Anemia IV - Hemolytic Anemias Flashcards
(40 cards)
Why is the RBC uniquely susceptible to stressors?
- Lacks a nucleus
- Cannot synthesize protein (except reticulocyte)
- Must rely on its content of vital proteins to last its lifetime -> any change in environment can damage it
What are the classifications of hemolytic anemia by site?
Extravascular - i.e. splenic removal
Intravascular - i.e. shear forces or autoimmunity
What are the classifications of hemolytic anemia by mechanism? How are they usually acquired? Give examples of them.
Intrinsic - usually genetic
Examples: G6PDH deficiency, hemoglobinopathies, PNH (actually acquired)
Extrinsic - usually acquired
Immune-mediated, microangiopathic, mechanical trauma-mediated
Do extravascular hemolytic anemias usually cause iron deficiency? Why or why not?
Usually not, because all components of the RBC are rapidly recycled via the RES.
i.e. globins returned to amino acid pool, heme made into unconjugated bilirubin and conjugated / recycled by liver, and IRON moved back into storage pool
Why is intravascular hemolysis more dangerous than extravascular?
Intravascular hemolysis leads to a dumping of a large amount of hemoglobin into the blood.
Some of that is scavenged by haptoglobin or albumin (makes methhemalbumin), but a large portion ends up in the kidneys causing hemoglobinuria / hemosiderinuria which is very damaging
Describe the clinical pictures of extravascular and intravascular hemolysis and give an example of each.
Extravascular - insidious onset with gradual icterus and pallor, i.e. hereditary spherocytosis
Intravascular - rapid onset with sudden icterus and pallor, fulminant course, i.e. PNH
What are general clinical findings of all hemolytic anemias?
Pallor, fatigue, jaundice, dark urine (hemoglobin), gallstones (bilirubin), aplastic crises with viral infections
What is hereditary spherocytosis a prototype of? What causes it?
Extravascular, intrinsic hemolysis
RBC cytoskeleton-membrane tethering proteins such as spectrin, ankyrin, or Band 3.
Vertical interactions cause blebbing of membrane and sphering outward. Horizontal interactions prevent forming of spectrin tetramers which make membrane unstable -> eaten in chunks by splenic macrophages
How can you tell a spherocyte on peripheral blood smear and why do they get eaten by the spleen? What will happen to the reticulocyte count?
Have no area of central pallor (not biconcave), get eaten because they don’t fight properly through splenic sinusoids
Reticulocyte count will also be elevated
What first test is used to diagnose spherocytosis?
Osmotic fragility test. Normal saline is ~0.9% sodium chloride. If you spherocytes, lysis will begin at an early point in hypotonic saline solution (spherocytes have less volume to swell than regular RBCs)
-> right shifted curve, cannot handle osmotic stress as well
What is the confirmatory test used to diagnose spherocytosis?
Eosin-maleimide (EMA) binding by flow. Spherocytosis will bind less EMA.
What is the inheritance pattern of hereditary spherocytosis?
Autosomal dominant with weak penetrance
How is spherocytosis managed?
Establish a steady state Hb to monitor for aplastic crises, anticipate gallstones, and give splenectomy for selected patients
Why is splenectomy effective for spherocytosis and what will be seen on peripheral blood smear?
Removes the site of extravascular hemolysis
Peripheral smear -> spherocytes persist, and Howell-Jolly bodies appear (fragments of nuclear material in RBCs which spleen normally removes)
What does the Embden-Meyerhoff pathway produce?
Another name for glycolysis, produces 2 ATP per 1 glucose
What does the Rappoport shunt produce?
2,3 DPG
Uses a mutase to make 1,3-DPG into 2,3-DPG, which is needed for RBC oxygen transport
Why is the hexose monophosphate shunt important for RBCs? What commonly upsets this?
G6PDH keeps glutathione in its reduced form so it can reduce oxidative stressors (including hydrogen peroxide and hydroxyl radical) back to water.
X-linked recessive mutations in G6PDH prevent formation of NADPH
What is the carrier frequency of G6PDH and why? What are the two variants?
Around 10%, offers protection against falciparum malaria
African variant - mildly reduced G6PDH halflife, less severe form
Mediterranean / Caucasian variant - significantly reduced halflife, chronic hemolytic anemia which may be transfusion dependent
What do cells look like on peripheral blood smear of G6PD? How are they seen on a special stain?
Mothball cells - look like a hanging basket, dense hemoglobin aggregates on one side of the cell, opposite side will be relatively clear
Associated with formation of Heinz bodies (visualized by special stain) which are removed by splenic macrophages to make bite cells (probably the same as mothball cells)
What things precipitate hemolysis in G6PD deficiency? is this intravascular or extravascular?
Predominantly intravascular hemolysis, so will cause kidney damage (no splenomegaly)
Antimalarials (i.e. primaquine), slufa drugs, nitrofurantoin, Fava beans, naphthelene (mothballs), overwhelming infections
What causes Paroxysmal Nocturnal Hemoglobinuria?
Acquired defect in glycosylphosphatidylinositol (GPI) gene within myeloid stem cells
-> lack of GPI anchor prevents expression of decay-accelerating factor (CD55) and CD59, which are needed to inhibit C3 convertase and thus fixation of complement
What is the primary clinical problem in PNH?
Thrombosis of hepatic, portal, and cerebral veins since platelets will also lack CD55 and thus be activated to form clots
Other than thrombosis, what other problems plague PNH patients? One of these things is a cancer.
Hemosiderinuria - and thus chronic iron deficiency due to loss of iron in urine
Progression to aplastic anemia and acute myeloid leukemia (AML)
-> think that other oncogenes can develop in that stem cell
How is the diagnosis of PNH made? What is the treatment?
Usually by flow cytometry showing lack of CD55/CD59
Treatment: Bone marrow transplant, immunosuppression, and eculizumab (C5 complement inhibitor, prevents formation of MAC)
