Endoplasmic Reticulum Stress and Vaso-Occlusive Crisis in Sickle Cell Anemia: A Review

Abstract

ickle cell anemia (SCA) is a genetic disorder characterized by the production of abnormal hemoglobin, specifically hemoglobin S (HbS), which leads to the sickling of red blood cells (RBCs) and subsequent microvascular occlusion. Vaso-occlusive crises (VOCs) are a hallmark of SCA, resulting in acute pain and potential organ damage. Recent studies have highlighted the role of endoplasmic reticulum (ER) stress in the pathophysiology of SCA, as it contributes to the accumulation of misfolded proteins and activates the unfolded protein response (UPR). This response, while initially adaptive, can become detrimental when prolonged, leading to cellular dysfunction and exacerbating the sickling process. The relationship between ER stress and VOCs involves several interconnected mechanisms, including the activation of pro-inflammatory cytokines, apoptosis of erythroid precursor cells, and oxidative stress. ER stress-induced inflammation promotes the adhesion of sickled RBCs and leukocytes to the endothelium, enhancing microvascular obstruction. Additionally, the effects of ER stress on erythropoiesis can lead to anemia and further hypoxia, creating a vicious cycle that perpetuates the risk of VOCs. Understanding these mechanisms provides critical insights into the complexities of SCA and the factors that contribute to the frequency and severity of VOCs. Targeting ER stress pathways presents a novel therapeutic strategy to improve clinical outcomes in patients with SCA. Pharmacological agents that alleviate ER stress or modulate the UPR may enhance RBC function and reduce the incidence of VOCs. Keywords: Sickle cell anemia, vaso-occlusive crisis, endoplasmic reticulum stress, red blood cells, hemoglobin, inflammation, therapeutic strategies