Robbins pg. 642-653

Question 1

What is the only hemolytic anemia caused by an

acquired genetic defect?

Answer 1

PNH

Question 2

A single mutation in a PIGA gene can cause PNH in both men and women. How?

Answer 2

PNH is X linked AND subject to lionization (random inactivation of one X chromosome in females)

Because the causative mutations occur in a hematopoietic stem cell,
all of its clonal progeny (red cells, white cells, and platelets) are deficient in GPI-linked proteins

Question 3

What three GPI-linke proteins are defective in PNH?

Answer 3

-DAF
-CD59 (a potent inhibitor of
C3 convertase)
-C8 complement protein

Question 4

Is the hemolysis seen in PNH mostly intra- or extravascular?

Answer 4

intravascular

which is caused
by the C5b-C9 membrane attack complex. The hemolysis is paroxysmal and nocturnal in only 25% of cases; chronic hemolysis without dramatic hemoglobinuria is more
typical.

Question 5

Why do red cell lyse at night in PNH?

Answer 5

due to a slight decrease in blood pH during sleep,

which increases the activity of complement

Question 6

What is the leading cause of death in PNH patients?

Answer 6

thrombosis (mechanism unclear) of the hepatic, portal, or cerebral veins

Question 7

How is PNH diagnosed?

Answer 7

flow cytometry, which provides a sensitive means for detecting red cells that are deficient in GPI-linked proteins such as CD59

Question 8

What drug is used in PNH treatment?

Answer 8

Eculizumab, which prevents conversion of C5 to C5a.

This inhibitor not only reduces the hemolysis and
attendant transfusion requirements, but also lowers the risk of thrombosis by up to 90%.

Question 9

Most WAIHA antibodies are of what class?

Answer 9

IgG (less commonly IgA)

Question 10

Red cell hemolysis in WAIHA is mostly ______.

Answer 10

extravascular because IgG-coated red cells bind to Fc receptors on phagocytes, which remove membrane fragments leading to sphericity formation which are removed in the spleen

Question 11

How does drug-induced IHA occur?

Answer 11

• antigenic drugs

- tolerance-breaking drugs

Question 12

What do antigenic drugs do to induce IHA?

Answer 12

• ex. penicillin and cephalosporin
• these drugs bind to the red cell membrane and are recognized by antidrug antibodies. Sometimes the antibodies bind only to the drug, as in penicillin-induced hemolysis. In other cases, such as in quinidine-induced hemolysis, the antibodies recognize a complex of the drug and a membrane
  protein. The responsible antibodies sometimes fix
  complement and cause intravascular hemolysis, but
  more often they act as opsonins that promote extravascular hemolysis within phagocytes.

Question 13

What do tolerance-breaking drugs do to induce IHA?

Answer 13

These drugs, of which the antihypertensive
agent α-methyldopa is the prototype, induce in some unknown manner the production of antibodies against red cell antigens, particularly the Rh
blood group antigens. About 10% of patients taking
α-methyldopa develop autoantibodies, as assessed by the direct Coombs test, and roughly 1% develop clinically significant hemolysis

Question 14

What is the main antibody type in CAHA?

Answer 14

IgM that bind red cells at low temps (0-4C)

Question 15

CAHA is common following which kinds of infections?

Answer 15

• Mycoplasma pneumoniae
• Epstein Barr virus
• Influenza, HIV, CMV

self-limited and asymptomatic here

Question 16

What is the main mechanism of hemolysis in CAHA?

Answer 16

IgM binding agglutinates red cells and fixes complement
rapidly. As the blood recirculates and warms, IgM is released, usually before complement-mediated hemolysis can occur. However, the transient interaction with IgM is
sufficient to deposit sublytic quantities of C3b, an excellent opsonin, which leads to the removal of affected red cells
by phagocytes in the spleen, liver, and bone marrow.

Question 17

Symptoms of CAHA?

Answer 17

The hemolysis is of variable severity. Vascular obstruction
caused by agglutinated red cells results in pallor, cyanosis, and Raynaud phenomenon in body parts
exposed to cold temperature

Question 18

The most common and important anemias

associated with red cell underproduction are those caused by ________.

Answer 18

nutritional deficiencies, followed by those that arise

secondary to renal failure and chronic inflammation

Question 19

The common theme among the various causes of megaloblastic anemia is what?

Answer 19

an impairment of DNA synthesis that leads to ineffective hematopoiesis and distinctive morphologic
changes, including abnormally large erythroid
precursors and red cells.

Question 20

B12 and folate
are considered later. For now it suffices that vitamin B12
and folic acid are coenzymes required for the synthesis
of what?

Answer 20

thymidine

Question 21

What is pernicious anemia caused by?

Answer 21

megaloblastic
anemia caused by an autoimmune gastritis that impairs the production of intrinsic factor, which is required for vitamin B12 uptake from the gut

Question 22

Do plants and veggies contain a lot of B12?

Answer 22

Nope, the source is micro-organisms so a source of B12 deficiency is veganism

The daily requirement is 2 to 3 μg. A diet that includes
animal products contains significantly larger amounts and normally results in the accumulation of intrahepatic stores of vitamin B12 that are sufficient to last for several years.

Question 23

How do IF/B12 complexes enter ileal enterocytes?

Answer 23

a cubilin receptor binds IF and internalizes the complex

Question 24

What happens to B12 within ileal cells?

Answer 24

vitamin B12 associates with a major carrier protein, transcobalamin II, and is secreted into the plasma where it is delivered by transcobalamin II to the liver, BM, and GI tract

Question 25

Are there any absorption mechanisms that allow B12 to bypass the need for IF?

