RHS18 - Red Cell Disorders 2

Question 1

Name and describe the two types of Hb defects

Answer 1

• Hemoglobinopathies - hereditary RBC disorders caused by mutations in the globin genes and leading to the production of defective Hb (e.g. - sickle cell)
• Thalassemias - hereditary RBC disorders caused by mutations in the globin genes and leading to decreased synthesis of globin chains of HbA (α-thalassemia, β-thalassemia)

Question 2

What globin chain acounts for 96% of normal adult Hb?

Answer 2

HbA

Question 3

Describe the pathogenesis of sickle cell disease.

Answer 3

1. A point mutation from GLU to VAL at position 6 in the β globin gene transforms HbA to HbS. Heterozygotes have only 50% HbS (sickle cell trait) while homozygotes have almost 100% HbS (sickle cell anemia)
2. Deoxygenated HbS molecules tend to aggregate and polymerize into long fibers that distort the shape of the RBC (sickling)
3. Originally the sickling is reversed with oxygenation but it eventually becomes permanent, making the RBC “sticky”
4. Distorted RBCs are more likely to become hemolysed and cause microvascular occlusion

Question 4

List the primary factors that affect the degree of RBC sickling in sickle cell diseases.

Answer 4

• Presence of Hb chains other than HbS
  
  • Increased presence of HbA or HbF (fetal) decreases sickling
  • Presence of HbC causes HbSC disease which increases sickling
• Concentration of HbS
  
  • Dehydration increases sickling
  • α-thalassemias decrease [Hb], decreasing sickling
• Acidity - low pH increases sickling
• Length of exposure to low O2 tension

Question 5

When do symptoms usually first to appear with Sickle Cell?

Answer 5

• For sickle cell trait (HbAS) patients are usually asymptomatic unless they are placed under severe hypoxic stress
• For Sickle Cell disease (HbSS), patients are asymptomatic until 6 months of age, when the shift from HbF to HvS is complete.

Question 6

What pathological changes are seen with sickle cell disease (HbSS)?

Answer 6

• Chronic intra- and extravascular hemolysis leading to moderate to severe anemia
• Hyperplastic changes in bone marrow which can be observed in the bony skull of children
• Splenomegaly in children that progresses into autosplenectomy (shrunken and nonfunctional) by early adulthood
• Increased Hb degredation causes hyperbilirubinemia (jaundice) and eventually can cause bilirubin gallstones.

Question 7

What is a sickle cell crisis? What usually causes them? List the types of crises

Answer 7

• An acute exacerbation of sickle cell precipitated by: infections, dehydration, exposure to cold, hypoxia, and acidosis
• Vaso-occlusive/painful cirses
• Sequestration crises
• Aplastic crises
• Hemolytic crises

Question 8

Describe what a vaso-occulsive/painful crisis is

Answer 8

• Painful (and possibly lethal) ischemic events caused by microvascular occulsion. Manifests in different ways:
  
  • Bones - dactylitis, hand-foot syndrome (very common)
  • Lungs - acute ches syndrome
  • Brain - stroke
  • Retina - proliferative retinopathy
  • Kidneys - renal infarctions
  • Penis - priapism (painful unwanted erections)
  • Leg Ulcers
• More commonly seen in children and young adults

Question 9

Describe what a sequestration crisis is

Answer 9

Massive entrapment of sickled RBCs in the spleen leading to rapid pooling of blood, causing splenomegaly, hypovolemia, and/or shock

Question 10

Describe what an aplastic and hemolytic crisis is

Answer 10

Aplastic Crisis - when the RBC progenitors are infected with parvovirus B19 causing a transient cessation of erythropoiesis and a sudden worsening of the anemia

Hemolytic Crisis - exaggeration of the hemolysis

Question 11

What are the lab findings for sickle cell disease?

Answer 11

• low CBC
• Peripheral blood - sickle cells, polychromatic cells, Howel-Jolly bodies
• Positive Sickling tests (mixing blood with an oxygen consuming substance to induce sickling)
• Hb Electrophoresis to confirm presence/percentages of HbS
• Prenatal diagnosis done by DNA screening

Question 12

What is the treatment for sickle cell disease?

Answer 12

• Supportive measures for crises - analgesics, rehydration, transfusions
• Folic acid supplementation
• Penicillin prophylaxis
• Hydroxyurea - increases amount of HbF and inhibits HbS polymerization
• Bone marrow transplantation

Question 13

What is a β-thalassemia? List the types of mutations seen in β thalassemias.

Answer 13

Diminished synthesis of structurally normal β-globin chains, with unimpaired α-chain production.

• β+ Mutations - mutations usually found in the promoter region which lead to reduced β chain synthesis
• β0 Mutations - mutations that usually affect splicing or chain termination resulting in NO β chain production

Question 14

List and describe the types fo β-thalassemia syndromes.

