4.5 Article

Increased histone-DNA complexes and endothelial-dependent thrombin generation in severe COVID-19

Journal

VASCULAR PHARMACOLOGY
Volume 142, Issue -, Pages -

Publisher

ELSEVIER SCIENCE INC
DOI: 10.1016/j.vph.2021.106950

Keywords

COVID-19; Endothelial cells; Fibrin; Histones; SARS-CoV-2; Thrombin

Funding

  1. National Institutes of Health (NIH) [R01GM123010, UM1HL120877, R35HL140039]
  2. NIH [1OT2HL156812]

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Coagulopathy in severe COVID-19 is characterized by elevated histone-DNA complexes, altered thrombin generation, and changes in fibrin structure. Endothelial cells play a crucial role in thrombin generation in COVID-19 patients. These findings contribute to our understanding of the underlying mechanisms of coagulopathy in COVID-19.
Coagulopathy in severe COVID-19 is common but poorly understood. The purpose of this study was to determine how SARS-CoV-2 infection impacts histone levels, fibrin structure, and endogenous thrombin potential in the presence and absence of endothelial cells. We studied individuals with SARS-CoV-2 infection and acute respiratory distress syndrome at the time of initiation of mechanical ventilation compared to healthy controls. Circulating histone-DNA complexes were elevated in the plasma of COVID-19 patients relative to healthy controls (n=6, each group). Using calibrated automated thrombography, thrombin generation was altered in COVID-19 patient plasma samples. Despite having increased endogenous thrombin potential, patient plasma samples exhibited prolonged lag times and times to peak thrombin in the presence of added tissue factor and PCPS. Strikingly different results were observed when endothelial cells were used in place of tissue factor and PCPS. While healthy control plasma samples did not generate measurable thrombin after 60 min, plasma samples from COVID-19+ patients formed thrombin (mean lag time similar to 20 min). Consistent with the observed alterations in thrombin generation, clots from COVID-19 subjects exhibited a denser fibrin network, thinner fibers and lower fibrin resolvability. Elevated histones, aberrant fibrin formation, and increased endothelial-dependent thrombin generation may contribute to coagulopathy in COVID-19.

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