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NOTES: Heme/Onc > 245/246 - Congenital & Acquired Hemolytic Anemias > Flashcards

245/246 - Congenital & Acquired Hemolytic Anemias Flashcards

1
Q

How long do red blood cells usually live?

A

90-120 days

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2
Q

What is the difference between extracorpuscular and intracorpuscular hemolysis?

A
  • Extracorpuscular = something is attacking the RBC
    • Immunologic
    • Mechanical
    • Infectious
    • Hypersplenism
  • Intracorpuscular = Something is wrong within the RBC
    • Hemoglobinopathies
    • Enzyme defects
    • Membrane abnormalities
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3
Q

What hemolytic anemia will demonstrate absent CD55 and CD59 expression on flow cytometry?

A

Paroxysmal nocturnal hemoglobinuria (PNH)

  • acquired disorder of stem cells caused by mutations in phosphatidyl-inositol-glycan A (PIG A) in the RBC membrane
    • GPI protein helps anchor proteins to the lipid bilayer
  • leads to complement mediated lysis of RBCs
  • may have acute hemolysis at night and wake up to red urine
  • Type 3 –> no GPI anchored molecules (most severe)
  • Type 2 –> reduced amount
  • Type 1 –> almost normal
  • Treatment: stem cell transplant is curative
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4
Q

Which protein is deficient in Southeast Asian Ovalocytosis?

A

Band 3

  • Southeast Asian Ovalocytosis is an autosomal dominant disease caused by Band 3 deficiency that displays mild anemia.
  • Band 3 plays a critical role in chloride, and bicarbonate exchange; binds cytoplasmic membrane components
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5
Q

What is the only FDA-approved, commonly used drug to treat sickle cell disease?

What is its effect?

A

Hydroxyurea

Results in increased fetal Hb

Fetal Hb does not sickle

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6
Q

What is the treatment for spur cell (acanthocyte) anemia?

A

Liver transplant

  • Spur cell anemia is caused by liver disease
    • -> has a membrane defect that results in excess cholesterol, but normal phospholipid
    • -> Fragility
  • results in severe anemia and splenomegaly
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7
Q

List 3 mechanisms by which drugs can induce hemolytic anemia

A
  • Haptan-induced
    • Antibody binds to the drug, that is bound to the RBC
    • Penicillin, cephalosporin, tetracyclinc
  • Immune-complex
    • Antibody binds to the drug-RBC complex (antibody forms complex w/ drug and RBC membrane component)
    • Quinine, quinidine, sulfonamides
  • Autoimmune
    • Drug induces formation of antibodies against RBCs
    • Drug does NOT need to be bound to RBC for antibody binding
    • Stopping the drug will not stop the hemolysis immediately

These are all warm autoimmune hemolytic anemias

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8
Q

Which inherited hemolytic anemia is most common?

Which protein is most commonly mutated in this disorder?

A

Hereditary spherocytosis

  • Deficiency in membrane proteins
    • Ankyrin >> spectrin > band 3
    • -> mechanical instability, membrane loss
    • Spheroid, fragile RBCs
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9
Q

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

A

Infection

  • People with SCD are more susceptible to infection by encapsulated bacteria (due to functional asplenia)
  • Viral infections (parvovirus) may trigger an aplastic crisis
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10
Q

What is the mechanism of hemolysis in hereditary spherocytosis?

A

Increased splenic trapping

  • > Erythrostasis
  • > Hemolysis
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11
Q

Where in the body is vaso-occlusion due to RBC sickling most likely to occur?

A

Post-capillary venules

  • This is where RBCs have the least oxygen => most prone to sickling (sickling more likely to occur when deoxygenated)
  • Also, these vessels are small
    • Sickling -> log jam -> more sickling -> :(((
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12
Q

List two medical complications associated with sickle cell trait

(one mutated copy, one normal copy)

A

Increased risk of:

  • Chronic kidney disease
  • Venous thromboembolism (VTE)

Previously thought that sickle cell trait did not cause any problems and was protective against malaria, but looks like it may confer increased risk of these conditions

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13
Q

What kind of immunoglobulin (IgM or IgG) is responsible for warm and cold hemolytic anemia?

A
  • Warm: IgG (or complement)
  • Cold: IgM
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14
Q

List 3 important proteins found in the red blood cell membrane

A
  • Band 3
    • Transmembrane
    • Binds cytoplasmic components of the RBC membrane
  • Spectrin
    • Peripheral
    • Supports the lipid bilayer
  • Ankyrin
    • Peripheral
    • Links spectrin and Band 3
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15
Q

Which virus may lead to an aplastic crisis in patients with sickle cell disease?

A

Parvovirus

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16
Q

What would you suspect if a patient has warm autoimmune hemolytic anemia with low reticulocytes?

A

Suspect secondary process, like iron deficiency

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17
Q

How is G6PD deficiency inherited?

