5.6/7 Normocytic Anemia with Intravascular Hemolysis and Anemia Due to Underproduction

Question 1

In a few words, what is paroxysmal nocturnal hemoglobinuria?

Answer 1

Acquired defect in myeloid stem cells that causes absence of GPI (glycosylphosphatidylinositol) on the membranes of RBC’s, WBC’s, Platelets
GPI binds DAF (decay accelerating factor) and MIRL to the membrane surface, they inhibit complement from attacking the cells
Absence of this molecule allows complement to lyse the cells

Question 2

In paroxysmal nocturnal hemoglobinuria, why is the cell lysis paroxysmal and most often at night?

Answer 2

Complement is activated by acidosis and when we sleep we breath slow and develop mild respiratory acidosis
Any other situation that can activate complement will have a similar effect

Question 3

Paroxysmal nocturnal hemoglobinuria causes intravascular hemolysis leading to what findings in the blood and urine?

Answer 3

hemoglobinuria, hemoglobinemia, hemosiderinuria days later

Question 4

How is paroxysmal nocturnal hemoglobinuria tested for?

Answer 4

Sucrose test is a screen, confirmed by acidified serum test or cytometry looking for CD55 (DAF) on RBC’s

Question 5

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

Answer 5

Thrombosis of hepatic, portal, cerebral veins

Destroyed platelets release cytoplasmic contents into circulation inducing thrombosis

Question 6

What are some complications of paroxysmal nocturnal hemoglobinuria?

Answer 6

Iron deficiency anemia from chronic loss in urine

Acute Myeloid Leukemia because the inciting defect is in myeloid stem cells

Question 7

Explain the biochemistry behind G6PD deficiency

Answer 7

G6PD regenerates NADPH which is needed to regenerate Glutathione after it has done it’s job to reduce H2O2 to harmless metabolites
It is one molecule in a chain of reactions that protect the RBC from the incessant oxidative stress present in the blood, especially from H2O2

Question 8

What is the inheritance pattern of G6PD and what is the actual defect?

Answer 8

X-linked recessive

Causes a reduced half-life of G6PD

Question 9

What are the two variants of G6PD?

Answer 9

African: mildly reduced half-life
Mediterranean: markedly reduced half-life

Question 10

Why is there a high carrier rate for G6PD deficiency?

Answer 10

Protective against falciparum malaria

Question 11

Explain why a shortened half-life for G6PD affects RBC’s

Answer 11

RBC’s have no nucleus and no way to produce proteins, the half-life of G6PD is usually long enough to last the life-time of the RBC (120 days)
If shortened, the RBC’s will begin to be lysed earlier in their life span leading to anemia

Question 12

What are Heinz bodies and when do they show up?

Answer 12

Heinz bodies are precipitated Hb that has precipitated due to oxidative stress

Question 13

What are the common oxidative stresses that cause a hemolytic episode in G6PD deficiency?

Answer 13

Infections, drugs (primaquine, sulfa, dapsone), fava beans

Question 14

Why are there bite cells in G6PD deficiency?

Answer 14

Oxidative stress leads to formation of Heinz bodies (precipitated Hb) that is removed by splenic macrophages
Though this occurs extravascularly, intravascular hemolysis still predominates

Question 15

How do you test for G6PD deficiency?

Answer 15

Screen with a Heinz preparation with Heinz stain

Enzyme studies are done weeks after a hemolytic episode to confirm deficiency

Question 16

How does G6PD often present?

Answer 16

Hemoglobinuria and back pain hours after the oxidative stress because Hb is nephrotoxic

Question 17

What are the 2 types of immune hemolytic anemia?

Answer 17

IgG and IgM mediated

Question 18

Describe IgG-mediated immune hemolytic anemia

Answer 18

Usually extravascular hemolysis
IgG binds RBC’s in warm temps, antibody covered RBC’s eaten by spleen macrophages leading to spherocytes
Assoc. c SLE (most common), CLL, drugs (penicillin, cephalosporin)
Drug may bind the RBC membrane itself and attract antibodies to it, or may cause production of autoantibodies
Treatment: stop drug, steroids, IVIG, spenectomy

Question 19

Describe IgM-mediated immune hemolytic anemia

Answer 19

Usually mostly extravascular, but has some intravascular as this involves activation of complement
IgM binds RBC’s in cold temps (cold agglutinin) and fixes and activates complement
RBC inactivates complement, but residual C3b remains and acts as opsonin leading to splenic macrophage bites and spherocytes
Most assoc. c Mycoplasma pneumoniae and Infectious Mononucleosis

Question 20

Explain the Coomb’s test

Answer 20

Direct: looks to see if antibody is already bound to RBC; add anti-IgG/complement to patients blood and look for agglutination

Indirect: looks to see if antibody alone is present in patient’s blood; add patients serum to test RBC’s and look for agglutination

Question 21

Explain microangiopathic hemolytic anemia

Answer 21

Intravascular hemolysis from vascular pathology leads to formation of schistocytes (hallmark) as RBC’s are damaged moving through the circulation and also iron deficiency anemia with chronic hemolysis
Occurs with microthrombi such as in TTP, HUS, DIC, HELLP; as well as with prosthetic heart valves and aortic stenosis that damage RBC’s as they pass through

Question 22

How does malaria lead to anemia and what are the fever patterns of the several types?

Answer 22

As part of the falciparum life cycle the RBC must lyse
Cyclic fevers are common:
P falciparum: daily
P vivax, ovale: every other day
Mostly intravascular hemolysis, but some extravascular as the spleen tries to remove infected cells

Question 23

Of the anemias, which have intravascular hemolysis?

Answer 23

Paroxysmal Nocturnal Hemoglobinuria
G6PD
Immune hemolytic anemia
Microangiopathic hemolytic anemia
Malaria

Question 24

Causes of anemia from underproduction

Answer 24

All causes of microcytic and macrocytic anemia
Renal failure leading to low EPO
Damage to marrow precursor cells leading to anemia and sometimes pancytopenia
Parvovirus B19
Aplastic anemia
Myelophthisic processes

Question 25

What is a biopsy finding assoc. c aplastic anemia?

Answer 25

Empty, fatty marrow lacking any sign of precursor cells