Skip to main content
Top

Open Access 10-03-2025 | Chronic Kidney Disease

Tissue factor pathway inhibitor levels and atherothrombotic events in patients with chronic kidney disease or diabetes

Authors: Rowena Brook, Mani Suleiman, Joseph Rigano, Brandon Lui, Harshal Nandurkar, Prahlad Ho, Hui Yin Lim

Published in: Journal of Thrombosis and Thrombolysis

Login to get access

Abstract

Increased tissue factor pathway inhibitor (TFPI) has been associated with cardiovascular disease (CVD). We aim to evaluate the predictive capability of TFPI for atherothrombotic events (ATE) in patients with chronic kidney disease (CKD) and diabetes. A prospective observational study was performed at Northern Health, Australia. Patients with CKD (estimated glomerular filtration ratio (eGFR) < 30 ml/min/1.73m2) and/or diabetes were recruited. Baseline total TFPI was measured and the median follow-up was 3.35 years. All patients with egfr < 30 ml/min/1.73m2 were analysed as CKD cohort while the diabetes cohort analysis excluded those with egfr < 30 ml/min/1.73m2. The primary outcome was ATE (myocardial infarction, stroke/transient ischaemic attack, critical limb ischaemia or sudden cardiac death). 220 patients were recruited, median age 63.5 years (IQR 51.0, 72.5) and 59.1% males (n = 130). No differences were seen in TFPI levels between the CKD (n = 77) and diabetes (n = 143) cohorts (35.4 vs. 36.4 ng/mL, p = 0.44). TFPI did not correlate with creatinine or HbA1c levels. 46 episodes of ATE were captured (6.69/100-person years (100PY)), with a higher rate in the CKD compared to the diabetes cohort (16.03/100PY vs. 2.53/100PY). In the CKD cohort, those who experienced ATE had higher TFPI with an optimal calculated cut-off (61.36ng/mL) associated with a subhazard ratio of 3.23 (95%CI 1.59–6.57). In the diabetes cohort however, TFPI was not significantly higher in those who experience ATE (40.1 vs. 34.4ng/mL, p = 0.35). We found elevated TFPI may predict prospective ATE, particularly in patients with CKD. While further validation studies are required, these findings highlight that coagulation changes may differ between high-risk CVD populations.
Literature
1.
2.
go back to reference Steffel J, Lüscher TF, Tanner FC (2006) Tissue factor in cardiovascular diseases. Circulation 113(5):722–731CrossRefPubMed Steffel J, Lüscher TF, Tanner FC (2006) Tissue factor in cardiovascular diseases. Circulation 113(5):722–731CrossRefPubMed
3.
go back to reference Keyloun JW, Le TD, Pusateri AE, Ball RL, Carney BC, Orfeo T et al (2021) Circulating Syndecan-1 and tissue factor pathway inhibitor, biomarkers of endothelial dysfunction, predict mortality in burn patients. Shock 56(2):237–244CrossRefPubMed Keyloun JW, Le TD, Pusateri AE, Ball RL, Carney BC, Orfeo T et al (2021) Circulating Syndecan-1 and tissue factor pathway inhibitor, biomarkers of endothelial dysfunction, predict mortality in burn patients. Shock 56(2):237–244CrossRefPubMed
4.
go back to reference Winckers K, Siegerink B, Duckers C, Maurissen LF, Tans G, Castoldi E et al (2011) Increased tissue factor pathway inhibitor activity is associated with myocardial infarction in young women: results from the RATIO study. J Thromb Haemost 9(11):2243–2250CrossRefPubMed Winckers K, Siegerink B, Duckers C, Maurissen LF, Tans G, Castoldi E et al (2011) Increased tissue factor pathway inhibitor activity is associated with myocardial infarction in young women: results from the RATIO study. J Thromb Haemost 9(11):2243–2250CrossRefPubMed
6.
go back to reference Dahm A, van Hylckama Vlieg A, Bendz B, Rosendaal F, Bertina RM, Sandset PM (2003) Low levels of tissue factor pathway inhibitor (TFPI) increase the risk of venous thrombosis. Blood 101(11):4387–4392CrossRefPubMed Dahm A, van Hylckama Vlieg A, Bendz B, Rosendaal F, Bertina RM, Sandset PM (2003) Low levels of tissue factor pathway inhibitor (TFPI) increase the risk of venous thrombosis. Blood 101(11):4387–4392CrossRefPubMed
