Download PDF
Thromb Haemost 2015; 114(02): 245-257
DOI: 10.1160/TH14-12-1043
Coagulation and Fibrinolysis
Schattauer GmbH

Genetic determinants of tissue factor pathway inhibitor plasma levels

Jessica Dennis
1   Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
,
Irfahan Kassam
1   Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
,
Pierre-Emmanuel Morange
2   Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Mixte de Recherche en Santé (UMR_S) 1062, Marseille, France
3   Inra, UMR_INRA 1260, Marseille, France
4   Aix Marseille Université, Marseille, France
,
David-Alexandre Trégouët
5   Institut National pour la Santé et la Recherche Médicale (INSERM), Unité Mixte de Recherche en Santé (UMR_S) 1166, Paris, France
6   Sorbonne Universités, Université Pierre et Marie Curie (UPMC Univ Paris 06), UMR_S 1166, Team Genomics & Pathophysiology of Cardiovascular DiseasesParis, France
7   Institute for Cardiometabolism and Nutrition (ICAN), Paris, France
,
France Gagnon
1   Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
› Author Affiliations Financial support: This work was supported by the Canadian Institutes of Health Research (Grant MOP 86466) and by the Heart and Stroke Foundation of Canada (Grant T6484). JD is a Vanier Canada Graduate Scholar and Fellow in the Canadian Institutes of Health Research Strategic Training for Advanced Genetic Epidemiology (CIHR STAGE) program. FG holds a Canada Research Chair.
Further Information

Publication History

Received: 15 December 2014

Accepted after minor revision: 24 February 2015

Publication Date:
21 November 2017 (online)

    Permissions and Reprints

Summary

Tissue factor pathway inhibitor (TFPI) impedes early stages of the blood coagulation response, and low TFPI plasma levels increase the risk of thrombosis. TFPI plasma levels are heritable, but specific genetic determinants are unclear. We conducted a comprehensive review of genetic risk factors for TFPI plasma levels and identified 26 studies. We included 16 studies, as well as results from two unpublished genome-wide studies, in random effects meta-analyses of four commonly reported genetic variants in TFPI and its promoter (rs5940, rs7586970/rs8176592, rs10931292, and rs10153820) and 10 studies were summarised narratively. rs5940 was associated with all measures of TFPI (free, total, and activity), and rs7586970 was associated with total TFPI. Neither rs10931292 nor rs10153820 showed evidence of association. The narrative summary included 6 genes and genetic variants (P151L mutation in TFPI, PROS1, F5, APOE, GLA, and V617F mutation in JAK2) as well as a genome-wide linkage study, and suggested future research directions. A limitation of the systematic review was the heterogeneous measurement of TFPI. Nonetheless, our review found robust evidence that rs5940 and rs7586970 moderate TFPI plasma levels and are candidate risk factors for thrombosis, and that the regulation of TFPI plasma levels involves genetic factors beyond the TFPI gene.

Keywords

Coagulation - genetic - systematic review - meta-analysis - tissue factor pathway inhibitor

 

