V. PATHOPHYSIOLOGY

Sickle cell anemia (SS) is an autosomal recessive disease that results in a chronic hemolytic anemia.

All types of hemoglobin are made of three components: heme, alpha (or alpha-like) globin, and beta (or beta-like) globin. Sickle hemoglobin is the result of a genetic change in the beta globin component of normal hemoglobin.

The beta globin gene is located on chromosome 11. The sickle cell form of the beta globin gene results from the substitution of a single DNA nucleotide, or genetic building-block. The change from adenine to thymine at codon (position) 6 of the beta globin gene leads to insertion of the hydrophobic amino acid valine (instead of the hydrophilic amino acid glutamic acid) at this same position in the beta globin protein. Sickle cell anemia (HbSS) is caused by a point mutation in the hemoglobin beta gene (HBB) found on chromosome 11p15.4.

Over 100 types of other mutations affect HBB, and deletion mutations are rare. Splice mutations and mutations that occur in the HBB gene promoter region tend to cause a reduction in, rather than a complete absence of, beta-globin chains. Nonsense mutations and frameshift mutations do not tend to produce any beta-globin chains leading to severe disease. Variants of these mutations may cause sickle-beta thalassemias (SB-thal+ or S-Bthal0), and Homozygous S/S (i.e., Hb SS). There are several possible mutations that result in compound heterozygotes (variants of sickle cell disease) including:

• Hb SC, Hb SD, Hb SO-Arab
• Hb Sβ°-thalassemia
• Some forms of Hb Sβ⁺-thalassemia

The red blood cells in sickle cell disease are rigid and have a shorter life-span than normal red blood cells (7-10 days vs. 21 days). The rigid red blood cells may cause vaso-occlusion due to their individual non-pliability in traversing microcapillaries, or due to the additive whole blood hyperviscosity imparted by erythrocytes which have been internally rigidified by crystallizing hemoglobin, irrespective of the proportion of cells which have undergone irreversible sickling. This can result in pain at the site of vaso-occlusion (soft tissue or bone). Vaso-occlusion in the lung tissue can result in pain, hypoxemia, and infiltrates in the lungs that are visible on CXR. This constellation of symptoms in the lung is also known as acute chest syndrome.

Acute chest syndrome is a clinical syndrome. Asthma contributes to the lung disease. Recently, asthma was associated with pain and acute chest syndrome in sickle cell disease.

Over 20% of children with hemoglobin SS will have a cerebral infarct. A history of acute chest syndrome is associated with an increased risk for infarct, as is hypertension. A patient such as the one in this case is at risk for a cerebral infarct because of acute chest syndrome and hypertension.