Congenital Hemolytic Anemias Flashcards Preview

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Flashcards in Congenital Hemolytic Anemias Deck (10):
1

Describe the important features of the RBC membrane.

  • The highly organized RBC membrane has evolved over time to allow the RBC to traverse the microcirculation while keeping its structural integrity (see figure)
  • The membrane is composed of a fluid lipid bilayer that makes up almost 50% of the RBC membrane and contains both free cholesterol and phospholipids
  • A two-dimensional network of skeletal and transmembrane proteins is also a major part of the membrane
  • Maintaining membrane cohesion and mechanical stability within the membrane is essential for the RBC to undergo the necessary shape changes during its long circulatory lifespan

2

What are the most important proteins of the RBC membrane and what happens when these are disrupted?

  • The most important skeletal proteins, which interact at the membrane surface only, are spectrin, ankyrin and protein 4.2
  • The principal transmembrane protein, which traverses the lipid bilayer, is band 3
  • Mutations in various membrane and skeletal proteins that result in either decreased membrane cohesion or mechanical instability lead to:
    • membrane surface area loss
    • decreased red cell life span
    • anemia in a variety of inherited red cell membrane disorders
  • The most common RBC membrane disorders are:
    • hereditary spherocytosis (HS)
    • hereditary elliptocytosis (HE)
    • hereditary pyropoikilocytosis (HPP)
    • Southeast Asian ovalocytosis (SAO)
  • Diagnosis is based largely upon clinical features and morphological characteristics on examination of the peripheral blood smear

3

Describe the pathophysiology and presentation of Hereditary spherocytosis? What is the treatment?

  • Hereditary spherocytosis is the most common inherited RBC membrane disorder, affecting up to 1 in 3000 individuals of northern European descent
  • In over 75% of cases, the disorder is inherited in an autosomal dominant fashion
  • Mutations that result in ankyrin deficiency account for the majority of cases in hereditary spherocytosis, followed by spectrin and less commonly, band 3 deficiency
    • Deficiencies in these proteins lead to:
      • loss of mechanical stability, membrane loss and formation of spheroid, fragile RBCs that are selectively trapped in the spleen and undergo hemolysis
  • Clinically, typical hereditary spherocytosis results in:
    • variable degrees of anemia
    • jaundice
    • gallstones
    • splenomegaly
  • Treatment includes supportive therapy, transfusions as needed and splenectomy

4

What is the pathophysiology and presentation of hereditary elliptocytosis? How is this different from hereditary pyropoikilocytosis?

  • Found most commonly in individuals of African or Mediterranean descent
  • Hereditary elliptocytosis and its variants are most commonly inherited in autosomal dominant fashion
    • Hereditary elliptocytosis is a both a genetically and clinically heterogeneous disorder
    • Most commonly, mutations that lead to a spectrin deficiency result in weakened lateral linkages to the skeletal membrane, a mechanistically unstable membrane and formation of elliptocytes
  • Hereditary elliptocytosis ranges in clinical severity from asymptomatic carrier state to severe, life threatening anemia
  • Hereditary pyropoikilocytosis is a clinically severe variant resulting from thermal sensitivity of the RBCs

5

What is the pathophysiology and presentation of Southeast Asian ovalocytosis?

  • Autosomal dominant disorder found most commonly in malaria endemic areas
  • A single gene mutation resulting in band 3 deficiency is the only known cause of Southeast Asian ovalocytosis
    • This band 3 mutation leads to marked rigidity of the RBC membrane and the disorder’s morphological RBC features, yet it results in minimal to almost no hemolysis and anemia

6

What are the major RBC metabolic pathways?

