Pathoma - RBC Disorders - Normocytic Anemia

Question 1

What are the two main causes of normocytic anemia and how do you differentiate them?

Answer 1

(1) Increased peripheral destruction
(2) Underproduction

Can differentiate the two via corrected reticulocyte count:
>3% = peripheral destruction
<3% = underproduction

Question 2

What do reticulocytes look like and what is the normal reticulocyte count?

Answer 2

Large cells with bluish cytoplasm due to residual RNA

Normal reticulocyte count is 1-2%

Question 3

How do you calculate corrected reticulocyte count

Answer 3

Reticulocyte count x (Hct/45)

Question 4

What is haptoglobin?

Answer 4

Protein within the blood that binds hemoglobin to bring to the spleen to recycle the iron

Question 5

What are the 2 types of peripheral RBC destruction and their clinical/laboratory findings?

Answer 5

Extravascular hemolysis (destruction of RBCs via reticuloendothelial system):

• Anemia with splenomegaly
• Jaundice due to unconjugated bilirubin
• Increased risk for bilirubin gallstones
• Marrow hyperplasia with retic count >3%

Intravascular hemolysis (destruction of RBCs within vessels):

• Hemoglobinemia
• Hemoglobinuria
• Hemosiderinuria (iron taken up by renal tubule being excreted with shedding tubular cells)
• Decreased serum haptoglobin (collects Hb within the blood to bring to the spleen)

Question 6

What is hereditary spherocytosis and what type of anemia does it cause

Answer 6

Inherited defect of RBC cytoskeleton

Causes normocytic anemia due to extravascular hemolysis

Question 7

Describe the mechanism behind RBC destruction in hereditary spherocytosis

Answer 7

Inherited defect of RBC membrane leads to blebs lost over time

Loss of membrane leads to formation of spherocytes (not enough membrane to create the normal disc shape)

Spherocytes cannot maneuver properly through spleen, so are destroyred by macrophages

Question 8

What are the clinical and lab findings in hereditary spherocytosis

Answer 8

Spherocytes with loss of central pallor

Increased RDW (increasing membrane loss over time)

Increased mean corpuscular hemoglobin concentration (MCHC) - cell shrinks but cytoplasm stays the same, leading to increased Hb concentration

Splenomegaly, jaundice, and risk for bilirubin gallstones (increased RBC destruction in the spleen)

Question 9

What is the osmotic fragility test and what does it test for?

Answer 9

Increased spherocyte fragility in hypotonic solution

Diagnostic for hereditary spherocytosis

Question 10

What is the treatment for Hereditary spherocytosis and what clinical finding is there after treatment?

Answer 10

Splenectomy

Will resolve anemia (spherocytes are functional - anemia was caused by their destruction)

Splenectomy results in Howell-Jolly bodies (RBCs with fragments of nuclear material that would usually be removed by the spleen)

Question 11

Describe the mutation in sickle cell anemia and how it results in anemia

Answer 11

Single amino acid change (from glutamic acid to valine) in the beta-chain of hemoglobin

HbS polymerizes (reversible) when deoxygenated, causing aggregation, leading to sickling of cells

Question 12

What is protective against cell sickling?

Answer 12

HbF (a2d2) and treatment with hydroxyurea, which increases levels of HbF

Question 13

How do sickle cells lead to anemia?

Answer 13

The continuous sickling and de-sickling leads to RBC membrane damage which causes:

• extravascular hemolysis
• intravascular hemolysis due to dehydration of RBCs (decreased haptoglobin and target cells)

Question 14

What are the effects of erythroid hyperplasia due to sickle cell anemia?

Answer 14

Expansion of hematopoiesis to skull (‘crewcut’ appearance) and facial bones (‘chipmunk facies’)

Extramedullary hematopoeisis with hepatomegaly

Risk of aplastic crisis with parvovirus B19

Question 15

What are the effects of vaso-occlusion in sickle cell anemia?

Answer 15

Vaso-occlusion caused by sickle cells obstructing vessels

Dactylitis (swollen hands and feet) - common presentation in infants

Autosplenectomy (due to vaso-occlusion of splenic artery)

Acute chest syndrome (vaso-occlusion of pulmonary microcirculation)

Pain crisis

Renal papillary necrosis (resulting in gross hematuria and proteinuria)

Question 16

What is the most common cause of death in adults and children with sickle cell disease?

