At a Glance
Compound heterozygosity for hemoglobin O-Arab and hemoglobin S is rare but should be suspected in patients with known sickle trait who have an unexpectedly severe course reminiscent of homozygous Sickle Cell Anemia or who have a family history of the same. Patients with hemoglobin S/O-Arab have a modestly elevated hemoglobin F (5-18% of the total hemoglobin), which counteracts the mildly increased oxygen dissociation in S/O-Arab and induces a mild erythropoeitin-stimulated increase in red cell production, thus, partially ameliorating the anemia. Characteristically, red blood cell (RBC) indices are normal in this condition (see chapter on Sick Cell Anemia). However, the clinical course is similar to Sickle Cell Anemia, with frequent hand-foot syndrome and acute splenic sequestration without autosplenectomy.
Additionally, osteopenia is frequently reported.
The presence of sickle trait with an equal proportion of another hemoglobin eluting closely with hemoglobin C should also prompt consideration of this combination, and, indeed, a number of patients carry the erroneous S/C disease diagnosis, which occurs at a frequency of 1 in 835 in African Americans.
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 then reveals the O-Arab trait in the other parent.
Hemoglobin O-Arab and hemoglobin S trait are each benign, and have been discussed as discrete clinical entities elsewhere (see chapters on Anemia Associated with Hemoglobin O-Arab and Sickle Trait). Here, they are considered coinherited mutations in which the interaction between the 2 hemoglobin species produces a significant sickling hemolytic disorder.
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)
In addition, the red cell distribution of hemoglobin F could be determined with the acid elution Kleinhauer-Betke test. Flow cytometry using fluorescently-labeled anti-hemoglobin F is increasingly being used for this purpose. A heterocellular distribution of hemoglobin F is expected in hemoglobin S/O Arab.
|Presumptive Diagnosis||Ratio Hgb O-Arab/Hgb A||Hgb A2 %||Hgb F% at >9 months of age||Sickling Test||Hgb g/dL||MCV fL||Morphology|
|A/O-Arab||40/60||<3.7||1-3||negative||11-15||80-100||rare target cells|
|Uncomplicated S/O-Arab (no thalassemia)||100/0 S and O-Arab in equal amounts||<3.7||5-17||positive||8-11||80-95||reticulocytosis many target cells, poikilocytosis, anisocytosis normoblasts few 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?
In S trait, the percentage of hemoglobin S (roughly 35%) is not usually sufficient to cause significant sickling, and the condition is relatively benign. With hemoglobin O-Arab, there is no tendency to sickle, even in the homozygous state. It is the interaction between these two singly-substituted hemoglobins S (ß6 Glu → Val) and O-Arab (ß121 Glu → Lys) that forms insoluble copolymers with a different shape to SS polymers. Characteristically, RBC indices are normal in this condition, which helps differentiate it from SC disease and SS disease. There are very few actual sickle shaped cells, rather the cells have a flattened aspect and are described as folded, similar in shape to the microcytic cells seen in S/C disease.
The distinction between hemoglobin S/O-Arab and the more common hemoglobin S/C disease is often a difficult call from the laboratory viewpoint. In both instances, the variant hemoglobins are present in equal relative percentages once the hemoglobin F is subtracted. Improvements in high performance liquid chromatography (HPLC) resolution now permit differentiation of hemoglobin C and the slightly earlier eluting O-Arab.
On isoelectric focusing (IEF), hemoglobin O-Arab runs slightly anodal to hemoglobin C (see chapter on Anemia Associated with Hemoglobin S-C). On acid electrophoresis (EP), these are distinguished as hemoglobin O-Arab runs between hemoglobins A and S quite distinctly from hemoglobin C, although on alkaline EP both run in the A2 position. Additionally, hemoglobin O-Arab produces a characteristic small peak in the hemoglobin S window on HPLC that is not seen with hemoglobin C. Providing that the percentages of hemoglobin F and A2 are normal, further testing is not usually warranted.
Another useful distinction is that the percentage of hemoglobin F is often, although not always, higher in S/O-Arab. In SC disease, the percentage of hemoglobin F rarely exceeds 4%. Elevated percentages of hemoglobin F are also seen in several conditions coinherited with hemoglobin S, and these have a wide variety of clinical presentations (see chapter on Anemia Associated with Hemoglobin S-Hereditary Persistence of Fetal Hemoglobin).
A heterocellular distribution of hemoglobin F is expected in S/O-Arab, which rules out a number of forms of hereditary persistence of fetal hemoglobin (HPFH), but not a concurrent ß+-thalassemia. However, these can be distinguished by having not only unequal distribution of hemoglobins S and O-Arab, but also an elevated hemoglobin A2 (see chapter on Anemia Associated with Hemoglobin S-Beta Thalassemia). If the ß+-thalassemia is on the S gene, the percentage of hemoglobin O-Arab will exceed that of hemoglobin S, and vice-versa.
What Lab Results Are Absolutely Confirmatory?
In practice, the demonstration of a positive Sickling test, equal sized peaks on HPLC and IEF corresponding to hemoglobin S and O-Arab 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 position 121 of the other ß-chain is diagnostic for S/O-Arab. 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 Trait. However, the correct identification of O-Arab may be more challenging. In the presence of such high concentrations of hemoglobin F neonatally, the Sickling test will likely be negative, especially in a pre-term infant.
The other tests required for diagnosis and follow-up are identical to those described for Sickle Cell Anemia.
What Confirmatory Tests Should I Request for My Clinical Dx? In addition, what follow-up tests might be useful?
Tests required 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 affect laboratory tests are identical to those described for Sickle Cell Anemia.
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- At a Glance
- What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?
- 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?
- What Lab Results Are Absolutely Confirmatory?
- What Confirmatory Tests Should I Request for My Clinical Dx? In addition, what follow-up tests might be useful?
- 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?