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Coagulation Abnormalities Play a Central Role in HIV Comorbidities and Should Be Therapeutically Targeted

He, Tianyu (2018) Coagulation Abnormalities Play a Central Role in HIV Comorbidities and Should Be Therapeutically Targeted. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Despite the success of antiretroviral therapy (ART) that drastically decreased the deaths of acquired immunodeficiency syndrome (AIDS), human immunodeficiency virus (HIV)-infected patients remain at higher risk for non-AIDS comorbidities than the normal population, especially cardiovascular (CV) diseases. As this population ages with significantly prolonged lifespans by ART, these commonly age-related CV events are becoming more of a pressing issue. A growing body of evidence show that the increased CV risk in HIV patients is driven both by a hypercoagulable state and HIV-associated chronic immune activation and inflammation. However, the exact mechanism remains unclear.
In this dissertation, we examined the link between hypercoagulation and immune activation and inflammation, and identified tissue factor (TF) as a critical mediator between the two. We found that a subset of CD14+ monocytes highly express TF during chronic HIV and pathogenic simian immunodeficiency virus (SIV) infection, and was not normalized even after ART. This subset of TFpos monocytes not only triggers activation of Factor X, thus initiating the coagulation cascade, but also is capable of producing multiple inflammatory cytokines upon thrombin stimulation via protease activated receptor-1 (PAR-1) signaling. In vivo blockade of TF in acutely SIV-infected pigtail macaques (PTMs) by an innovative TF inhibitor, Ixolaris, resulted in reduction of coagulation marker D-dimer levels as well as markers of immune activation and inflammation. We also administered a direct thrombin inhibitor (dabigatran) and PAR-1 inhibitor (vorapaxar) in SIV-infected PTMs and monitored a large array of biomarkers related to hypercoagulation and immune activation and inflammation in all three treatment groups. Dabigatran and vorapaxar also induced reduction of both hypercoagulation and immune activation and inflammation, although not to the extent of Ixolaris, and may have impacted different aspects of HIV/SIV pathogenesis. Altogether, these results point to a critical role of TF in bridging hypercoagulation and immune activation and inflammation to fuel HIV-associated comorbidities, and therapeutically targeting TF-related coagulation pathways is beneficial in reducing the risk of these comorbidities.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
He, Tianyutih19@pitt.edutih190000-0002-9427-6694
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairMars, Wendywmars@pitt.eduwmars
Thesis AdvisorIvona, Pandreapandrea@pitt.edupandrea
Committee MemberApetrei, Cristianapetreic@pitt.eduapetreic
Committee MemberVillanueva, Flordelizavillanuevafs@upmc.edu
Committee MemberOury, Timtdoury@pitt.edutdoury
Date: 19 April 2018
Date Type: Publication
Defense Date: 13 April 2018
Approval Date: 19 April 2018
Submission Date: 18 April 2018
Access Restriction: 3 year -- Restrict access to University of Pittsburgh for a period of 3 years.
Number of Pages: 158
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Cellular and Molecular Pathology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Hypercoagulation, cardiovascular comorbidity
Date Deposited: 19 Apr 2018 13:53
Last Modified: 19 Apr 2018 13:53
URI: http://d-scholarship.pitt.edu/id/eprint/33948

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