Factors associated with D-dimer levels in HIV-infected individuals

Alvaro H Borges, Jemma L O'Connor, Andrew N Phillips, Jason V Baker, Michael J Vjecha, Marcelo H Losso, Hartwig Klinker, Gustavo Lopardo, Ian Williams, Jens D Lundgren, INSIGHT SMART Study Group, ESPRIT Study Group, SILCAAT Scientific Committee

Abstract

Background: Higher plasma D-dimer levels are strong predictors of mortality in HIV+ individuals. The factors associated with D-dimer levels during HIV infection, however, remain poorly understood.

Methods: In this cross-sectional study, participants in three randomized controlled trials with measured D-dimer levels were included (N = 9,848). Factors associated with D-dimer were identified by linear regression. Covariates investigated were: age, gender, race, body mass index, nadir and baseline CD4+ count, plasma HIV RNA levels, markers of inflammation (C-reactive protein [CRP], interleukin-6 [IL-6]), antiretroviral therapy (ART) use, ART regimens, co-morbidities (hepatitis B/C, diabetes mellitus, prior cardiovascular disease), smoking, renal function (estimated glomerular filtration rate [eGFR] and cystatin C) and cholesterol.

Results: Women from all age groups had higher D-dimer levels than men, though a steeper increase of D-dimer with age occurred in men. Hepatitis B/C co-infection was the only co-morbidity associated with higher D-dimer levels. In this subgroup, the degree of hepatic fibrosis, as demonstrated by higher hyaluronic acid levels, but not viral load of hepatitis viruses, was positively correlated with D-dimer. Other factors independently associated with higher D-dimer levels were black race, higher plasma HIV RNA levels, being off ART at baseline, and increased levels of CRP, IL-6 and cystatin C. In contrast, higher baseline CD4+ counts and higher high-density lipoprotein cholesterol were negatively correlated with D-dimer levels.

Conclusions: D-dimer levels increase with age in HIV+ men, but are already elevated in women at an early age due to reasons other than a higher burden of concomitant diseases. In hepatitis B/C co-infected individuals, hepatic fibrosis, but not hepatitis viral load, was associated with higher D-dimer levels.

Conflict of interest statement

Competing Interests: JVB receives research support from Gilead Pharmaceuticals and ViiV Health Care. VC and JE are affiliated with International Drug Distribution (CTS Inc., Durham, NC). The SILCAAT trial was supported by grants from Chiron and Novartis. There are no patents, products in development or marketed products to declare. This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials.

Figures

Figure 1. Demographics and D-dimer levels.
Figure 1. Demographics and D-dimer levels.
(a) SMART/ESPRIT/SILCAAT; adjusted for demographics, HIV-specific variables and biomarkers of inflammation. (b) SMART/ESPRIT; as in (a) and also adjusted for co-morbidities (CVD, DM and hepatitis B/C) and eGFR. (c) SMART only; as in (b) and also adjusted for smoking, cystatin C and cholesterol levels.
Figure 2. Figure 2. D-dimer levels across…
Figure 2. Figure 2. D-dimer levels across age groups stratified by gender (a).
(a) SMART/ESPRIT/SILCAAT; adjusted for demographics, HIV-specific variables and biomarkers of inflammation.
Figure 3. HIV-specific variables and D-dimer levels.
Figure 3. HIV-specific variables and D-dimer levels.
(a) SMART/ESPRIT/SILCAAT (N = 9848; 821 of whom were off ART at baseline); adjusted for demographics, HIV-specific variables and biomarkers of inflammation. (b) SMART/ESPRIT (N = 6928); as in (a) and also adjusted for co-morbidities (CVD, DM and hepatitis B/C) and eGFR. (c) SMART (N = 4488); as in (b) and also adjusted for smoking, cystatin C and cholesterol levels.
Figure 4. Biomarkers of Inflammation and D-dimer…
Figure 4. Biomarkers of Inflammation and D-dimer levels.
(a) SMART/ESPRIT/SILCAAT (N = 9848); adjusted for demographics, HIV-specific variables and biomarkers of inflammation. (b) SMART/ESPRIT (N = 6928); as in (a) and also adjusted for co-morbidities (CVD, DM and hepatitis B/C) and eGFR. (c) SMART (N = 4488); as in (b) and also adjusted for smoking, cystatin C and cholesterol levels.
Figure 5. Correlation between D-dimer and IL-6…
Figure 5. Correlation between D-dimer and IL-6 levels*.
* Plotted values refer to log10 transformed levels of units of measurement based on the molecular masses of D-dimer and IL-6 (nmol/L for D-dimer and fmol/L for IL-6).

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