Answer 25

Yes, not understood but ~1% of very large doses of B12 can be absorbed

Question 26

What reactions require B12?

Answer 26

1) methylcobalamin serves as an essential cofactor to convert homocysteine to methionine by methionine synthase (gets the methyl from N5-methyl THF). THF can then convert dUMP to dTMP for DNA

2) isomerization of methylmalonyl coenzyme A to succinyl CoA. So no B12= high MMA (B12 as adenosylcobalamin acts
as a prosthetic group on the enzyme methylmalonyl-coenzyme A mutase)

Question 27

What is the most direct cause of anemia in b12 deficiency?

Answer 27

folic acid being trapped as N5-methyl-THF so no THF. no THF= no dTMP

so folic acid infusion helps anemia

Question 28

Does folic acid infusion help the neurologic symptoms of B12 deficiency?

Answer 28

Nope, only worsened

Question 29

So what causes neurologic problems in B12 deficiency?

Answer 29

Interruption of conversion of MMA to succinyl CoA and the consequent
buildup of methylmalonate and propionate (a
precursor) could lead to the formation and incorporation
of abnormal fatty acids into neuronal lipids. It has been
suggested that this biochemical abnormality predisposes
to myelin breakdown and thereby produces the neurologic complications of vitamin B12 deficiency.
However, rare individuals with hereditary deficiencies of methylmalonyl-coenzyme A mutase do not suffer from the
neurologic abnormalities seen in vitamin B12 deficiency,
casting doubt on this explanation.

Question 30

How does pernicious anemia work?

Answer 30

Pernicious anemia is believed to result from an autoimmune attack on the gastric mucosa. Histologically, there is a chronic atrophic gastritis marked by a loss of parietal
cells

Question 31

Why would you have fatigue with iron deficiency anemia?

Answer 31

About 80% of the functional iron is found in hemoglobin; myoglobin and iron-containing enzymes such
as catalase and the cytochromes contain the rest. So low iron= no oxidative phosphorylation

Question 32

Where is transferrin made?

Answer 32

liver

Question 33

Intra-cellular iron is contained where in the cell?

Answer 33

Intracellular ferritin is
located in the cytosol and in lysosomes, in which partially
degraded protein shells of ferritin aggregate into hemosiderin granules.

Question 34

How is Fe2+ iron oxidized to Fe3+ iron as it leaves enterocytes?

Answer 34

iron oxidases hephaestin and ceruloplasmin.

Question 35

What happens to hepcidin in anemia of chronic inflammation?

Answer 35

it is increased

Question 36

Secondary hemochromatosis can occur in diseases associated with what?

Answer 36

ineffective erythropoiesis, such as β-thalassemia
major and myelodysplastic syndromes

Through incompletely understood mechanisms, ineffective erythropoiesis suppresses hepatic hepcidin production, even when iron stores are high.

Question 37

How much iron should be absorbed daily to maintain balance?

Answer 37

1mg. Because only 10% to 15% of ingested iron is absorbed, the daily iron requirement is 7 to 10 mg for adult men and 7 to 20 mg for adult women.

Question 38

T or F. Heme iron is much more absorbable

than inorganic iron, the absorption of which is influenced by other dietary contents.

Answer 38

T. NOTE: most in the form of heme is contained
in animal products, with the remainder being inorganic
iron is in vegetables.

Question 39

Absorption of inorganic iron is enhanced by what things?

Answer 39

ascorbic acid, citric acid, amino acids, and

sugars in the diet

Question 40

Absorption of inorganic iron is inhibited by what things?

Answer 40

tannates (found in tea),

carbonates, oxalates, and phosphates.

Question 41

What groups are at risk of dietary iron insufficiency even in developed countries?

Answer 41

• Infants, who are at high risk due to the very small
amounts of iron in milk. Human breast milk provides
only about 0.3 mg/L of iron. Cow’s milk contains about
twice as much iron, but its bioavailability is poor.

• The impoverished, who can have suboptimal diets for
socioeconomic reasons at any age

• Older adults, who often have restricted diets with little
meat because of limited income or poor dentition

• Teenagers who subsist on “junk” food

-pregnancy

Question 42

_____ is the most common cause of iron

deficiency in the Western world.

Answer 42

Chronic blood loss

Includes External hemorrhage or bleeding into the gastrointestinal, urinary, or genital tracts that depletes iron reserves.

Question 43

Lab findings with anemia of chronic disease?

Answer 43

low serum iron, reduced total iron-binding capacity,

and abundant stored iron in tissue macrophages.

Question 44

Anemia of chronic disease

The anemia is usually mild, and the dominant symptoms
are those of the underlying disease. The red cells can
be normocytic and normochromic, or hypochromic and
microcytic, as in anemia of iron deficiency. The presence
of increased storage iron in marrow macrophages, a high
serum ferritin level, and a reduced total iron-binding
capacity readily rule out iron deficiency as the cause of
anemia. Only successful treatment of the underlying condition
reliably corrects the anemia. However, some patients,
particularly those with cancer, benefit from administration
of erythropoietin.

Answer 44

Anemia of chronic disease

The anemia is usually mild, and the dominant symptoms
are those of the underlying disease. The red cells can
be normocytic and normochromic, or hypochromic and
microcytic, as in anemia of iron deficiency. The presence
of increased storage iron in marrow macrophages, a high
serum ferritin level, and a reduced total iron-binding
capacity readily rule out iron deficiency as the cause of
anemia. Only successful treatment of the underlying condition
reliably corrects the anemia. However, some patients,
particularly those with cancer, benefit from administration
of erythropoietin.