Answer 14

• β-thalassemia major - β0/β0, β+β+, or β+β0 - severe transfusion dependent anemia
• β-thalassemia minor/trait - β+/β, or β0/β - mild asymptomatic anemia
• β-thalassemia intermedia - any gene combination except β0/β0 or β/β that causes moderately severe anemia which does NOT require regular transfusion

Question 15

Describe the pathogenesis of β-thalassemia major

Answer 15

1. Reduced β-globin causes hypochromic microcytic anemia
2. The excess α-globin precipitates and causes reduced survival or RBCs due to membrane damage, which can result in:
   
   • Hepato- and/or spleenomegaly from extravascular hemolysis
   • Ineffective erythropoiesis with 75% of RBC precursors dying in the hyperplastic bone marrow
   • Expansion of hematopoietic marrow leading to prominent facial bones, erosion of bondy cortex, and new bone formation (refer to image)
   • Excessive dietary iron absorption and regular blood transfusions which can cause iron overload (hemosiderosis) affecting the heart liver, skin, and pancreas

Question 16

What are the lab findings for β-thalassemia major?

Answer 16

• low CBC
• Peripheral blood findings
  
  • Microcytic hypochromic anemia
  • Anisopoikilocytosis (abnormal shaped RBCs)
  • Polychromatic cells
• Hb electrophoresis
  
  • reduction of absence of HbA
  • Increased level of HbF
  • HbA2 normal or increased

Question 17

What are the clinical features of β-thalassemia minor

Answer 17

• Usually asymptomatic
• Patients have mild hypochromic microcytic anemia with normal RDW
• Hb electrophoresis shows reduced Hba, increased HbA2, ane normal to increased HbF

Question 18

What disease is it very important to not confuse with β-thalassemia minor with?

Answer 18

Iron deficiency anemia

Question 19

Wha are the primary concerns for β-thalassemia minor patients and how are these concerns prevented.

Answer 19

• Growth retardation and death - prevented with regular blood transfusions
• Cardiac failure from severe anemia (high output failure) or iron overload (cardiomyophathy) - prevented with blood transfusions and iron chelators, respectively

Question 20

What is α-thalassemia? List and describe the types of α-thalassemias.

Answer 20

Genetic deletion involving one or more of the α-globin chains

• α-thalassemia minima (silent carrier) - 1 α-gene is deleted - (α/α, α/-)
• α-thalassemia minor/trait - 2 α-genes deleted - (α/α, -/-) mainly seen in Asia, or (α/-, α/-) mainly seen in Africa. Only the asian variety can produce offspring with severe α-thalassemia
• Hemoglobin H disease - 3 α-genes are deleted (α/-, -/-)
• Hemoglobin Barts - all 4 α genes are deleted

Question 21

What are the clinical features of α-thalassemia minima and α-thalassemia minor?

Answer 21

• α-thalassemia minima (silent carrier)
  
  • Asymptomatic
  • Affected individuals aren’t even anemic or microcytic
• α-thalassemia minor
  
  • Asymptomatic
  • Mild hypochromatic microcytic anemia

Question 22

What is the pathogenesis and clinical features of Hemoglobin H disease?

Answer 22

• The excess β-globin chains form a tetramer known as HbH, which has a high affinity for O2 and is prone to oxidation
• High [HbH} concentration leads to severe tissue hypoxia
• In older RBCs, oxidized HbH precipitates into inclusion bodies that lead to increased extravascular hemolysis and moderate anemia which usually does NOT require transfusions

Question 23

What are the clinical features and pathogenesis of Hemoglobin Barts (hydrops fetalis)?

Answer 23

• The complete absence of α-globin chains means no fetal hemoglobin (HbF) can be made and the excess γ-globin chains form tetramers (γ4) called Hb Barts, which have a high O2 affinity
• Without intrauterine transfusions, the baby usually dies in utero with a massively enlarged liver and spleen (hydrops fetalis)

Question 24

What does paroxysmal mean?

Answer 24

A sudden recurrence of a disease

Question 25

Describe the pathogenesis of paroxysmal nocturnal hemoglobinuria (PNH).

Answer 25

• An acquired mutation in the X-linked PIGA gene leads to a malfunctioning phosphatidylinositol glycan class-A enzyme which synthesizes the GPI anchor that holds dozens of cell-surface proteins to the PM on hematopoietic cells.
• Three of these proteins regulate complement activity: decay-accelerating factor (CD55), membrane inhibitor of reactive lysis (CD59), and C8 binding protein.
• RBCs deficient in these proteins are lysed or injured by complements at an increased rate (intravascular hemolysis)
• Paroxysms or nocturnal hemolysis occurs in about 1/4 of PNH patients because the blood becomes more acidic during sleep, which increases complement activity

Question 26

What are the clinical feature of PNH?

Answer 26

• Typical anemia Sx
• Hemoglobinuria/Hemosiderinuria, possible causing an iron deficiency
• Pancytopenia (aplastic anemia)
• Refractory anemia
• Coombs negative hemolytic anemia
• Thrombosis (leading cause of death in PNH patients)
  
  • Platelet dysfunction
• Renal insufficiency caused by chronic hemoglobinuria

Question 27

What lab diagnositcs are used to diagnose PNH?

Answer 27

• Flow cytoemtry to check for CD55 and CD59 on blood cells
  
  • Absence of CD55 and CD59
• Fluorescent Aerolysin Cytometry (FLAER) which uses a reagent that binds directly to GPI anchors

Question 28

What is the typical treatment for PNH?

Answer 28

• Immunosuppression
• Bone marrow transplantation