Thromb Haemost 2011; 105(01): 66-71
DOI: 10.1160/TH10-06-0399
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

Increased risk of gestational vascular complications in women with low free tissue factor pathway inhibitor plasma levels out of pregnancy

Antoine Ittel
1   Department of Haematology, North University Hospital, Marseille, France
,
Florence Bretelle
2   Department of Obstetrics, North University Hospital, Marseille, France
4   Inserm UMR-S608, Aix-Marseille 2 University, Marseille, France
,
Jean-Christophe Gris
3   Haematology Laboratory, University Hospital, Nîmes, France
,
Cécile Chau
2   Department of Obstetrics, North University Hospital, Marseille, France
,
Gérard Sébahoun
1   Department of Haematology, North University Hospital, Marseille, France
,
Léon Boubli
2   Department of Obstetrics, North University Hospital, Marseille, France
,
Dominique Arnoux
1   Department of Haematology, North University Hospital, Marseille, France
› Author Affiliations
Further Information

Publication History

Received: 24 June 2010

Accepted after major revision: 08 October 2010

Publication Date:
22 November 2017 (online)

Summary

Tissue factor pathway inhibitor (TFPI) plays a crucial role in haemostasis by regulating TF-induced initiation of coagulation. Since it is expressed by endothelial and trophoblastic cells, TFPI is of particular importance at the placental level and might be involved in the occurrence of gestational vascular complications (GVC). In the present study, we investigated plasma free TFPI antigen in four groups of women: healthy non-pregnant women without history of pregnancy complications; women at the beginning (<12 weeks) and women during the third trimester of a normal pregnancy; women with late pregnancy complications (pre-eclampsia / HELLP syndrome, intra-uterine fetal death, fetal growth retardation) at the time of obstetrical event and/or at distance from pregnancy. In normal pregnancy, TFPI increased between first trimester and delivery (median 5.0 ng/ml vs. 7.1 ng/ml; p<0.0001) but remained lower than in non-pregnant controls (median 8.2 ng/ml; p<0.0001). In patients, when measured concomitantly to the obstetrical event, TFPI showed no difference with normal late pregnancy levels. In contrast, at distance from pregnancy, in the absence of any hormonal influence, TFPI was significantly lower than in non-pregnant controls (median 5.9 vs. 8.2ng/ml, p < 0.0001). After categorisation into quartiles, an inverse dose-effect relationship was demonstrated between TFPI categories recorded apart from pregnancy and GVC risk, with a crude odds ratio of 43.5 (95% confidence interval 8.2–230) for patients with TFPI values in the lowest quartile (< 5.7 ng/ml). In conclusion, low free TFPI at distance from pregnancy appears to be a strong indicator of GVC risk.

