Overview of Hemoglobinopathies

Hemoglobinopathies Overview

• Hemoglobinopathies are disorders involving the production of normal adult hemoglobin, which is either partially or completely suppressed, or replaced by a variant hemoglobin.

Hemoglobin Structure and Types

• Hemoglobin consists of globin chains and heme units with iron atoms.
• Adult hemoglobin (HbA) is composed of two alpha and two beta chains (α₂β₂).
• Fetal hemoglobin (HbF), prevalent in newborns, has two alpha and two gamma chains (α₂γ₂).
• HbA₂ is a minor component with two alpha and two delta chains (α₂δ₂).
• HbA1c shows attached glucose residues, its levels increase in diabetes.

Classification of Hemoglobinopathies

• Qualitative: Hemoglobinopathies where the amino acid sequence of the globin chain is different from the normal hemoglobin, e.g., sickle cell anemia.
• Quantitative: Hemoglobinopathies with decreased hemoglobin due to reduced synthesis of a specific globin chain, e.g., thalassemia.

Sickle Cell Anemia and Sickle Cell Trait

• Sickle cell anemia is an inherited, autosomal recessive disorder.
• HbS results from a point mutation causing valine to substitute for glutamic acid in the beta-globin chain.
• Sickle cell trait (AS) has both HbA and HbS.
• Individuals with sickle cell anemia (SS) are homozygous for HbS and have severe anemia.
• Sickling occurs when oxygen levels decrease; cells become rigid and block blood flow causing pain, tissues, and organs damage.
• Individuals with sickle cell trait (AS) have increased resistance to malaria.
• HbS differs in the amino acid sequence of the beta-globin chain (Valine replacing Glutamic acid).
• Sickle cell anemia is diagnosed by electrophoresis.
• Sickle cells show on blood film.
• Sickling is reversible, but reduced oxygen levels trigger the process.
• Pathophysiology includes decreased oxygen, pH, high altitude, high CO2, and dehydration of patient.

Clinical Findings in Sickle Cell Anemia

• Clinical signs appear at 6 months old.
• Patients experience symptoms of anemia, slowed growth and sexual maturity, painful crises triggered by deoxygenation (exercise, illness).
• Sickle cells clog small capillaries and lead to tissue damage, organ infarction, and pain.

Sickle Cell Anemia: Affected Organs

• Organs like the liver, heart, spleen, skin, kidney, and lungs may be affected, showing enlargement, malfunction, jaundice (hyperbilirubinemia), ulcers, infiltrations leading to fibrosis and organ failure.

Special Hematological Tests in Sickle Cell Anemia

• Electrophoresis on cellulose acetate shows the presence of HbS, ranging from 85% to 100%.
• Decreased osmotic fragility is observed in blood samples.

Chemistry Tests in Sickle Cell Anemia

• Bilirubin levels are elevated due to hemolysis.
• Decreased haptoglobin levels are common.

Sickle Cell Anemia: Treatment

• Infection prevention is crucial.
• Organ damage reduction is achieved through Hydroxyurea which increases fetal hemoglobin (HbF), chemotherapeutic agents and avoiding crisis-inducing scenarios.
• Pain management, through measures like blood transfusion

Median Age at Death

• Median age at death in male sickle-cell anemia patients is 42 and 48 for females.

Sickle Cell Trait

• Heterozygous AS, with more HbA than HbS, compensated for, normal life span.
• Usually asymptomatic, occasional hematuria episodes.
• Sickling occurs under drastic oxygen reduction conditions, such as severe respiratory infection, air travel, anesthesia, or congestive heart failure.
• Exercise that leads to lactic acid buildup causes sickling due to decreased pH.

Lab Features of Sickle Trait

• Normal complete blood count (CBC), although some target cells or sickle cells may appear.
• Electrophoresis reveals presence of both HbA and HbS.

HbC (glu→lys)

• Rare patients homozygous for HbC show a mild chronic hemolytic anemia without infarctive crises.
• If HbC and HbS are present, the resultant sickling disorder resembles homozygous HbS disease yet is less frequent and severe.

Methemoglobinemia (Hb M)

• Oxidation of hemoglobin's heme component to Fe3+ forms methemoglobin (cannot bind oxygen).
• This is caused by drugs such as nitrates or endogenous products (reactive oxygen intermediates).
• Characterized by "chocolate cyanosis", in which the skin and mucous membranes brown/bluish, with chocolate-colored blood.

Causes of Methemoglobinemia

• Certain drugs including various antibiotics (trimethoprim, sulfonamides, dapsone), local anesthetics (articaine, benzocaine, prilocaine), aniline dyes, and some chemicals like chlorates, bromates, and nitrites.
• Nitrates, often used in fertilizers are suspected causes, given the risks of contaminating water sources.

Treatment of Methemoglobinemia

• Methylene blue is used to treat methemoglobinemia. It functions as an electron shuttle, enabling NADPH to reduce methemoglobin, potentially reducing methemoglobin to the ferrous form.

Thalassemia

• Thalassemia results from abnormalities in hemoglobin synthesis.
• Effects both alpha and beta globin clusters.
• Deficiencies in Beta-globin synthesis result in beta-thalassemia. Deficiencies in alpha globin result in alpha-thalassemia.

Thalassemia: Cause and Types

• β-thalassemias result from decreased or absent production of β-globin chains due to mutations.
• a-thalassemias result from decreased or absent production of a-globin chains due to deletions or mutations. This involves inactivation of 1 to all 4 a-globin genes.

Thalassemia: Effect

• β-thalassemia major: Patients require frequent blood transfusions for survival.
• β-thalassemia minor: Heterozygous β-thalassemia; individuals have compromised β-globin synthesis.
• The clinical situation worsens if only one a-globin gene is operational causing a severe disease HbH disease (HbH).
• If no a-globin is functional, fetal death or prenatal loss can occur due to lack of oxygen carrying capacity

Thalassemia: Clinical Manifestations (General)

• At birth, most thalassemias are asymptomatic but can develop severe anemia after birth with slowed growth and malnutrition, thinner bone cortices and increased rate of fractures.
• Hepatosplenomegaly (enlarged liver and spleen) occurs because the organs try to increase hematopoiesis to compensate for the anemia.
• Frequent infections are common due to suppressed immune systems from the disease and anemia. Anemia results and causes organ failure in the long term from accumulations of iron from transfusions.

a-thalassemias: Various States

• Silent carrier: 3 of the 4 a-globin genes are functional, asymptomatic.
• a-thalassemia trait - 2 of the 4 a-globin genes are functional, mild anemia.
• HbH disease - 1 a- globin gene is functional, resulting in mild to moderate anemia.
• Hydrops fetalis: No a-globin genes are functional, severe, usually fatal.

This quiz covers hemoglobinopathies, including their structure, types, and classifications. It highlights the differences between qualitative and quantitative disorders, such as sickle cell anemia and thalassemia. Test your knowledge on the composition and implications of various hemoglobin types.