Thyroid stimulating hormone (TSH) is a glycoprotein hormone produced by the anterior pituitary, widely known for its role in the production of the hormones triiodothyronine (T3) and thyroxine (T4) by the thyroid gland (MAGNER, 1990). TSH acts by binding to the TSH receptor (TSHR), which is a G protein-coupled receptor (GPCR) known to be present on the basolateral surface of thyroid follicular cells (PIRAHANCHI; TORO; JIALAL, 2022). However, the TSH receptor has already been identified in tissues other than the thyroid, such as the anterior pituitary; hypothalamus; (BROKKEN et al., 2001; PRUMMEL et al., 2000; PRUMMEL; BROKKEN; WIERSINGA, 2004) ovary; testicle (DAVIES; SMITH; HALL, 1978; KUMAR et al., 2000); skin (BODÓ et al., 2010; SLOMINSKI et al., 2002); kidney (DUTTON et al., 2009; SELLITTI et al., 2000); immune system; bone marrow; white and brown adipose tissue (BAHN et al., 1998; WANG et al., 2003); orbital preadipocyte fibroblasts(VALYASEVI et al., 1999), bones, NK cells (WANG et al., 2003; YANG et al., 2022), and also in erythrocytes (BALZAN et al., 2009).
Erythrocytes are anucleated, biconcave disk-shaped cells present in the blood. They are produced in the bone marrow, have a life of approximately 120 days and are composed of hemoglobin molecules (Hb), whose main function is to transport oxygen and carbon dioxide to all tissues of the body. Hb is a tetramer consisting of two subunits of globin chains, each linked to a heme group (MOREIRA et al., 2011; SANTOS; CHIN, 2012). Hemoglobinopathies are a group of diseases characterized by mutation and disfunction of hemoglobin. There are several hemoglobinopathies that can affect erythrocytes and their structures, such as sickle cell disease (SCD), which is an autosomal recessive genetic disease that affects approximately millions of people around the world, and in Brazil, each year, 3,500 children are born with DF and 200,000 with sickle cell trait (FELIX; SOUZA; RIBEIRO, 2010; SUNDD; GLADWIN; NOVELLI, 2019).
When sickled erythrocytes are exposed to HbS deoxygenation in tissues with high oxygen demand, exposure of hydrophobic sites on HbS tetramers occurs, so the β1 and β2 chains bind to two hemoglobin molecules to hide the hydrophobic sites, initiating the formation of a polymer of HbS. These HbS polymers grow rapidly and form long fibers that increase cellular rigidity and distort the erythrocyte membrane, leading to sickling of erythrocytes, cellular energy failure and stress, dehydration, low deformability, impaired rheology, and premature hemolysis (REES; WILLIAMS; GLADWIN, 2010; SUNDD; GLADWIN; NOVELLI, 2019)
SCD has several clinical manifestations, such as vaso-occlusion, which promotes ischemia-reperfusion injury, and is the predominant pathophysiology responsible for vaso-occlusive crisis (VOC), an acute systemic painful crisis (MANWANI; FRENETTE, 2013). Vaso-occlusion causes interaction between impaired blood rheology, increased adhesion of erythrocytes with inflammatory cells and vascular endothelium, and hemostatic activation (ZHANG et al., 2016). The damage that sickling causes to erythrocyte membranes also promotes the exposure of adhesion molecules and binding sites that are not normally expressed, such as phosphatidylserine (PS), basal cell adhesion molecule-1/Lutheran (B-CAM-1). /Lu), integrin-associated protein (IAP) and intercellular adhesion molecule-4 (ICAM-4) (SUNDD; GLADWIN; NOVELLI, 2019) and increased circulating thrombospondin-1, which is supposedly generated by activated platelets and increases the adhesion of erythrocytes to the endothelium through the CD47 receptor. In addition, thrombospodin-1 has already been described as an inhibitor of the vasodilatory, antiadhesive and homeostatic effects of nitric oxide signaling pathways and also of vascular endothelial growth factor, which may affect the regulation of tissue perfusion and vascular tone, leading to inflammation frame. (CAMUS et al., 2015; NOVELLI et al., 2019). Another recurring problem in the pathophysiology of SCD is hemolytic anemia, which is influenced by the polymerization of HbS. It is already known that as the aging of patients with SCD, the risks of vasculopathies increase, characterized by systemic and pulmonary hypertension, endothelial dysfunction and changes in the intima and smooth muscle of blood vessels. In addition to progressive vasculopathy, hemolysis causes anemia, fatigue, and cholelithiasis (GLADWIN et al., 2004; KATO; GLADWIN, 2008; KATO; GLADWIN; STEINBERG, 2007)
It has already been described that patients with SCD have metabolic and endocrine disorders, which may be the result of hypoxia, chronic anemia, iron overload or genetic influence. In Garadah et al. 2016, it was described that 7% of patients with SCD have clinical hypothyroidism and high concentrations of TSH (6.4 mIU/L)(GARADAH et al., 2016). These endocrine disorders can cause growth retardation and delayed puberty. Repeated blood transfusions and hemolysis can cause iron overload, and consequent disruption of tissue vitalization during vaso-occlusive crisis and increase in inflammatory mediators that mainly cause metabolic and endocrine dysfunction(ELALFY et al., 2019; GARADAH et al., 2016; ÖZEN et al., 2013). In Elalfy, M. S. et al., 2019, observed impaired thyroid microcirculation and decreased thyroid volume among patients with SCD, and these factors were related to disease duration, but the results were not related to thyroid function, suggesting that these disorders can happen independently of the accumulation of iron (ELALFY et al., 2019).
Thus, our work aims to study the effects of TSH, in a dose-dependent manner, on the erythrocytes of sickle cell patients, based on the parameters of polymerization, deformability and static adhesion.