 
  • References

  • 1 Sandset PM. Tissue factor pathway inhibitor (TFPI)--an update. Haemostasis 1996; 26 (Suppl. 04) 154-165.
  • 2 Hackeng TM, Sere KM, Tans G. et al. Protein S stimulates inhibition of the tissue factor pathway by tissue factor pathway inhibitor. Proc Natl Acad Sci USA 2006; 103: 3106-3111.
  • 3 Hansen JB, Huseby KR, Huseby NE. et al. Effect of cholesterol lowering on intravascular pools of TFPI and its anticoagulant potential in type II hyperlipoproteinemia. Arterioscler Thromb Vasc Biol 1995; 15: 879-885.
  • 4 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.
  • 5 Pedersen B, Holscher T, Sato Y. et al. A balance between tissue factor and tissue factor pathway inhibitor is required for embryonic development and hemostasis in adult mice. Blood 2005; 105: 2777-2782.
  • 6 Huang ZF, Higuchi D, Lasky N. et al. Tissue factor pathway inhibitor gene disruption produces intrauterine lethality in mice. Blood 1997; 90: 944-951.
  • 7 Aharon A, Brenner B, Katz T. et al. Tissue factor and tissue factor pathway inhibitor levels in trophoblast cells: implications for placental hemostasis. Thromb Haemost 2004; 924: 776-786.
  • 8 Aharon A, Lanir N, Drugan A. et al. Placental TFPI is decreased in gestational vascular complications and can be restored by maternal enoxaparin treatment. J Thromb Haemost 2005; 03: 2355-2357.
  • 9 Sandset PM, Hellgren M, Uvebrandt M. et al. Extrinsic coagulation pathway inhibitor and heparin cofactor II during normal and hypertensive pregnancy. Thromb Res 1989; 55: 665-670.
  • 10 Sarig G, Blumenfeld Z, Leiba R. et al. Modulation of systemic hemostatic parameters by enoxaparin during gestation in women with thrombophilia and pregnancy loss. Thromb Haemost 2005; 94: 980-985.
  • 11 Rosenkranz A, Hiden M, Leschnik B. et al. Calibrated automated thrombin generation in normal uncomplicated pregnancy. Thromb Haemost 2008; 99: 331-337.
  • 12 Schjetlein R, Abdelnoor M, Haugen G. et al. Hemostatic variables as independent predictors for fetal growth retardation in preeclampsia. Acta Obstet Gynecol Scand 1999; 78: 191-197.
  • 13 Abdel Gader AM, Al-Mishari AA, Awadalla SA. et al. Total and free tissue factor pathway inhibitor in pregnancy hypertension. Int J Gynaecol Obstet 2006; 95: 248-253.
  • 14 Dusse LM, Carvalho MG, Getliffe K. et al. Total plasma tissue factor pathway inhibitor levels in pre-eclampsia. Clin Chim Acta 2008; 388: 230-232.
  • 15 Erez O, Romero R, Hoppensteadt D. et al. Tissue factor and its natural inhibitor in pre-eclampsia and SGA. J Matern Fetal Neonatal Med 2008; 21: 855-869.
  • 16 Freeman DJ, Tham K, Brown EA. et al. Fetal corticotrophin-releasing hormone mRNA, but not phosphatidylserine-exposing microparticles, in maternal plasma are associated with factor VII activity in pre-eclampsia. J Thromb Haemost 2008; 06: 421-427.
  • 17 Hillman S, Chant I, Gu M. et al. Tissue pathway factor inhibitor (TFPI) activity is elevated in pregnant patients at 20 weeks gestation who subsequently develop preeclampsia. Thromb Haemost 2009; 101: 778-780.
  • 18 Teng Y, Jiang R, Lin Q. et al. The relationship between plasma and placental tissue factor, and tissue factor pathway inhibitors in severe pre-eclampsia patients. Thromb Res 2010; 126: e41-45.
  • 19 Dahm A, Rosendaal FR, Andersen TO. et al. Tissue factor pathway inhibitor anticoagulant activity: risk for venous thrombosis and effect of hormonal state. Br J Haematol 2006; 132: 333-338.
  • 20 Harris GM, Stendt CL, Vollenhoven BJ. et al. Decreased plasma tissue factor pathway inhibitor in women taking combined oral contraceptives. Am J Hematol 1999; 60: 175-180.
  • 21 van Vliet HA, Bertina RM, Dahm AE. et al. Different effects of oral contraceptives containing different progestogens on protein S and tissue factor pathway inhibitor. J Thromb Haemost 2008; 06: 346-351.
  • 22 Sandset PM, Abildgaard U, Larsen ML. Heparin induces release of extrinsic coagulation pathway inhibitor (EPI). Thromb Res 1988; 50: 803-813.
  • 23 Hansen JB, Sandset PM, Huseby KR. et al. Depletion of intravascular pools of tissue factor pathway inhibitor (TFPI) during repeated or continuous intravenous infusion of heparin in man. Thromb Haemost 1996; 76: 703-709.
  • 24 Hansen JB, Sandset PM, Huseby KR. et al. Differential effect of unfractionated heparin and low molecular weight heparin on intravascular tissue factor pathway inhibitor: evidence for a difference in antithrombotic action. Br J Haematol 1998; 101: 638-646.
  • 25 Dusse LM, Carvalho MG, Cooper AJ. et al. Tissue factor and tissue factor pathway inhibitor: a potential role in pregnancy and obstetric vascular complications?. Clin Chim Acta 2006; 372: 43-46.
  • 26 Rey E, Kahn SR, David M. et al. Thrombophilic disorders and fetal loss: a meta-analysis. Lancet 2003; 361: 901-908.
  • 27 Kovalevsky G, Gracia CR, Berlin JA. et al. Evaluation of the association between hereditary thrombophilias and recurrent pregnancy loss: a meta-analysis. Arch Intern Med 2004; 164: 558-563.
  • 28 Lin J, August P. Genetic thrombophilias and preeclampsia: a meta-analysis. Obstet Gynecol 2005; 105: 182-192.
  • 29 Zdoukopoulos N, Zintzaras E. Genetic risk factors for placental abruption: a HuGE review and meta-analysis. Epidemiology 2008; 19: 309-323.
  • 30 Facco F, You W, Grobman W. Genetic thrombophilias and intrauterine growth restriction: a meta-analysis. Obstet Gynecol 2009; 113: 1206-1216.
  • 31 Gardiner C, Cohen H, Austin SK. et al. Pregnancy loss, tissue factor pathway inhibitor deficiency and resistance to activated protein C. J Thromb Haemost 2006; 04: 2724-2726.
  • 32 Nadir Y, Henig I, Naroditzky I. et al. Involvement of Heparanase in early pregnancy losses. Thromb Res 2010; 125: e251-257.
  • 33 Nadir Y, Brenner B, Gingis-Velitski S. et al. Heparanase induces tissue factor pathway inhibitor expression and extracellular accumulation in endothelial and tumor cells. Thromb Haemost 2008; 99: 133-141.
  • 34 Aharon A, Katzenell S, Tamari T. et al. Microparticles bearing tissue factor and tissue factor pathway inhibitor in gestational vascular complications. J Thromb Haemost 2009; 07: 1047-1050.
  • 35 Dahm A, Van Hylckama Vlieg A, Bendz B. et al. Low levels of tissue factor pathway inhibitor (TFPI) increase the risk of venous thrombosis. Blood 2003; 101: 4387-4392.
  • 36 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.
  • 37 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.
  • 38 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 Haemost 1998; 80: 345-346.
  • 39 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.
  • 40 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.
  • 41 Evans GD, 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.
  • 42 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.
  • 43 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.
  • 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.
  • 45 Lincz LF, Adams MJ, Scorgie FE. et al. Polymorphisms of the tissue factor pathway inhibitor gene are associated with venous thromboembolism in the antiphospholipid syndrome and carriers of factor V Leiden. Blood Coagul Fibrinolysis 2007; 18: 559-564.
  • 46 Ariens RA, Alberio G, Moia M. et al. Low levels of heparin-releasable tissue factor pathway inhibitor in young patients with thrombosis. Thromb Haemost 1999; 81: 203-207.
  • 47 Martinuzzo M, Iglesias Varela ML, Adamczuk Y. et al. Antiphospholipid antibodies and antibodies to tissue factor pathway inhibitor in women with implantation failures or early and late pregnancy losses. J Thromb Haemost 2005; 03: 2587-2589.