W1-10 Hemogloinopathies and associated anemias

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Which of the following is the underlying mutation in HbC disease?

Point mutation (Glu —> Val at amino acid 6) in β-globin (HBB) gene

What is the major cause of pathogenesis in sickle cell disease?

Polymerization of deoxygenated HbS

What type of anemia is sickle cell disease?

Normocytic hemolytic anemia with extravascular hemolysis

Which population is primarily affected by sickle cell disease?

African Americans

What is the genetic nature of sickle cell disease?

Autosomal recessive disorder

What proportion of sickled RBCs undergo intravascular hemolysis?

A small proportion

Which condition is characterized by the loss of three α-globin genes, relative excess of β-globin chains, and the formation of stable β4 tetramers?

HbH disease

What is the consequence of deletion of all four α-globin genes?

Lethal in utero due to virtually no oxygen-delivering capacity

In which condition does the excess in γ-globin chains lead to the formation of γ4 tetramers (Hb Barts)?

Hydrops fetalis

Which condition is characterized by the proportional severity of the disease to the number of missing α-globin genes?

Silent carrier state

Which test is considered the best for diagnosing sickle cell disease?

High performance liquid chromatography (HPLC)

What is the characteristic feature seen in HbC disease on peripheral blood smear (PBS)?

HbC crystals

What is the clinical behavior of HbSC disease?

Similar to sickle cell anemia (SCA) but with a milder clinical course

What demographic is endemic for thalassemias?

Mediterranean, African, and Asian regions

Which type of thalassemia is characterized by decreased/absent α-globin chains with excess of β-globin chains?

Alpha-thalassemia

What is the primary mechanism of anemia in β-thalassemia?

Inadequate HbA formation

What is the characteristic feature of HbC disease in terms of erythrocyte morphology?

Target cells with increased MCHC

Which test is used in review books but is not clinically indicated for screening or managing sickle cell disorders?

"Sickledex" sodium metabisulfite test

What does the presence of Howell-Jolly bodies in patients with sickle cell anemia indicate?

Hyposplenism or autosplenectomy

What is the result of a high serum bilirubin level in patients with sickle cell anemia?

Intravascular hemolysis

What feature distinguishes HbSC disease from sickle cell anemia (SCA)?

Presence of nucleated RBCs in peripheral blood smear (PBS)

What is the primary consequence of excess unpaired α-chains in β-thalassemia?

Production of insoluble hemoglobin precipitates

What is the primary event in the pathogenesis of β-thalassemia?

Destruction of erythroid precursors

In β-thalassemia, what results in extensive extramedullary hematopoiesis and hepato- and splenomegaly?

Erythroferrone release

What is the genetic basis for the clinical classification of β-thalassemia?

Severity of anemia and gene defect

Which type of β-thalassemia is characterized by severe anemia but does not require regular blood transfusions?

β-thal intermedia

What is a characteristic morphological change in the peripheral blood smear (PBS) of β-thalassemia major?

Microcytic, hypochromic cells with basophilic stippling

What is a common complication in β-thalassemia that leads to 'bronze diabetes'?

Secondary hemochromatosis

What is the cause of α-thalassemia?

Deletion of one or more α-globin genes

In α-thalassemia, which type of genetic deletion results in the most severe manifestations?

-- -- -- +

What type of hemoglobin is predominant in normal adult individuals?

HbA/HbA

Which type of Hb spectrum (%) is characteristic of sickle cell trait?

HbA/HbS

What are the predominant types of hemoglobin in sickle cell trait?

HbS/HbC

What is the most common manifestation of vaso-occlusion in sickle cell disease?

Acute chest syndrome

What is the primary cause of death in children with sickle cell disease?

Infection with encapsulated bacteria

What does the presence of Howell-Jolly bodies on peripheral blood smear indicate in sickle cell disease?

Autosplenectomy

What is the common cause of death in adults with sickle cell disease?

Acute chest syndrome

What condition results from the infection of red cell progenitors by parvovirus B19 in sickle cell disease?

Aplastic crisis

Which manifestation in sickle cell disease is characterized by rapid splenic enlargement, hypovolemia, and shock?

Sequestration crisis

What is the primary cause of chronic anemia in sickle cell anemia?

Irreversible sickled RBCs

Which type of crisis in sickle cell disease is associated with an acute drop in hemoglobin and high reticulocyte count?

Hyperhemolytic crisis

What is the characteristic bone change seen in individuals with sickle cell anemia?

"Crew-cut" appearance on skull x-ray

"Dactylitis" (hand-foot syndrome) in infants with sickle cell disease is characterized by:

Bone infarcts with swelling of hands and feet

What is the primary consequence of deletion of all four α-globin genes?

Excess of γ-globin and formation of γ-globin tetramers (Hb Barts)

What is the characteristic morphological change in the peripheral blood smear (PBS) of HbH Disease?

HbH aggregates

What condition results from a decline in Hb Portland production in Trimester 3?

Hydrops fetalis

Which manifestation is characteristic of Hb Barts Disease?

