Heme Hemoglobinopathy

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Hemoglobin c

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Incorrect

Right answer is B) Hemoglobin C (Homozygotes).

Hemoglobin C is a type of hemoglobin characterized by the substitution of lysine for glutamic acid at position 6 of the beta chain. HbC reduces the normal plasticity of erythrocytes.

While heterozygotes (Hb C trait) usually have no anemia, nearly all homozygotes have moderate normocytic hemolytic anemia

Patients normally have a component of hemolytic anemia

A peripheral blood smear shows: HbC crystals, micropherocytes, target cells

Hypothyroidism, liver disease and chronic alcohol use normally lead to macrocytic anemia

Alpha-thalassemia normally leads to microcytosis

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Hemoglobin e

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Incorrect

Right answer is E) Hemoglobin E has a single point mutation in the β chain at position 6, glutamic acid>lysine. HbC occurs with glutamic acid->lysine residue at the 26th position of the β-globin chain.

Hemoglobin E has single point mutation in the β chain at position 26, glutamic acid>lysine. Hb E common occurs in people of Asian descent and clinically has a phenotype like β thalassemia

HbC occurs with glutamic acid>lysine residue at the 6th position of the β-globin chain

Fucharoen S et al. The hemoglobin E thalassemias. Cold Spring Harb Perspect Med 2012 Aug 1;2(8)

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Inh red cell aplasia

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Incorrect

Right answer is A) δ-Aminolevulinate-synthase.

Isoniazid can cause pure red cell aplasia (normochromic/normocytic anemia, low reticulocyte count) and sideroblastic anemia (deficient heme synthesis and increase in ringed sideroblasts in the bone marrow)

Isoniazid induced sideroblastic anemia is thought to occur in part due to Vitamin B6 deficiency. However, Isoniazid also can inhibit δ-Aminolevulinate synthase which results in the marked depletion of heme synthesis.

Pyridoxine acts as a co-factor in synthesis of δ-aminolevulinate. Vitamin B6 is inhibited by Isoniazid

**Pearl: Marrow findings of sideroblastic anemia from alcohol use resolve rapidly (if alcohol use is stopped)

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Sickle cell beta thalassemia

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Incorrect

Right answer is A) HbS/beta0 thalassemia.

HbS/beta0 thalassemia: This is a double heterozygote and clinically hard to distinguish from HbSS

HbSC: This is a double heterozygote. Patients have an intermediate clinical severity

HbS/beta+ thalassemia: Mild to moderate severity. The presents of some beta globin enables the production of HbA

HbS/hereditary persistence of fetal Hb: Normally symptom free

HbS/HbE: Overall rare and has a mild clinical course

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Hemoglobin c/c

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Correct

HbC occurs due to a substitution of glutamic acid>lysine residue at the 6th position of the β-globin chain.

Hb C/C (homozygotes) have mild anemia. Patients have an elevated MCHC due to water loss

The blood smear mentioned crystals in the red cells; this was likely precipitated HbC

Hemoglobin C can migrate as Hb A2 on electrophoresis

Fabry ME et al. Some aspects of the pathophysiology of homozygous Hb CC erythrocytes J Clin Invest. May 1981; 67(5): 1284—1291

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Hemoglobin s beta thal +

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Correct

Hb S/β+ normally has more mild anemia compared to sickle cell disease (Hb S/S).

This disorder occurs when mutations that produce HbS and Beta thalassemia occur together. These patients normally have a > 60% HbS

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Hemoglobin h

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Incorrect

Right answer is D) Hb H: β2δ2 (beta2, delta2).

HbH consists of β4. Hb H is the most common form of thalassemia intermedia. It results from double heterozygosity for alpha(0)-thalassemia due to deletions removing both linked alpha-globin genes and alpha(+)-thalassemia from single alpha-globin gene deletions (--/- α).

