Background:  Patients with HIV disease and AIDS are at heightened risk for vascular thrombosis. We hypothesized that this may be related, in part, to the microbial translocation and increased immune activation seen in HIV⁺ patients, as the procoagulant nature of inflammation and the up-regulated expression of tissue factor (TF) by lipopolysaccharide (LPS) are both well-described.

Methods:  Peripheral blood was taken from HIV infected individuals and uninfected controls. Surface expression of tissue factor on monocytes and indices of cellular activation on T cells were measured by flow cytometry in fresh whole blood samples and also in peripheral blood mononuclear cells after cultivation with bacterial Toll-like receptor (TLR) ligands. Levels of D-dimers (a measure of fibrinolysis), and soluble CD14 (a measure of TLR 4 ligation by LPS) were measured by ELISA. Statistical analysis was performed using Wilcoxon signed rank tests.

Results:  LPS and flagellin stimulation increased surface expression of TF on monocytes in vitro (mean percentage of TF + monocytes:  unstimulated = 9.32%, LPS = 42.67%, flagellin = 44.1%, n = 7, p <0.001). The proportion of freshly obtained monocytes expressing TF differed significantly among HIV^- donors, HIV⁺ patients with controlled (viral load <400) and uncontrolled viremia (viral load >400) (medians = 11%, 29%, and 47%, respectively, p <0.05). Up-regulation of TF expression correlated with indices of immune activation (percentage of CD38⁺ HLA-DR⁺ CD8⁺ T cells, R² = 0.52). Among HIV⁺ individuals (n = 30) compared with controls (n = 10), plasma levels of soluble CD14 (median = 1592 and 1159 pg/mL, respectively, p <0.017) and levels of D-dimers (means = 434 and 213 fibrinogen equivalent units, respectively, p <0.05) were significantly increased, suggesting increased microbial translocation and fibrinolysis in patients. Tissue factor expression directly correlated with D-dimer and soluble CD14 levels in HIV⁺ patients with uncontrolled viremia (R² = 0.68 and 0.33, respectively)

Conclusions:  Microbial TLR ligands induce monocyte surface expression of the procoagulant TF. Monocyte TF expression is increased in HIV infected persons and correlates well with indices of immune activation. Among untreated patients, TF levels also correlate with markers of TLR ligation and fibrinolysis. We propose that sustained microbial translocation contributes to immune activation and the tendencies to thrombosis seen in HIV infection.