title: Viral myocarditis and coagulopathy: increased tissue factor expression and plasma thrombogenicity.
abstract: We investigated the effects of viral infection on Tissue Factor (TF) expression and activity in mice within the myocardium to understand increased thrombosis during myocarditis. Mice were infected with coxsackie virus B3 (CVB3) and the hearts were collected at day 4, 8 and 28 post infection (p.i.). Myocardial TF expression and cellular activity as well as plasma activity were analyzed from CVB3 infected mice by Western blot, chromogenic Factor Xa generation assay, in situ staining for active TF and immunohistochemistry. In addition to TF expression, hemodynamic parameters were measured during the time course of infection. Furthermore, we analyzed myocardial tissues from patients with suspected inflammatory cardiomyopathy. TF protein expression was maximally 5-fold elevated 8 days p.i. in mice and remained increased on day 28 p.i. (P<0.001 vs. non-infected controls). Alterations in TF expression were associated with fibrin deposits within the myocardium. The TF pathway inhibitor protein expression in the myocardium was not altered during myocarditis. Active cellular TF co-localized with CD3 positive cells and VCAM-1 positive endothelial cells in the myocardium. The TF expression was positively correlated with the amount of infiltrating CD3 and Mac3 positive cells (Spearman-Rho rho=0.749 P<0.0001 for CD3(+) and rho=0.775 P<0.0001 for Mac3(+); N=35). Increased myocardial TF expression was associated with a 2-fold elevated plasma activity (P<0.05 vs. non-infected controls). In the human hearts, the TF expression correlated positively with an endothelial cell activation marker (rho=0.523 P<0.0001 for CD62E; N=54). Viral myocarditis is a hypercoagulative state which is associated with increased myocardial TF expression and activity. Upregulation of TF contributes to a systemic activation of the coagulation cascade.
authors.affiliation: CharitéCentrum11 - Herz-, Kreislauf- und Gefässmedizin, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany.
authors.forename: Silvio
authors.initials: S
authors.lastname: Antoniak
authors.forename: Ulrike
authors.initials: U
authors.lastname: Boltzen
authors.forename: Alexander
authors.initials: A
authors.lastname: Riad
authors.forename: Angela
authors.initials: A
authors.lastname: Kallwellis-Opara
authors.forename: Maria
authors.initials: M
authors.lastname: Rohde
authors.forename: Andrea
authors.initials: A
authors.lastname: Dörner
authors.forename: Carsten
authors.initials: C
authors.lastname: Tschöpe
authors.forename: Michel
authors.initials: M
authors.lastname: Noutsias
authors.forename: Matthias
authors.initials: M
authors.lastname: Pauschinger
authors.forename: Heinz-Peter
authors.initials: HP
authors.lastname: Schultheiss
authors.forename: Ursula
authors.initials: U
authors.lastname: Rauch
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D001777:Blood Coagulation; D017252:CD3 Complex / Q000378:metabolism; D003384:Coxsackievirus Infections / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D004770:Enterovirus; D005337:Fibrin / Q000378:metabolism; D006439:Hemodynamics; D006801:Humans; D051379:Mice; D009205:Myocarditis / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology / Q000821:virology; D019851:Thrombophilia / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology / Q000821:virology; D013925:Thromboplastin / Q000096:biosynthesis*; D013997:Time Factors; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D000943:Antigens, Differentiation; D017252:CD3 Complex; D019010:Vascular Cell Adhesion Molecule-1; C036763:monocyte-macrophage differentiation antigen; D005337:Fibrin; D013925:Thromboplastin