Robbins pg. 642-653 Flashcards
What is the only hemolytic anemia caused by an
acquired genetic defect?
PNH
A single mutation in a PIGA gene can cause PNH in both men and women. How?
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
What three GPI-linke proteins are defective in PNH?
-DAF
-CD59 (a potent inhibitor of
C3 convertase)
-C8 complement protein
Is the hemolysis seen in PNH mostly intra- or extravascular?
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.
Why do red cell lyse at night in PNH?
due to a slight decrease in blood pH during sleep,
which increases the activity of complement
What is the leading cause of death in PNH patients?
thrombosis (mechanism unclear) of the hepatic, portal, or cerebral veins
How is PNH diagnosed?
flow cytometry, which provides a sensitive means for detecting red cells that are deficient in GPI-linked proteins such as CD59
What drug is used in PNH treatment?
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%.
Most WAIHA antibodies are of what class?
IgG (less commonly IgA)
Red cell hemolysis in WAIHA is mostly ______.
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
How does drug-induced IHA occur?
- antigenic drugs
- tolerance-breaking drugs
What do antigenic drugs do to induce IHA?
- 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.
What do tolerance-breaking drugs do to induce IHA?
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
What is the main antibody type in CAHA?
IgM that bind red cells at low temps (0-4C)
CAHA is common following which kinds of infections?
- Mycoplasma pneumoniae
- Epstein Barr virus
- Influenza, HIV, CMV
self-limited and asymptomatic here
What is the main mechanism of hemolysis in CAHA?
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.
Symptoms of CAHA?
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
The most common and important anemias
associated with red cell underproduction are those caused by ________.
nutritional deficiencies, followed by those that arise
secondary to renal failure and chronic inflammation
The common theme among the various causes of megaloblastic anemia is what?
an impairment of DNA synthesis that leads to ineffective hematopoiesis and distinctive morphologic
changes, including abnormally large erythroid
precursors and red cells.
B12 and folate
are considered later. For now it suffices that vitamin B12
and folic acid are coenzymes required for the synthesis
of what?
thymidine
What is pernicious anemia caused by?
megaloblastic
anemia caused by an autoimmune gastritis that impairs the production of intrinsic factor, which is required for vitamin B12 uptake from the gut
Do plants and veggies contain a lot of B12?
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.
How do IF/B12 complexes enter ileal enterocytes?
a cubilin receptor binds IF and internalizes the complex
What happens to B12 within ileal cells?
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
Are there any absorption mechanisms that allow B12 to bypass the need for IF?
Yes, not understood but ~1% of very large doses of B12 can be absorbed
What reactions require B12?
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)
What is the most direct cause of anemia in b12 deficiency?
folic acid being trapped as N5-methyl-THF so no THF. no THF= no dTMP
so folic acid infusion helps anemia
Does folic acid infusion help the neurologic symptoms of B12 deficiency?
Nope, only worsened
So what causes neurologic problems in B12 deficiency?
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.
How does pernicious anemia work?
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
Why would you have fatigue with iron deficiency anemia?
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
Where is transferrin made?
liver
Intra-cellular iron is contained where in the cell?
Intracellular ferritin is
located in the cytosol and in lysosomes, in which partially
degraded protein shells of ferritin aggregate into hemosiderin granules.
How is Fe2+ iron oxidized to Fe3+ iron as it leaves enterocytes?
iron oxidases hephaestin and ceruloplasmin.
What happens to hepcidin in anemia of chronic inflammation?
it is increased
Secondary hemochromatosis can occur in diseases associated with what?
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.
How much iron should be absorbed daily to maintain balance?
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.
T or F. Heme iron is much more absorbable
than inorganic iron, the absorption of which is influenced by other dietary contents.
T. NOTE: most in the form of heme is contained
in animal products, with the remainder being inorganic
iron is in vegetables.
Absorption of inorganic iron is enhanced by what things?
ascorbic acid, citric acid, amino acids, and
sugars in the diet
Absorption of inorganic iron is inhibited by what things?
tannates (found in tea),
carbonates, oxalates, and phosphates.
What groups are at risk of dietary iron insufficiency even in developed countries?
• 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
_____ is the most common cause of iron
deficiency in the Western world.
Chronic blood loss
Includes External hemorrhage or bleeding into the gastrointestinal, urinary, or genital tracts that depletes iron reserves.
Lab findings with anemia of chronic disease?
low serum iron, reduced total iron-binding capacity,
and abundant stored iron in tissue macrophages.
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.
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.
