Does cell-free DNA promote coagulation and inhibit fibrinolysis in patients with unprovoked venous thromboembolism?

Sarah K Medeiros; Brittney Emery; Vinai Bhagirath; Sameer Parpia; Dhruva J Dwivedi; Naviya J Dwivedi; Clive Kearon; Patricia C Liaw

doi:10.1016/j.thromres.2019.11.030

Does cell-free DNA promote coagulation and inhibit fibrinolysis in patients with unprovoked venous thromboembolism?

Thromb Res. 2020 Feb:186:13-19. doi: 10.1016/j.thromres.2019.11.030. Epub 2019 Nov 30.

Authors

Sarah K Medeiros¹, Brittney Emery¹, Vinai Bhagirath², Sameer Parpia³, Dhruva J Dwivedi², Naviya J Dwivedi¹, Clive Kearon², Patricia C Liaw⁴

Affiliations

¹ Thrombosis and Atherosclerosis Research Institute (TaARI), McMaster University, Hamilton, Ontario, Canada.
² Thrombosis and Atherosclerosis Research Institute (TaARI), McMaster University, Hamilton, Ontario, Canada; Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
³ Department of Oncology, McMaster University, Hamilton, Ontario, Canada.
⁴ Thrombosis and Atherosclerosis Research Institute (TaARI), McMaster University, Hamilton, Ontario, Canada; Department of Medicine, McMaster University, Hamilton, Ontario, Canada. Electronic address: patricia.liaw@taari.ca.

PMID: 31838139
DOI: 10.1016/j.thromres.2019.11.030

Abstract

Introduction: Cell-free DNA (CFDNA) is the major structural component of neutrophil extracellular traps (NETs). CFDNA contributes to the prothrombotic potential of NETs by promoting thrombin generation and inhibiting fibrinolysis. Patients with venous thromboembolism (VTE) have elevated circulating nucleosomes (i.e. DNA-histone complexes). In this study, we investigated if CFDNA contributes to a procoagulant and an antifibrinolytic state in patients with unprovoked VTE.

Materials and methods: Plasma samples from patients with a first episode of unprovoked VTE were obtained from the D-Dimer Optimal Duration Study (DODS). We measured CFDNA plasma levels in 263 patients while on warfarin and 1-month after stopping. Thrombin generation assays and clot lysis assays were measured in patients after stopping warfarin. Comparisons were made with healthy controls.

Results: CFDNA levels in VTE patients who stopped warfarin (5.53 μg/mL; 95%CI: 5.34-5.72) were higher than during warfarin therapy (3.11 μg/mL; 95%CI: 2.98-3.25; p < .001), and higher than in healthy controls (2.77 μg/mL; 95%CI: 2.42-3.11; p < .001). VTE patients had a procoagulant state as evidenced by a shorter lag time (30.8 min; 95%CI: 29.2-32.4) compared to controls (48.2 min; 95%CI :41.0-55.5; p < .001) and a greater endogenous thrombin potential (2656 nM∗min; 95%CI: 2479-2836) compared to healthy controls (1198 nM ∗ min; 95%CI: 793-1603). There was a higher proportion of clots generated from patient plasma that were resistant to lysis (43.7%) compared to healthy controls (46.3%; p < .05). CFDNA levels were not associated with enhanced thrombin generation or impaired fibrinolysis in VTE patients.

Conclusion: CFDNA levels are elevated in patients with unprovoked VTE but do not correlate with the procoagulant or anti-fibrinolytic properties of patient plasma. This study suggests that additional factors in addition to CFDNA may contribute to the pathogenesis of VTE.

Keywords: Biomarker; Blood; Cell-free DNA; Coagulation; Fibrinolysis.; Venous thromboembolism (VTE).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell-Free Nucleic Acids*
Fibrin Clot Lysis Time
Fibrinolysis
Histones
Humans
Venous Thromboembolism* / drug therapy

Substances

Cell-Free Nucleic Acids
Histones