MLT 251 - Hemoglobinopathies + Thalassemias OBJs

List the four normal types of hemoglobin produced from conception to adulthood in relation to the polypeptide chains.

They are hemoglobin A, hemoglobin A2, hemoglobin F, and embryonic hemoglobin (Gower 1 and Gower 2). These hemoglobins are composed of different combinations of alpha and beta polypeptide chains.

Recall the type of chains in each type of normal hemoglobin.

Normal hemoglobins include HbA (α2β2), HbA2 (α2δ2), HbF (α2γ2), and embryonic forms like HbE (ζ2ε2), each composed of specific polypeptide chains.

Recall the normal levels (percentage) of each hemoglobin from conception to adulthood.

Normal hemoglobin levels vary with age: HbA is 95-98% in adults, HbA2 is 2-3%, and HbF is less than 1% after infancy. Newborns typically have higher levels of HbF, around 60-80%.

Know the structural makeup of the hemoglobin molecule.

The hemoglobin molecule consists of four polypeptide chains (two alpha and two beta in adults), each bound to a heme group, allowing it to transport oxygen in the blood.

Define the term 'hemoglobinopathy'.

A hemoglobinopathy refers to a group of disorders caused by abnormalities in the structure or production of hemoglobin, leading to various clinical manifestations and health issues.

Explain the following terms and discuss the levels of each type of hemoglobin in each.

a. homozygous beta hemoglobinopathy

b. heterozygous beta hemoglobinopathy

c. heterozygous alpha hemoglobinopathy

d. homozygous alpha hemoglobinopathy

e. double heterozygous for 2 beta chains

a. Homozygous beta hemoglobinopathy involves two copies of mutated beta globin genes, resulting in diseases like sickle cell anemia, with levels of HbS significantly increased and HbA decreased.

b. Heterozygous beta hemoglobinopathy occurs when one normal and one mutated beta globin gene are present, leading to conditions like sickle cell trait with normal HbA and some HbS production.

c. Heterozygous alpha hemoglobinopathy includes one normal and one mutated alpha globin gene, often resulting in alpha-thalassemia trait with mostly normal Hb levels but possible minor reductions in HbA.

d. Homozygous alpha hemoglobinopathy involves two mutated alpha globin genes, which can lead to severe conditions like hemoglobin H disease, characterized by low levels of HbA and increased HbH.

e. Double heterozygous for two beta chains means carrying two different mutations in the beta globin gene, possibly leading to compounded effects from both mutations, affecting overall hemoglobin levels and clinical presentation.

Recall the amino acid substitution and the type of chain affected in hemoglobin S disease and trait.

Hemoglobin S disease is caused by a substitution of valine for glutamic acid in the beta chain of hemoglobin, leading to sickle-shaped red blood cells. In contrast, hemoglobin S trait shows a similar substitution but typically presents with milder symptoms.

List the factors which enhance the sickling process.

Factors that enhance the sickling process include dehydration, acidosis, hypoxia, increased temperature, and certain infections. These conditions promote the polymerization of hemoglobin S, leading to distorted red blood cell shapes.

Differentiate between the terms: “disease” and “trait” as related to zygosity.

Disease refers to the homozygous state with significant clinical manifestations, while trait refers to the heterozygous state, usually asymptomatic or with mild effects.

Differentiate between hemoglobinopathy and thalassemia.

Hemoglobinopathy refers to genetic disorders affecting the structure of hemoglobin, while thalassemia involves a deficiency in the production of one or more hemoglobin chains, leading to anemia.

Compare clinical manifestations and laboratory findings of Sickle cell disease versus Sickle cell trait.  

Sickle cell disease presents with severe anemia, pain episodes, and complications such as infections and organ damage. In contrast, sickle cell trait is usually asymptomatic and characterized by a normal hemoglobin level and a lower percentage of hemoglobin S.

Recall the amino acid substitution and the type of chain affected in hemoglobin C disease and trait.

Hemoglobin C disease is caused by a substitution of lysine for glutamic acid in the beta chain. In contrast, hemoglobin C trait has a similar substitution with generally mild or no symptoms.

Compare clinical manifestations and laboratory findings of the hemoglobin C disease versus hemoglobin C trait.

Hemoglobin C disease typically presents with mild to moderate anemia and splenomegaly and may show target cells on a blood smear, whereas hemoglobin C trait is usually asymptomatic, with a normal hemoglobin level and minimal laboratory abnormalities.

Discuss how electrophoresis can be used to identify abnormal hemoglobin.

