Elevated Plasma von Willebrand Factor Levels Are Associated With Subsequent Ischemic Stroke in Persons With Treated HIV Infection

Susan M Graham; Robin M Nance; Junmei Chen; Jennie Le; Dominic W Chung; Mark M Wurfel; David L Tirschwell; Joseph R Zunt; Christina M Marra; Emily L Ho; Andrew Huffer; Felicia C Chow; Jeffrey N Martin; Alice S Ryan; Heidi M Crane; José A López; W Conrad Liles

doi:10.1093/ofid/ofab521

Elevated Plasma von Willebrand Factor Levels Are Associated With Subsequent Ischemic Stroke in Persons With Treated HIV Infection

Open Forum Infect Dis. 2021 Oct 21;8(11):ofab521. doi: 10.1093/ofid/ofab521. eCollection 2021 Nov.

Authors

Susan M Graham^{1

2

3}, Robin M Nance², Junmei Chen⁴, Jennie Le⁴, Dominic W Chung⁴, Mark M Wurfel², David L Tirschwell⁵, Joseph R Zunt^{1

2

3

5}, Christina M Marra^{2

5}, Emily L Ho⁵, Andrew Huffer⁵, Felicia C Chow⁶, Jeffrey N Martin⁷, Alice S Ryan⁸, Heidi M Crane^{2

9}, José A López⁴, W Conrad Liles^{1

2

10

11}

Affiliations

¹ Department of Global Health, University of Washington, Seattle, Washington, USA.
² Department of Medicine, University of Washington, Seattle, Washington, USA.
³ Department of Epidemiology, University of Washington, Seattle, Washington, USA.
⁴ Bloodworks Research Institute, Seattle, Washington, USA.
⁵ Department of Neurology, University of Washington, Seattle, Washington, USA.
⁶ Departments of Neurology and Medicine, University of California at San Francisco, San Francisco, California, USA.
⁷ Departments of Epidemiology and Biostatistics, University of California at San Francisco, San Francisco, California, USA.
⁸ Department of Medicine, University of Maryland, Baltimore, Maryland, USA.
⁹ Department of Health Services, University of Washington, Seattle, Washington, USA.
¹⁰ Department of Pathology, University of Washington, Seattle, Washington, USA.
¹¹ Department of Pharmacology, University of Washington, Seattle, Washington, USA.

Abstract

Background: We assessed whether key biomarkers of endothelial activation and hemostasis/thrombosis were elevated in individuals receiving effective antiretroviral therapy (ART) in the year before ischemic stroke.

Methods: We conducted a case-control study nested in the CFAR Network of Integrated Clinical Systems cohort, comparing 42 adjudicated cases with ischemic stroke with 83 controls matched for ART regimen. Angiopoietin-1, angiopoietin-2, C-reactive protein, interleukin-6, plasminogen activation inhibitor-1, P-selectin, serum amyloid-A, soluble CD14, ICAM-1, VCAM-1, apolipoprotein A1, ADAMTS13, and von Willebrand factor (VWF) were measured in stored plasma collected before the stroke event. We used conditional logistic regression to identify associations with ischemic stroke, with and without adjustment for Atherosclerotic Cardiovascular Disease (ASCVD) and Veterans Aging Cohort Study (VACS) scores.

Results: After adjustment for age and sex, higher plasma viral load and higher angiopoeitin-2, soluble CD14, and VWF were associated with increased odds of ischemic stroke; higher nadir CD4 count was associated with decreased odds of ischemic stroke. VWF remained associated with subsequent ischemic stroke after adjustment for ASCVD score (adjusted odds, 1.74; 95% CI, 1.01-2.98 per log₂ increment). In a separate model adjusting for VACS score, only VWF (adjusted odds, 1.80; 95% CI, 1.04-3.12 per log₂ increment) was associated with subsequent ischemic stroke. In a sensitivity analysis excluding participants with viral load ≥400 copies/mL, associations between VWF and ischemic stroke were attenuated, with risk estimates ranging from 1.59 to 1.64 per log₂ increment.

Conclusions: Endothelial activation and related release and attachment of VWF may play an important role in ischemic stroke among persons with treated HIV infection.

Keywords: HIV infection; endothelial activation; hemostasis/thrombosis; ischemic stroke; von Willebrand factor.

Grants and funding

R21 HL129526/HL/NHLBI NIH HHS/United States