Plasma thrombospondin-1 is increased during acute sickle cell vaso-occlusive events and associated with acute chest syndrome, hydroxyurea therapy, and lower hemolytic rates

Abstract

Platelets are activated in sickle cell disease (SCD), and particularly during vaso-occlusive episodes (VOE). Thrombospondin-1 (TSP1), a major secretory product of activated platelets, is increased in the circulation in VOE and binds to sickle red blood cells (RBC) promoting vascular adhesion. Thus, we hypothesized that TSP1 may represent a plasma biomarker of disease severity in SCD. We tested the plasma collected from patients in steady state (n = 27) and VOE (n = 14), as well as healthy controls (n = 17) at the University of Pittsburgh Medical Center (UPMC), and from patients in steady state enrolled in the walk-PHaSST clinical trial (n = 483). We found that TSP1 levels were increased in VOE in the UPMC cohort. Among steady-state patients at UPMC, TSP1 values correlated positively with lifetime history of acute chest syndrome (r = 0.72, P < 0.0001) and hemoglobin concentration (r = 0.49, P = 0.01), and negatively with markers of hemolysis, such as LDH (r = -0.50, P = 0.009). Analysis of the walk-PHaSST cohort also showed a positive association between TSP1 levels and hydroxyurea use (r = 0.14, P = 0.003), and confirmed the negative associations with the severity of hemolysis. Our results suggest that TSP1 levels are associated with more VOE, hydroxyurea use and lower rates of hemolysis. High TSP1 concentrations may indicate higher risk of the viscosity/vaso-occlusion phenotype of SCD.

Figure 1

Plasma thrombospondin-1 (TSP1) is increased in patients with HbSS and a lifetime history of acute chest syndrome (ACS) and is associated with hydroxyurea therapy and lower hemolytic rates. Patients with HbSS and a lifetime history of at least one episode of ACS in the UPMC cohort had higher plasma levels of TSP1 (median (IQ range) = 3470 (676.4–5366) ng/mL as compared to patients without a history of ACS (228.2 (113.4–300.5) ng/mL, Panel A). Correlations of TSP1 with hydroxyurea use, hemoglobin F and LDH among patients with steady state HbSS in the walk-PHaSST cohort (Spearman correlation, Panels B-D). Plasma TSP1 levels were measured by ELISA.