LabMed

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.

Table 1

Test Results Indicative of the Disorder
Sickling Test Hgb Analysis Morphology
positive F < 2% A2 < 3.7% S = 45% C = 45% S/C poikilocytes clam or boat shaped cells absent sickle cells

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications - OTC drugs or Herbals - that might affect the lab results?

Factors affecting laboratory results are indentical to those given for Sickle Cell Anemia.

What Lab Results Are Absolutely Confirmatory?

In practice, the demonstration of a positive Sickling test, equal sized peaks on high performance liquid chromatography (HPLC) and isoelectric focusing (IEF) corresponding to hemoglobins S and C, with a normal A2 is considered confirmatory. The demonstration of a substitution of valine for glutamic acid in the sixth position of 1 ß-chain and substitution of lysine for glutamic acid at this same position of the other ß-chain is diagnostic for S/C Disease. This can be confirmed by genetic testing, although the expense is rarely justified.

Many Newborn Screening programs include tests for common hemoglobinopathies and will have no difficulty identifying the presence of S/C Disease. However, in the presence of such high concentrations of hemoglobin F neonatally, the Sickling test will likely be negative, especially in a preterm infant.

Other testing modalties are as described for Sickle Cell Anemia.

What Confirmatory Tests Should I Request for 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.

What Factors, If Any, Might Affect the Confirmatory Lab Results? In particular, does your patient take any medications - OTC drugs or Herbals - that might affect the lab results?

Factors that might affect laboratory results are identical to those described for Sickle Cell Anemia.

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