Download PDF
Thromb Haemost 2009; 101(03): 471-477
DOI: 10.1160/TH08-10-0667
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

Plasma free tissue factor pathway inhibitor (TFPI) levels and TF-induced thrombin generation ex vivo in men with low testosterone levels

Ingvild Agledahl
1   Department of Medicine, University Hospital of North Norway, Tromsø, Norway
,
Ellen Brodin
1   Department of Medicine, University Hospital of North Norway, Tromsø, Norway
2   Center for Atherothrombotic Research, Department of Medicine, Institute of Clinical Medicine, University of Tromsø, Tromsø, Norway
,
Johan Svartberg
1   Department of Medicine, University Hospital of North Norway, Tromsø, Norway
3   Department of Medicine, Institute of Clinical Medicine, University of Tromsø, Norway
,
Bjarne Hansen
1   Department of Medicine, University Hospital of North Norway, Tromsø, Norway
2   Center for Atherothrombotic Research, Department of Medicine, Institute of Clinical Medicine, University of Tromsø, Tromsø, Norway
› Author Affiliations
Further Information

Publication History

Received: 14 October 2008

Accepted after major revision: 11 February 2008

Publication Date:
24 November 2017 (online)

Also available at
    Permissions and Reprints

Summary

Low testosterone levels in men have been associated with cardiovascular risk factors, some prothrombotic factors, and lately also an increased risk of both cardiovascular disease and all-cause mortality. Experimental studies have shown increased synthesis and release of tissue factor pathway inhibitor (TFPI) by physiological levels of testosterone in endothelial cells. Our hypothesis was that elderly men with low testosterone levels would have lower plasma levels of plasma free TFPI with subsequent increased thrombin generation. Elderly men with low (n=37) and normal (n=41) testosterone levels were recruited from a general population, and tissue factor (TF)-induced thrombin generation ex vivo and plasma free TFPI Ag were measured. Elderly men with low testosterone levels had lower plasma free TFPI Ag (10.9 ± 2.3 ng/ml vs. 12.3 ± 3.0 ng/ml, p=0.027) and shorter initiation phase of TF-induced coagulation assessed by lag-time (5.1 ± 1.0 min vs. 5.7 ± 1.3, p=0.039). The differences between groups remained significant and were strengthened after adjustment for waist circumference and other cardiovascular risk factors. Lag-time increased linearly across quartiles of plasma free TFPI Ag (p<0.001). Multiple regression analysis revealed that total and free testosterone were independent predictors of plasma free TFPI Ag. Our findings suggest that low testosterone levels in elderly men is associated with low plasma free TFPI Ag and subsequent shortened initiation phase of TF-induced coagulation.

