Chapter 17: The Sickle Cell Diseases and Related Disorders

DEFINITIONS

The molecular biology of these hemoglobinopathies is well understood, but clinical progress in treatment has been limited.
Hemoglobin variants were initially designated by letter, but after the letters of the alphabet were exhausted, newly identified variants were named according to the place in which they were first found. If they had a particular feature previously described by a letter, the location was added as a subscript (e.g., Hb M_Saskatoon).
In a fully characterized hemoglobin variant, the amino acid position and change is described in a superscript to the appropriate globin chain (e.g., Hb S, α₂ β₂^6Glu-Val).
The term sickle cell disorder describes states in which sickling of red cells occurs on deoxygenation.
Sickle cell anemia (Hb SS), hemoglobin SC, sickle cell–β thalassemia, and hemoglobin 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.
Hb E might be the most prevalent abnormal hemoglobin and is found principally in Burma, Thailand, Laos, Cambodia, Malaysia, and Indonesia.

ETIOLOGY AND PATHOGENESIS

Hemoglobin Polymerization

The hemoglobin S mutation is the result of the substitution of valine for glutamic acid at position 6 in the β chain.
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 endothelium.
The sickling process is initially reversible, but repeated sickling and unsickling leads to irreversibly sickled cells due to 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 hemoglobin concentration, presence of hemoglobins other than hemoglobin S (e.g., Hg F), blood oxygen tension, pH, temperature, and 2,3-BPG levels.
Cellular dehydration (such as in the hyperosmolar milieu in renal papillae) increases sickling by increasing the concentration of intracellular hemoglobin, and some of the clinical findings of sickle trait individuals, such as inability to concentrate urine and rarely hematuria, are to the result of this phenomenon.
Some protection against sickling is conferred by elevated hemoglobin F levels; apparently a threshold phenomenon exists, so that there is no effect beneath a certain level of hemoglobin 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 hemoglobin S. Because the duration of hypoxia 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 have splenic atrophy from multiple infarctions by early adulthood.