  • References

  • 1 Wood JP, Ellery PER, Maroney SA. et al. Biology of tissue factor pathway inhibitor. Blood 2014; 123: 2934-2943.
    CrossrefPubMedGoogle Scholar
  • 2 Huang ZF, Higuchi D, Lasky N. et al. Tissue factor pathway inhibitor gene disruption produces intrauterine lethality in mice. Blood 1997; 90: 944-951.
    PubMedGoogle Scholar
  • 3 Zakai NA, Lutsey PL, Folsom AR. et al. Total tissue factor pathway inhibitor and venous thrombosis. The Longitudinal Investigation of Thromboembolism Etiology. Thromb Haemost 2010; 104: 207-212.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 4 Morange PE, Simon C, Alessi MC. et al. Endothelial cell markers and the risk of coronary heart disease: the Prospective Epidemiological Study of Myocardial Infarction (PRIME) study. Circulation 2004; 109: 1343-1348.
    CrossrefPubMedGoogle Scholar
  • 5 Winckers K, Cate ten H, Hackeng TM. The role of tissue factor pathway inhibitor in atherosclerosis and arterial thrombosis. Blood Rev 2013; 27: 119-132.
    CrossrefPubMedGoogle Scholar
  • 6 Almasy L, Soria JM, Souto JC. et al. A locus on chromosome 2 influences levels of tissue factor pathway inhibitor: results from the GAIT study. Arterioscler Thromb Vasc Biol 2005; 25: 1489-1492.
    CrossrefPubMedGoogle Scholar
  • 7 Warren DM, Soria JM, Souto JC. et al. Heritability of hemostasis phenotypes and their correlation with type 2 diabetes status in Mexican Americans. Hum Biol 2005; 77: 1-15.
    CrossrefPubMedGoogle Scholar
  • 8 Bladbjerg EM, de Maat MPM, Christensen K. et al. Genetic influence on thrombotic risk markers in the elderly--a Danish twin study. J Thromb Haemost 2006; 04: 599-607.
    CrossrefPubMedGoogle Scholar
  • 9 Bladbjerg EM, Madsen JS, Kristensen SR. et al. Effect of long-term hormone replacement therapy on tissue factor pathway inhibitor and thrombin activatable fibrinolysis inhibitor in healthy postmenopausal women: a randomized controlled study. J Thromb Haemost 2003; 01: 1208-1214.
    CrossrefPubMedGoogle Scholar
  • 10 Morange PE, Renucci JF, Charles MA. et al. Plasma levels of free and total TFPI, relationship with cardiovascular risk factors and endothelial cell markers. Thromb Haemost 2001; 85: 999-1003.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 11 Broze GJ, Girard TJ. Tissue factor pathway inhibitor: structure-function. Front Biosci (Landmark Ed) 2012; 17: 262-280.
    CrossrefPubMedGoogle Scholar
  • 12 Summerhayes R. Laboratory Methods for the Assay of Tissue Factor Pathway Inhibitor in Human Plasma. In: Methods in Molecular Biology. Totowa, NJ: Humana Press;; 2013. pp. 289-300.
    Google Scholar
  • 13 Hansen JB, Huseby KR, Huseby NE. et al. Tissue factor pathway inhibitor in complex with low density lipoprotein isolated from human plasma does not possess anticoagulant function in tissue factor-induced coagulation in vitro. Thromb Res 1997; 85: 413-425.
    CrossrefPubMedGoogle Scholar
  • 14 Sanchez-Solana B, Motwani M, Li DQ. et al. p21-activated Kinase-1 Signaling Regulates Transcription of Tissue Factor and Tissue Factor Pathway Inhibitor. J Biol Chem 2012; 287: 39291-39302.
    CrossrefPubMedGoogle Scholar
  • 15 Lupu C, Zhu H, Popescu NI. et al. Novel protein ADTRP regulates TFPI expression and function in human endothelial cells in normal conditions and in response to androgen. Blood 2011; 118: 4463-4471.
    CrossrefPubMedGoogle Scholar
  • 16 Schuepbach RA, Velez K, Riewald M. Activated protein C up-regulates procoagulant tissue factor activity on endothelial cells by shedding the TFPI Kunitz 1 domain. Blood 2011; 117: 6338-6346.
    CrossrefPubMedGoogle Scholar
  • 17 Ohkura N, Enjyoji K-I, Kamikubo Y-I. et al. A novel degradation pathway of tissue factor pathway inhibitor: incorporation into fibrin clot and degradation by thrombin. Blood 1997; 90: 1883-1892.
    PubMedGoogle Scholar
  • 18 Kleesiek K, Schmidt M, Gotting C. et al. A first mutation in the human tissue factor pathway inhibitor gene encoding [P151L]TFPI. Blood 1998; 92: 3976-3977.
    PubMedGoogle Scholar
