Plasma lipopolysaccharide-binding protein is a biomarker for future venous thromboembolism: Results from discovery and validation studies

Søren Beck Jensen; Nadezhda Latysheva; Kristian Hindberg; Thor Ueland

doi:10.1111/joim.13502

Plasma lipopolysaccharide-binding protein is a biomarker for future venous thromboembolism: Results from discovery and validation studies

J Intern Med. 2022 Sep;292(3):523-535. doi: 10.1111/joim.13502. Epub 2022 Apr 27.

Authors

Søren Beck Jensen¹, Nadezhda Latysheva², Kristian Hindberg², Thor Ueland^{1

2}

Affiliations

¹ Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
² K. G. Jebsen Thrombosis Research and Expertise Center, Department of Clinical Medicine, UiT-The Arctic University of Norway, Tromsø, Norway.

Abstract

Background: Effect-size underestimation impedes biomarker identification. Long follow-up time in prospective studies attenuates effect-size estimates for transient biomarkers, while disease category-specific biomarkers are affected by merging of categories. Venous thromboembolism (VTE) encompasses deep vein thrombosis (DVT) and pulmonary embolism (PE).

Objectives: (i) To re-analyze untargeted proteomic data to identify biomarker candidates for future VTE that differ between DVT and PE and are attenuated by extended time between sampling and VTE. (ii) To perform targeted candidate validation.

Patients/methods: A VTE case-control discovery study and a nested case-control validation study were derived from the general population surveyed in 1994-95. Plasma was obtained at study enrollment, and VTE events were registered until 2007. Untargeted proteomic data were re-analyzed for candidate discovery. Lipopolysaccharide-binding protein (LBP) was validated by enzyme-linked immunosorbent assay.

Results: Elevated LBP was discovered as a candidate DVT biomarker in women with less than 3 years between blood sampling and DVT. In the validation study, the odds ratio (OR) for DVT was 2.03 (95% confidence intervals [CI]: 1.53-2.74) per standard deviation (SD) increase in LBP for women with less than 3 years between blood sampling and DVT. Adjustment for age, body mass index, and C-reactive protein attenuated the OR to 1.79 (95% CI: 1.25-2.62) per SD. In the validation study, we observed an OR for VTE of 0.47 (95% CI: 0.28-0.77) for men in the 25^th to 50^th percentiles when compared to the lowest quartile.

Conclusions: We discovered and validated increased LBP as a predictive biomarker for DVT in women. We found an increased VTE risk for men in the lowest quartile of LBP.

Keywords: biomarkers; proteomics; regression dilution bias; sex differences; thromboembolism; venous; venous thrombosis.

MeSH terms

Acute-Phase Proteins
Biomarkers
Carrier Proteins
Female
Humans
Male
Membrane Glycoproteins
Prospective Studies
Proteomics
Pulmonary Embolism* / epidemiology
Risk Factors
Venous Thromboembolism*
Venous Thrombosis* / diagnosis

Substances

Acute-Phase Proteins
Biomarkers
Carrier Proteins
Membrane Glycoproteins
lipopolysaccharide-binding protein