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

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...

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Published in:Thrombosis research 2020-02, Vol.186, p.13-19
Main Authors: Medeiros, Sarah K., Emery, Brittney, Bhagirath, Vinai, Parpia, Sameer, Dwivedi, Dhruva J., Dwivedi, Naviya J., Kearon, Clive, Liaw, Patricia C.
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Language:English
Subjects:
Biomarker
Blood
Cell-free DNA
Coagulation
Fibrinolysis
Venous thromboembolism (VTE)
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container_title Thrombosis research
container_volume 186
creator Medeiros, Sarah K.
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Bhagirath, Vinai
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Dwivedi, Dhruva J.
Dwivedi, Naviya J.
Kearon, Clive
Liaw, Patricia C.
description 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. 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. 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 
doi_str_mv 10.1016/j.thromres.2019.11.030
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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. 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. 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 &lt; .001), and higher than in healthy controls (2.77 μg/mL; 95%CI: 2.42–3.11; p &lt; .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 &lt; .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 &lt; .05). CFDNA levels were not associated with enhanced thrombin generation or impaired fibrinolysis in VTE patients. CFDNA levels are elevated in patients with unprovoked VTE but do not correlate with the procoagulant or anti-fibrinolytic properties of patient plasma. 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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. 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. 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 &lt; .001), and higher than in healthy controls (2.77 μg/mL; 95%CI: 2.42–3.11; p &lt; .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 &lt; .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 &lt; .05). CFDNA levels were not associated with enhanced thrombin generation or impaired fibrinolysis in VTE patients. 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. •Plasma samples from unprovoked VTE patients are procoagulant and anti-fibrinolytic.•CFDNA is elevated in idiopathic VTE patients after stopping warfarin therapy.•CFDNA levels do not correlate with coagulation or fibrinolysis parameters.•Factors in addition to CFDNA may modulate hemostasis in unprovoked VTE patients.</abstract><cop>United States</cop><pub>Elsevier Ltd</pub><pmid>31838139</pmid><doi>10.1016/j.thromres.2019.11.030</doi><tpages>7</tpages></addata></record>
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subjects Biomarker
Blood
Cell-free DNA
Coagulation
Fibrinolysis
Venous thromboembolism (VTE)
title Does cell-free DNA promote coagulation and inhibit fibrinolysis in patients with unprovoked venous thromboembolism?
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