Anemia Associated with Hemoglobin S-C

At a Glance

Compound heterozygosity for Hemoglobin C and Hemoglobin S should be suspected in a patient with known sickle trait who has an unexpectedly severe clinical picture or who has a family history of the same. Patients with hemoglobin S-C follow a clinical course similar to, but milder than, Sickle Cell Anemia (see chapter on Sickle Cell Disease). Typically, one parent has known S trait with a positive Sickling test, but the other does not, and, thus, the severity of the disorder in the offspring is unexpected. Family testing can then reveal the hemoglobin C trait in the other parent.

Patients with mild anemia whose peripheral smear shows irregularly shaped cells containing misshapen crystals (S/C poikilocytes), clam or boat shaped cells with a folded appearance, without classic hemoglobin C polyhedric crystal inclusions should also be suspected of having this disorder. (This finding is also seen in the much rarer S/O-Arab hemoglobinopathy (see chapter on Anemia Associated with Hemoglobin S-O Arab)).

The presence of sickle trait with an equal proportion (50%) of hemoglobin C should also prompt consideration of S/C disease. This combination of hemoglobinopathies is identified reliably on Newborn Screening. The carrier rate for both of these traits is high in the African American population (1 in 13 for hemoglobin S and 1 in 33 for hemoglobin C), so the double heterozygote S/C combination is not that rare (1 in 835) in this ethnic group.

Hemoglobin C and hemoglobin S trait are each benign and have been discussed as discrete clinical entities elsewhere. Here, they are considered coinherited mutations in which the interaction between the 2 hemoglobin species produces a significant sickling hemolytic disorder (see chapters on Anemia Associated with Hemoglobin S-C and Sickle Cell Anemia).

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

The testing strategies for diagnosis and follow-up are identical to those described for Sickle Cell Anemia.(Table 1)

If the percentages of hemoglobins S and C are not in the expected 50:50 split or the amount of hemoglobins A2 or F are not as expected, then further testing is indicated to rule out coinheritance of thalassemias or Hereditary Persistence of Fetal Hemoglobin (HPFH; see chapters on Anemia Associated with Hemoglobin A-Alpha Thalassemia, Anemia Associated with S-Beta Thalassemia, and Anemia Associated with Hemoglobin S-Hereditary Persistence of Fetal Hemoglobin).

The pathogenesis of the sickling manifestations in S/C disease is controversial. Although it is commonly suspected that hemoglobins C and S copolymerize, this may not actually be the case. The percentage of hemoglobin S in S/C disease is somewhat higher than in S trait (50 vs 40%), and, although this difference seems insignificant, the cellular dehydration that occurs with hemoglobin C increases the red blood cell (RBC) concentration of hemoglobin S above its polymerizing threshold. The crystal produced is much longer (Washington monument shaped) than in homozygous C conditions.

In comparison to Sickle Cell Anemia, the hemolytic anemia is mild to moderate with a hemoglobin A greater than 10 g/dL, and, therefore, complications attributed to hemolysis (e.g., cholelithiasis, leg ulcers, hepato- and cardio-megaly) are less frequent. Painful vaso-occlusive crises are less frequent, and infarctive damage is less debilitating. Splenomegaly is not as prevalent and only 25% of patients have autosplenectomy. However, increased blood viscosity leads to a greater incidence of retinal hemorrhage, renal papillary necrosis, and aseptic necrosis of the femoral head.