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Thromb Haemost 1999; 81(02): 203-207
DOI: 10.1055/s-0037-1614443
Review Articles
Schattauer GmbH

Low Levels of Heparin-releasable Tissue Factor Pathway Inhibitor in Young Patients with Thrombosis

R. A. S. Ariëns
1   From the Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Ospedale Maggiore IRCCS and University of Milan, Italy
,
G. Alberio
1   From the Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Ospedale Maggiore IRCCS and University of Milan, Italy
,
M. Moia
1   From the Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Ospedale Maggiore IRCCS and University of Milan, Italy
,
P. M. Mannucci
1   From the Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Ospedale Maggiore IRCCS and University of Milan, Italy
› Institutsangaben
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Publikationsverlauf

Received08. Mai 1998

Accepted after resubmission26. Oktober 1998

Publikationsdatum:
08. Dezember 2017 (online)

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Summary

An association between deficiency of tissue factor pathway inhibitor (TFPI) and thrombosis has not been clearly demonstrated in humans, but previous studies have focused on the measurement of plasma TFPI, which is only a small part of the total body TFPI. The major fraction of this natural anticoagulant can be measured in plasma after release by heparin injection. To investigate if deficiency of heparin-releasable TFPI is associated with thrombosis, we measured TFPI activity in plasma before and 10 min after intravenous injection of 7500 IU unfractionated heparin in 64 young patients with venous thrombosis, 49 young patients with arterial thrombosis and 38 healthy individuals. Post-heparin TFPI activity levels were significantly lower in the group of patients with venous thrombosis than in controls (mean ± SD: 230% ± 39 vs 260% ± 34, p = 0.0002), whereas there was no difference for patients with arterial thrombosis. Defining the normal range as the mean ± 2 SD of TFPI activity in controls, twelve patients had low post-heparin TFPI activity levels, seven with venous and five with arterial thrombosis. Low levels of TFPI activity were confirmed by immunoassay in six of the seven patients with venous thrombosis and two of the five patients with arterial thrombosis, and were present also in at least one first degree relative of six patients, suggesting that the defect might be inheritable. However, the causative role of low heparin-releasable TFPI remains uncertain, because co-segregation of the defect with thrombotic symptoms could not be demonstrated in the small number of families studied.

 

