Thromb Haemost 2001; 85(06): 999-1003
DOI: 10.1055/s-0037-1615954
Review Article
Schattauer GmbH

Plasma Levels of Free and Total TFPI, Relationship with Cardiovascular Risk Factors and Endothelial Cell Markers

P. E. Morange
1   Lab. Hématologie CHU Timone Marseille, Genevilliers, France
,
J. F. Renucci
2   Centre de Prévention et de Détection de l’Athérosclérose (CDPA) CHU Timone Marseille, Genevilliers, France
,
M. A. Charles
3   INSERM u258 Paris, Genevilliers, France
,
M. F. Aillaud
1   Lab. Hématologie CHU Timone Marseille, Genevilliers, France
,
F. Giraud
4   Lab. Radioanalyse Hop. Conception Marseille, Genevilliers, France
,
M. Grimaux
5   Serbio, Diagnostica Stago, Genevilliers, France
,
I. Juhan-Vague
1   Lab. Hématologie CHU Timone Marseille, Genevilliers, France
› Author Affiliations
Further Information

Publication History

Received 07 July 2000

Accepted after resubmission 16 January 2001

Publication Date:
12 December 2017 (online)

Summary

Free-TFPI (f-TFPI) presents high anticoagulant activity and its plasma level correlates with unfavorable outcomes in unstable angina. Total TFPI (t-TFPI) represents mainly the lipid-bound form which seems to have a poor anticoagulant activity. Until now, it is not known whether the variations of f-TFPI plasma levels are determined by environmental factors. The aim of our study was to evaluate the influence of cardiovascular risk factors on plasma levels of f-TFPI and relations with other endothelial derived molecules in a population of 626 patients (277 men and 349 women) attending a metabolic ward for primary prevention of coronary disease.

Free and total TFPI plasma levels were poorly correlated. f-TFPI levels increased with age in both sexes, t-TFPI in women only. Ageadjusted correlations of TFPI levels with conventional cardiovascular risk factors and endothelial cell markers showed different patterns for f-TFPI and t-TFPI. f-TFPI correlated with parameters associated with insulin resistance, particularly in females. f-TFPI was also positively associated in both genders with fibrinogen and endothelial cell markers: t-PA, thrombomodulin (TM) and von Willebrand factor (vWF). t-TFPI correlated strongly with LDL-C in both sexes. It also correlated negatively with parameters of the insulin resistance syndrome. t-TFPI also correlated with TM but not with other endothelial cell markers. The results of the multivariate step by step analysis showed that cardiovascular risk factors poorly explained the f-TFPI variability (7% and 4% in men and women, respectively), whereas they explained 16 and 20% of t-TFPI variability in men and women respectively (mostly related to LDL-C).

In conclusion, this study showed that free- and total-TFPI are regulated differently. f-TFPI strongly correlates with endothelial cell markers and t-TFPI is more related to conventional cardiovascular risk factors. The strong gender effect on f-TFPI levels remains to be explained.