Electrophoresis is a laboratory technique that separates hemoglobin types based on their size and charge. This allows for the identification of abnormal hemoglobin variants, including those associated with hemoglobinopathies.

Compare the relative positions of hemoglobin C, S, F and A in alkaline vs acid electrophoresis.

In alkaline electrophoresis, hemoglobin A migrates the farthest towards the anode, followed by F, C, and S; in acid electrophoresis, hemoglobin S migrates the farthest, with C migrating slower than A and F.

Describe the sickle cells preparation and the dithionite tube test for sickle cell anemia.

Sickle cell preparation involves mixing a blood sample with a reducing agent to promote the sickling of red blood cells. At the same time, the dithionite tube test uses dithionite to induce sickling and assess the presence of hemoglobin S in a sample.

Compare sickle cell prep/dithionite tube test results for each of the hemoglobinopathies.

The sickle cell preparation involves mixing a blood sample with a reducing agent, such as dithionite, which allows the observation of sickled red blood cells, indicating sickle cell anemia. In the dithionite tube test, normal hemoglobin remains soluble while sickle cell hemoglobin precipitates, confirming the diagnosis.

Describe the term hemoglobin M and explain its clinical importance.

Hemoglobin M is an abnormal form of hemoglobin resulting from mutations that cause higher stability in the Ferric state. Clinically, it can lead to cyanosis and other symptoms due to its reduced oxygen-carrying capacity.

Recall the hemoglobinopathy that occurs most frequently in the U.S.

Sickle cell disease, which is characterized by abnormal hemoglobin S.

Define the term ‘thalassemia’ and describe the clinical and laboratory findings in each of the following:

a. Beta thalassemia major

b. Beta thalassemia minor

c. Alpha thalassemia (silent carrier, trait, HbH disease and homozygous)

Thalassemia is a group of inherited blood disorders characterized by reduced or absent production of hemoglobin chains. Clinical findings include anemia, splenomegaly, and specific laboratory findings such as microcytic hypochromic red blood cells and elevated fetal hemoglobin in beta thalassemia major; minimal symptoms in beta thalassemia minor; and varying degrees of anemia in alpha thalassemia carriers, with complications in HbH disease and in homozygous forms.

Describe the globin chains present in each of the following:

a. Beta thalassemia major

b. Beta thalassemia minor

c. Alpha thalassemia (silent carrier and trait)

d. HbH disease

e. Homozygous alpha thalassemia

In beta thalassemia major, there is absent or severely reduced production of beta globin chains, leading to an excess of alpha chains. In beta-thalassemia minor, reduced beta-globin chain production results in excess alpha chains. In alpha thalassemia, silent carriers and trait carriers have reduced alpha-globin chain production, with varying degrees of chain imbalance. HbH disease features a significant decrease in alpha-globin chains, leading to an excess of beta-globin chains. Homozygous alpha thalassemia results in the absence of alpha chains, producing incompatible levels of gamma chains.

Recall the morphological class of anemia associated with thalassemia.

Thalassemia is associated with microcytic hypochromic anemia, characterized by smaller-than-normal red blood cells and decreased hemoglobin content.

Summarize characteristics of hemoglobin F.

Hemoglobin F (fetal hemoglobin) is the primary hemoglobin produced during fetal development, consisting of two alpha and two gamma chains. It has a higher affinity for oxygen compared to adult hemoglobin, facilitating oxygen transport from the mother to the fetus.

Compare the presence of HbF in HPFH vs. that of thalassemia.

Elevated levels of HbF characterize hereditary persistence of fetal hemoglobin (HPFH), while thalassemia typically shows reduced HbF levels due to impaired globin chain production.

Explain the purpose and principle of the Kleihauer Betke test.

The Kleihauer-Betke test is used to detect and quantify fetal hemoglobin in maternal blood, helping to assess fetal-maternal hemorrhage. It uses an acid elution technique to differentiate fetal red blood cells from maternal red blood cells based on their resistance to acid.

Categorize as to their morphological classification each of the hemoglobinopathies and thalassemia.

Hemoglobinopathies and thalassemias can be classified into various morphological types based on the structural abnormalities of the hemoglobin molecule and the patterns of hemoglobin production. This includes alterations such as sickle cell disease, beta-thalassemia, and alpha-thalassemia, which affect red blood cell morphology as seen in blood smears.

Summarize the most characteristic findings for each of the anemias studied in this lesson.

Characteristic findings include microcytic hypochromic anemia in iron deficiency anemia, normocytic anemia in acute blood loss, and megaloblastic anemia featuring macrocytic cells, often due to vitamin B12 or folate deficiency.