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Coronavirus-associated coagulopathy is postulated to be driven by systemic macrophage activation after severe acute respiratory syndrome coronavirus 2 infection and presents with an increased risk of thrombogenesis and hyperfibrinolysis. Previous work shows that the histone methyltransferase KMT2A/MLL1 is a key mediator of inflammatory signaling in monocytes and macrophages (Mo/Mφs). In this study, we sought to identify the regulation of factors important in coronavirus-associated coagulopathy by MLL1.
Mice with myeloid specific knockout of MLL1 (Cre+) and littermate controls (Cre–) underwent intranasal inoculation of 2 × 105 pfu of the murine coronavirus MHVA59, an established model which phenocopies severe acute respiratory syndrome coronavirus 2 infection. Splenic Mφs (surrogate for circulating Mo/Mφs) were isolated and RNA and protein levels of urokinase (Plau; profibrinolytic), urokinase receptor (Plaur; profibrinolytic), and tissue factor (F3/TF; procoagulant) were analyzed using quantitative reverse-transcriptase polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. Thromboelastography on whole blood and urokinase activity assays from mouse plasma were performed. Urokinase and tissue factor activity assays were performed on plasma from human samples.
RNA (Figure, top panel) and protein (Figure, bottom) levels of Plau, Plaur, and F3 were suppressed in the splenic Mφs harvested from sham (intranasal phosphate-buffered saline) and infected Cre+ animals (white bars) compared with splenic Mφs harvested from Cre– animals (blue bars; Figure, A). Cre– mice displayed a shortened reaction time as measured by thromboelastography (Figure, B) and elevated plasma urokinase activity levels (not shown). Hospitalized coronavirus disease 2019-positive patients displayed elevated plasma urokinase and tissue factor activity levels (Figure, C).
We identify a role for MLL1 for basal expression and for coronavirus-mediated induction of factors important for fibrinolysis and coagulation in murine Mo/Mφs and in driving coagulopathy. Our results suggest that MLL1 blockade may be an attractive strategy to combat coronavirus associated coagulopathy.
Published online: June 10, 2022
Author Disclosures: S. B. Sharma: Nothing to disclose; P. K. Henke: Nothing to disclose; T. W. Wakefield: Nothing to disclose; K. A. Gallagher: Nothing to disclose; A. T. Obi: Nothing to disclose; W. J. Melvin: Nothing to disclose; C. O. Audu: Nothing to disclose; Y. Kanthi: Honoraria, Surface Oncology; Other, Pending patent to the University of Michigan on use of biogases in cardiovascular disease; J. S. Knight: Nothing to disclose; N. Rhoads: Nothing to disclose; R. Adili: Nothing to disclose; M. A. Holinstat: Ownership Interest, Veralox Therapeutics; Research Grant, National Institutes of Health, Cereno Scientific; B. B. Moore: Nothing to disclose