  • 19 González-Conejero R, Lozano ML, Corral J. et al. The TFPI 536C-->T mutation is not associated with increased risk for venous or arterial thrombosis. Thromb Haemost 2000; 83: 787-788.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 20 Evans G, Langdown J, Brown K. et al. The C536T transition in the tissue factor pathway inhibitor gene is not a common cause of venous thromboembolic disease in the UK population. Thromb Haemost 2000; 83: 511.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 21 Paciaroni K, Rossi E, Bazzan M. et al. Prevalence of the C536T mutation in the tissue factor pathway inhibitor (TFPI) gene among patients with venous thromboembolic disease. Thromb Haemost 2001; 85: 938-939.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 22 Junker R, Glahn J, Tidow N. et al. The tissue factor pathway inhibitor C536T mutation is not associated with the risk of stroke in young adults. Thromb Hae-most 2002; 87: 920.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 23 Moatti D, Seknadji P, Galand C. et al. Polymorphisms of the Tissue Factor Pathway Inhibitor (TFPI) Gene in Patients With Acute Coronary Syndromes and in Healthy Subjects : Impact of the V264M Substitution on Plasma Levels of TFPI. Arterioscler Thromb Vasc Biol 1999; 19: 862-869.
    CrossrefPubMedGoogle Scholar
  • 24 Amini-Nekoo A, Futers TS, Moia M. et al. Analysis of the tissue factor pathway inhibitor gene and antigen levels in relation to venous thrombosis. Br J Haematol 2001; 113: 537-543.
    CrossrefPubMedGoogle Scholar
  • 25 Mues GI, Sarode R. Allele frequencies of tissue factor pathway inhibitor polymorphisms in African-American, Hispanic and Caucasian populations. Thromb Haemost 2002; 88: 875-877.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 26 Ishikawa J, Okada H, Kato H. et al. Association of Asn221Ser mutation in tissue factor pathway inhibitor- with plasma total tissue factor pathway inhibitor level. Blood Coagul Fibrinolysis 2009; 20: 22-26.
    CrossrefPubMedGoogle Scholar
  • 27 van der Logt CP, Reitsma PH, Bertina RM. Intron-exon organization of the human gene coding for the lipoprotein-associated coagulation inhibitor: the factor Xa dependent inhibitor of the extrinsic pathway of coagulation. Biochemistry 1991; 30: 1571-1577.
    CrossrefPubMedGoogle Scholar
  • 28 Moatti D, Haidar B, Fumeron F. et al. A new T-287C polymorphism in the 5’ regulatory region of the tissue factor pathway inhibitor gene. Association study of the T-287C and C-399T polymorphisms with coronary artery disease and plasma TFPI levels. Thromb Haemost 2000; 84: 244-249.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 29 Miyata T, Sakata T, Kumeda K. et al. C-399T polymorphism in the promoter region of human tissue factor pathway inhibitor (TFPI) gene does not change the plasma TFPI antigen level and does not cause venous thrombosis. Thromb Hae-most 1998; 80: 345.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 30 Petit L, Lesnik P, Dachet C. et al. The promoter of human tissue factor pathway inhibitor gene: identification of potential regulatory elements. Thromb Res 1999; 95: 255-262.
    CrossrefPubMedGoogle Scholar
  • 31 Amini Nekoo A, Iles D. Analysis of a T-287C polymorphism in the tissue factor pathway inhibitor gene and identification of a repressor element in the promoter. Thromb Res 2008; 121: 813-819.
    CrossrefPubMedGoogle Scholar
  • 32 Skretting G, Stavik B, Landvik NE. et al. Functional characterization of polymorphisms in the human TFPI gene. Biochem Biophys Res Commun 2010; 397: 106-111.
    CrossrefPubMedGoogle Scholar
  • 33 Lincz LF, Adams MJ, Scorgie FE. et al. Polymorphisms of the tissue factor pathway inhibitor gene are associated with venous thromboembolism in the anti-phospholipid syndrome and carriers of factor V Leiden. Blood Coagul Fibrinolysis 2007; 18: 559-564.
    CrossrefPubMedGoogle Scholar
  • 34 Sayer MS, Cole VJ, Adams MJ. et al. Polymorphisms in the tissue factor pathway inhibitor gene are not associated with ischaemic stroke. Blood Coagul Fibrinolysis 2007; 18: 703.
    CrossrefPubMedGoogle Scholar
  • 35 Opstad TB, Pettersen A, Weiss T. et al. Gender differences of polymorphisms in the TF and TFPI genes, as related to phenotypes in patients with coronary heart disease and type-2 diabetes. Thrombosis J 2010; 08: 7.
    CrossrefPubMedGoogle Scholar
