Sickle Cell Disease

Overview

Sickle Cell Disease (SCD) is caused by a single point mutation in hemoglobin that ultimately results in the generation of deformed and adherent erythrocytes. These sickle-shaped RBCs display two important features, structural instability and a tendency to aggregate, that account for the major clinical consequences of Sickle Cell disease: hemolysis and vasoocclusion.

Genetics and Epidemiology

SCD is caused by a single nucleotide point mutation in the beta-globin chain which converts the sixth amino acid in the molecule from a glutamate to a valine residue. Disease is only seen when both alleles of the beta-globin gene are affected. Consequently, only those homozygous for the mutation are affected and transmission occurs in a autosomal recessive pattern. Heterozygous individuals are largely asymptomatic and act as carriers.
Sickle Cell Disease is largely seen in those of African descent and affects roughly 100,000 African Americans whereas 2 million are thought to be asymptomatic carriers. The high prevalence of sickle trait in populations of African descent is thought to be of evolutionary origin as heterozygotes appear to be more resistant to Malaria.

Pathogenesis

When two mutated beta-globin chains are incorporated into the α₂β₂ hemoglobin tetramer, the result is termed Hemoglobin S (HbS). HbS tetramers have a tendency to polymerize under conditions of low oxygen tension which affects the membrane properties and shape of erythrocytes. These changes render erythrocytes sticky and deform their shape from their normal pliable biconvex shape to that of a rigid crescent, reminiscent of a farmer's sickle. Although these changes are initially reversible, with repeated exposure to low-oxygen environments, erythrocytes become permanently deformed and sticky, yielding the two major pathogenic sequelae: Hemolysis and Microvascular Vasoocclusion.

Rigid sickled erythrocytes are more readily recognized and eliminated by the cells of the reticuloendothelial system, thus displaying higher rates of extravascular hemolysis. Additionally, sickled cells are relatively fragile and can undergo intravascular hemolysis as well. Consequently, patients with SCD tend to display a high background of chronic hemolysis and a hypercellular bone marrow that generates large numbers of reticulocytes in an effort to compensate for chronic peripheral RBC destruction.

The membrane of sickled cells appear to express increased levels of adhesion molecules and is thus abnormally sticky, resulting in slowing and ultimately clogging of microvascular beds, yielding micro-infarctions throughout multiple organs. Sadly, these vasooclussive events tend to reduce local oxygen tension, further promoting hypoxic sickling of erythrocytes, thus yielding a vicious cycle.

Clinical Consequences

As described above, hemolysis and vasoocclusion are responsible for the clinical consequences of SCD. While chronic hemolysis yields a chronic hemolytic anemia, vasoocclusion can affect virtually any organ and often occurs in acute repeated episodes throughout life.

As described above, patients with SCD display a chronic background of both intra- and extra-vascular hemolysis. As a result, patients are chronically anemic with low baseline hemoglobin concentrations and often require repeated transfusions. In compensation for this peripheral destruction, a patient's bone marrow is hypercellular, releasing vast amounts of reticulocytes seen peripherally as reticulocytosis.

Occasionally, sickle cell patients will have an exacerbation of their baseline anemia with an inappropriately low level of reticulocytes, indicating a lack of bone marrow compensation. This occurs during context of viral infections, especially with Parvovirus B19 which can suppress hematopoiesis.

Acute Chest Syndrome is a unique clinical entity specific to patients with SCD that manifests as a syndrome of acute-onset chest pain in the context of symptomology indicative of pulmonary dysfunction including hypoxemia, tachypnea, cough, and so on. Acute Chest Syndrome is thought to be caused by sickling and vasooclusion within the pulmonary vasculature, a particularly dangerous scenario as the consequently reduced systemic oxygen tension can promote massive sickling throughout the body. The syndrome itself may have a number of triggers, especially pulmonary infections and fat emboli due to bone infarctions (See below).

The lives of patients with SCD are frequently marked by intense episodes of acute onset bone pain, thought to be caused by vasoocclussion within the bone marrow. In some cases this can lead to bone marrow infarction and the creation of fat emboli which may travel to the lungs and secondarily trigger an episode of Acute Chest Syndrome (see above).

Sickling and vasoocclusion within the penile venous outflow tract can lead to priapism, ultimately leading to permanent impotence in many male patients with SCD.

Sickling and vasooclussion within the spleen, leading to accumulated infarctions, is so common in SCD that virtually all patients exit their childhood with a small fibrotic spleen that is functionally inert. As a consequence, adults with SCD display an infection susceptibility to encaspulated bacteria, especially Salmonella.

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