A

X-linked recessive mutation in G6PD gene

Heterozygous 46,XX individuals may have variable expression

  • G6PD plays a big role in the pentose phosphate pathway (major metabolic pathway for RBCs)
  • G6PD is present in all cells, but can’t be replaced in RBCs
  • RBCs w/ have decreased NADPH, decrease of the reduced form of glutathione, and decreased protection from oxidative stress
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18
Q

List 4 possible genotypes that can result in sickle cell disease

A
  • Hb S/S
  • Hb S/C
  • Hb S/Beta null
  • Hb S/Beta (+)

Wild type is Hb A/A

Basically, any combination of 2 non-A alleles can result in sickled red blood cells

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19
Q

What kind of antibodies are responsible for Rh hemolytic disease of the fetus/newborn?

A

IgG (the Ig that can cross the placenta)

  • Note: ABO antibodies are IgG or IgM, but Rh hemolytic disease is more serious (but less common)*
  • Fetus does not produce much ABO antigen as Rh (D) antigen*
20
Q

What mutation causes paroxysmal nocturnal hemoglobinuria?

A

Mutation in phosphatidyl-iositol-glycan A

  • Results in GPI-anchored protein deficiencies
    • Proteins that protect RBC from complement destruction cannot bind (CD55, CD59)
  • Results in complement-mediated lysis or RBCs
21
Q

Which protein is deficient in hereditary eliptocytosis?

A

Alpha or beta spectrin

May result in carrier state or severe condition (hereditary pyropoikilocytosis)

22
Q

List the most common acute complications of sickle cell disease

A
  • Acute pain episodes
  • Acute chest syndrome = fever, abnormal CXR, and respiratory symptoms
  • Functional asplenia
    • -> increased risk of infections w/encapsulated bacteria
  • Splenic sequestration
  • Stroke/ CNS injury
  • Aplastic crisis

End orgen damage = later complication

23
Q

What RBC morphology will you see in warm antibody hemolytic anemia?

How are the RBCs destroyed?

A

Spherocytes

Parts of the membrane are chomped off due to antibody binding -> spherocytes

24
Q

List the two hemoglobin “switches” that occur during development

Which globins are present in each type of hemoglobin?

A
  • Embryonic Hb (δ2ε2) -> Fetal Hb (α2γ2)
    • Occurs at 10 weeks gestational age
  • Fetal Hb (α2γ2) -> Adult Hb (α2β2)
    • Occurs after birth, around 6 months fetal Hb will be gone
25
Q

What molecules mediate the hemolysis:

  • Warm antibody autoimmune hemolysis:
  • Cold antibody autoimmune hemolysis:
A
  • Warm antibody autoimmune hemolysis: antibodies coat the RBCs, these RBCs are removed in the spleen (extravascular hemolysis)
    • can also have complement mediated lysis of the membrane
  • Cold antibody autoimmune hemolysis: occurs through complement fixation –> hemolysis is intravascular
26
Q

List the 2 metabolic pathways that RBCs use to produce energy

What is the major product of each pathway?

A
  • Pentose phosphate pathway: NADPH
    • Protection from oxidative stress
  • Glycolysis (anaerobic): ATP
    • Energy!
27
Q

What conditions are associated with cold antibody hemolytic anemia? (2 acute, 2 chronic)

A
  • Acute:
    • Mycoplasma
    • EBV
  • Chronic
    • Lymphoproliferative disorders
    • Idiopathic
28
Q

In a patient with sickle cell disease, what is the most common reason for presenting to the ED?

A

Pain crisis

  • Caused by vaso-occlusive episode
29
Q

On which chromosome is each genetic loci found?

  • Beta-globin:
  • Alpha-globin:
A
  • Beta-globin: Chromosome 11
  • Alpha-globin: Chromosome 16

Regulatory components are upstream (toward the 5’) of each locus

30
Q

After RBC sickling in sickle cell disease, what is the next step in the pathogenesis that eventually leads to pain, disability, and end organ damage?

A

Vaso-occlusion

Most likely to occur in post-capillary venules

(lowest O2 concentration -> RBCs most prone to sickling)

31
Q

What is the treatment for paroxysmal nocturnal hemoglobinuria?

A

Goal is to prevent complement from destroying RBCs

  • Eculizumab
    • Antibody against C5
  • Stem cell transplant is curative

Paroxymsal nocturnal hemoglobinuria = acquired PIG-A mutation –> impaired GPI anchor synthesis for CD55 and CD59 (which protect RBC membrane from complement) –> complement mediated intravascular hemolysis

32
Q

List 6 major pathophysiologic processes that contribute to vaso-occlusion in sickle cell disease

A
  • Inflammation
  • Leukocyte / platelet activation
  • Nitric oxide dysregulation
  • Endothelial dysfunction
  • Hypercoagulability
  • Oxidative stress from reperfusion injury
33
Q

What is the difference in the management of Rh hemolytic disease and ABO hemolytic disease of the newborn?

