Abdominal Pain and Anemia in a Child

Allison King, MD, MPH and John DiPersio, MD, PhD

Washington University School of Medicine, St. Louis, MO

This case was reviewed and updated in June 2013 by Dr. Ted Wun and members of the Teaching Cases Subcommittee.

Copyright of the American Society of Hematology, 2006. ISSN: 1931-6860.

V. PATHOPHYSIOLOGY

Sickle cell anemia (HbSS) is an autosomal recessive disease that results in a chronic hemolytic anemia and intermittent vascular occlusion that often results in permanent end-organ damage.

In the adult, hemoglobins are composed of an iron containing heme moiety and two alpha and beta globin chains. Sickle hemoglobin is the result of a mutation in the beta globin gene.

The beta globin gene is located on chromosome 11p15.4. The sickle cell form of the beta globin gene results from the substitution of a single DNA nucleotide. The change from adenine to thymine at codon (position) 6 of the beta globin gene leads to substitution of the hydrophobic amino acid valine for the hydrophilic amino acid glutamic acid.

Over 100 types of other mutations affect the beta globin gene, and deletion mutations are rare. Splice mutations and mutations that occur in the beta globin 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 disease.

There are several possible mutations that result in compound heterozygotes (variants of sickle cell disease) including:

  • Hb SC, Hb SD, Hb SOArab
  • Hb Sβ0-thalassemia
  • Some forms of Hb Sβ+-thalassemia

The red blood cells in sickle cell disease are more rigid than normal red blood cells and have a shorter life-span than normal red blood cells (half-life by Cr51 labeling 7-10 days as opposed to 24-28 days in normals). When oxygenated, sickle hemoglobin is soluble in the red blood cell as is normal HbA. Upon deoxygenation, sickle hemoglobin can polymerize in the red blood cell, interacting with the red cell membrane to make the red blood cell more rigid and even form the classic sickle cell. The red cell can undergo cycles of sickling and unsickling, which leads to permanent membrane abnormalities. Even in the absence of sickling, the sickle red blood cell is abnormally adhesive to inflamed endothelial cells and other blood cells. These abnormalities are thought to underlie the intermittent vaso-occlusion that typically manifests as pain in soft tissue or bone: a vaso-occlusive crisis (VOC). Vaso-occlusion in the lung tissue is thought to be one of the causes of acute chest syndrome (e.g. infiltrates, hypoxemia, tachypnea, pleuritic chest pain, fever).

Reactive airway disease is more prevalent in children with sickle cell disease than in age- and ethnically-matched controls. Whether the pathogenesis is similar to asthma in children without sickle cell disease is not known. Nonetheless, children with sickle cell disease and diagnosed asthma have increased incident ACS.

Over 20% of children with sickle cell anemia will have a cerebral infarct. Nearly a third more have been shown to have silent cerebral ischemia as defined by evidence of small vessel cerebral infarction by MRI. 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. Children who have had clinical stroke are placed on chronic transfusion, which has been shown to reduce the risk of recurrent stroke significantly. Transcranial Doppler screening can identify children at high risk for stroke, and chronic transfusions have been shown to reduce stroke incidence by nearly 90% in such high-risk patients.

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