Understanding and mitigating persistent inflammation and coagulation activation is central to improving the quality and quantity of life for contemporary HIV-positive persons. Epidemiologic data demonstrate that HIV infection is associated with ongoing coagulation abnormalities that also predict long-term clinical event risk, though questions remain regarding the underlying pathogenesis. We propose a model where hypercoagulation contributes to disease risk by amplifying inflammatory pathways, in addition to the direct effects of thrombogenesis. We hypothesize that increased generation of activated factor X (FXa) contributes to a systemic elevation in pro-inflammatory cytokine levels (e.g. interleukin-6 [IL-6]) among HIV positive patients. This occurs, in part, via FXa activation of protease activated receptor 2 (PAR-2) on monocytes and tissue macrophages, which perpetuates innate inflammation. We will test this hypothesis with low dose of an oral antagonist to FXa (rivaroxaban at 10mg daily), using a randomized placebo-controlled cross-over trial design. Treatment effects within participants (compared to placebo) will be characterized over 4 months among n=40 HIV positive patients with viral suppression and D-dimer levels >100ng/mL.
In aim 1, we will determine if inhibition of factor Xa down regulates systemic inflammation (reflected in interleukin-6 levels), as well as coagulation activity.
In aim 2, we wil specifically study the effects of factor Xa inhibition on monocyte- mediated inflammation and tissue factor activity.
In aim 3, we will study tolerability of rivaroxaban and estimate the potental clinical risk reduction predicted by the observed treatment effects. Supported by preliminary data, we proposed that FXa, PAR-2, and monocytes are key mediators linking hypercoagulation to systemic inflammation. This central hypothesis, our laboratory methods, and our interventional strategy are novel, innovative and have not been tested in the context of HIV infection. Findings will provide a clearer understanding of inflammation-coagulation cross talk in the context of treated HIV disease, and inform future development of treatment strategies to improve the quality and quantity of life for persons with HIV infection.
This collaborative multi-disciplinary project will study whether HIV-related hypercoagulation contributes to disease risk, in part, by amplifying inflammatory pathways. Findings from our innovative translational study will provide a clearer understanding of inflammation-coagulation cross talk in the context of treated HIV disease, and inform future development of novel treatment strategies for contemporary HIV patients.
|Longenecker, Chris T; Sullivan, Claire; Baker, Jason V (2016) Immune activation and cardiovascular disease in chronic HIV infection. Curr Opin HIV AIDS 11:216-25|