Keywords

Men - testosterone - TFPI - thrombin generation
 

  • References

  • 1 Svartberg J, von Mühlen D, Sundsfjord J. et al. Waist circumference and testosterone levels in community dwelling men. The Tromso study. Eur J Epidemiol 2004; 19: 657-663.
    PubMedGoogle Scholar
  • 2 Svartberg J, von Mühlen D, Schirmer H. et al. Association of endogenous testosterone with blood pressure and left ventricular mass in men. The Tromso Study. Eur J Endocrinol 2004; 150: 65-71.
    CrossrefPubMedGoogle Scholar
  • 3 Agledahl I, Skjaerpe PA, Hansen JB. et al. Low serum testosterone in men is inversely associated with non-fasting serum triglycerides: the Tromso study. Nutr Metab Cardiovasc Dis 2008; 18: 256-262.
    CrossrefPubMedGoogle Scholar
  • 4 Svartberg J, Midtby M, Bonaa KH. et al. The associations of age, lifestyle factors and chronic disease with testosterone in men: the Tromso Study. Eur J Endocrinol 2003; 149: 145-152.
    CrossrefPubMedGoogle Scholar
  • 5 Ding EL, Song Y, Malik VS. et al. Sex differences of endogenous sex hormones and risk of type 2 diabetes: a systematic review and meta-analysis. J Am Med Assoc 2006; 295: 1288-1299.
    CrossrefPubMedGoogle Scholar
  • 6 Hak AE, Witteman JC, de Jong FH. et al. Low levels of endogenous androgens increase the risk of atherosclerosis in elderly men: the Rotterdam study. J Clin Endocrinol Metab 2002; 87: 3632-3639.
    CrossrefPubMedGoogle Scholar
  • 7 Svartberg J, von Mühlen D, Mathiesen E. et al. Low testosterone levels are associated with carotid atherosclerosis in men. J Intern Med 2006; 259: 576-582.
    CrossrefPubMedGoogle Scholar
  • 8 Khaw KT, Dowsett M, Folkerd E. et al. Endogenous testosterone and mortality due to all causes, cardiovascular disease, and cancer in men: European prospective investigation into cancer in Norfolk (EPIC-Norfolk) Prospective Population Study. Circulation 2007; 116: 2694-2701.
    CrossrefPubMedGoogle Scholar
  • 9 Laughlin GA, Barrett-Connor E, Bergstrom J. Low serum testosterone and mortality in older men. J Clin Endocrinol Metab 2008; 93: 68-75.
    CrossrefPubMedGoogle Scholar
  • 10 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.
    CrossrefPubMedGoogle Scholar
  • 11 Broze Jr GJ, Miletich JP. Characterization of the inhibition of tissue factor in serum. Blood 1987; 69: 150-155.
    PubMedGoogle Scholar
  • 12 Meade TW, Mellows S, Brozovic M. et al. Haemostatic function and ischaemic heart disease: principal results of the Northwick Park Heart Study. Lancet 1986; 2: 533-537.
    PubMedGoogle Scholar
  • 13 Heinrich J, Balleisen L, Schulte H. et al. Fibrinogen and factor VII in the prediction of coronary risk. Results from the PROCAM study in healthy men. Arterioscler Thromb 1994; 14: 54-59.
    CrossrefPubMedGoogle Scholar
  • 14 Sandset PM, Warn-Cramer BJ, Rao LV. et al. Depletion of extrinsic pathway inhibitor (EPI) sensitizes rabbits to disseminated intravascular coagulation induced with tissue factor: evidence supporting a physiologic role for EPI as a natural anticoagulant. Proc Natl Acad Sci USA 1991; 88: 708-712.
    CrossrefPubMedGoogle Scholar
  • 15 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.
    PubMedGoogle Scholar
  • 16 Van DP, Grosley M, Cost H. Total and free levels of tissue factor pathway inhibitor: a risk factor in patients with factor V Leiden?. Blood Coagul Fibrinolysis 1999; 10: 115-116.
    CrossrefPubMedGoogle Scholar
  • 17 Dahm A, van Hylckama V, Bendz B. et al. Low levels of tissue factor pathway inhibitor (TFPI) increase the risk of venous thrombosis. Blood 2003; 101: 4387-4392.
    CrossrefPubMedGoogle Scholar
  • 18 Saigo M, Abe S, Ogawa M. et al. Imbalance of plasminogen activator inhibitor-I/ tissue plasminogen activator and tissue factor/tissue factor pathway inhibitor in young Japanese men with myocardial infarction. Thromb Haemost 2001; 86: 1197-1203.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 19 Smith EB. Fibrinogen, fibrin and fibrin degradation products in relation to atherosclerosis. Clin Haematol 1986; 15: 355-370.
    PubMedGoogle Scholar
  • 20 Niewiarowski S, Rao AK. Contribution of thrombogenic factors to the pathogenesis of atherosclerosis. Prog Cardiovasc Dis 1983; 26: 197-222.
    CrossrefPubMedGoogle Scholar
  • 21 Tremoli E, Camera M, Toschi V, Colli S. Tissue factor in atherosclerosis. Atherosclerosis 1999; 144: 273-283.
    CrossrefPubMedGoogle Scholar
  • 22 Li YH, Teng JK, Tsai WC. et al. Prognostic significance of elevated hemostatic markers in patients with acute myocardial infarction. J Am Coll Cardiol 1999; 33: 1543-1548.
    CrossrefPubMedGoogle Scholar
  • 23 Peternel P, Terbizan M, Tratar G. et al. Markers of hemostatic system activation during treatment of deep vein thrombosis with subcutaneous unfractionated or low-molecular weight heparin. Thromb Res 2002; 105: 241-246.
    CrossrefPubMedGoogle Scholar
  • 24 Ardissino D, Merlini PA, Bauer KA. et al. Coagulation activation and long-term outcome in acute coronary syndromes. Blood 2003; 102: 2731-2735.
    CrossrefPubMedGoogle Scholar
  • 25 Soncini M, Gasparini P, Lorena M. et al. Prognostic significance of markers of thrombin generation in the acute and chronic phases of non cardioembolic ischemic stroke. Minerva Cardioangiol 2000; 48: 349-356.
    PubMedGoogle Scholar
  • 26 Hemker HC, Giesen P, AlDieri R. et al. The calibrated automated thrombogram (CAT): a universal routine test for hyper- and hypocoagulability. Pathophysiol Haemost Thromb 2002; 32: 249-253.
