Objective:

To determine the independent and joint associations of GPLD1 and physical activity (PA) with coagulation, inflammation, and vascular-remodeling biomarkers and to examine their relationships with cognitive outcomes in people with HIV (PWH) enrolled in a 24-week randomized mHealth intervention (iSTEP).

Background:

PA and circulating glycosylphosphatidylinositol‐specific phospholipase D1 (GPLD1) have each been linked to reduced neuroinflammation and better cognition in PWH, but their combined effects on coagulation and vascular biomarkers remain unclear.

Design/Methods:

One hundred PWH (85% male, mean age 52 years) participated in a 24-week intervention promoting moderate PA with or without a Mediterranean-style diet. PA was quantified using Fitbit-derived activity metrics and accelerometry. Neurocognitive performance was measured with a standardized battery quantifying global and domain deficit scores. In a subset of participants, plasma biomarkers were assayed for procoagulation (fibrinogen, P-selectin, tissue factor, von Willebrand factor [vWF]), anticoagulation (antithrombin, protein C, thrombomodulin), fibrinolysis, and vascular remodeling (angiopoietin-2, VEGF). Associations were tested with linear models.

Results:

At the baseline visit, higher plasma P-selectin correlated with greater global cognitive impairment (r=0.27, p<0.05), with a similar trend for vWF (p=0.10). GPLD1 positively correlated with thrombomodulin (r= 0.34, p<0.01), consistent with anticoagulant pathway activation. Participants with an increase in both GPLD1 and PA at the end of the study exhibited medium to large effect sizes for lower mean levels of IL-1β (Cohen’s d=0.66), VEGF (d=0.59), and P-selectin (d=0.85), and significantly lower vWF (d=2.53, p<0.05) compared to participants with a reduction in GPLD1 and/or lower PA. VEGF elevations, though sometimes neuroprotective, are associated with vascular pathology when excessive.

Conclusions:

Concurrent elevation of GPLD1 and PA was associated with reduced procoagulation and vascular remodeling markers, supporting a model in which GPLD1 and PA exert additive anticoagulant and anti-inflammatory effects on vascular health that may protect cognition in PWH.