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.

Regulation of Cellular Redox Signaling by Matricellular Proteins in Vascular Biology, Immunology, and Cancer

“…In patients with hypertension, elevated plasma TSP1 was noted in association with decreased forearm-mediated vasodilation (18). However, in this study, TSP1 levels appeared elevated in controls compared to TSP1 levels reported in controls elsewhere (184), suggesting possible confounding by platelet activation. Nonetheless, elevation of plasma TSP1 in individuals with hypertension has been confirmed (80,241), although interpretation of these other studies is complicated by the presence of other cardiovascular comorbidities.…”

“…Tempol can inhibit the Fenton reaction, a source of hydroxyl radical that limits arterial vasodilation (263). This may be clinically relevant in conditions of dysregulated iron metabolism such as sickle cell disease wherein Fenton chemistry and circulating TSP1 are enhanced (184,203).…”

“…In adult sickle cell disease subjects, plasma TSP1 is increased in vaso-occlusive events (VOEs) (184). Patients experiencing active VOEs had significantly elevated plasma TSP1 levels [median (IQ range) = 898 ng/ml (381-1657)] versus sickle cell disease patients not in VOEs [303 ng/ml (187-939) and healthy controls (239 ng/ml (125-344) p = 0.001]) (184).…”

“…Patients experiencing active VOEs had significantly elevated plasma TSP1 levels [median (IQ range) = 898 ng/ml (381-1657)] versus sickle cell disease patients not in VOEs [303 ng/ml (187-939) and healthy controls (239 ng/ml (125-344) p = 0.001]) (184). As TSP1 is found preformed in platelets, these studies in sickle cell disease cohorts are important in that these authors observed a protocol to mitigate platelet activation during blood collection and processing.…”

Cellular, Pharmacological, and Biophysical Evaluation of Explanted Lungs from a Patient with Sickle Cell Disease and Severe Pulmonary Arterial Hypertension

“…Interestingly, the proadhesive protein thrombospondin 1 (TSP1) was recently reported to inhibit NO signaling 23,24 while promoting PAH in preclinical models 25 and to be upregulated in SCD patient plasma. 26 Although studies have documented the hemodynamics and outcomes of SCD-associated PAH and interrogated the systemic vascular function of these patients, there have been no human studies directly evaluating the pulmonary vasculature. We herein describe ex vivo benchtop profiling that includes molecular, cellular, mechanical, genetic, and functional signatures of the explanted SCDassociated PAH lungs from a patient who underwent successful lung transplantation.…”