Redefining clinical venous thromboembolism phenotypes: a novel approach using latent class analysis

Maria A. de Winter, Alicia Uijl, Harry R. Büller, Marc Carrier, Alexander T. Cohen, John Bjarne Hansen, Karin H.A.H. Kaasjager, Ajay K. Kakkar, Saskia Middeldorp, Gary E. Raskob, Henrik Toft Sørensen, Philip S. Wells, Mathilde Nijkeuter, Jannick A.N. Dorresteijn*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


BACKGROUND: Patients with venous thromboembolism (VTE) are commonly classified by the presence or absence of provoking factors at the time of VTE to guide treatment decisions. This approach may not capture the heterogeneity of the disease and its prognosis. OBJECTIVES: To evaluate clinically important novel phenotypic clusters among patients with VTE without cancer and to explore their association with anticoagulant treatment and clinical outcomes. METHODS: Latent class analysis was performed with 18 baseline clinical variables in 3062 adult patients with VTE without active cancer participating in PREFER in VTE, a noninterventional disease registry. The derived latent classes were externally validated in a post hoc analysis of Hokusai-VTE (n = 6593), a randomized trial comparing edoxaban with warfarin. The associations between cluster membership and anticoagulant treatment, recurrent VTE, bleeding, and mortality after initial treatment were studied. RESULTS: The following 5 clusters were identified: young men cluster (n = 1126, 37%), young women cluster (n = 215, 7%), older people cluster (n = 1106, 36%), comorbidity cluster (n = 447, 15%), and history of venous thromboembolism cluster (n = 168, 5%). Patient characteristics varied by age, sex, medical history, and treatment patterns. Consistent clusters were evident on external validation. In Cox proportional hazard models, recurrence risk was lower in the young women cluster (hazard ratio [HR], 0.27; 95% CI, 0.12-0.61) compared with the comorbidity cluster, after adjusting for extended anticoagulation. The risk of bleeding was lower in young men, young women, and older people clusters (HR, 0.50; 95% CI, 0.38-0.66; HR, 0.23; 95% CI, 0.11-0.46; and HR, 0.55; 95% CI 0.41-0.73, respectively). CONCLUSION: The heterogeneity of VTE cases extends beyond the distinction between provoked and unprovoked VTE.

Original languageEnglish
Pages (from-to)573-585
Number of pages13
JournalJournal of thrombosis and haemostasis : JTH
Issue number3
Publication statusPublished - 1 Mar 2023


  • anticoagulants
  • bleeding
  • cluster analysis
  • deep venous thrombosis
  • venous thromboembolism


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