Abstract
Sickle cell disease (SCD) is an inherited hemolytic anemia whose pathophysiology is driven by polymerization of the hemoglobin S (Hb S), leading to hemolysis and vaso-occlusive events. Inflammation is a fundamental component in these processes and a continuous inflammatory stimulus can lead to tissue damages. Thus, pro-resolving pathways emerge in order to restore the homeostasis. For example there is the annexin A1 (ANXA1), an endogenous anti-inflammatory protein involved in reducing neutrophil-endothelial interactions, accelerating neutrophil apoptosis and stimulating macrophage efferocytosis. We investigated the expression of ANXA1 in plasma of SCD patients and its relation with anemic, hemolytic and inflammatory parameters of the disease. Three SCD genotypes were considered: the homozygous inheritance for Hb S (Hb SS) and the association between Hb S and the hemoglobin variants D-Punjab (Hb SD) and C (Hb SC). ANXA1 and proinflammatory cytokines were quantified by ELISA in plasma of SCD patients and control individuals without hemoglobinopathies. Hematological and biochemical parameters were analyzed by flow cytometry and spectrophotometer. The plasma levels of ANXA1 were about three-fold lesser in SCD patients compared to the control group, and within the SCD genotypes the most elevated levels were found in Hb SS individuals (approximately three-fold higher). Proinflammatory cytokines were higher in SCD groups than in the control individuals. Anemic and hemolytic markers were higher in Hb SS and Hb SD genotypes compared to Hb SC patients. White blood cells and platelets count were higher in Hb SS genotype and were positively correlated to ANXA1 levels. We found that ANXA1 is down-regulated and differentially expressed within the SCD genotypes. Its expression seems to depend on the inflammatory, hemolytic and vaso-occlusive characteristics of the diseased. These data may lead to new biological targets for therapeutic intervention in SCD.
Highlights
Sickle cell disease (SCD) is a hemolytic anemia caused by the presence of hemoglobin S (Hb S) in homozygous, named sickle cell anemia (SCA), or associated with thalassemias and other hemoglobin variants [1,2]
Fifty samples from SCD patients were genotyped and we found 24 (48.0%) corresponding to Hb SS, eight (16.0%) to hemoglobin variants D-Punjab (Hb SD) and 18 (36.0%) to Hb SC genotypes
SCD is considered a chronic inflammatory disease due to persistent activation of leukocytes, platelets, and endothelial cells, resulting from hemolysis and vaso-occlusion mediated by ischemia-reperfusion cycles
Summary
Sickle cell disease (SCD) is a hemolytic anemia caused by the presence of hemoglobin S (Hb S) in homozygous, named sickle cell anemia (SCA), or associated with thalassemias and other hemoglobin variants [1,2]. Phenotypic expression of the SCD is variable and depends on the associated genotype and other factors that alter the hemoglobin concentration or the blood flow. The beta-globin gene cluster haplotypes associated with Hb S (βS-haplotypes) are potential modulators of the phenotypic heterogeneity in SCD, mainly due their relation with fetal hemoglobin (Hb F) levels. The mutation for Hb S occurs in the beta globin gene (HBB:c.20A>T; rs334) and it is responsible for the hemoglobin polymerization under conditions of hypoxia, acidosis or dehydration, altering the erythrocytes morphology for a sickling state [1,2]. As Hb S concentration is a determining factor for the SCD clinical severity, double heterozygous genotypes usually, but not always, are less clinically severe than SCA [3,4]. The Hb SC inheritance is considered a mild genotype [4], while Hb SD results in mild to moderate symptoms, severe conditions have been reported [8]
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