Normocytic Anemia – Red Blood Cell Pathology (RBC)

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare but serious acquired hemolytic anemia with periodic exacerbations. This anemia is caused by nonmalignant clonal expansion of ≥ 1 hematopoietic stem cells that have acquired a somatic mutation of the phosphatidylinositol N-acetylglucosaminyltransferase subunit A (PIG-A) gene. Clonal expansion of affected stem cells are deficient in glycosylphosphatidylinositol-anchored proteins (GPI-APs). Deficiency of the GPI-APs CD55 and CD59, which regulate complement, results in intravascular hemolysis. The classic triad of PNH is hemolytic anemia, marrow failure, and thrombophilia. Patients may be treated with the monoclonal antibody eculizumab or with stem cell transplantation, in addition to being treated for associated complications.

Erythrocytes, or red blood cells (RBCs), are the most abundant cells in the blood. While erythrocytes in the fetus are initially produced in the yolk sac then the liver, the bone marrow eventually becomes the main site of production. Erythropoiesis starts with hematopoietic stem cells, which develop into lineage-committed progenitors and differentiate into mature RBCs. The process occurs in stages, and extrusion of the nuclei and organelles occurs prior to maturation. Thus, mature RBCs lack nuclei and have a biconcave shape. RBCs carry hemoglobin, and the shape allows efficient oxygen transport. Billions of RBCs are produced daily, as the life span is 120 days. Senescent or deformed RBCs are removed by macrophages in the spleen, liver, and bone marrow.

Iron deficiency anemia is the most common type of anemia worldwide. This form of anemia is caused by insufficient iron due to a decreased supply, an increased loss, or an increased demand. Iron deficiency anemia is seen across all ages, sexes, and socioeconomic strata; however, children, women of childbearing age, and patients from lower socioeconomic strata are at higher risk. Symptoms include pallor, particularly of the mucous membranes, easy fatigability, and headaches. Iron studies are the key to diagnosis. Treatment is based on the underlying cause of iron deficiency and consists of supplementation.

Aplastic anemia (AA) is a rare, life-threatening condition characterized by pancytopenia and hypocellularity of the bone marrow (in the absence of any abnormal cells) reflecting damage to hematopoietic stem cells. Aplastic anemia can be acquired or inherited, however, most cases of AA are acquired and caused by autoimmune damage to hematopoietic stem cells. Specifically known acquired causes and associations of AAs include medications, chemicals, high doses of whole-body radiation, viral infections, immune diseases, and pregnancy. Inherited or constitutional syndromes associated with AA include Fanconi anemia, dyskeratosis congenita, and Down syndrome. Therapies include transfusion support, immunosuppression, and bone marrow transplantation.

Hereditary spherocytosis (HS) is the most common type of hereditary hemolytic anemia. The condition is caused by a cytoskeletal protein deficiency in the RBC membrane. This results in loss of membrane stability and deformability of the RBC, giving the cell its spherical shape (spherocyte). These cells are predisposed to splenic degradation, leading to hemolysis. Examination may show jaundice and splenomegaly, while laboratory tests are consistent with hemolytic anemia and increased hemoglobin concentration. Among multiple confirmatory tests for HS, the eosin-5’-maleimide (EMA) binding test is preferred. The only definitive treatment for HS is splenectomy.

Anemia is a condition in which individuals have low Hb levels, which can arise from  various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia may occur from blood loss, decreased RBC production such as in iron deficiency, or increased RBC destruction such as in hemolysis. Management is aimed at improving Hb levels and treating the underlying conditions.