A matched cross-sectional study of the association between circulating tissue factor activity, immune activation and advanced liver fibrosis in hepatitis C infection

Abstract

BackgroundTissue factor (TF) is a protein that mediates the initiation of the coagulation cascade. TF expression is increased in patients with poorly-controlled HIV, and may be associated with increased immune activation that leads to cardiovascular morbidity. The role of TF in immune activation in liver disease in hepatitis C virus (HCV)-monoinfection and HIV/HCV-coinfection has not been explored.MethodsFifty-nine patients were stratified: A) HIV-monoinfection (N = 15), B) HCV-monoinfection with chronic hepatitis C (CHC) (N = 15), C) HIV/HCV-coinfection with CHC (N = 14), and D) HIV/HCV-seropositive with cleared-HCV (N = 15). All HIV+ patients had undetectable HIV viremia. Whole blood was collected for CD4/CD8 immune activation markers by flow cytometry and plasma was assayed for microparticle TF (MPTF) activity. Subjects underwent transient elastography (TE) to stage liver fibrosis. Undetectable versus detectable MPTF was compared across strata using Fisher's Exact test.ResultsMPTF activity was more frequently detected among patients with HCV-monoinfection (40%), compared to HIV-monoinfection and HIV/HCV-seropositive with cleared HCV (7%) and HIV/HCV-coinfection with CHC (14%) (p = 0.02). Mean TE-derived liver stiffness score in kPa was higher in patients with detectable MPTF (12.4 ± 8.5) than those with undetectable MPTF (6.4 ± 3.0) (p = 0.01). Mean CD4 + HLADR+ and CD4 + CD38-HLADR+ expression were higher in those with detectable MPTF (44 ± 9.8% and 38 ± 8.7%, respectively) than those with undetectable MPTF (36 ± 11% and 31 ± 10.4% respectively) (p = 0.05 and 0.04 respectively).ConclusionsHCV-monoinfection and HIV/HCV-coinfection with CHC were associated with MPTF activity. MPTF activity is also associated with advanced liver fibrosis and with CD4 + HLADR+ immune activation.

Hepatitis C Virus Infection Associated With an Increased Risk of Deep Vein Thrombosis

“…Previous literatures have suggested higher thrombin level and elevated tissue factor level are associated with advanced hepatic fibrosis. 37 , 38 Therefore, one could expect that HCV patients with chronic active hepatitis who require treatment may have higher risk of VTE. Second, previous literatures have reported microvascular thrombosis as a rare complication of interferon treatment.…”

HIV infection and immune activation

“…This is consistent with a cross-sectional study from the MACS cohort that found HCV/HIV co-infection to be an independent risk factor for subclinical atherosclerosis assessed by non-contrast CT and CT angiography [85]. A small study reported evidence of higher tissue factor activity (measured as microparticles tissue factor), a procoagulant factor, and associated CD4 T cell activation in HCV patients both mono- and HIV-coinfected suggesting a potential mechanism of immune activation and coagulopathy that may predispose to cardiovascular disease [86]. In another prospective study, immune activation markers were compared between HIV monoinfecetd and HIV/HCV coinfected (with and without cirrhosis) ART treated patients with suppressed plasma HIV viremia during 12 months [87].…”

Alternatively spliced tissue factor levels are elevated in the plasma of patients with chronic liver diseases

“…The lack of a correlation between grade of liver fibrosis and plasma asTF levels may be owing to a contribution to the formation of microthrombi in hepatic sinusoids promoting liver disease progression rather than a direct involvement of asTF in the fibrogenic process. Interestingly, it has been reported that the amount of TF was higher in patients with HIV, HCV, and HIV/HCV coinfection with advanced fibrosis than those with low fibrosis [29]. Indeed, Villa et al [30] reported previously that an anticoagulant treatment with enoxaparin, which acts on microthrombosis, improves liver function and Child-Pugh score, thus decreasing the progression of liver disease.…”