Severe pallor, generalized edema, and massive hepatosplenomegaly

What is the clinical presentation of α-Thal: Hb Barts Disease (-/- -/-)?

Severe pallor, generalized edema, and massive hepatosplenomegaly

What does the excess in γ-globin chains lead to in Hb Barts Disease?

Formation of γ-globin tetramers (Hb Barts)

What is the primary mechanism of anemia in β-thalassemia?

Reduced hemoglobin synthesis

What is the characteristic bone change seen in individuals with sickle cell anemia?

Avascular necrosis of the hip

What is the consequence of deletion of all four α-globin genes?

Hydrops fetalis

Which condition exhibits manifestations similar to β-thalassemia minor?

Alpha-thalassemia trait

What is the genetic nature of sickle cell disease?

Autosomal recessive

What is the clinical behavior of HbSC disease?

More severe than HbAS but milder than HbSS

Which type of crisis in sickle cell disease is associated with an acute drop in hemoglobin and high reticulocyte count?

Aplastic crisis

What is the common cause of death in adults with sickle cell disease?

Acute chest syndrome

Which type of thalassemia is characterized by decreased/absent α-globin chains with excess of β-globin chains?

Beta-thalassemia minor

What is the primary event in the pathogenesis of β-thalassemia?

Reduced hemoglobin synthesis

What demographic is endemic for thalassemias?

Mediterranean and Southeast Asians

Which population is primarily affected by sickle cell disease?

Africans and African Americans

Which type of hemoglobin is predominant in normal adult individuals?

HbA

What is the primary cause of chronic anemia in sickle cell anemia?

Vaso-occlusion

What is the genetic basis for the clinical classification of β-thalassemia?

Reduced expression of beta-hemoglobin

What feature distinguishes HbSC disease from sickle cell anemia (SCA)?

Different types of hemoglobin present

What is the primary pathophysiological mechanism in β-thalassemia major?

Severely reduced production of β-Hb chains

In β-thalassemia, what is the specific consequence of the surplus of β-like chains?

Formation of homo-tetramers

What is the characteristic phenotype of HbE/HbE homozygotes?

Mild hypochromic, microcytic anemia

Which type of thalassemia exhibits a mixed process as it changes both the content and amount of protein?

HbE/ -thalassemia compound heterozygotes

What is the primary consequence of deletion of all four α-globin genes?

Surplus production of γ-Hb chains

What is the underlying mutation in HbC disease?

Substitution GAG-to-AAG in codon 26 leading to Glu26Lys

What is the characteristic feature seen in HbC disease on peripheral blood smear (PBS)?

Presence of Howell-Jolly bodies

Which condition results from the infection of red cell progenitors by parvovirus B19 in sickle cell disease?

-Thalassemia trait

Study Notes

  • The text discusses sickle cell disease (SCD) and associated anemias, with a focus on sickle cell disease, HbC disease, and β- and α-thalassemia.
  • Sickle cell disease is a normocytic hemolytic anemia with extravascular hemolysis, affecting African Americans and caused by a point mutation in the β-globin gene (HBB).
  • The disease results from the formation of sickle polymers when HbS deoxygenates, leading to sickled RBCs and various complications.
  • Sickle cell anemia (homozygosity) presents with severe anemia, irreversible sickled RBCs, and frequent crises, while sickle cell trait (heterozygosity) is usually asymptomatic.
  • Enhancing factors for sickling include hypoxia, dehydration, acidosis, and high altitude, while preventive factors include HbF and hydroxyurea.
  • Sickle cell disease crises include vaso-occlusive, sequestration, aplastic, and hyperhemolytic, each presenting with distinct clinical features and complications.
  • Vaso-occlusive crises result from vaso-occlusion and ischemia caused by sickled RBCs, leading to pain, infarctions, and organ damage.
  • Sequestration crisis occurs in children with an intact spleen, resulting in rapid splenic enlargement, hypovolemia, and shock.
  • Aplastic crisis is caused by infection of red cell progenitors by parvovirus B19, leading to transient cessation of erythropoiesis and worsening anemia.
  • Hyperhemolytic crisis is characterized by an acute drop in hemoglobin and high reticulocyte count, often resulting from infection or other stressors.
  • Complications of sickle cell disease include splenic infarcts, infections, and bone changes, as well as damage to various organs.
  • Treatments for sickle cell disease include supportive care, hydroxyurea, and bone marrow transplantation, while prevention includes newborn screening, gene therapy, and vaccinations.
  • SCD can lead to chronic anemia, jaundice, pigmented gallstones, and reticulocytosis, as well as crises and organ damage if left untreated.
  • HbC disease is caused by a different mutation in the β-globin gene, leading to the production of HbC and HbE, which form inclusions in RBCs.
  • β- and α-thalassemia are genetic disorders affecting the production of β- or α-globin chains, respectively, leading to various hemoglobin abnormalities and complications.

Explore the etiology, pathogenesis, morphological changes, clinical presentation, complications, laboratory data, treatment, and prognosis of sickle cell disease. Understand the implications of splenic infarct and Howell-Jolly bodies.

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