A
  • Rh hemolytic disease
    • Give anti-D immune globulin to Rh negative pregnant women during all pregnancies, in 3rd trimester, and any time there may be maternal-fetal bood exchange (goal is to prevent mom from developing antibodies; if she has them, goal is to prevent antibodies from killing the baby)
  • ABO hemolytic disease
    • Transfusions in utero before delivery, if there is evidence of hemolysis
    • ABO heomlytic disease is more common, but less serious than Rh hemolytic disease
34
Q

Describe the pathophysiology of hereditary spherocytosis (spherocyte formation)

A

2 possible pathways, depending on which protein is mutated

Spectrin or ankyrin deficiency -> Unsupported membrane

OR

Band 3 deficiency -> Clustered lipids in the phospholipid membrane

Both result in budding off of membrane parts -> spherocyte formation

35
Q

What test is used to confirm diagnosis of hereditary spherocytosis?

A

Osmotic fragility testing

  • RBCs cannot accomodate swelling in hyposmotic solutions; they just pop :(
36
Q

List the 2 primary structural components that make up the RBC membrane

A
  • Lipid bilayer
  • Network of skeletal and transmembrane proteins
37
Q

What defines acute chest syndrome in a patient with sickle cell disease? (3)

A

Fever + Abnormal chest X-ray + Any respiratory sign/sx

  • Etiology is multifactorial
    • Infection, pulmonary infarction, fat emboli
    • Often preceded by pain episode
38
Q

What is actually happening in a red blood cell when it sickles?

What is the major trigger for sickling?

A

Hb Polymerization -> sickling

Occurs during deoxygenation

Sickling may be exacerbated by:

  • Increased HbS concentration
  • More acidic pH
  • Cation homeostasis: activation of the KCl cotransporter
  • Dehydration
39
Q

What is the major complication that results from Paroxysmal nocturnal hemoglobinuria?

A

Thrombis, especially in unusual sites

  • Portal vein
  • Cerebral vessels
  • Cutaneous veins

Results from complemented-mediated destruction of RBCs -> membranes in the circulation -> clots

40
Q

What does the Direct Coombs Test detect?

How does it work?

A

Detects auto-antibody or complement directly bound to patient’s RBCs

  • Take pt’s RBCs, add standard antiglobulin (ex: anti-IgG, anti-IgM, anti-complement, or a mix) (these are antibodies against the antibodies that bind to the RBCs)
  • Look to see if these antiglobulins (anti-antibodies) bind to the pt’s RBCs (clumping)
    • If so, they are boud to IgG, IgM, or complement (depending on the antiglobulin used)

Usually do all anti-globulins together, and then if positive do them individually

Indirect Coombs takes normal RBCs and mixes with pt plasma, detects both autoantibodies and alloantibodies in the plasma

41
Q

Describe the mutation and resulting amino acid substitution that causes sickle hemoglobin

A

A -> T in the 6th codon of the beta-globin gene

Results in glutamic acid -> valine substitution

42
Q

How will the following change in hemolytic anemia?

  • Reticulocytes:
  • Haptoglobin:
  • Bilirubin:
  • LDH:
A

Hemolytic anemia

  • Reticulocytes: Increased (trying to replace decreased RBCs)
  • Haptoglobin: Decreased (haptoglobin binds to free Hb from lysed RBCs, then cleared by phagocytes)
  • BIlirubin: Increased indirect (excess bilirubin from heme breakdown is unconjugated)
  • LDH: Increased (released by damaged RBCs, but not specific to hemolysis)

Differences in amt of change in extravascular vs. intravascular

43
Q

What red blood cell morphology will result from pyruvate kinase deficiency?

A

Echinocytes (Burr cells)

44
Q

Describe the pathophysiology of cold antibody hemolytic anemia

A

Cold agglutinin antibodies (usually IgM) interact with polysaccharides on the RBC surface

hemolysis is then due to complement formation

45
Q

List 2 scenarios in which 46,XX individuals who are heterozygous for G6PD deficiency will be symptomatic

A
  • X chromoxome inactivation
  • Skewed lyonization (skewed X chromosome inactivation)
46
Q

What does the Indirect Coombs Test detect?

How does it work?

A

Can find both autoantibodies and alloantibodies in the patient’s plasma

Pts may have developed antobodies to previously transfused blood

  • Mix normal RBCs with patient’s plasma
  • If binding occurs, implies that there are antibodies in the plasma

vs. Direct coombs measures antibodies that are bound to RBCs, can only detect autoantibodies

47
Q

What is the mechanism of action of hemolysis in G6PD deficiency?

A

No G6PD -> cannot make NADPH -> cannot reduce glutathione

-> cannot deal with oxidative stress

Oxidative stress -> hemoglobin denatures -> hemolysis

Will see Heinz bodies and Bite Cells (degmacytes) in RBCs

NOTES: Heme/Onc (36 decks)

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