Congenital Hemolytic Anemias Flashcards Preview

Heme/Onc > Congenital Hemolytic Anemias > Flashcards

Flashcards in Congenital Hemolytic Anemias Deck (10):

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


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


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


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


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


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


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


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


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


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