Haptoglobin: an emerging candidate for phenotypic modulation of sickle cell anemia?

Abstract

Sickle cell anemia (SCA) is characterized by a single homozygous mutation (A→T) in the sixth codon of the -globin gene that results in hemoglobin S (Hb S), in which a glutamic acid residue is substituted by valine in the sixth position of the -globin chain (HBB; glu(E)6val(A); GAG-GTG; rs334).1 This change leads to a wide variety of symptoms, including chronic intravascular hemolysis, increased cell-free plasma hemoglobin (Hb) and heme levels and vascular alterations.2 SCA has been characterized as a chronic inflammatory state with abnormal endothelial activation as a result of various associated factors. The mechanisms that induce the production of inflammatory mediators and the effects of these molecules on the inflammatory response are little understood in this disease.3 Sickled red blood cells are stiff and therefore have a predisposition to hemolysis; one third of the cells are destroyed in the intravascular space leading to increased cell-free plasma Hb and heme levels.4 The pathophysiological effects associated with free Hb/heme are acute hemodynamic instability and acute or chronic vascular injury.5 The toxicity and inflammatory nature of free Hb are a result of the greater nitric oxide consumption it promotes and the consequent accumulation of hydroxyl radicals and reactive oxygen species in the blood vessels. The organism’s first defense mechanism against the harmful effects of free Hb involves haptoglobin (Hp), whose primary function is to bind to free Hb in the plasma, thereby preventing the excretion of iron by the kidneys and protecting blood vessels from its oxidative effects.6,7 In addition to being an antioxidant, Hp is a positive acute-phase glycoprotein present in plasma with immunomodulatory properties.6,7