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Flashcards in Sickle Cell Disease Deck (11):
1

Describe the structure of hemoglobin.

  • Hemoglobin consists of 2 alpha and 2 beta globin polypeptide chains
  • A heme group, composed of an iron complex within a protoporphyrin ring (ferroprotoporphyrin IX) is linked covalently at a specific site to each chain (see figure)
  • In the reduced or ferrous state, the heme group binds reversibly to gaseous ligands such as oxygen or carbon monoxide

2

How is the hemoglobin gene expressed? What are its components?

  • In humans, 2 gene clusters direct the production of hemoglobin during fetal and postnatal development (see figure)
  • Alpha locus, which consists of the embryonic z gene and 2 adult a genes
  • Beta locus, which consists of the embryonic e gene as well as the Gg, Ag, d and b genes
  • Both loci are controlled by major regulatory elements located upstream of the structural genes

 

3

What is hemoglobin switching and what are the resulting phenotypes?

  • Two major globin gene switches occur in development, the embryonic to fetal switch and the fetal to adult switch
  • This occurs at 2 important gene clusters that regulate the production of the globin chains that comprise hemoglobin:
    • b-globin gene locus on chromosome 11
    • a-globin gene locus on chromosome 16
  • Genes are arranged in the order of expression during embryonic, fetal and postnatal development
    • After early embryonic development, a globin gene expression predominates on the a locus
    • However, genes at the b locus are expressed differentially throughout early development and the postnatal period and continue to be expressed into adulthood
  • Importantly, b globin gene expression does not occur until the postnatal period
  • Isoforms that are formed from the expression of genes in the b locus other than the b gene also represent functional hemoglobins.  Distribution of hemoglobin in children over 6 months of age and adults follows the usual pattern:
    • Hemoglobin A (a2b2): 90 to 97%, adult hemoglobin (HbA)
    • Hemoglobin F (a2g2): ~1%, fetal hemoglobin (HbF)
    • Hemoglobin A2 (a2d2): ~2% (HbA2)

4

What are the most common hemoglobin mutations and what are the associated conditions?

  • More than 500 structural hemoglobin variants have been discovered to date through population surveys, most of which are not clinically relevant
    • point mutations
    • nucleotide insertions
    • deletions
    • crossovers
  • These mutations may affect hemoglobin solubility, synthesis or oxygen affinity, and the resulting hemoglobin disorders are often classified into the following:
    • Sickle cell syndromes (clinically most relevant) ® Hb SS, SC, S/b thalassemia
    • Structural mutants resulting in thalassemia phenotype ® Hb E, Lepore, Constant Spring
    • Unstable hemoglobins ® over 100 described, may result in congenital Heinz body hemolytic anemia
    • Hemoglobins with abnormal affinity for oxygen ® may result in low and high affinity oxygen binding

5

What kind of mutation leads to sickle cell disease?

  • Sickle cell disease (SCD) is the most clinically important hemoglobinopathy in the US
  • A single nucleotide substitution (GTG for GAG) in the 6th codon of the b globin gene results in the replacement of glutamic acid by valine
    • The mutant globin chain is referred to as bS globin
  • The regions with the highest prevalence of sickle cell trait correspond to areas endemic for malaria, suggesting a protective effect against malaria as a result of the mutation
  • The mutation is an example of balanced polymorphism since the heterozygous state has a protective effect against endemic malaria but the homozygous state is associated with premature death from complications related to the disease

6

What is the epidemiology of sickle cell disease?

  • The scope of African-Americans affected by SCD in the United States is large
  • One in 12 is a carrier for the sickle cell trait
  • One in 500 births is affected by SCD, accounting for approximately 75,000 to 80,000 people currently with the disease

7

What is the phenotypic outcome results from the sickle cell hemoglobin mutation?

