Sickle Cell Disease

Sickle cell anemia is an autosomal recessive disorder that results from sickle-shaped RBCs caused by a variant of hemoglobin, hemoglobin S (HbS). This arises from a missense mutation in the beta globin gene on chromosome 11, where glutamic acid is replaced by valine due to a GAG to GTG mutation. In sickle cells, replacing the negatively charged glutamic acid with nonpolar valine enhances hydrophobic interactions in hemoglobin. This triggers the polymerization of deoxy-HbS into fibers that distort the RBC shape. Factors like hypoxia, cellular dehydration, and acidosis facilitate this polymerization and sickling.

The cycle of polymerization and depolymerization damages sickle cells, leading to potassium leakage and further cellular dehydration, which exacerbate sickling. These sickle cells become rigid, making them especially vulnerable to extravascular hemolysis within the spleen. They are also susceptible to intravascular hemolysis, though to a lesser degree.

Carriers with one mutated beta globin allele display sickle cell trait and usually lack anemia symptoms due to the presence of normal beta subunits that offset low deoxy-HbS levels, inhibiting polymerization. Nevertheless, extreme circumstances such as severe hypoxia or acidosis can trigger sickling.

Having two HbS mutations leads to full-blown sickle cell disease, marked by anemia and vasoocclusive complications from increased adhesion molecules on sickle cells. Initially, patients experience the abnormally shaped RBC collect in the spleen, causing splenomegaly. Over time, the spleen becomes fibrotic and dysfunctional, leading to the presence of Howell-Jolly bodies in blood smears that signify compromised splenic function. Most patients with SCD eventually undergo autosplenectomy, increasing vulnerability to encapsulated bacterial infections and necessitating vaccinations and penicillin prophylaxis.

For children with SCD, preventive care includes vaccination for encapsulated bacteria such as Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae to mitigate serious infection risks. A common pediatric complication is splenic sequestration, where rapid blood accumulation in the spleen leads to drops in hemoglobin, hematocrit, and triggers hypotension from reduced intravascular volume.

SCD can trigger an aplastic crisis, often induced by Parvovirus B19, leading to a rapid decrease in both hemoglobin and hematocrit levels. Reticulocyte count is decreased in aplastic crisis due to inhibition of bone marrow RBC production. Another hallmark of SCD is vasoocclusion, where sickle cells block small capillaries and result in multi-organ pain and damage. Clinical features include dactylitis, or hand-foot syndrome, along with severe complications such as avascular necrosis of the femoral head and acute chest syndrome.

In acute chest syndrome, CXR commonly show pulmonary infiltrates, mimicking pneumonia. Extramedullary hematopoiesis gives the skull a ‘crew cut’ appearance on X-ray. SCD can lead to neurological and genitourinary issues like ischemic stroke, priapism, hematuria, and eventually chronic kidney disease due to renal micro-infarcts. Another SCD adaptation is extramedullary hematopoiesis, where hematopoiesis extends from medullary to cortical bone in response to ongoing hemolysis.

Sickle cell trait provides a protective effect against Plasmodium falciparum, and hemoglobin electrophoresis in sickle cell trait shows primarily HbA1, the normal adult hemoglobin, with a smaller HbS band. Conversely, sickle cell disease is characterized by a predominance of HbS on electrophoresis, along with prolonged production of fetal hemoglobin (HbF) into adulthood. Hydroxyurea serves as an essential treatment for sickle cell disease by promoting HbF production. When sickle cell trait coexists with another beta globin defect, such as beta thalassemia trait, the phenotype resembles sickle cell disease.

Hemoglobin C results from a missense mutation in the beta globin gene and causes mild hemolytic anemia when homozygous. Hemoglobin SC disease, resulting from one HbS and one HbC mutation, results in a condition that is similar to but milder than sickle cell disease.