  • 36 Little J, Higgins J, Bray M. et al. The HuGENet™ HuGE review handbook, version 1.0. Office of Public Health Genomics Human Genome Epidemiology Network, Centers for Disease Control and Prevention 2006
    PubMedGoogle Scholar
  • 37 Oudot-Mellakh T, Cohen W, Germain M. et al. Genome wide association study for plasma levels of natural anticoagulant inhibitors and protein C anticoagulant pathway: the MARTHA project. Br J Haematol 2012; 157: 230-239.
    CrossrefPubMedGoogle Scholar
  • 38 Antoni G, Morange PE, Luo Y. et al. A multi-stage multi-design strategy provides strong evidence that the BAI3 locus is associated with early-onset venous thromboembolism. J Thromb Haemost 2010; 08: 2671-2679.
    CrossrefPubMedGoogle Scholar
  • 39 Viechtbauer W. Conducting meta-analyses in R with the metafor package. J Stat Software 2010; 36: 1-48.
    PubMedGoogle Scholar
  • 40 Borenstein M, Hedges LV, Higgins JPT. et al. Effect Sizes Based on Means. In: Introduction to Meta-Analysis. Chichester, United Kingdom: John Wiley & Sons, Ltd; 2009. pp. 21-32.
    CrossrefGoogle Scholar
  • 41 Gleser L, Olkin I. Stochastically Dependent Effect Sizes. In: Cooper H, Hedges LV, Valentine JC. eds. The Handbook of Research Synthesis and Meta-Analysis. New York:: Russell Sage Foundation;; 2009. pp. 357-376.
    Google Scholar
  • 42 Thakkinstian A, Thompson JR, Minelli C. et al. Choosing between per-geno-type, per-allele, and trend approaches for initial detection of gene–disease association. J Appl Stat 2009; 36: 633-646.
    CrossrefPubMedGoogle Scholar
  • 43 Moatti D, Meirhaeghe A, Ollivier V. et al. Polymorphisms of the tissue factor pathway inhibitor gene and the risk of restenosis after coronary angioplasty. Blood Coagul Fibrinolysis 2001; 12: 317-323.
    CrossrefPubMedGoogle Scholar
  • 44 Ameziane N, Seguin C, Borgel D. et al. The –33T-->C polymorphism in intron 7 of the TFPI gene influences the risk of venous thromboembolism, independently of the factor V Leiden and prothrombin mutations. Thromb Haemost 2002; 88: 195-199.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 45 Sidelmann JJ, Bladbjerg E-M, Gram J. et al. Tissue factor pathway inhibitor relates to fibrin degradation in patients with acute deep venous thrombosis. Blood Coagul Fibrinolysis 2008; 19: 405-409.
    CrossrefPubMedGoogle Scholar
  • 46 Opstad TB, Eilertsen AL, Høibraaten E. et al. Tissue factor pathway inhibitor polymorphisms in women with and without a history of venous thrombosis and the effects of postmenopausal hormone therapy. Blood Coagul Fibrinolysis 2010; 21: 516-521.
    CrossrefPubMedGoogle Scholar
  • 47 Opstad TB, Pettersen A-AR, Bratseth V. et al. The Influence of Tissue Factor and Tissue Factor Pathway Inhibitor Polymorphisms on Thrombin Generation in Stable Coronary Artery Disease. Pathophysiol Haemos Thromb 2009; 37: 98-103.
    CrossrefPubMedGoogle Scholar
  • 48 Segers O, van Oerle R, Cate ten H. et al. Thrombin generation as an intermediate phenotype for venous thrombosis. Thromb Haemost 2010; 103: 114-122.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 49 Kleesiek K, Schmidt M, Gotting C. et al. The 536C-->T transition in the human tissue factor pathway inhibitor (TFPI) gene is statistically associated with a higher risk for venous thrombosis. Thromb Haemost 1999; 82: 1-5.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 50 Nordøy A, Bønaa KH, Sandset PM. et al. Relationship between apolipoprotein E polymorphism, postprandial hyperlipemia and hemostatic variables in patients with combined hyperlipemia. Nutr Metab Cardiovasc Dis 2000; 10: 15-23.
    PubMedGoogle Scholar
  • 51 Fedi S, Gensini F, Gori AM. et al. Homocysteine and tissue factor pathway inhibitor levels in patients with Fabry’s disease. J Thromb Haemost 2005; 03: 2117-2119.
    CrossrefPubMedGoogle Scholar
  • 52 Duckers C, Simioni P, Spiezia L. et al. Low plasma levels of tissue factor pathway inhibitor in patients with congenital factor V deficiency. Blood 2008; 112: 3615-3623.
    CrossrefPubMedGoogle Scholar
  • 53 Marchetti M, Castoldi E, Spronk HMH. et al. Thrombin generation and activated protein C resistance in patients with essential thrombocythemia and polycythemia vera. Blood 2008; 112: 4061-4068.
    CrossrefPubMedGoogle Scholar