Normally, patients with Hb H diseases have a Hb between 9-10 g/dL

α1 and α2 genes are located on chromosome 16

γ(gamma), β, and δ (delta) are located on chromosome 11

Fucharoen S et al. Hb H disease: clinical course and disease modifiers. Hematology Am Soc Hematol Educ Program 2009:26-34

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Alpha thal gene expression

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Correct

Homozygotes for α0 normally die <40 weeks gestation. The fetus cannot live once outside the uterus. There is tetrameric γ chains (Hb Barts)

Silent carrier: (--,α) (α,α)

Alpha thalassemia trait: (--,α) (--,α)

Alpha thalassemia trait: (--,--) (α,α)

Hemoglobin H disease: (--,--) (--,α)

Hydrops fetalis: (--, --) (--, --)

Hemoglobin H disease consists of 2 unstable hemoglobins

Hb Barts: (tetrameric γ chains)

Hb H: (tetrameric β chains).

**Heinz bodies are precipitated HbH

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Hb constant spring

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Incorrect

Right answer is C) It is an ? thalassemia and heterozygotes normally show no hematologic abnormalities.

A point mutation leads to abnormal elongation of the alpha globin chain (Hb Constant Spring). It is a nondeletional α-thalassemia

Liao C et al. Screening for Hb Constant Spring in the Guangdong Province, South China, using the Sebia capillary electrophoresis system. Hemoglobin 2011;35(1):87-90.

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B thal variants

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Incorrect

Right answer is C) Hb β+/β+.

Hb β/β+ or Hb β0β: Thalassemia minor. Only _1_ β globin allele carries a mutation. Normally a patient will have microcytic anemia. Will see a Hb A2>3.5%

Hb β+/β+ or Hb β0/β+: Thalassemia intermedia. Patients are often asymptomatic. However, more pronounced anemia and may require an occasional transfusion. This patient has fairly significant anemia and 2 pRBC in his life, thus likely has intermedia and not minor disease.

Hb β0/β0: Thalassemia major. Both β alleles have mutations. There is severe microcytic anemia. Can see severe anemia, bone abnormalities, splenomegaly. Requires frequent blood transfusions (watch for iron overload). Treatment includes bone marrow transplantation. Also known as Cooley’s anemia

Of note, precipitation of α chains can lead to premature RBC destruction (hence, signs of hemolysis)

**Pearl: Watch for Yersinia and Vibrio infections

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Persistence fetal hemoglobin

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Hereditary persistence of fetal hemoglobin is a condition that is benign. It occurs when HbF continues to be produced into adulthood. By 6 months, there is a normal shift from gamma globin to beta globin. This reduces production of HbF and increases production of HbA

Delta/Beta thalassemia also lead to elevation of HbF. Heterozygotes have 5-20% HbF.

It is caused by a mutation in the β gene. Homozygotes can have 100% HbF. Heterozygotes can have 20-30% HbF

**Pearls: Hb E: Causes decreased beta chain production. Mild anemia

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Methhemoglobinemia

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Methemoglobinemia is characterized by the presence of a higher than normal level of ferric [Fe3+] rather than ferrous [Fe2+] hemoglobin. Methemoglobin cannot release oxygen effectively to body tissues. When methemoglobin concentration is elevated in red cells, a patient can have tissue hypoxia. Any methemoglobin > 1% can lead to symptoms of oxygen deprivation (SOB, cyanosis, fatigue) Arterial blood in methemoglobinemia will have a chocolate-brown color. Patients have low O2 saturation, but normal arterial p02. Oxygen saturation refers to the percentage of available heme binding sites saturated with oxygen. P02 refers to free oxygen molecules in the arterial blood (molecules dissolved in plasma but not that bound to hemoglobin) NADH Diaphorase deficiency is an enzyme that reduces cytochrome b5. This in turn reduces methemoglobin to hemoglobin Methemoglobinemia treatment: oxygen and methylene blue (IV). Methylene blue allows the iron in Hb to resume being ferrous (Fe2+) allowing it to resume its normal oxygen carrying state

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Procrit Red Cell Aplasia

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Epoetin-associated pure red cell aplasia is rare, but occurs when neutralizing antibodies that are produced against the recombinant epoetin alfa, then target endogenous erythropoietin One can test for antibodies for rHuEPO by radioimmuno-precipitation assays. Normally, over time the antibody titer will decline spontaneously and the anemia should improve. Of course, do not give more Epoetin alfa products. While the red cells may recover, often these patients will need immunosuppressive therapy