7.
go back to reference Ariens R, Alberio G, Moia M, Mannucci P (1999) Low levels of heparin-releasable tissue factor pathway inhibitor in young patients with thrombosis. Thromb Haemost 81(02):203–207CrossRefPubMed Ariens R, Alberio G, Moia M, Mannucci P (1999) Low levels of heparin-releasable tissue factor pathway inhibitor in young patients with thrombosis. Thromb Haemost 81(02):203–207CrossRefPubMed
8.
go back to reference van Paridon PCS, Panova-Noeva M, van Oerle R, Schulz A, Prochaska JH, Arnold N et al (2021) Relation between tissue factor pathway inhibitor activity and cardiovascular risk factors and diseases in a large population sample. Thromb Haemost 121(2):174–181CrossRefPubMed van Paridon PCS, Panova-Noeva M, van Oerle R, Schulz A, Prochaska JH, Arnold N et al (2021) Relation between tissue factor pathway inhibitor activity and cardiovascular risk factors and diseases in a large population sample. Thromb Haemost 121(2):174–181CrossRefPubMed
9.
go back to reference Mitchell CT, Kamineni A, Palmas W, Cushman M (2009) Tissue factor pathway inhibitor, vascular risk factors and subclinical atherosclerosis: the Multi-Ethnic study of atherosclerosis. Atherosclerosis 207(1):277–283CrossRefPubMedPubMedCentral Mitchell CT, Kamineni A, Palmas W, Cushman M (2009) Tissue factor pathway inhibitor, vascular risk factors and subclinical atherosclerosis: the Multi-Ethnic study of atherosclerosis. Atherosclerosis 207(1):277–283CrossRefPubMedPubMedCentral
10.
go back to reference Sakkinen PA, Cushman M, Psaty BM, Kuller LH, Bajaj SP, Sabharwal AK et al (1998) Correlates of antithrombin, protein C, protein S, and TFPI in a healthy elderly cohort. Thromb Haemost 80(07):134–139CrossRefPubMed Sakkinen PA, Cushman M, Psaty BM, Kuller LH, Bajaj SP, Sabharwal AK et al (1998) Correlates of antithrombin, protein C, protein S, and TFPI in a healthy elderly cohort. Thromb Haemost 80(07):134–139CrossRefPubMed
11.
go back to reference Novo G, Caplice N, Tantillo R, Bonura F (2005) TFPI antigen and activity levels in patients with asymptomatic atherosclerosis and target organ acute and chronic complications. Int Angiol 24(4):366PubMed Novo G, Caplice N, Tantillo R, Bonura F (2005) TFPI antigen and activity levels in patients with asymptomatic atherosclerosis and target organ acute and chronic complications. Int Angiol 24(4):366PubMed
13.
go back to reference Leon BM, Maddox TM (2015) Diabetes and cardiovascular disease: epidemiology, biological mechanisms, treatment recommendations and future research. World J Diabetes 6(13):1246–1258CrossRefPubMedPubMedCentral Leon BM, Maddox TM (2015) Diabetes and cardiovascular disease: epidemiology, biological mechanisms, treatment recommendations and future research. World J Diabetes 6(13):1246–1258CrossRefPubMedPubMedCentral
14.
go back to reference Association AD (2013) Diagnosis and classification of diabetes mellitus. Diabetes Care 37(Supplement1):S81–S90 Association AD (2013) Diagnosis and classification of diabetes mellitus. Diabetes Care 37(Supplement1):S81–S90
15.
go back to reference Wilcox JN, Smith KM, Schwartz SM, Gordon D (1989) Localization of tissue factor in the normal vessel wall and in the atherosclerotic plaque. Proc Natl Acad Sci U S A 86(8):2839–2843CrossRefPubMedPubMedCentral Wilcox JN, Smith KM, Schwartz SM, Gordon D (1989) Localization of tissue factor in the normal vessel wall and in the atherosclerotic plaque. Proc Natl Acad Sci U S A 86(8):2839–2843CrossRefPubMedPubMedCentral
16.
