Pathology > Basic Hematology > Red Cell Disorders > Structural Abnormalities of Hgb (Part 2)

Structural Abnormalities of Hgb (Part 2)

In sickle cell trait (Hgb SA) 25 - 45% of the hemoglobin is Hgb S; the remainder being Hgb A and as well as Hgb F and Hgb A2.

No anemia and normal RBC morphology is the rule in sickle cell trait.

Only two rare complications, hematuria and splenic infarction are associated with sickle trait.

There is no risk from anesthesia, surgery, pregnancy, or strenuous physical activity. However, sickle cell trait has been associated with an extremely small increase in sudden death in individuals under severe stress (US Armed Forces study).

Individuals with sickle cell trait have normal growth and development, normal life spans and should not be considered ill.

Hb S may be combined with other defects of hemoglobin.

The most common is S-ß-thalassemia. People with S-ß-thalassemia have the clinical manifestations of sickle cell disease. The MCV is low as would be expected in ß-thalassemia.

Also frequent is SC disease. Mild anemia and splenomegaly is often present. The PBS shows numerous RBC targets and may show intracellular Hgb C 'crystals'. The MCHC is often increased due to loss of water. Larger amounts of Hgb S are made in SC disease than in sickle trait (SA).

Patients with SC disease have increased viscosity of the blood causing a high incidence of proliferative retinopathy, painful aseptic nerosis of the femoral head (more than in SS disease), and acute chest syndrome.

Aseptic necrosis of the femoral head. Note the collapse and retraction of the bone underlying the cartilage, causing deformation of the femoral head.

Slide courtesy Robert E Fechner.

Hemoglobin C disease results in a mild - moderate anemia with large numbers of RBC targets seen on the PBS. Hgb C 'crystals' can usually be found. Rhomboid 'Washington' monument crystals may distort the cell. Spherocytes may also be seen. Splenomegaly is common.

Persons with Hgb AC (trait or carrier state) have only a few RBC targets.

The upper image shows numerous target cells. A crystal distorts an erythrocyte in the lower image.

The upper image shows numerous target cells. A crystal distorts an erythrocyte in the lower image.

 

Hemoglobin D causes a mild hemolytic anemia and splenomegaly in the homozygous state (Hgb DD), where as no morphologic or clinical abnormality is seen in the heterozygous state (Hgb AD).

How would you distinguish Hgb D trait from sickle cell trait?

It is difficult to distinguish Hgb D from Hgb G. Any ideas?

Hemoglobin E is the result of a ß-chain mutation (AÆG) in codon 26 changing glutamine Æ Iysine. This creates a new splice site which competes with the normal splice site causing decreased production of an unstable hemoglobin.

Hgb E disease (Hgb EE) causes a hypochromic microcytic (Hgbª10; MCV ª60) anemia with many targets and some basophilic stippling.

In Hgb E trait (Hgb AE) the anemia is mild with microcytosis (Hgbª12; MCV ª75) and occasional targets.

Hemoglobin E is unstable as tested for by heat and isopropanol tests.

 

Worldwide hemoglobin E is the second most common abnormal hemoglobin (est. 80 million cases,1990), after Hgb S. Hgb E is common in people of Southeast Asian ancestry.

When Hgb E is combined with ß-thalassemia trait, the anemia is usually severe (Hgb 3-7; MCV ª50) depending on the ß-thalassemia and splenomegaly is present.

Hgb E/ß-thalassemia is becoming increasingly common in the US.

Microcytic hypochromic RBCs with target cells

O-Arab, is found in African, Middle Eastern, Central European, African- American, and Jamaican peoples. O-Arab is a b-chain variant (b121 GluÆLys), characterized by mild anemia with hemolysis, RBC targets and splenomegaly.

Hgb S/O-Arab has the phenotypic expression of sickle cell disease.

Unstable hemoglobin variants are an uncommon cause of extravascular hemolysis. A variety of amino acid substitutions cause instabilities in the Hgb molecule resulting in Hgb denaturation. The denatured Hgb forms small round masses called Heinz bodies. These intracellular Hgb precipitates cause RBC destruction by splenic macrophages.

Heinz bodies can be visualized with crystal-violet staining as small spheroidal blue-purple inclusions.

Many unstable Hgb variants cannot be detected by Hgb electrophoresis. Positive heat and isopropanol tests are characteristic of unstable Hgb variants.

Heinz bodies are visible as faint blue blushes in the RBCs. A recticulocyte is seen at lower left.

High O2 affinity hemoglobins, avidly bind O2, but do not readily release O2 to tissue (left shift of O2-dissociation curve). The resulting tissue hypoxia stimulates production of erythropoietin and causes an erythrocytosis (≠Hgb, ≠Hct, and ≠RBCs). Persons with high O2 affinity Hgbs (autosomal dominant inheritance and virtually always heterozygous) are asymptomatic. Homozygous forms are usually incompatible with life.

Low O2 affinity hemoglobins readily release O2 to tissue, but are poorly saturated, producing a right shift of the O2-dissociation curve. Erythropoietin decreases as O2 tissue levels increase, causing a mild anemia. Low O2 saturation may result in cyanosis.

The structural hemoglobin abnormalities introduced on the preceding cards are due to polypeptide sequence alterations, changing the molecular structure and, as a result, often changing globin chain function.

In addition there are quantitative abnormalities of hemoglobin secondary to decreased rates of globin chain synthesis. Thalasemmia, the best example of such a decrease is described in the section "decreased hgb synthesis" under "Decreased RBC Production". See Navigational Outline.

Hemoglobinopathies whether structural or quantitative may result in hemolysis due to changes in hemoglobin solubility or because of an unstable hemoglobin molecule.

Following a few questions on hemoglobinopathies we will begin a discussion of antibody mediated hemolytic anemia.

 

HEMATOPATHOLOGY

What hemoglobin abnormality is suggested from the above PB smear?

A. Hgb AS
B. Hgb AC
C. Hgb CC
D. Hgb SC
E. Hgb SS

All of the following are associated with sickle cell anemia EXCEPT:

A. normal RBC Hgb concentration
B. normal reticulocyte count
C. normal or small spleen
D. abnormal susceptibility to hypoxia
E. abnormal reduced RBC life span

The Smiths have two children. Mr. Smith has sickle cell trait and Mrs. Smith hemoglobin C trait. While their daughter is healthy, a number of target cells were seen on her peripheral blood smear. Their son has a hemolytic anemia requiring occasional blood transfusions. Which combination of the following genotypes is most likely for the two children.

A. Hgb AA & SC
B. Hgb AC & SC
C. Hgb AS & SC
D. Hgb AS & AC
E. Hgb SS & AC

 

A 24 year old Laotian woman appears in your office complaining of menstrual irregularities. You find that her Hct is .42 L/L; Hgb 142 g/L; and MCV 76fL. The blood smear shows RBC microcytosis and mild hypochromia with occasional target cells. Hgb electrophoresis shows a band in the C and A posittions at pH8.6 and only in the A position at pH6.2. Which of the following hemoglobin disorders is most likely?

A. Hgb C
B. Hgb D
C. Hgb E trait
D. Hgb O Arab
E. Hgb SC

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