Answer 16

Children - infection with encapsulated organisms due to autosplenectomy

Adults - acute chest syndrome

Question 17

What is the metabisulfite screen?

Answer 17

Causes cells to sickle with any amount of HbS

Will be positive in disease and in trait

Usually cells do not sickle with trait because RBCs need > 50% HbS in order to sickle

Question 18

What will Hb electrophoresis reveal in sickle cell disease and trait?

Answer 18

Disease:
90% HbS; 8% HbF; 2% HbA2; No HbA

Trait:
55% HbA; 43% HbS; 2% HbA2

Question 19

What is the mutation in Hemoglobin C?

Answer 19

Single amino acid mutation (from glutamic acid to lysine) in the beta globin chain

Question 20

What are the effects of Hemoglobin C

Answer 20

Mild anemia due to extravascular hemolysis

Characteristic HbC crystals

Question 21

What are some of the causes of anemia caused by intravascular hemolysis?

Answer 21

Paroxysmal nocturnal hemoglobinuria

G6PD Deficiency

Immune hemolytic anemia

Microangiopathic hemolytic anemia

Malaria

Question 22

What is paroxysmal nocturnal hemoglobinuria (PNH)

Answer 22

Acquired defect in myeloid stem cells resulting in absent GPI (which is the anchoring protein for surface receptors that protect RBCs against complement)

Question 23

Why does intravascular hemolysis occur at night in paroxysmal nocturnal hemoglobinuria?

Answer 23

Shallow breathing at night leads to mild respiratory acidosis, which activates complement

Question 24

What test confirms the diagnosis of paroxysmal nocturnal hemoglobinuria?

Answer 24

Flow cytometry detecting lack of CD55 (aka DAF)

DAP and MIRL are the surface proteins that usually bind to GIP to protect against complement

Question 25

What is the main cause of death in paroxysmal nocturnal hemoglobinuria?

Answer 25

Thrombosis

GIP is deficient on platelets as well, so when platelets are destroyed by complement they can activate the coagulation cascade

Question 26

How does G6PD deficiency result in anemia?

Answer 26

G6PD produces NADPH, which is necessary to reduce glutathione

Reduced glutathione is needed to neutralize H2O2 in order to prevent oxidative injury and intravascular hemolysis of RBCs

Question 27

What are the two major variants of G6PD deficiency?

Answer 27

African variant - mildly reduced half-life of G6PD (mild intravascular hemolysis)

Mediterranean variant - markedly reduced half-life of G6PD (marked intravascular hemolysis)

Question 28

What is the effect of oxidative stress in G6PD deficiency?

Answer 28

Oxidate stress causes precipitation of Hb as Heinz bodies

Heinz bodies are removed from RBCs by splenic macrophages, resulting in bite cells

Question 29

Where is the body does IgG-mediated immune hemolytic anemia occur and what type of hemolysis is involved?

What disease is it associated with?

Answer 29

IHA is antibody-mediated destruction of RBCs

IgG-mediated involves extravascular hemolysis
-IgG binds in warm temperatures of central body

Associated with SLE, CLL, and certain drugs

Question 30

Where is the body does IgM-mediated immune hemolytic anemia occur and what type of hemolysis is involved?

What disease is it associated with?

Answer 30

IHA is antibody-mediated destruction of RBCs

IgM-mediated involves intravascular hemolysis
-IgM binds in cold temperatures of extremities

Associated with Mycoplasma pneumoniae and infectious mononucleosis

Question 31

Describe direct vs. indirect Coombs test

Answer 31

Direct Coombs:
confirms presence of antibody- or complement-coated RBCs

Indirect Coombs:
confirms presence of antibodies in patient’s serum

Question 32

What are some causes of anemia due to underproduction?

Answer 32

Causes of micro- and macrocytic anemia

Renal failure (decreased EPO production)

Damage to bone marrow precursor cells:
= = Parvovirus B19 (infects progenitor RBCs)
= = Aplastic anemia (damage to hematopoietic stem cells resulting in pancytopenia)
= = Myelophthisic process (pathologic process, e.g. metastatic cancer, that replaces bone marrow)

Question 33

What are the most commonly defective proteins in hereditary spherocytosis?

Answer 33

ankyrin, spectrin, band 3