  • Due to their lack of nuclei and mitochondria, RBCs must rely on 2 major metabolic pathways, the pentose phosphate shunt and glycolysis, to ensure they meet the metabolic requirements for sustaining their intravascular life cycle (see figure)
    • The pentose phosphate shunt relies on the breakdown of glucose to generate reducing potential, in the form of NADPH, for protecting the RBC against oxidative stress
      • In the oxidative phase of this reaction, the enzyme glucose-6-phosphate dehydrogenase (G6PD) plays a major role in the conversion of glucose-6-phosphate to generate NADPH equivalents
  • Mature red blood cells are incapable of producing energy through the normal oxidative pathways (Kreb cycle) due to the absence of nuclei and mitochondria
  • Instead, red blood cells depend on glycolysis, which is the anaerobic conversion of glucose by the Embden-Meyerhof pathway, for the generation and storage of high-energy phosphates
    • The veolocity of glycolysis depends in part on 3 major rate-limiting enzymes in the pathway:
      • hexokinase
      • phosphofructokinase
      • pyruvate kinase

7

What is the underlying pathophysiology of most red blood cell enzyme deficiencies? How is this diagnosed?

  • Abnormalities that result in RBC enzyme deficiencies, known as RBC “enzymopathies”, are associated with phenotypic variability
  • The lack of characteristic morphological changes in the RBC differentiates this group of disorders from RBC membrane disorders and disorders of hemoglobin
  • In general, red blood cell enzyme disorders cause chronic non-spherocytic hemolytic anemia (CNSHA)
    • The lack of sufficient energy and other metabolic derangements result in shortened lifespan of the mature RBC
    • The degree of hemolysis is variable and dependent on the relative importance of the affected enzyme and the functional properties of the variant enzyme
  • Diagnosis is made upon quantifying specific enzyme activity in the RBC in setting of clinical suspicion

8

Describe the mechanism and presentation of G6PD deficiency. What is the treatment?

  • Represents one of the most common hematological disorders worldwide, caused by more than 300 variants in the G6PD gene that encodes the enzyme
    • A major role of the enzyme is to help generate NADPH for the reduction of glutathione
    • Reduced glutathione ensures that the RBC is protected from oxidative stress
    • This process is variably impaired depending on the specific genetic mutation, rendering the RBC susceptible to oxidation-induced hemoglobin damage
  • The G6PD gene is encoded on the X chromosome, and thus, inheritance is X-linked
    • Although males are most severely affected, female carriers may exhibit symptoms in the setting of lyonization
  • Most clinically important variants result in acute intermittent hemolysis
  • Oxidative stress and triggers (e.g. infections, certain foods and medications) may result in:
    • fever
    • GI symptoms
    • jaundice
    • hematuria
    • variable degrees of anemia
  • Treatment is supportive but may include transfusion therapy for severe, life-threatening anemia

9

Describe the mechanism and presentation of Pyruvate kinase (PK) deficiency. What is the treatment?

  • Most common cause of non-spherocytic hemolytic anemia due to defective glycolysis in the Caucasian population
  • PK deficiency results in 2 major metabolic derangements, ATP depletion and an increase in 2,3-diphosphoglycerate (DPG) production
    • Importantly, an increase in RBC 2,3-DPG content leads to a rightward shift in the oxygen dissociation curve, thus ameliorating the impact of anemia by facilitation oxygen delivery
  • PK deficiency is inherited in an autosomal recessive manner and results in:
    • variable anemia
    • jaundice
    • splenomegaly
  • As with hereditary spherocytosis and other RBC enzyme deficiencies, a history of hyperbilirubinemia is common in the neonatal period
  • Affected adults are at risk for developing gallstones and leg ulcers
  • Treatment involves transfusion support as needed as well as splenectomy

10

What are some less common enzyme deficiencies that can cause RBC dysfunction?

  • A number of other clinically important RBC disorders result from deficiencies of enzymes in the Embden-Meyerhof pathway
  • These result from deficiencies of major pathway enzymes, including:
    • hexokinase
    • aldolase
    • glucose-6-phosphate isomerase
    • triosephosphate isomerase
    • phosphoglycerate kinase
  • In general, these disorders of glycolysis are inherited in an autosomal recessive manner and result in various degrees of non-spherocytic hemolytic anemia