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Elevated Microparticle Tissue Factor Activity Is Associated With Carotid Artery Plaque in HIV-Infected Women

Lin, Juan, PhDa; Xue, Xiaonan, PhDa; Anastos, Kathryn, MDa,b; Cohen, Mardge H., MDc; Gange, Stephen J., PhDd; Lazar, Jason M., MDe; Liu, Chenglong, PhDf; Mack, Wendy J., PhDg; Tien, Phyllis C., MDh,i; Tilley, Cathy, BSj; Hodis, Howard N., MDg; Landay, Alan L., PhDk; Tracy, Russell P., PhDj; Kaplan, Robert C., PhDa,l; Hanna, David B., PhDa

JAIDS Journal of Acquired Immune Deficiency Syndromes: May 1, 2019 - Volume 81 - Issue 1 - p 36–43
doi: 10.1097/QAI.0000000000001988

Background: Expression of tissue factor (TF) on the surface of activated monocytes may trigger thrombosis, leading to clotting risk, inflammation, and atherosclerosis. TF-positive microparticles (MP-TF) represent a functionally active form of TF that may be promulgated by long-term HIV infection. We hypothesized that greater MP-TF activity is associated with carotid artery plaque in HIV+ women.

Setting: In a case–control study nested within the Women's Interagency HIV Study (WIHS), eligible HIV+ participants underwent B-mode carotid artery ultrasound at 2 study visits occurring 7 years apart. Cases were defined by the presence of at least 1 carotid artery plaque assessed at either visit. Cases were matched 1:2 to controls who were found not to have carotid artery plaques.

Methods: Conditional logistic regression estimated the association of MP-TF activity with the presence of carotid artery plaque, adjusting for demographic and behavioral characteristics, HIV-related factors, cardiometabolic risk factors, and serum inflammation biomarkers (high-sensitivity C-reactive protein, IL-6, sCD14, sCD163, Gal-3, and Gal-3BP).

Results: Elevated MP-TF activity (>0.537 pg/mL) was found to be significantly associated with greater odds of plaque (adjusted odds ratio 3.86, 95% confidence interval: 1.06 to 14.07, P = 0.04). The association was attenuated after further adjustment for IL-6 but was unaffected by adjustment for other biomarkers including those denoting monocyte activation.

Conclusions: Our findings suggest a link among HIV infection, innate immune system perturbation, coagulation, and atherosclerosis.

aDepartment of Epidemiology and Population Health, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY;

bDepartment of Medicine, Albert Einstein College of Medicine, Bronx, NY;

cDepartment of Medicine, John H. Stroger Hospital, Chicago, IL;

dDepartment of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD;

eDepartment of Medicine, SUNY-Downstate Medical Center, Brooklyn, NY;

fDepartment of Medicine, Georgetown University Medical Center, Washington, DC;

gDepartment of Preventive Medicine, University of Southern California, Los Angeles, CA;

hDepartment of Veterans Affairs, University of California, San Francisco, San Francisco, CA;

iDepartment of Medicine, University of California, San Francisco, San Francisco, CA;

jDepartment of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Burlington, VT;

kDepartment of Immunology and Microbiology, Rush University Medical Center, Chicago, IL; and

lPublic Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA.

Correspondence to: Robert C. Kaplan, PhD, Department of Epidemiology and Population Health, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Belfer 1312 Bronx, NY 10461 (e-mail:

Supported by R01-HL-126543 (Kaplan), with additional support from R01-HL-083760, R01-HL-095140, R21-HL-120394, R01-HL-132794, and R01-HL-140976. Data in this manuscript were collected by the Women's Interagency HIV Study (WIHS). The contents of this publication are solely the responsibility of the authors and do not represent the official views of the National Institutes of Health (NIH). WIHS (Principal Investigators): UAB-MS WIHS (Mirjam-Colette Kempf and Deborah Konkle-Parker), U01-AI-103401; Atlanta WIHS (Ighovwerha Ofotokun and Gina Wingood), U01-AI-103408; Bronx WIHS (Kathryn Anastos and Anjali Sharma), U01-AI-035004; Brooklyn WIHS (Howard Minkoff and Deborah Gustafson), U01-AI-031834; Chicago WIHS (Mardge Cohen and Audrey French), U01-AI-034993; Metropolitan Washington WIHS (Seble Kassaye), U01-AI-034994; Miami WIHS (Margaret Fischl and Lisa Metsch), U01-AI-103397; UNC WIHS (Adaora Adimora), U01-AI-103390; Connie Wofsy Women's HIV Study, Northern California (Ruth Greenblatt, Bradley Aouizerat, and Phyllis Tien), U01-AI-034989; WIHS Data Management and Analysis Center (Stephen Gange and Elizabeth Golub), U01-AI-042590; Southern California WIHS (Joel Milam), U01-HD-032632 (WIHS I–WIHS IV). The WIHS is funded primarily by the National Institute of Allergy and Infectious Diseases (NIAID), with additional cofunding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the National Cancer Institute (NCI), the National Institute on Drug Abuse (NIDA), and the National Institute on Mental Health (NIMH). Targeted supplemental funding for specific projects is also provided by the National Institute of Dental and Craniofacial Research (NIDCR), the National Institute on Alcohol Abuse and Alcoholism (NIAAA), the National Institute on Deafness and other Communication Disorders (NIDCD), and the NIH Office of Research on Women's Health. WIHS data collection is also supported by UL1-TR000004 (UCSF CTSA), UL1-TR000454 (Atlanta CTSA), and P30-AI-050410 (UNC CFAR). D.B.H. was supported by K01-HL-137557.

Presented in part as a poster presentation at the Conference on Retroviruses and Opportunistic Infections (CROI); March, 2018; Boston, MA.

A.L.L. has served on advisory boards for Merck and Tobira. The remaining authors have no conflicts of interest to disclose.

J.L. drafted the paper. A.L.L., R.P.T., and R.C.K. conceived the work. X.X., H.N.H., A.L.L., R.P.T., and D.B.H. contributed to design of the work. K.A., M.H.C., S.J.G., J.M.L., C.L., W.J.M., P.C.T., R.P.T., and D.B.H. contributed to acquisition of data. C.T. performed the TF assays. J.L. and X.X. performed statistical analyses. J.L., X.X., K.A., M.H.C., S.J.G, J.M.L., C.L., W.J.M., P.C.T., C.T., H.N.H., A.L.L., R.P.T., R.C.K., and D.B.H. contributed to the interpretation of data for the work, revised the work critically for important intellectual content, approved the version to be published, and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy of integrity of any part of the work are appropriately investigated and resolved.

Received September 18, 2018

Accepted January 04, 2019

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