At a Glance
Coinheritance of hereditary persistence of fetal hemoglobin (HPFH) with homozygous SS disease should be suspected in a patient with known Sickle Anemia who has a less severe clinical presentation than expected or a family history of the same. These patients have a modestly elevated hemoglobin F (up to about 30% of the total hemoglobin) in the absence of hydroxyurea moderating therapy, which persists beyond infancy.
HPFH along with α-thalassemias are the main genetic moderating influences on morbidity and mortality in Sickle Cell Anemia. HPFH is a quantitatively inherited increased amount of hemoglobin F in red blood cells (RBCs), which serves not only to decrease the relative percentage of hemoglobin S, but also to maintain a higher oxygen tension, since F is a high oxygen affinity hemoglobin (see chapter on Anemia Associated with Hemoglobin S-Alpha Thalassemia). In addition, increasing the percentage of hemoglobin F induces a mild erythropoeitin-stimulated increase in red cell production, thus, partially ameliorating the anemia.
HPFH and hemoglobin S have been discussed as discrete clinical entities elsewhere. Here, they are considered coinherited mutations (See chapter on Sickle Cell Anemia).
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What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?
The tests required for diagnosis and follow-up are identical to those described for hemoglobin S.(Table 1)
Elevated percentages of hemoglobin F are seen in a several combinations with hemoglobin S, and these have a wide variety of clinical presentations. Careful attention to the relative percentages of the hemoglobin species is important for obtaining the correct diagnosis of Sickle Cell Anemia with HPFH.
To this end, 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 pancellular distribution of hemoglobin F is expected in all 3 common African American forms of HPFH, and this helps distinguish the common δß-deletional form of HPFH from the more serious δß-thalassemia. Another useful distinction between these two conditions is that hemoglobin S ß0-thal has an elevated A2, whereas hemoglobin S-HPFH has no detectable hemoglobin A2 in its homozygous state and a low hemoglobin A2 in trait. This is an important distinction that has implications for counseling, treatment, and prognosis.
Table 1
| Diagnosis | % Hgb F | Distribution | % Hgb A2 | Hgb % S | Clinical Features |
|---|---|---|---|---|---|
| HbSS | <2 at 2 yrs | Pancellular | 3-4 | 95 | severe hemolytic anemia early autosplenectomy |
| Hb S-HPFH (δß-trait) | 15-30 | Pancellular | 1-2.5 | 70-85 | no anemia |
| Hb S-HPFH trait (non-deletional) | 15-30 | Pancellular in African Americans Heterocellular in Greek | 2-2.5 | 65-80 | no anemia |
| HbSS α-thal | 8-16 | Pancellular | 2-2.5 | 80 | mild anemia |
| HbS ß+-thal | 4-5 | Heterocellular | 4-5 | 90 | variable presentation asymptomatic to anemic splenomegaly common |
| HbS ß0-thal | 3-8 | Heterocellular | 3.7-7 | 90 | hemolytic anemia splenomegaly common past childhood |
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?
It has long been known that the presentation of Sickle Anemia can vary widely and that certain geographic/ethnic similarities can be identified.
The combination of HPFH and Sickle Cell Anemia has been shown to increase life expectancy and reduce the frequency of acute pain crises and leg ulcers. Its effects are not as pronounced on prevention of hemolysis as is a coinherited α-thalassemia, which also causes a sustained modest elevation in hemoglobin F. It is important, therefore, to determine the correct cause of the elevated hemoglobin F for both counseling and treatment options.
HPFH represents a heterogeneous group of disorders. Three major loci have been identified that cause persistence of hemoglobin F into adulthood:
Xmn1 polymorphism in the promoter region of the G globin genes
HMIP locus on chromosome 6q23.3
BCL11A on chromosome 2
Genetic diversity in these loci is likely to account for some 50% of the clinical diversity seen in Sickle Cell Disease and has already been reported for acute pain. This could be targeted to help improve prenatal diagnosis and accuracy of neonatal prognostication.
Other causes of elevated hemoglobin F should be considered:
Hydroxyurea therapy is widely used in treatment of Sickle Anemia to boost the production of hemoglobin F. This is important, since hemoglobin S only denatures in its deoxygenated state. However, the drug is also given in polycythemia and as chemotherapeutic agent. If the drug history is unknown, an elevated hemoglobin F should be interpreted with caution.
In patients without Sickle Anemia, hemoglobin F concentrations are expected to decline to adult concentrations within 6 months. In Sickle Anemia, this process takes about 2 years.
Transfused blood is always assumed to be 95% hemoglobin A, with less than 2% hemoglobin F, but, since HPFH is often silent, there is a possibility that a transfused unit could contain a significant percentage of hemoglobin F. A transient rise in hemoglobin F after transfusion is indicative of this.
Performing a test to determine the distribution pattern of hemoglobin F may not contribute much to the diagnosis. Family studies can be informative in this regard and may negate the need for the expense of gene analysis.
Additionally, since nondeletional forms of HPFH involve point mutations in only one of the two γ-globin genes, quantitation of the individual γ-chains shows an abnormal ratio of the G to A gene product. (These proteins differ only by a single amino acid at position 136.) Again, this is costly.
What Lab Results Are Absolutely Confirmatory?
Many Newborn Screening programs include tests for common hemoglobinopathies. The hemoglobin S disease will be readily identified and can be differentiated from S Trait. However, HPFH may not be detected until later in life when hemoglobin F should have declined to adult levels of less than 2%.
It is, therefore, important to follow the percentage of hemoglobin F in a patient with hemoglobin S, and, after 2 years of age, the diagnosis may need reassessment.
The other tests required for diagnosis and follow-up are identical to those described for hemoglobin S.
What Confirmatory Tests Should I Request for My Clinical Dx? In addition, what follow-up tests might be useful?
Additional tests are identical to those described for hemoglobin S.
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 hemoglobin S.
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