Coagulation, Protease-Activated Receptors, and Viral Myocarditis

Abstract

The coagulation protease cascade plays an essential role in hemostasis. In addition, a clot contributes to host defense by limiting the spread of pathogens. Coagulation proteases induce intracellular signaling by cleavage of cell surface receptors called protease-activated receptors (PARs). These receptors allow cells to sense changes in the extracellular environment, such as infection. Viruses activate the coagulation cascade by inducing tissue factor expression and by disrupting the endothelium. Virus infection of the heart can cause myocarditis, cardiac remodeling and heart failure. Recent studies using a mouse model have shown that tissue factor, thrombin and PAR-1 signaling all positively regulate the innate immune during viral myocarditis. In contrast, PAR-2 signaling was found to inhibit interferon-β expression and the innate immune response. These observations suggest that anticoagulants may impair the innate immune response to viral infection and that inhibition of PAR-2 may be a new target to reduce viral myocarditis..

Viral heart disease — treatment

“…Inflammation and HF itself are pro-thrombotic states [10]. Parvovirus B19 (PVB19) and human herpes virus 6 (HHV-6) activate the coagulation cascade by inducing tissue factor expression and by disrupting the endothelium [10].…”

“…There are no clear data on the benefits of anti-thrombotic therapy. Aspirin decreases platelet reactivity, but it is associated with increased inflammation and mortality in animal models of MC [10]. Heparin and fondaparinux in mouse models of MC reduced fibrosis but at the same time increased inflammation [10].…”

“…Aspirin decreases platelet reactivity, but it is associated with increased inflammation and mortality in animal models of MC [10]. Heparin and fondaparinux in mouse models of MC reduced fibrosis but at the same time increased inflammation [10]. Therefore, anti-platelet and anti-coagulant drugs are not currently considered standard therapies in VHD.…”

Review and Updates in Regenerative and Personalized Medicine, Preclinical Animal Models, and Clinical Care in Cardiovascular Medicine

“…Coxsackievirus B3 (CVB3) infection in mice is a wellestablished model for viral myocarditis and dilated cardiomyopathy sharing many characteristics with clinical myocarditis and dilated cardiomyopathy including the following: (1) a male bias to the disease, (2) evidence for autoimmunity to cardiac antigens, and (3) viral persistence in the heart resulting in chronic myocarditis and dilated cardiomyopathy (whereas viral clearance during the acute phase leads to disease resolution) [36]. CVB3 infection activates TLR3 which upregulates tissue factor expression and a hypercoagulative state [37]. Ventricular thrombi occur in both clinical and experimental myocarditis.…”

Effect of AMP-activated protein kinase activation on cardiac fibroblast proliferation induced by coxsackievirus B3

“…Autoimmune myocarditis, which is characterized by autoimmune injury induced by the viral infection, is the second stage and involves the expression and secretion of numerous inflammatory cytokines and chemokines. Finally, in the last phase, inflammation progressively subsides, although the viral genomes persist in the heart (2). Myocardial fibrosis and pathological remodeling, which lead to impaired heart function, may occur during the early and late stages of viral myocarditis.…”