OC 53.4 - Quantitative targeted proteomics identifies novel biomarkers for prediction of major bleeding during anticoagulation: a prospective case-cohort study.

Tuesday, June 25, 2024

10:15 – 10:30 ICT

Room: Ballroom B3

Presenting Author(s)

Eleonora Camilleri, MD

MD PhD candidate
Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands
Leiden, Zuid-Holland, Netherlands

Co-Author(s)

Bv

Bart JM van Vlijmen

PhD, associate professor
Department of Thrombosis & Hemostasis, Leiden University Medical Center, Leiden, The Netherlands
Leiden, Zuid-Holland, Netherlands
MW

Manfred Wuhrer

PhD, prof
Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherland
Leiden, Zuid-Holland, Netherlands
CB

Christoph H. Borchers

Prof
Gerald Bronfman Department of Oncology, McGill University, Montreal, Canada
Montreal, Quebec, Canada
Suzanne C. Cannegieter

MD, PhD, prof
Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
Leiden, Zuid-Holland, Netherlands
Yassene Mohammed

PhD, assistant professor
Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherland
Leiden, Zuid-Holland, Netherlands
Nienke van Rein

PhD
Leiden University Medical Center, department of Clinical Pharmacy and Toxicology and Clinical Epidemiology
Leiden, Zuid-Holland, Netherlands

Background: About 3% of patients on oral anticoagulants suffer a major bleeding annually. Existing risk assessment models insufficiently identify high-risk patients, and addition of novel biomarkers has the potential to improve this.

Aims: To identify novel circulating biomarkers for major bleeding during anticoagulation through quantitative targeted proteomics.

Methods: The BLEEDS is a population-based cohort including 16,570 patients initiating a vitamin K antagonist between 2012-2014 and a mean follow-up of 13 months. For efficiency reasons, we established a case-cohort study, and included all 326 patients with major bleeding during follow-up and a random subcohort of 414 patients. Plasma concentration of 270 proteins was measured at baseline (i.e., before the bleeding event occurred) using quantitative targeted proteomics with internal standards. Plasma levels were compared between major bleeding patients and the subcohort with Wilcoxon rank-sum test (p-value≤0.05 adjusted for false discovery rate) and stratified by sex. Association with major bleeding was assessed through Cox regression, with proteins modeled both continuously and categorical (quartiles) and further adjusted for age and sex.

Results: Plasma was available for 264 major bleeding patients and 362 subcohort members. 139/270 proteins passed the quantification criteria. Neuropilin-2, insulin-like growth factor-binding protein 2, protein AMBP, β-2-microglobulin and leucine-rich α-2-glycoprotein were, among others, ≥15% increased in the major bleeding patients compared to the subcohort. Decreased and increased proteins were different by sex and stronger in males compared with females (Figure 1). Neuropilin-2 levels in quartile 3 were associated with a 1.7-fold increased risk of major bleeding compared to levels in quartile 1 (95%CI 1.1-2.4), which remained 1.5-fold (95%CI 1.0-2.2) when adjusted (Figure 2). Patients with elevated fibrinogen-γ had also a 2.0-fold increased risk of major bleeding (95%CI 1.4-2.9).

Conclusion(s): Elevated levels of proteins related to inflammation and vascular dysfunction were associated with major bleeding during anticoagulation and can be used to optimize its prediction.