Thromb Haemost
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/).

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.

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

Publication Date:
27 August 2020 (online)

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