Final Diagnosis -- Hemoglobin S/Hemoglobin C disease




Figure 1 shows folded erythrocytes seen characteristically in HbSC disease. The peripheral blood findings in HbSC disease are characteristic. There are usually irregularly shaped cells, which appear to contain misshapen crystals, which have been called "S/C poikilocytes". Although S/C poikilocytes appear to contain crystals, classic polyhedral HbC crystals are unusual. Target cells are usually increased. True sickle cells are rare. Anisocytosis is mild to severe.

A practical method for routine hemoglobin electrophoresis is cellulose acetate at alkaline pH (Figure 2). It is done at pH of 8.4 to 8.8 which separate the hemoglobins into bands based on net charge. Bands can be quantitated by densitometry. Some hemoglobins migrate together on alkaline gel. Hb S, D, and G migrate to the same place. Hemoglobin A2, C, E, and O also migrate together on the gel. In this patient there are bands seen at presumptive positions of HbS (17.3%) and HbC (12.7%). However, for both of these bands further investigation needed to rule out other overlapping hemoglobins at those positions. Citrate agar electrophoresis at an acid pH (Figure 3) provides ready separation of many hemoglobins that migrate together on cellulose acetate. If an S band is present, a solubility test or sickling test must be done. The sickle cell preparation yielded a positive result in this patient.

HbSC disease is caused by heterozygous inheritance of a HbS gene ( 6Glu > Val ) and a HbC gene ( 6Glu > Lys ). In HbSC disease electrophoresis shows HbS and C in about equal amounts (40 to 50% each). HbF ranges from normal to slightly increased. Note that because no normal chains can be produced, HbA is absent. In our case unexpectedly HbA is the dominant hemoglobin. When one finds HbA, HbS, and HbC all present in a single specimen, there are only two possibilities: 1) the patient has been transfused; or 2) two or more specimens were inadvertently mixed (rare but not impossible). This patient had history of multiple blood transfusions which have caused the pattern seen in his Hb electrophoresis. A similar pattern may be seen on alkaline electrophoresis only in specimens from patients who have both HbS trait and HbG-Philadelphia. However, in such cases, acid electrophoresis demonstrates no abnormal hemoglobin in the HbC position. In addition, the combination of HbS and HbC will look identical to Hb S/E and Hb S/O-Arab on alkaline electrophoresis. Other methods such as acid electrophoresis, HPLC, globin chain electrophoresis, or isoelectric focusing will easily differentiate these combinations.

The prevalence of HbSC disease in African Americans is 0.13%. These patients have moderate normocytic normochromic anemia with increased MCHC, and splenomegaly. The severity is intermediate between sickle cell trait and sickle cell disease. The onset is usually in childhood, but real difficulties do not occur until later in life. Fatigue, dyspnea on effort, attacks of mild jaundice (this patient has laboratory features of hemolysis), and arthralgias are seen. Life expectancy is usually only slightly shortened. Painful vaso-occlusive crises are less frequent than in sickle cell disease. Interestingly, thromboembolic complications, renal papillary necrosis, and proliferative retinopathy are more frequent in S/C disease than in sickle cell anemia.


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Contributed by Franklin Sedarat MD, MSc and Dmitriy W. Gutkin MD, PhD

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