Levels of soluble endothelium-derived adhesion molecules in patients with sickle cell disease are associated with pulmonary hypertension, organ dysfunction, and mortality

Abstract

Endothelial cell adhesion molecules orchestrate the recruitment and binding of inflammatory cells to vascular endothelium. With endothelial dysfunction and vascular injury, the levels of endothelial bound and soluble adhesion molecules increase. Such expression is modulated by nitric oxide (NO), and in patients with sickle cell disease (SCD), these levels are inversely associated with measures of NO bioavailability. To further evaluate the role of endothelial dysfunction in a population study of SCD, we have measured the levels of soluble endothelium-derived adhesion molecules in the plasma specimens of 160 adult patients with SCD during steady state. Consistent with a link between endothelial dysfunction and end-organ disease, we found that higher levels of soluble vascular cell adhesion molecule-1 (sVCAM-1) were associated with markers indicating renal dysfunction and hepatic impairment. Analysis of soluble intercellular cell adhesion molecule-1 (sICAM-1), sE-selectin and sP-selectin levels indicated partially overlapping associations with sVCAM-1, with an additional association with inflammatory stress and triglyceride levels. Importantly, increased soluble adhesion molecule expression correlated with severity of pulmonary hypertension, a clinical manifestation of endothelial dysfunction. Soluble VCAM-1, ICAM-1, and E-selectin were independently associated with the risk of mortality in this cohort. Our data are consistent with steady state levels of soluble adhesion molecules as markers of pulmonary hypertension and risk of death.

Fig 1

Soluble adhesion molecules in patients with sickle cell disease compared with normal control subjects. Median plasma levels of sVCAM-1, sE-selectin, and sP-selectin are significantly higher in patients with sickle cell disease (SCD) (n = 148, 143, 139, and 144, respectively) compared with normal controls (P < 0.001 for each comparison, Wilcoxon rank-sum test). No significant difference was seen in median levels of sICAM-1 between normal controls and SCD patients, although a wider range of sICAM-1 values was seen in patients with SCD. Horizontal bars indicate median values.

Fig 2

Soluble adhesion molecules in patients with sickle cell disease with and without pulmonary hypertension. The level of sVCAM-1 is higher in patients with TRV 2.5–2.9 m/s (mild pulmonary hypertension, PHT) and in patients with TRV >2.9 m/s (moderate to severe pulmonary hypertension) than in patients with TRV <2.5 m/s (normal range). The difference was significant by test for linearity with Kruskal–Wallis ANOVA (n = 144, P = 0.009). Horizontal bars indicate median values. Similar trends are seen for sICAM-1 (n = 139, P = 0.02), sE-selectin (n = 135, P = 0.054), and sP-selectin (n = 140, P = 0.10).

Fig 3

Survival, sICAM-1 and sE-selectin values. Shown are Kaplan–Meier plots of survival fraction for three subgroups of SCD patients by adhesion molecule level: Low, representing the quartile of patients with the lowest soluble adhesion molecule levels; Mid, representing the second and third quartiles combined; and high, representing the quartile with the highest soluble adhesion molecule levels. (A) sICAM-1 level: Low (<141 ng/ml), Mid (141–256 ng/ml), High (>256 ng/ml) (Logrank test for trend, P < 0.0001). (B) sE-selectin levels: Low (<53 ng/ml), Mid (53–93 ng/ml), High (>93 ng/ml) (Logrank test for trend, P = 0.002). The number of patients at risk is shown below the horizontal axis at 10 month intervals.