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Flashcards in Sickle Cell Disease Deck (11):

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


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



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)


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


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


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


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


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


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


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.


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