Novel Plasma Biomarkers Identified for Venous Thromboembolism in a New Study
USA: A new large-scale proteomics study has discovered several new plasma protein biomarkers associated with venous thromboembolism (VTE), with evidence suggesting that some may play a causal role in disease development. These findings enhance understanding of VTE biology and may improve risk prediction. Additionally, they open new avenues for preventive strategies and targeted therapeutic interventions.
The study, published in Circulation, was led by Weihong Tang from the Division of Epidemiology & Community Health at the University of Minnesota School of Public Health and involved multiple international cohorts. Although VTE remains one of the most common cardiovascular conditions, its underlying mechanisms are not fully understood, particularly in cases that occur without cancer or obvious triggers.
Researchers analyzed data from four large prospective cohorts: ARIC (Atherosclerosis Risk in Communities), CHS (Cardiovascular Health Study), MESA (Multi-Ethnic Study of Atherosclerosis), and the HUNT study (Trøndelag Health Study). The analysis included 20,737 participants, among whom 1,371 developed incident noncancer VTE over follow-up periods ranging from 10 to 29 years.
Baseline plasma samples were assessed using the SomaScan platform, an aptamer-based high-throughput proteomics technology capable of measuring approximately 5,000 to 7,000 proteins simultaneously. Investigators examined the prospective association between circulating protein levels and future VTE risk using Cox proportional hazards models. Top findings were subsequently tested in an external replication cohort from the UK Biobank, which included 783 additional VTE cases among 39,097 participants and used the Olink proteomics platform.
In the discovery analysis, 23 proteins met stringent statistical thresholds and were successfully replicated. Of these, 15 had not previously been linked to VTE. Three novel proteins—TAGLN, SVEP1, and TIMP4—remained significant after conservative correction for multiple testing in the HUNT cohort. Among 16 proteins available for validation in the UK Biobank dataset, 11 were independently confirmed.
To explore whether these associations might reflect causal relationships rather than correlation alone, the team conducted Mendelian randomization analyses. This approach supported a potential causal role for TIMD4 in VTE risk, with additional suggestive evidence for TIMP4 and CST3. Interestingly, for some proteins, the direction of association in genetic analyses differed from observational findings, highlighting the complexity of underlying biological pathways.
The identified proteins were linked to processes extending beyond traditional coagulation pathways. These included extracellular matrix regulation, immune responses, interactions between immune cells and vascular endothelium, vascular aging, and fibrosis. Notably, some proteins such as COL6A3 and EPHA4 have been considered therapeutic targets in other diseases, raising the possibility of drug repurposing.
Although the study had limitations—including reliance on single baseline protein measurements and variations in VTE ascertainment across cohorts—the findings consistently demonstrated that incorporating proteomic markers improved VTE risk prediction beyond established clinical factors.
Overall, the study broadens insight into the biological mechanisms driving VTE and identifies promising biomarkers that could refine risk stratification and guide safer, more targeted prevention and treatment strategies.
Reference:
Tang W, Li A, Austin TR, Brækkan SK, Nøst TH, Li X, Deo R, Dubin R, Ganz P, Guan W, Cao R, Hansen JB, Hveem K, Hoogeveen RC, Jonasson C, Rotter JI, Matsushita K, Liu G, Pankow JS, Pankratz N, Psaty BM, Taylor KD, Thibord F, Boerwinkle E, Smith NL, Cushman M, Folsom AR. Novel Plasma Proteomic Markers and Risk of Venous Thromboembolism. Circulation. 2026 Feb 16. doi: 10.1161/CIRCULATIONAHA.125.074493. Epub ahead of print. PMID: 41693575.
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