 6. Cary, NC: SAS Institute; 1987
    Search in Google Scholar
  • 32 Ariens RAS, Faioni EM, Mannucci PM. Repeated release of the tissue factor pathway inhibitor. Thromb Haemost 1994; 72: 327-328
    Thieme ConnectPubMedSearch in Google Scholar
  • 33 Novotny WF, Brown SG, Miletich JP, Rader DJ, Broze GJ. Jr Plasma antigen levels of lipoprotein-associated coagulation inhibitor in patient sam-pies. Blood 1991; 78: 387-393
    PubMedSearch in Google Scholar
  • 34 Warn-Cramer BJ, Maki SL, Zivelin A, Rapaport SI. Partial purification and characterization of extrinsic pathway inhibitor (the factor Xa-dependent plasma inhibitor of factor Vila/tissue factor). Thromb Res 1987; 48: 11-22
    CrossrefPubMedSearch in Google Scholar
  • 35 Hubbard AR, Jennings CA. Inhibition of the tissue factor-factor VII complex: involvement of factor Xa and lipoproteins. Thromb Res 1987; 46: 527-537
    CrossrefPubMedSearch in Google Scholar
  • 36 Iversen N, Sandset PM, Abildgaard U, Rao LVM, Nordfang O. Binding of recombinant tissue factor pathway inhibitor (rTFPI) to endothelial cells: Influence of glucosaminoglycans. Thromb Haemost 1993; 69: 368 (abstract)
    PubMedSearch in Google Scholar
  • 37 Petersen JGL, Meyn G, Rasmussen JS, Christiansen L, Petersen J, Bjprn SE, Jonassen I, Norfang O. Characterization of human tissue factor pathway inhibitor (TFPI) variants expressed in saccharomyces cerevisae. J Biol Chem 1993; 268: 13344-13351
    PubMedSearch in Google Scholar
  • 38 Wesselschmidt R, Likert K, Huang Z, Broze Jr GJ. Structural requirements for tissue factor pathway inhibitor interactions with factor Xa and heparin. Blood Coagul Fibrinolysis 1993; 4: 661-669
    CrossrefPubMedSearch in Google Scholar
  • 39 Valentin S, Lamkjaer A, Ostergaard P, Nielsen JI, Norfang O. Characterization of the binding between tissue factor pathway inhibitor and glycosaminoglycans. Thromb Res 1994; 75: 173-183
    CrossrefPubMedSearch in Google Scholar
  • 40 Valentin S, Norfang O, Bregengard C, Wildgoose P. Evidence that the C-terminus for tissue factor pathway inhibitor (TFPI) is essential for its in vitro and in vivo interaction with lipoproteins. Blood Coagul Fibrinolysis 1993; 4: 713-720
    CrossrefPubMedSearch in Google Scholar
  • 41 Palmier MO, Hall LJ, Reisch CM, Baldwin MK, Wilson AG, Wun TC. Clearance of recombinant tissue factor pathway inhibitor (TFPI) in rabbits. Thromb Haemost 1992; 68: 33-36
    Thieme ConnectPubMedSearch in Google Scholar
  • 42 Bregengaard C, Norfang O, Ostergaard P, Petersen JGL, Meyn G, Diness V, Svendsen O, Hedner U. Pharmakokinetics of full length and two-domain tissue factor pathway inhibitor in combination with heparin in rabbits. Thromb Haemost 1993; 70: 454-457
    Thieme ConnectPubMedSearch in Google Scholar
  • 43 Warshawsky I, Broze Jr GJ, Schwartz AL. The low density lipoprotein receptor-related protein mediates the cellular degradation of tissue factor pathway inhibitor. Proc Natl Acad Sci USA 1994; 91: 6664-6668
    CrossrefPubMedSearch in Google Scholar
  • 44 Warshawsky I, Bu G, Mast A, Saffitz JE, Broze Jr GJ, Schwartz AL. The carboxy-terminus of tissue factor pathway inhibitor is required for interacting with hepatoma cells in vitro and in vivo. J Clin Invest 1995; 95: 1773-1781
    CrossrefPubMedSearch in Google Scholar
  • 45 Almus FE, Rao LVM, Rapaport SI. Regulation of factor Vila/tissue factor functional activity in an umbilical vein model. Arterioscler Thromb 1993; 13: 105-111
    CrossrefPubMedSearch in Google Scholar
  • 46 Grabowski EF, Zuckerman DB, Nemerson Y. The functional expression of tissue factor by fibroblasts and endothelial cells under flow conditions. Blood 1993; 81: 3265-3270
    PubMedSearch in Google Scholar
  • 47 Sandset PM, Warn-Cramer BJ, Rao LVM, Maki SL, Rapaport SI. Depletion of extrinsic pathway inhibitor (EPI) sensitizes rabbits to disseminated intravascular coagulation induced with tissue factor: evidence supporting a physiological role for EPI as a natural anticoagulant. Proc Natl Acad Sci USA 1991; 88: 70812
    PubMedSearch in Google Scholar
  • 48 Hommes DW, Bara A, Mazzolai L, Biiller HR, ten Cate JW. Subcutaneous treatment compared with continuous intravenous heparin administration in the initial treatment of deep vein thrombosis. Ann Int Med 1992; 116: 279-284
    CrossrefPubMedSearch in Google Scholar