Arterial thrombosis in the context of HCV-associated vascular disease can be prevented by protein C

Abstract

Hepatitis C virus (HCV) infection is a major problem worldwide. HCV is not limited to liver disease but is frequently complicated by immune-mediated extrahepatic manifestations such as glomerulonephritis or vasculitis. A fatal complication of HCV-associated vascular disease is thrombosis. Polyriboinosinic:polyribocytidylic acid (poly (I:C)), a synthetic analog of viral RNA, induces a Toll-like receptor 3 (TLR3)-dependent arteriolar thrombosis without significant thrombus formation in venules in vivo. These procoagulant effects are caused by increased endothelial synthesis of tissue factor and PAI-1 without platelet activation. In addition to human umbilical endothelial cells (HUVEC), human mesangial cells (HMC) produce procoagulatory factors, cytokines and adhesion molecules after stimulation with poly (I:C) or HCV-containing cryoprecipitates from a patient with a HCV infection as well. Activated protein C (APC) is able to prevent the induction of procoagulatory factors in HUVEC and HMC in vitro and blocks the effects of poly (I:C) and HCV-RNA on the expression of cytokines and adhesion molecules in HMC but not in HUVEC. In vivo, protein C inhibits poly (I:C)-induced arteriolar thrombosis. Thus, endothelial cells are de facto able to actively participate in immune-mediated vascular thrombosis caused by viral infections. Finally, we provide evidence for the ability of protein C to inhibit TLR3-mediated arteriolar thrombosis caused by HCV infection.

Understanding Infection-Induced Thrombosis: Lessons Learned From Animal Models

“…TLR-3 expression on platelets and megakaryocytes has been reported and its ligation on platelets can potentiate platelet aggregation by other classical platelet agonists (46). The use of Poly I:C for studying thrombosis is not as widespread as for other models, but injection with Poly I:C has been described to induce TLR-3-dependent arterial thrombosis, but a more minimal thrombosis in the venules (47). As there is limited data for the use of Poly I:C in this context, more work is needed to better understand the strengths and limitations of its use to recapitulate what is observed after viral infection.…”

Perivascular Mesenchymal Stem/Stromal Cells, an Immune Privileged Niche for Viruses?

“…MC participates in both mechanisms. Indeed, MCs were demonstrated to be targeted by various viruses [ 212 , 214 , 219 , 279 , 280 , 281 , 282 , 283 ]. First, HIV was shown to infect MCs [ 212 ] with an orphan G protein-coupled receptor 1 (GPR1) as a co-receptor [ 213 ].…”

“…The pathology associated with HCV is mostly liver disease, but with frequent extrahepatic complications, such as glomerulonephritis. HCV triggers TLR3 activation of MC leading to the release of procoagulant factors that causes vascular thrombosis and finally glomerulonephritis [ 279 ]. Furthermore, MCs may be infected by ZIKV.…”

Platelet Innate Immune Receptors and TLRs: A Double-Edged Sword

“…IL-1β secretion required longer stimulation [ 177 ]. However, another set of experiments suggested that the poly(I:C) stimulation of platelets did not induce platelet aggregation or activation [ 178 ]. Thus, TLR3-stimulation could potentiate platelet aggregation upon hemostatic stimulation, rather than inducing aggregation by itself, as evidenced by D’Atri et al [ 177 ].…”