  • References

  • 1 Rao LVM, Rapaport I. S. Studies of a mechanism inhibiting the initiation of the extrinsic pathway of coagulation. Blood 1987; 69: 645-51.
    PubMedSuche in Google Scholar
  • 2 Broze Jr GJ, Miletich JP. Characterization of the inhibition of tissue factor in serum. Blood 1987; 69: 150-5.
    PubMedSuche in Google Scholar
  • 3 Lindahl AK, Sandset PM, Abildgaard U. The present status of tissue factor pathway inhibitor. Blood Coag Fibrinol 1992; 3: 439-49.
    CrossrefPubMedSuche in Google Scholar
  • 4 Broze Jr GJ, Warren LA, Novotny WF, Higuchi DA, Girard JJ, Miletich JP. The lipoprotein-associated coagulation inhibitor that inhibits the factor VII-tissue factor complex also inhibits factor Xa: insight into its possible mechanism of action. Blood 1988; 71: 335-43.
    PubMedSuche in Google Scholar
  • 5 Warn-Cramer BJ, Rao LVM, Maki SL, Rapaport I. S. Modifications of extrinsic pathway inhibitor (EPI) and factor Xa that affect their ability to interact and to inhibit factor VIIa/tissue factor: evidence for a two-step model of inhibition. Thromb Haemost 1988; 60: 453-6.
    Thieme ConnectPubMedSuche in Google Scholar
  • 6 Sandset PM, Abildgaard U, Larsen ML. Heparin induces release of extrinsic coagulation pathway inhibitor (EPI). Thromb Res 1988; 50: 803-13.
    CrossrefPubMedSuche in Google Scholar
  • 7 Hubbard AR, Jennings CA. Inhibition of the tissue factor-factor VII complex: involvement of factor Xa and lipoproteins. Thromb Res 1987; 46: 527-37.
    CrossrefPubMedSuche in Google Scholar
  • 8 Novotny WF, Girard TJ, Miletich JP, Broze Jr. GJ. Platelets secrete a coagulation inhibitor functionally and antigenically similar to the lipoprotein associated coagulation inhibitor. Blood 1988; 72: 2020-5.
    PubMedSuche in Google Scholar
  • 9 Wun TC, Kretzmer KK, Girard TJ, Miletich JP, Broze Jr. GJ. Cloning and characterization of a cDNA coding for the lipoprotein-associated coagulation inhibitor shows that it consists of three tandem Kunitz-type inhibitory domains. J Biol Chem 1988; 263: 6001-4.
    PubMedSuche in Google Scholar
  • 10 Ariëns RAS, Faioni EM, Mannucci PM. Repeated released of the tissue factor pathway inhibitor. Thromb Haemost 1994; 72: 327-8.
    Thieme ConnectPubMedSuche in Google Scholar
  • 11 Anderson S, Cohen AT, Melissari E, Scully MS, Kakkar VV. Loss of heparin-releasable tissue factor pathway inhibitor in patients undergoing PTCA. Thromb Haemost 1995; 73: 328-9.
    Thieme ConnectPubMedSuche in Google Scholar
  • 12 Hansen JB, Sandset PM, Huseby KR, Huseby NE, Nordøy A. Depletion of intravascular pools of tissue factor pathway inhibitor (TFPI) during repeated or continuous intravenous infusion of heparin in man. Thromb Haemost 1996; 76: 703-9.
    Thieme ConnectPubMedSuche in Google Scholar
  • 13 Bauer KA, Kass BL, ten Cate H, Hawiger JJ, Rosenberg RD. Factor IX is activated in vivo by the tissue factor mechanism. Blood 1990; 76: 731-6.
    PubMedSuche in Google Scholar
  • 14 Bauer KA, Mannucci PM, Gringeri A, Tradati F, Barzegar S, Kass BL, ten Cate H, Kestin AS, Brettler DB, Rosenberg RD. Factor IXa-factor VIIIa-cell surface complex does not contribute to the basal activation of the coagulation mechanism in vivo. Blood 1992; 79: 2039-47.
    PubMedSuche in Google Scholar
  • 15 ten Cate H, Bauer KA, Levi M, Edgington TS, Sublett RD, Barzegar S, Kass BL, Rosenberg RD. The activation of factor X and prothrombin by recombinant factor VIIa in vivo is mediated by tissue factor. J Clin Invest 1993; 92: 1207-12.
    CrossrefPubMedSuche in Google Scholar
  • 16 Sandset PM, Warn-Cramer BJ, Rao LVM, Maki SL, Rapaport I. S. 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 Nat Acad Sci USA 1991; 88: 708-12.
    CrossrefPubMedSuche in Google Scholar
  • 17 Sandset PM, Warn-Cramer BJ, Maki SL, Rapaport I. S. Immunodepletion of extrinsic pathway inhibitor sensitizes rabbits to endotoxin-induced intravascular coagulation and the generalized Shwartzman reaction. Blood 1991; 78: 1496-502.
    PubMedSuche in Google Scholar
  • 18 Novotny WF, Brown SG, Miletich JP, Rader DJ, Broze Jr. GJ. Plasma antigen levels of the lipoprotein-associated coagulation inhibitor in patient samples. Blood 1991; 78: 387-93.
    PubMedSuche in Google Scholar
  • 19 Goodwin CA, Melissari E, Kakkar VV, Scully MF. Plasma levels of tissue factor pathway inhibitor in thrombophilic patients. Thromb Res 1993; 72: 363-6.
    CrossrefPubMedSuche in Google Scholar
  • 20 Teien AN, Lie M, Abildgaard U. Assay of heparin in plasma using a chromogenic substrate for activated factor X. Thromb Res 1976; 8: 413-6.
    CrossrefPubMedSuche in Google Scholar
  • 21 Holst J, Lindblad B, Wedeberg E, Bergqvist D, Nordfang O, Østergaard PB, Hedner U. Tissue factor pathway inhibitor (TFPI) and its response to heparin in patients with spontaneous deep vein thrombosis. Thromb Res 1993; 72: 467-70.
    CrossrefPubMedSuche in Google Scholar
  • 22 Llobet D, Falkon L, Mateo J, Vallve C, Martinez E, Fontcuberta J, Borrell M. Low levels of tissue factor pathway inhibitor (TFPI) in two out of three members of a family with thrombophilia. Thromb Res 1995; 80: 413-22.
    CrossrefPubMedSuche in Google Scholar
  • 23 Hubbard AR, Weller LJ, Gray E. Measurement of tissue factor pathway inhibitor in normal and post-heparin plasma. Blood Coag Fibrinol 1994; 5: 819-23.
    CrossrefPubMedSuche in Google Scholar
  • 24 Huang Z-F, Broze Jr. GJ. Consequences of tissue factor pathway inhibitor gene-disruption in mice. Thromb Haemost 1997; 78: 699-704.
    Thieme ConnectPubMedSuche in Google Scholar