go back to reference Winckers K, ten Cate H, Hackeng TM (2013) The role of tissue factor pathway inhibitor in atherosclerosis and arterial thrombosis. Blood Rev 27(3):119–132CrossRefPubMed Winckers K, ten Cate H, Hackeng TM (2013) The role of tissue factor pathway inhibitor in atherosclerosis and arterial thrombosis. Blood Rev 27(3):119–132CrossRefPubMed
17.
go back to reference Borissoff JI, Heeneman S, Kilinç E, Kassák P, Van Oerle R, Winckers K et al (2010) Early atherosclerosis exhibits an enhanced procoagulant state. Circulation 122(8):821–830CrossRefPubMed Borissoff JI, Heeneman S, Kilinç E, Kassák P, Van Oerle R, Winckers K et al (2010) Early atherosclerosis exhibits an enhanced procoagulant state. Circulation 122(8):821–830CrossRefPubMed
18.
go back to reference Westrick RJ, Bodary PF, Xu Z, Shen YC, Broze GJ, Eitzman DT (2001) Deficiency of tissue factor pathway inhibitor promotes atherosclerosis and thrombosis in mice. Circulation 103(25):3044–3046CrossRefPubMed Westrick RJ, Bodary PF, Xu Z, Shen YC, Broze GJ, Eitzman DT (2001) Deficiency of tissue factor pathway inhibitor promotes atherosclerosis and thrombosis in mice. Circulation 103(25):3044–3046CrossRefPubMed
19.
go back to reference Hembrough TA, Ruiz JF, Papathanassiu AE, Green SJ, Strickland DK (2001) Tissue factor pathway inhibitor inhibits endothelial cell proliferation via association with the very low density lipoprotein receptor. J Biol Chem 276(15):12241–12248CrossRefPubMed Hembrough TA, Ruiz JF, Papathanassiu AE, Green SJ, Strickland DK (2001) Tissue factor pathway inhibitor inhibits endothelial cell proliferation via association with the very low density lipoprotein receptor. J Biol Chem 276(15):12241–12248CrossRefPubMed
20.
go back to reference Lim HY, Lui B, Tacey M, Barit D, Patel SK, Donnan G et al (2023) Global coagulation assays in patients with chronic kidney disease and their role in predicting thrombotic risk. Thromb Res 226:127–135CrossRefPubMed Lim HY, Lui B, Tacey M, Barit D, Patel SK, Donnan G et al (2023) Global coagulation assays in patients with chronic kidney disease and their role in predicting thrombotic risk. Thromb Res 226:127–135CrossRefPubMed
21.
go back to reference Małyszko J, Małyszko JS, Myśliwiec M (2004) Endothelial cell injury markers in chronic renal failure on Conservative treatment and continuous ambulatory peritoneal dialysis. Kidney Blood Press Res 27(2):71–77CrossRefPubMed Małyszko J, Małyszko JS, Myśliwiec M (2004) Endothelial cell injury markers in chronic renal failure on Conservative treatment and continuous ambulatory peritoneal dialysis. Kidney Blood Press Res 27(2):71–77CrossRefPubMed
22.
go back to reference Pawlak K, Tankiewicz J, Mysliwiec M, Pawlak D (2009) Tissue factor/its pathway inhibitor system and kynurenines in chronic kidney disease patients on Conservative treatment. Blood Coagul Fibrinolysis 20(7):590–594CrossRefPubMed Pawlak K, Tankiewicz J, Mysliwiec M, Pawlak D (2009) Tissue factor/its pathway inhibitor system and kynurenines in chronic kidney disease patients on Conservative treatment. Blood Coagul Fibrinolysis 20(7):590–594CrossRefPubMed
23.
go back to reference Kamikura Y, Wada H, Yamada A, Shimura M, Hiyoyama K, Shiku H et al (1997) Increased tissue factor pathway inhibitor in patients with acute myocardial infarction. Am J Hematol 55(4):183–187CrossRefPubMed Kamikura Y, Wada H, Yamada A, Shimura M, Hiyoyama K, Shiku H et al (1997) Increased tissue factor pathway inhibitor in patients with acute myocardial infarction. Am J Hematol 55(4):183–187CrossRefPubMed
24.
go back to reference Rossouw JE, Johnson KC, Pettinger M, Cushman M, Sandset PM, Kuller L et al (2012) Tissue factor pathway inhibitor, activated protein C resistance, and risk of ischemic stroke due to postmenopausal hormone therapy. Stroke 43(4):952–957CrossRefPubMedPubMedCentral Rossouw JE, Johnson KC, Pettinger M, Cushman M, Sandset PM, Kuller L et al (2012) Tissue factor pathway inhibitor, activated protein C resistance, and risk of ischemic stroke due to postmenopausal hormone therapy. Stroke 43(4):952–957CrossRefPubMedPubMedCentral