  • Intracellular polymerization of sickle hemoglobin (Hb S) under deoxygenated state is the primary event in the pathogenesis of SCD
  • Process is dependent on the following intracellular factors:
    • Hb S concentration: correlation exists between gelation and Hb S concentration
    • Oxygenation status: polymerization occurs only during deoxygenated state
    • Concentration of other non-sickle Hb: Hb F, A and A2 have direct inhibitory effect
    • Cation homeostasis and hydration status:  activated K+ efflux channel (Gardos) and KCl- co-transporter promote polymerization
    • pH concentration: solubility of deoxygenated Hb S is lowest between 6.0 and 7.2

8

What is the implication of heterozygosity for sickle cell? What are the common genotypes that lead to clinically significant sickling syndromes?

  • Heterozygosity for the sickle mutation (sickle cell trait) is clinically insignificant for the most part
  • SCD encompasses all genotypes in which at least one b globin gene carries the sickle mutation
  • The most common genotypes that result in clinically significant sickling syndromes include homozygous SCD or compound heterozygous states in which the sickle cell mutation is co-inherited with either the HbC mutation or a b thalassemia mutation
    • Hb C is the result of another single nucleotide substitution at the 6th codon of the b gene that results in the replacement of lysine for glutamine acid
    • Hb C induces relative intracellular dehydration and precipitates sickling in the presence of Hb S
  • Any mutation in the b gene that results in decreased or absent production of b chains and thus, a thalassemia phenotype, may also precipitate sickling in the presence of Hb S
  • Although there are exceptions, the following genotypes are listed in their usual order of clinical severity:
    • Hb SS disease
    • Hb S/b0 thalassemia
    • Hb SC disease
    • Hb S/b+ thalassemia

9

What is the pathophysiology of sickl cell disease?

  • Decreased solubility of Hb S under hypoxic conditions and increased polymerization result in the classic “sickle form”
    • This is due to deoxygenated Hb S polymers that form highly ordered fiber aggregates, elongate the cell and distort it
  • Sickle red blood cells are prone to hemolysis and have a shortened life span, resulting in anemia
  • Because of decreased deformability, sickle cells also cause vaso-occlusion, mostly in the post-capillary venules (log jamming effect).
  • Vaso-occlusion due to red blood cell adhesion is the classic pathophysiologic process in SCD but may be affected by the following additional factors:
    • Inflammation and abnormal leukocyte-endothelial interactions
    • Platelet activation and trapping
    • Nitric oxide dysregulation and abnormal vasomotor tone
    • Damaged endothelium and coagulation activation
    • Reperfusion injury and oxidative stress

10

How is sickle cell disease diagnosed?

  • SCD may be diagnosed at birth by abnormal testing on mandatory newborn state screening
  • In older children, anemia and reticulocytosis develops by 4 to 6 months of age
  • The clinical manifestations of SCD comprise a spectrum of complications that result from vaso-occlusion and affect virtually every organ
  • Pain episodes, which result from bone infarction and may be severe, represent the hallmark of SCD and occur throughout all age groups
  • Functional asplenia and infection with encapsulated organisms also remain lifelong risks
  • Other early complications include:
    • acute chest syndrome
    • splenic sequestration
    • stroke and aplastic crises (due to parvovirus B19 infection)
  • Late complications and end organ damage resulting in:
    • avascular necrosis
    • retinopathy
    • gallstones
    • renal insufficiency
    • cardiopulmonary disease
  • Late complications mostly in adulthood, although they may appear in late childhood.

11

What is the treatment of sickle cell disease?

  • The treatment of SCD consists mostly of supportive measures, which includes:
    • judicious use of oxygen
    • increased hydration
    • pain medications
    • blood transfusions
    • antibiotics when needed
  • Agents aimed at increasing Hb F production, such as hydroxyurea, are currently used in patients with severe disease to modify the pathophysiologic process in SCD
  • Stem cell transplant remains the only curative option to date, although factors such as availability of appropriate donors remain an important obstacle