Chapter 16: The Sickle Cell Diseases and Related Disorders

DEFINITIONS

• The molecular biology of hemoglobinopathies is well understood, but clinical progress in treatment has been limited. The vast majority of hemoglobinopathies are the result of single-nucleotide substitutions in the α, β, δ, or γ chains within the hemoglobin (Hb) tetramer.

• Hb variants are designated by letters of the alphabet, but after the letters of the alphabet were exhausted, newly identified variants were named according to the place in which they were first found (eg, Hb _Zurich). If they had a particular feature previously described by a letter, the location was added as a subscript (eg, Hb M_Saskatoon).

• In a fully characterized Hb variant, the amino acid position and change are described in a superscript to the appropriate globin chain (eg, Hb S, α₂ β₂^6Glu-Val).

SICKLE CELL DISORDERS

• The term sickle cell disorder describes states in which sickling of red cells occurs on deoxygenation, not the genotype (ie, Hb SS, S/beta thal, SE).

• Hb S homozygosity (Hb SS), Hb SC, sickle cell–β thalassemia, and Hb SD produce significant morbidity and are therefore designated sickle cell diseases. These diseases are marked by periods of relative well-being interspersed with episodes of illness, but the severity of clinical manifestations varies widely among patients. Generally, sickle cell anemia is the most severe, but there is considerable overlap in clinical behavior among these diseases.

ETIOLOGY AND PATHOGENESIS

Hemoglobin Polymerization

• The Hb S mutation is the result of the substitution of valine for glutamic acid at position 6 in the β chain. Hb S polymerization is the central event in disease pathophysiology.

• Molecules of deoxyhemoglobin S have a strong tendency to aggregate and form polymers. Polymer formation alters the biophysical properties of the red cells, making them much less deformable and adherent to the endothelium.

• The sickling process is initially reversible, but repeated sickling and unsickling leads to irreversibly sickled cells because of membrane damage.

• Sickle cells lead to vascular stasis, tissue damage, and increase in microvascular blood viscosity.

• Susceptibility to sickling is dependent on several factors, including intracellular Hb concentration (mean cell hemoglobin concentration, MCHC), presence of Hb other than Hb S that may interfere with the rate or degree of polymerization of Hb S (eg, Hb F), blood oxygen tension, pH, temperature, and 2,3-biphosphoglycerate levels.

• Some protection against sickling is conferred by elevated Hb F levels; apparently a threshold phenomenon exists, so that there is no effect beneath a certain level of Hb F.

• In the microvasculature, flow is affected by the rigidity of the sickled cells and adherence to the endothelium. Shear stresses in higher flow areas can break down the gel structure of Hb S. Because the duration of hypoxemia is also important, areas of vascular stasis (such as the spleen) with lower oxygen tension are particularly prone to vascular occlusion and infarction. Most patients with sickle cell anemia ...