Monocytes tied to HIV-associated thrombosis

In this issue of Blood, Funderburg and colleagues provide new evidence that may help explain why HIV infection is associated with an increased risk of thrombosis.¹  These researchers elegantly show that increased risk for HIV-infected persons have increased proportions of monocytes expressing the procoagulant cell surface tissue factor and propose that this may contribute to increased clotting in vivo.

HIV infection has emerged as a well-recognized prothrombotic condition. Venous thrombotic events (VTE) occur more commonly among HIV-infected persons than in the general population, and they often occur in relatively young patients.²  HIV-infected persons receiving antiretroviral treatment (ART) have also been shown to exhibit greater atherosclerotic disease compared with their HIV-negative counterparts. Cardiovascular disease is likely to increase with enhanced longevity in HIV-positive persons on highly active antiretroviral therapy.

The mechanisms by which HIV infection causes thrombosis are multifactorial and complex.³  HIV-associated factors, as opposed to traditional risk factors (eg, smoking, immobility, family history, hospitalization), are believed to be central to the pathogenesis of thrombosis. Several coagulation abnormalities have been reported among HIV-infected patients including the presence of antiphospholipid antibodies, increased levels of von Willebrand factor, elevated homocysteine, and deficiencies of protein C, protein S, antithrombin III, and heparin cofactor II.²  Previous studies suggest that ART, in particular HIV protease inhibitors, negatively impacts the cardiovascular system.²  However, there are also several publications in which patients reported to manifest with VTE did not receive ART.²  Advanced HIV disease may be another risk factor for the development of thromboses, perhaps due to an increased inflammatory state or the presence of concurrent comorbidities, such as infections.² 

In the Strategies for Management of Antiretroviral Therapy (SMART) trial, mortality from non-AIDS events such as cardiovascular disease was found to be higher for participants randomized to intermittent, CD4-guided ART (drug conservation arm) than to continuous ART (viral suppression arm).⁴  This resulted in researchers stopping the trial prematurely. An increased risk of death was associated with higher levels of high-sensitivity C-reactive protein (hsCRP), interleukin 6 (IL-6), and D-dimers. IL-6 and D-dimer increased at 1 month by 30% and 16%, respectively, in the drug conservation arm but by only 0% and 5%, respectively, in the viral suppression arm (P < .0001). Moreover, the increases in these inflammatory/thrombotic markers in the drug conservation arm were related to HIV RNA levels at 1 month (P < .0001). These findings led the investigators to suggest that HIV-induced activation of inflammation and a hypercoagulable state increases the risk of death among HIV-positive patients, and that interrupting ART further increases this risk.⁵ 

Funderburg et al suggest that the increased risk for coagulation in HIV-infected persons may be related to increased expression of the procoagulant tissue factor (TF, thromboplastin). They further demonstrate that monocyte expression of TF correlates with HIV RNA and D-dimer levels in plasma. A total of 60 HIV-infected patients in this study were analyzed, whom the investigators subdivided into viremic (28 patients) and aviremic (32 patients) groups, depending on whether their HIV viremia was above or below 400 copies/mL of HIV RNA. Although they mention that 13 of their patients (46%) in the viremic group were on highly active antiretroviral therapy, their paper failed to report whether ART in this subgroup in any way influenced their findings.

Recent findings suggest that, in addition to HIV viral replication, other factors (eg, microbial translocation) could drive immune activation.⁶  Accordingly, it is of great interest that Funderburg et al demonstrate that the bacterial Toll-like receptor, ligands lipopolysaccharide from Escherichia coli and flagellin from Salmonella typhimurium, induced monocyte TF expression in vitro. On the basis of their findings, these investigators propose that direct activation of monocytes by microbial products (eg, via bacterial translocation from the gut) may be a key player in promoting thrombosis in HIV infection.¹ 

The findings of Funderburg et al bring us ever closer to elucidating the mechanism by which HIV infection promotes thrombosis. More work in this field is needed, including the use of TF⁺ monocytes as a potential thrombotic marker (eg, for DVT prophylaxis) among HIV-infected patients, and the justification for using immunomodulators as adjuvant therapy to ART.