    CrossrefPubMedGoogle Scholar
  • 27 Rosano GM, Leonardo F, Pagnotta P. et al. Acute anti-ischemic effect of testosterone in men with coronary artery disease. Circulation 1999; 99: 1666-1670.
    CrossrefPubMedGoogle Scholar
  • 28 Webb CM, Adamson DL, de Zeigler D. et al. Effect of acute testosterone on myocardial ischemia in men with coronary artery disease. Am J Cardiol 1999; 83: 437-439 A9.
    CrossrefPubMedGoogle Scholar
  • 29 Smith AM, English KM, Malkin CJ. et al. Testosterone does not adversely affect fibrinogen or tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) levels in 46 men with chronic stable angina. Eur J Endocrinol 2005; 152: 285-291.
    CrossrefPubMedGoogle Scholar
  • 30 Jin H, Lin J, Fu L. et al. Physiological testosterone stimulates tissue plasminogen activator and tissue factor pathway inhibitor and inhibits plasminogen activator inhibitor type 1 release in endothelial cells. Biochem Cell Biol 2007; 85: 246-251.
    CrossrefPubMedGoogle Scholar
  • 31 Agledahl I, Hansen JB, Svartberg J. Postprandial triglyceride metabolism in elderly men with subnormal testosterone levels. Asian J Androl 2008; 10: 542-549.
    CrossrefPubMedGoogle Scholar
  • 32 Vermeulen A, Verdonck L, Kaufman JM. A critical evaluation of simple methods for the estimation of free testosterone in serum. J Clin Endocrinol Metab 1999; 84: 3666-3672.
    CrossrefPubMedGoogle Scholar
  • 33 Hemker HC, Giesen P, Al Dieri R. et al. Calibrated automated thrombin generation measurement in clotting plasma. Pathophysiol Haemost Thromb 2003; 33: 4-15.
    CrossrefPubMedGoogle Scholar
  • 34 Morrissey JH, Macik BG, Neuenschwander PF. et al. Quantitation of activated factor VII levels in plasma using a tissue factor mutant selectively deficient in promoting factor VII activation. Blood 1993; 81: 734-744.
    PubMedGoogle Scholar
  • 35 Novotny WF, Palmier M, Wun TC. et al. Purification and properties of heparin-releasable lipoprotein-associated coagulation inhibitor. Blood 1991; 78: 394-400.
    PubMedGoogle Scholar
  • 36 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
  • 37 Veer C, Mann KG. Regulation of tissue factor initiated thrombin generation by the stoichiometric inhibitors tissue factor pathway inhibitor, antithrombinIII, and heparin cofactor-II. J Biol Chem 1997; 272: 4367-4377.
    CrossrefPubMedGoogle Scholar
  • 38 Brodin E, Appelbom H, Østerud H. et al. Regulation of thrombin generation by TFPI in plasma without and with heparin. J Lab Clin Med. 2008 in print.
    PubMedGoogle Scholar
  • 39 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.
    CrossrefPubMedGoogle Scholar
  • 40 Anderson RA, Ludlam CA, Wu FC. Haemostatic effects of supraphysiological levels of testosterone in normal men. Thromb Haemost 1995; 74: 693-697.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 41 Toorians AW, Thomassen MC, Zweegman S. et al. Venous thrombosis and changes of hemostatic variables during cross-sex hormone treatment in transsexual people. J Clin Endocrinol Metab 2003; 88: 5723-5729.
    CrossrefPubMedGoogle Scholar
  • 42 Mannhalter C, Quehenberger P. Laboratory methods in the haemostatic laboratory. Thromb Haemost 2006; 96: 545-546.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 43 Tappenden KA, Gallimore MJ, Evans G. et al. Thrombin generation: a comparison of assays using platelet-poor and -rich plasma and whole blood samples from healthy controls and patients with a history of venous thromboembolism. Br J Haematol 2007; 139: 106-112.
    CrossrefPubMedGoogle Scholar
  • 44 van Hylckama V, Christiansen SC, Luddington R. et al. Elevated endogenous thrombin potential is associated with an increased risk of a first deep venous thrombosis but not with the risk of recurrence. Br J Haematol 2007; 138: 769-774.
    CrossrefPubMedGoogle Scholar
  • 45 Tripodi A, Legnani C, Chantarangkul V. et al. High thrombin generation measured in the presence of thrombomodulin is associated with an increased risk of recurrent venous thromboembolism. J Thromb Haemost 2008; 6: 1327-1333.
    CrossrefPubMedGoogle Scholar
  • 46 Hron G, Kollars M, Binder BR. et al. Identification of patients at low risk for recurrent venous thromboembolism by measuring thrombin generation. J Am Med Assoc 2006; 296: 397-402.
    CrossrefPubMedGoogle Scholar
  • 47 Brodin E, Borvik T, Sandset PM. et al. Coagulation activation in young survivors of myocardial infarction (MI)--a population-based case-control study. Thromb Haemost 2004; 92: 178-184.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 48 Danielsen R, Onundarson PT, Thors H. et al. Activated and total coagulation factor VII, and fibrinogen in coronary artery disease. Scand Cardiovasc J 1998; 32: 87-95.
    CrossrefPubMedGoogle Scholar
  • 49 Moor E, Silveira A, van’t Hooft F, Suontaka AM. et al. Coagulation factor VII mass and activity in young men with myocardial infarction at a young age. Role of plasma lipoproteins and factor VII genotype. Arterioscler Thromb Vasc Biol 1995; 15: 655-664.
    CrossrefPubMedGoogle Scholar
  • 50 De Stavola BL, Meade TW. Long-term effects of hemostatic variables on fatal coronary heart disease: 30-year results from the first prospective Northwick Park Heart Study (NPHS-I). J Thromb Haemost 2007; 5: 461-471.
    CrossrefPubMedGoogle Scholar
  • 51 Junker R, Heinrich J, Schulte H. et al. Coagulation factor VII and the risk of coronary heart disease in healthy men. Arterioscler Thromb Vasc Biol 1997; 17: 1539-1544.
    CrossrefPubMedGoogle Scholar