25.
go back to reference Morange PE, Blankenberg S, Alessi MC, Bickel C, Rupprecht HJ, Schnabel R et al (2007) 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 5(3):475–482CrossRefPubMed Morange PE, Blankenberg S, Alessi MC, Bickel C, Rupprecht HJ, Schnabel R et al (2007) 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 5(3):475–482CrossRefPubMed
26.
go back to reference El-Hagracy RS, Kamal GM, Sabry IM, Saad AA, Abou El Ezz NF, Nasr HA (2010) Tissue factor, tissue factor pathway inhibitor and factor VII activity in cardiovascular complicated type 2 diabetes mellitus. Oman Med J 25(3):173–178CrossRefPubMedPubMedCentral El-Hagracy RS, Kamal GM, Sabry IM, Saad AA, Abou El Ezz NF, Nasr HA (2010) Tissue factor, tissue factor pathway inhibitor and factor VII activity in cardiovascular complicated type 2 diabetes mellitus. Oman Med J 25(3):173–178CrossRefPubMedPubMedCentral
27.
go back to reference Leurs PB, van Oerle R, Wolffenbuttel BH, Hamulyak K (1997) Increased tissue factor pathway inhibitor (TFPI) and coagulation in patients with insulin-dependent diabetes mellitus. Thromb Haemost 77(3):472–476CrossRefPubMed Leurs PB, van Oerle R, Wolffenbuttel BH, Hamulyak K (1997) Increased tissue factor pathway inhibitor (TFPI) and coagulation in patients with insulin-dependent diabetes mellitus. Thromb Haemost 77(3):472–476CrossRefPubMed
29.
go back to reference Cetin O, Bekpinar S, Unlucerci Y, Turkmen A, Bayram C, Ulutin T (2006) Hyperhomocysteinemia in chronic renal failure patients: relation to tissue factor and platelet aggregation. Clin Nephrol 65(2):97–102CrossRefPubMed Cetin O, Bekpinar S, Unlucerci Y, Turkmen A, Bayram C, Ulutin T (2006) Hyperhomocysteinemia in chronic renal failure patients: relation to tissue factor and platelet aggregation. Clin Nephrol 65(2):97–102CrossRefPubMed
30.
go back to reference Kaikita K, Takeya M, Ogawa H, Suefuji H, Yasue H, Takahashi K (1999) Co-localization of tissue factor and tissue factor pathway inhibitor in coronary atherosclerosis. J Pathol 188(2):180–188CrossRefPubMed Kaikita K, Takeya M, Ogawa H, Suefuji H, Yasue H, Takahashi K (1999) Co-localization of tissue factor and tissue factor pathway inhibitor in coronary atherosclerosis. J Pathol 188(2):180–188CrossRefPubMed
Metadata
Title
Tissue factor pathway inhibitor levels and atherothrombotic events in patients with chronic kidney disease or diabetes
Authors
Rowena Brook
Mani Suleiman
Joseph Rigano
Brandon Lui
Harshal Nandurkar
Prahlad Ho
Hui Yin Lim
Publication date
10-03-2025
Publisher
Springer US
Published in
Journal of Thrombosis and Thrombolysis
Print ISSN: 0929-5305
Electronic ISSN: 1573-742X
DOI
https://doi.org/10.1007/s11239-025-03077-3

Elevate your expertise in aplastic anemia (Link opens in a new window)

Transform the way you care for your patients with aplastic anemia with our 3-module series using real-world case studies and expert insights. Discover why early diagnosis matters, explore the benefits and risks of current treatments, and develop tailored approaches for complex cases. 

Supported by:
  • Pfizer
Developed by: Springer Healthcare IME
Learn more

Keynote series | Spotlight on menopause

Menopause can have a significant impact on the body, with effects ranging beyond the endocrine and reproductive systems. Learn about the systemic effects of menopause, so you can help patients in your clinics through the transition.   

Prof. Martha Hickey
Dr. Claudia Barth
Dr. Samar El Khoudary
Developed by: Springer Medicine
Watch now
Video