Download PDF
Thromb Haemost 2021; 121(01): 070-075
DOI: 10.1055/s-0040-1715459
New Technologies, Diagnostic Tools and Drugs

High Soluble Thrombomodulin Is Associated with an Increased Risk of Major Bleeding during Treatment with Oral Anticoagulants: A Case–Cohort Study

Myrthe M. A. Toorop
1   Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
,
Nienke van Rein
1   Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
2   Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands
3   Department of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, The Netherlands
,
Suzanne C. Cannegieter
1   Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
3   Department of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, The Netherlands
,
Felix J. M. van der Meer
3   Department of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, The Netherlands
,
Pieter H. Reitsma
3   Department of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, The Netherlands
4   Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands
,
Willem M. Lijfering
1   Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
,
Mettine H. A. Bos
3   Department of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, The Netherlands
4   Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands
› Author Affiliations Funding This study was supported by the Center for Translational Molecular Medicine (01 C-201; http://www.ctmm.nl/nl) and Hartstichting (99.165; https://www.hartstichting.nl/).
› Further Information
    Permissions and Reprints

Abstract

Background Major bleeding occurs in 1 to 3% of patients treated with oral anticoagulants per year. Biomarkers may help to identify high-risk patients. A proposed marker for major bleeding while using anticoagulants is soluble thrombomodulin (sTM).

Methods Plasma was available from 16,570 patients of the BLEEDS cohort that consisted of patients who started treatment with vitamin K antagonists between 2012 and 2014. A case–cohort study was performed including all patients with a major bleed (n = 326) during follow-up and a random sample of individuals selected at baseline (n = 652). Plasma sTM levels were measured and stratified by percentiles. Patients were also categorized by international normalized ratio (INR). Adjusted hazard ratios (for age, sex, hypertension, and diabetes) with 95% confidence intervals (CIs) were estimated by means of Cox regression.

Results Plasma sTM levels were available for 263 patients with a major bleed and 538 control subjects. sTM levels were dose-dependently associated with risk of major bleeding, with a 1.9-fold increased risk (95% CI: 1.1–3.1) for levels above the 85th percentile versus the <25th percentile. A high INR (≥4) in the presence of high (≥70th percentile) sTM levels was associated with a 7.1-fold (95% CI: 4.1–12.3) increased risk of major bleeding, corresponding with a bleeding rate of 14.1 per 100 patient-years.

Conclusion High sTM levels at the start of treatment are associated with major bleeding during vitamin K antagonist treatment, particularly in the presence of a high INR.

Keywords

thrombomodulin - anticoagulants - hemorrhage

Authors' Contributions

M.M.A.T., N.-v.R., and W.M.L. designed the research.N.-v.R and M.H.A.B. collected the data. M.M.A.T. and N.-v.R. analyzed the data. M.M.A.T. and N.-v.R. wrote the manuscript. F.J.M.-v.-d.M., P.H.R., M.H.A.B., W.M.L., and S.C.C. critically revised the manuscript for important intellectual content. P.H.R. and M.H.A.B. obtained funding for the research.