  • 54 Castoldi E, Simioni P, Tormene D. et al. Hereditary and acquired protein S deficiencies are associated with low TFPI levels in plasma. J Thromb Haemost 2010; 08: 294-300.
    CrossrefPubMedGoogle Scholar
  • 55 Castoldi E, Maurissen LFA, Tormene D. et al. Similar hypercoagulable state and thrombosis risk in type I and type III protein S-deficient individuals from families with mixed type I/III protein S deficiency. Haematologica 2010; 95: 1563-1571.
    CrossrefPubMedGoogle Scholar
  • 56 Mulder R, Kate ten MK, Kluin-Nelemans HC. et al. PROS1 Heerlen polymorphism is associated with increased free plasma tissue factor pathway inhibitor levels. Thromb Haemost 2012; 107: 594-596.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 57 Trégouët D-A, Morange P-E.. Marseille Thrombosis Association Study (MARTHA). Unpublished Data.
    PubMedGoogle Scholar
  • 58 Gagnon F. French-Canadian family study on Factor V Leiden thrombophilia (FVL Family Study). Unpublished Data.
    PubMedGoogle Scholar
  • 59 Kanse SM, Declerck PJ, Ruf W. et al. Factor VII-Activating Protease Promotes the Proteolysis and Inhibition of Tissue Factor Pathway Inhibitor. Arterioscler Thromb Vasc Biol 2012; 32: 427-433.
    CrossrefPubMedGoogle Scholar
  • 60 Warshawsky I, Herz J, Broze GJ. et al. The low density lipoprotein receptor-related protein can function independently from heparan sulfate proteoglycans in tissue factor pathway inhibitor endocytosis. J Biol Chem 1996; 271: 25873-25879.
    CrossrefPubMedGoogle Scholar
  • 61 Arnaud E, Moatti D, Emmerich J. et al. No link between the TFPI V264M mutation and venous thromboembolic disease. Thromb Haemost 1999; 82: 159-160.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 62 Morgan TM, Xiao L, Lyons P. et al. Investigation of 89 candidate gene variants for effects on all-cause mortality following acute coronary syndrome. BMC Med Genet 2008; 09: 66.
    PubMedGoogle Scholar
  • 63 Prabhakar P, De T, Nagaraja D. et al. The intron 7–33T>C polymorphism in TFPI gene and cerebral venous thrombosis: evidence for a protective role. Thromb Res 2012; 130: 687-689.
    CrossrefPubMedGoogle Scholar
  • 64 Lee C, Kong M. An Interactive Association of Common Sequence Variants in the Neuropeptide Y Gene With Susceptibility to Ischemic Stroke. Stroke 2007; 38: 2663-2669.
    CrossrefPubMedGoogle Scholar
  • 65 Pedersen A, Hanson E, Olsson S. et al. TFPI gene variation and ischemic stroke. Thromb Res 2012; 130: 565-567.
    CrossrefPubMedGoogle Scholar
  • 66 Vincent LM, Tran S, Livaja R. et al. Coagulation factor VA2440G causes east Texas bleeding disorder via TFPI . J Clin Invest 2013; 123: 3777-3787.
    CrossrefPubMedGoogle Scholar
  • 67 Holroyd EW, Simari RD. Interdependent biological systems, multi-functional molecules: the evolving role of tissue factor pathway inhibitor beyond anti-coagulation. Thromb Res 2010; 125 (Suppl. 01) S57-59.
    CrossrefPubMedGoogle Scholar
  • 68 Morange PE, Blankenberg S, Alessi MC. et al. Prognostic value of plasma tissue factor and tissue factor pathway inhibitor for cardiovascular death in patients with coronary artery disease: the AtheroGene study. J Thromb Haemost 2007; 05: 475-482.
    CrossrefPubMedGoogle Scholar
  • 69 López S, Buil A, Ordoñez J. et al. Genome-wide linkage analysis for identifying quantitative trait loci involved in the regulation of lipoprotein a (Lpa) levels. Eur J Hum Genet 2008; 16: 1372-1379.
    CrossrefPubMedGoogle Scholar
  • 70 Nagato LC, de Souza Pinhel MA, de Godoy JMP. et al. Association of ApoE genetic polymorphisms with proximal deep venous thrombosis. J Thromb Thrombolysis 2011; 33: 116-119.
    PubMedGoogle Scholar
  • 71 Bennet AM, Di Angelantonio E, Ye Z. et al. Association of apolipoprotein E genotypes with lipid levels and coronary risk. J Am Med Assoc 2007; 298: 1300-1311.
    CrossrefPubMedGoogle Scholar
  • 72 Hoke M, Kyrle PA, Minar E. et al. Tissue factor pathway inhibitor and the risk of recurrent venous thromboembolism. Thromb Haemost 2005; 94: 787-790.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 73 Novotny WF, Brown SG, Miletich JP. et al. Plasma antigen levels of the lipoprotein-associated coagulation inhibitor in patient samples. Blood 1991; 78: 387-393.
    PubMedGoogle Scholar