 
  • References

  • 1 Broze Jr GJ, Girard TJ, Novotny WF. Regulation of coagulation by a multivalent Kunitz-type inhibitor. Broze Jr GJ, Girard TJ, Novotny WF. Biochemistry 1990; 29: 7539-46.
  • 2 Bajaj MS, Kuppuswamy MN, Saito H, Spitzer SG, Bajaj SP. Cultured normal human 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: 8869-73.
  • 3 Sandset PM. Tissue factor pathway inhibitor (TFPI) – an update. Haemostasis 1996; 26 (Suppl. 04) 154-65.
  • 4 Kokawa T, Enjyoji K, Kumeda K, Kamikubo Y, Harada-Shiba M, Koh H, Tsushima M, Yamamoto A, Kato H. Measurement of the free form of TFPI antigen in hyperlipidemia-Relationship between free and endothelial cell-associated forms of TFPI. Arterioscler Thromb Vasc Biol 1996; 16: 802-8.
  • 5 Kawaguchi A, Miyao Y, Noguchi T, Nonogi H, Yamagishi M, Miyatake K, Kamikubo Y, Kumeda K, Tsushima M, Yamamoto A, Kato H. Intravascular free tissue factor pathway inhibitor is inversely correlated with HDL cholesterol and postheparin lipoprotein lipase but proportional to apolipoprotein A-II. Arterioscler Thromb Vasc Biol 2000; 20: 251-8.
  • 6 Bridey F, Lacombe C, Sustendal L, Moatti D, Combe F, Mammes O, de Prost D. Development of a method to separate lipoprotein-bound and lipoprotein-depleted tissue factor pathway inhibitor. Measurement of free tissue factor pathway inhibitor activity. Blood Coagul Fibrinolysis 1998; 9: 637-43.
  • 7 Lindahl AK, Jacobsen PB, Sandset PM, Abildgaard U. Tissue factor pathway inhibitor with high anticoagulant activity is increased in post-heparin plasma and in plasma from cancer patients. Blood Coagul Fibrinolysis 1991; 2: 713-21.
  • 8 Hansen JB, Huseby KR, Huseby NE, Ezban M, Nordoy A. 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: 413-25.
  • 9 Caplice NM, Mueske CS, Kleppe LS, Simari RD. Presence of tissue factor pathway inhibitor in human atherosclerotic plaques is associated with reduced tissue factor activity. Circulation 1998; 98: 1051-7.
  • 10 Badimon JJ, Lettino M, Toschi V, Fuster V, Berrozpe M, Chesebro JH, Badimon L. Local inhibition of tissue factor reduces the thrombogenicity of disrupted human atherosclerotic plaques: effects of tissue factor pathway inhibitor on plaque thrombogenicity under flow conditions. Circulation 1999; 99: 1780-7.
  • 11 Sandset PM, Sirnes PA, Abildgaard U. Factor VII and extrinsic pathway inhibitor in acute coronary disease. Br J Haematol 1989; 72: 391-6.
  • 12 Falciani M, Gori AM, Fedi S, Chiarugi L, Simonetti I, Dabizzi RP, Prisco D, Pepe G, Abbate R, Gensini GF, Neri Serneri GG. Elevated tissue factor and tissue factor pathway inhibitor circulating levels in ischaemic heart disease patients. Thromb Haemost 1998; 79: 495-9.
  • 13 Soejima H, Ogawa H, Yasue H, Kaikita K, Nishiyama K, Misumi K, Takazoe K, Miyao Y, Yoshimura M, Kugiyama K, Nakamura S, Tsuji I, Kumeda K. Heightened tissue factor associated with tissue factor pathway inhibitor and prognosis in patients with unstable angina. Circulation 1999; 99: 2908-13.
  • 14 Henry M, Tregouet DA, Alessi MC, Aillaud MF, Visvikis S, Siest G, Tiret L, Juhan-Vague I. Metabolic determinants are much more important than genetic polymorphisms in determining the PAI-1 activity and antigen plasma concentrations: a family study with part of the Stanislas Cohort. Arterioscler Thromb Vasc Biol 1998; 18: 84-91.
  • 15 Blann AD, Amiral J, McCollum CN, Lip GYH. Difference in free and total tissue factor pathway inhibitor, and tissue factor in peripheral artery disease compared to healthy controls. Atherosclerosis 2000; 152: 29-34.
  • 16 Kario K, Matsuo T, Kobayashi H, Matsuo M, Sakata T, Miyata T. Activation of tissue factor-induced coagulation and endothelial cell dysfunction in non-insulin-dependent diabetic patients with microalbuminuria. Arterioscler Thromb Vasc Biol 1995; 15: 1114-20.
  • 17 Yokoyama H, Myrup B, Rossing P, Ostergaard PB. Increased tissue factor pathway inhibitor activity in IDDM patients with nephropathy. Diabetes Care 1996; 19: 441-5.
  • 18 Matsuda T, Morishita E, Jokaji H, Asakura H, Saito M, Yoshida T, Takemoto K. Mechanism on disorders of coagulation and fibrinolysis in diabetes. Diabetes 1996; 45 (Suppl. 03) S109-110.
  • 19 Leurs PB, van Oerle R, Wolffenbuttel BH, Hamulyak K. Increased tissue factor pathway inhibitor (TFPI) and coagulation in patients with insulin-dependent diabetes mellitus. Thromb Haemost 1997; 77: 472-6.
  • 20 Rao AK, Chouhan V, Chen X, Sun L, Boden G. Activation of the tissue factor pathway of blood coagulation during prolonged hyperglycemia in young healthy men. Diabetes 1999; 48: 1156-61.
  • 21 Chandler WL, Alessi MC, Aillaud MF, Henderson P, Vague P, Juhan-Vague I. Clearance of tissue plasminogen activator (TPA) and TPA/plasminogen activator inhibitor type 1 (PAI-1) complex: relationship to elevated TPA antigen in patients with high PAI-1 activity levels. Circulation 1997; 96: 761-8.