Supplementary Material



Publication History

Received: 01 April 2020

Accepted: 04 July 2020

Article published online:
27 August 2020

© 2020. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Schulman S, Kearon C. Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost 2005; 3 (04) 692-694
    CrossrefPubMedGoogle Scholar
  • 2 Linkins LA. Bleeding risks associated with vitamin K antagonists. Blood Rev 2013; 27 (03) 111-118
    CrossrefPubMedGoogle Scholar
  • 3 van der Meer FJ, Rosendaal FR, Vandenbroucke JP, Briët E. Bleeding complications in oral anticoagulant therapy. An analysis of risk factors. Arch Intern Med 1993; 153 (13) 1557-1562
    CrossrefPubMedGoogle Scholar
  • 4 van Rein N, Lijfering WM, Bos MH. et al. Objectives and design of BLEEDS: a cohort study to identify new risk factors and predictors for major bleeding during treatment with vitamin K antagonists. PLoS One 2016; 11 (12) e0164485
    Google Scholar
  • 5 Zhu W, He W, Guo L, Wang X, Hong K. The HAS-BLED score for predicting major bleeding risk in anticoagulated patients with atrial fibrillation: a systematic review and meta-analysis. Clin Cardiol 2015; 38 (09) 555-561
    CrossrefPubMedGoogle Scholar
  • 6 Ansell J, Hirsh J, Hylek E, Jacobson A, Crowther M, Palareti G. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133 (6, Suppl): 160S-198S
    Google Scholar
  • 7 Jansson JH, Boman K, Brännström M, Nilsson TK. High concentration of thrombomodulin in plasma is associated with hemorrhage: a prospective study in patients receiving long-term anticoagulant treatment. Circulation 1997; 96 (09) 2938-2943
    CrossrefPubMedGoogle Scholar
  • 8 van der Heijden JF, Rekké B, Hutten BA. et al. Non-fatal major bleeding during treatment with vitamin K antagonists: influence of soluble thrombomodulin and mutations in the propeptide of coagulation factor IX. J Thromb Haemost 2004; 2 (07) 1104-1109
    CrossrefPubMedGoogle Scholar
  • 9 Lind M, Boman K, Johansson L. et al. Thrombomodulin as a marker for bleeding complications during warfarin treatment. Arch Intern Med 2009; 169 (13) 1210-1215
    CrossrefPubMedGoogle Scholar
  • 10 Roldán V, Marín F, Muiña B. et al. Plasma von Willebrand factor levels are an independent risk factor for adverse events including mortality and major bleeding in anticoagulated atrial fibrillation patients. J Am Coll Cardiol 2011; 57 (25) 2496-2504
    CrossrefPubMedGoogle Scholar
  • 11 Hijazi Z, Oldgren J, Lindbäck J. et al; ARISTOTLE and RE-LY Investigators. The novel biomarker-based ABC (age, biomarkers, clinical history)-bleeding risk score for patients with atrial fibrillation: a derivation and validation study. Lancet 2016; 387 (10035): 2302-2311
    CrossrefPubMedGoogle Scholar
  • 12 Hijazi Z, Wallentin L, Siegbahn A. et al; ARISTOTLE Investigators. High-sensitivity troponin T and risk stratification in patients with atrial fibrillation during treatment with apixaban or warfarin. J Am Coll Cardiol 2014; 63 (01) 52-61
    CrossrefPubMedGoogle Scholar
  • 13 Federation of Dutch Anticoagulation Clinics (Trombosediensten FvN). FNT-NORMEN 2018. Accessed July 19, 2020 at: https://www.fnt.nl/kwaliteit/fnt-veldnorm
    Google Scholar
  • 14 Rosendaal FR, Cannegieter SC, van der Meer FJ, Briët E. A method to determine the optimal intensity of oral anticoagulant therapy. Thromb Haemost 1993; 69 (03) 236-239
    Article in Thieme ConnectPubMedGoogle Scholar
  • 15 Prentice RL. A case-cohort design for epidemiologic cohort studies and disease prevention trials. Biometrika 1986; 73 (01) 1-11
    CrossrefPubMedGoogle Scholar
  • 16 van Rein N, Cannegieter SC, Rosendaal FR, Reitsma PH, Lijfering WM. Suspected survivor bias in case-control studies: stratify on survival time and use a negative control. J Clin Epidemiol 2014; 67 (02) 232-235
    CrossrefPubMedGoogle Scholar
  • 17 Öhlin AK, Larsson K, Hansson M. Soluble thrombomodulin activity and soluble thrombomodulin antigen in plasma. J Thromb Haemost 2005; 3 (05) 976-982
    CrossrefPubMedGoogle Scholar
  • 18 Hagström E, James SK, Bertilsson M. et al; PLATO Investigators. Growth differentiation factor-15 level predicts major bleeding and cardiovascular events in patients with acute coronary syndromes: results from the PLATO study. Eur Heart J 2016; 37 (16) 1325-1333
    CrossrefPubMedGoogle Scholar
  • 19 Genees- en hulpmiddelen Informatie Project (GIP), Zorginstituut Nederland. Top 25 van geneesmiddelen die het sterkst zijn gestegen in het aantal DDD's in 2017 [Internet]. Accessed 2019 at: https://www.gipdatabank.nl/
    Google Scholar
  • 20 Barnes GD, Lucas E, Alexander GC, Goldberger ZD. National trends in ambulatory oral anticoagulant use. Am J Med 2015; 128 (12) 1300-5.e2
    CrossrefPubMedGoogle Scholar
  • 21 Loo SY, Dell'Aniello S, Huiart L, Renoux C. Trends in the prescription of novel oral anticoagulants in UK primary care. Br J Clin Pharmacol 2017; 83 (09) 2096-2106
    CrossrefPubMedGoogle Scholar
  • 22 van Diepen M, Ramspek CL, Jager KJ, Zoccali C, Dekker FW. Prediction versus aetiology: common pitfalls and how to avoid them. Nephrol Dial Transplant 2017; 32 (02) (Suppl. 02) ii1-ii5
    CrossrefPubMedGoogle Scholar
  • 23 Gage BF, Yan Y, Milligan PE. et al. Clinical classification schemes for predicting hemorrhage: results from the National Registry of Atrial Fibrillation (NRAF). Am Heart J 2006; 151 (03) 713-719
    CrossrefPubMedGoogle Scholar
  • 24 Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest 2010; 138 (05) 1093-1100
    CrossrefPubMedGoogle Scholar
  • 25 Fang MC, Go AS, Chang Y. et al. A new risk scheme to predict warfarin-associated hemorrhage: the ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) study. J Am Coll Cardiol 2011; 58 (04) 395-401
    CrossrefPubMedGoogle Scholar