The role of the tissue factor and its inhibitor in the development of subclinical atherosclerosis in people living with HIV

Abstract

IntroductionHIV infection is associated with an increased risk of cardiovascular disease in connection with atherosclerosis and thromboembolic complications. The pathogenesis of atherosclerosis is still unclear in this group of patients. Studies on pathogenesis of atherosclerosis in the general population emphasize the role of the extrinsic pathway of blood coagulation, particularly the tissue factor (TF) and tissue factor pathway inhibitor (TFPI). The effect of persistent activation of the immune system on enhanced expression of TF on the surface of monocytes in subjects infected with HIV is known to be correlated with the level of HIV RNA in blood serum.Study aimThe aim of this study was to evaluate the concentration of TF and its inhibitor TFPI in blood plasma, the impact of traditional and non-traditional cardiovascular risk factors on their concentration and the impact of both markers of haemostasis on the severity of subclinical atherosclerosis as assessed by the intima-media measurement of the carotid artery in HIV infected patients.MaterialsThe study included 121 HIV-infected people with known clinical, immunological and virological status. The control group consisted of 42 healthy individuals, selected in terms of age and sex.Results and conclusionsHigher concentrations of TF occurred in HIV-infected patients with a low current plasma HIV RNA level, nadir CD4+ T-cell count and longer duration of cumulative antiretroviral treatment. In multivariate analysis, it was the length of cumulative NRTI treatment that impacted on the concentration of TF. The determinants of cardiovascular disease (CVD) risk factors and inflammatory markers did not show any effect on the concentrations of TF.The TFPI level in HIV-infected patients was significantly higher than in the control group and was negatively correlated with the current level of HIV RNA and nadir CD4+ T-cell count, being higher in patients subjected to antiretroviral treatment. It was shown that the higher the cardiovascular risk and the higher the levels of total cholesterol, low-density lipoprotein cholesterol (LDL) and non-high-density lipoprotein cholesterol (non-HDL), the higher the concentrations of TFPI observed. The levels of TF and TFPI were positively correlated with carotid intima media thickness (cIMT); in the multivariate analysis, TF, non-HDL cholesterol and lifetime smoking (pack-years) independently affected the growth of cIMT. A similar effect on cIMT was demonstrated by TFPI.

Evidence for Persistent Monocyte and Immune Dysregulation After Prolonged Viral Suppression Despite Normalization of Monocyte Subsets, sCD14 and sCD163 in HIV-Infected Individuals

“…In contrast, we did see subtle abnormalities of surface marker expression, such as increased CD163 and decreased PD1, as well as a trend toward increased tissue factor (TF). TF is of particular interest, as it is thought to be a key driver of SNAEs through activation of coagulation pathway mediators [49]. The aberrant TF expression in these subjects was less marked than has been described in individuals with shorter durations of ART, given the median > 7 years of ART therapy in our subjects.…”

Increased biomarkers of cardiovascular risk in HIV-1 viremic controllers and low persistent inflammation in elite controllers and art-suppressed individuals

“…Thus, TF is considered a monocyte activation marker that links this population to hypercoagulability, persistent inflammation, and atherogenesis. The similar levels of TF + monocytes between groups for all the evaluated subsets with or without stimuli indicate that the increased levels of soluble TF observed in some studies 4 , 39 , 44 , 47 – 49 must have originated from sources other than monocytes.…”

“…Endothelial and monocyte activation are also associated with an increase in the expression of tissue factor (TF), a receptor and cofactor for (F)VII/VIIa, which activates coagulation cascade, correlates with atherogenesis, and is overexpressed during HIV infection 39 , 44 , 47 – 49 . Thus, TF can be a link between inflammation and the hyperactivation of platelets observed in HIV infection 30 , 50 – 55 , favoring peripheral arterial disease and ischemic events.…”

Novel mediators of statin effects on plaque in HIV

“…One such protein is tissue factor inhibitor (TFPI) which was recently shown to be elevated in PLHIV. 44 Tissue factor is produced by activated monocytes, prevalent in PLHIV, and represents an extrinsic mechanism for thrombosis important to conversion of stable atherosclerosis to an acute coronary syndrome. Reduction in TFPI levels, a counter regulatory protein to tissue factor, as suggested for the first time in HIV in this study, likely reflects a reduction of tissue factor (which has a shorter half-life challenging in-vitro diagnostic measures).…”