Glossary of Hemolytic Anemias

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What is the definition of a hemolytic anemia?
Anemia due to the Decreased life span of a RBC, due to increased destruction.
What are the most important lab findings in a hemolytic anemia?
What signs of increased destruction do blood cells exhibit in hemolytic anemias?

(3 things in spcfc re: Red cell (production/shape), and Bone marrow)
1. Increased erythropoeisis: polychromasia, incr. retic count, nRBCs
2. BM Hyperplasia - incidental increase in WBCs and plts
3. RBC poik and fragments
What Chemistry tests show increased destruction? (4)
1. Decreased haptoglobin
2. Increased bilirubin
3. Increased urobilinogen
4. Increased LD!*
What are 4 clinical symptoms of Hemolytic anemia seen in patients?
1. Jaundice (from bilirubin)
2. Associated symptoms
3. Anemia
4. Splenomegaly
What are 4 associated symptoms of hemolytic anemia?

pigmented gallstones
obstructive jaundice
iron overload
leg ulcers
What are 5 systems for classifying hemolytic anemias?

1. **Hereditary vs. Acquired**
2. Extra vs. intravascular
3. Extrinsic vs. Intrins cause
4. Immune vs. Non-immune
5. Acute vs. Chronic
what are 3 causes/categories of Hereditary Hemolytic Anemias based on physiologic defect?
1. RBC membrane defects
2. Metabolism defects
3. Hemoglobin defects
What are the 6 types of
RBC Membrane defect HA?
1. Acanthocytosis
2. Elliptocytosis
3. Pyropoikilocytosis
4. Spherocytosis
5. Stomatocytosis
6. Xerocytosis
What is the DAT test?
What is it for?
Direct Antiglobulin Test
-determines if Immunoglobulins are coating red blood cells to see if the anemia is an IMMUNE process.
Is Hereditary Spherocytosis an immune process? How do you know?
No: it is DAT neg.
What genetically causes HS?
autosomal dominant genetics OR a spontaneous mutation
What is the basic problem that causes HS?
an Unstabilized cell membrane
What 4 things destabilize the cell membrane in hereditary spherocytosis?
-Damage to the Spectrin lattice
-Loss of surface area
-Splenic conditioning
-Change in cell's normal volume
What is the purpose of spectrin?
to allow flesibility and deformibility - depends on ATP
What is Splenic conditioning?
Trapping of dmgd cells b/c less deformable; leads to more damage and loss of membrane when the spleen picks at it.
What is the characteristic RBC morphology of a spherocyte?
-Very round, but normo/normo.
Normal MCV
What is the PB smear like in Hered sphero, how does it affect the MCHC, MCV, RDW, and RPI??
-Increased MCHC but normal MCV
-Wide RDW
-Normo/normo just smaller
-Incr. retics, high RPI
-Spheros, stomatos, shistos
what are some clinical symptoms of HSphero?
Jaundice, splenomegaly, anemia
What are diagnostic tests for HS?
Osmotic fragility
-Initial = .65%
-Complete = .35%

DAT = neg
If a patient with HS has a splenectomy, what would you see on the periph blood smear?
-When would you splenectomize?
-Howell jollies
-As a last resort therapy
What's a normal Osmotic fragility?
-Initial: .45%
-Complete: .35%
What is the HS osm. fragility?
Initial: .65%
Complete: .45%
Why does hemolysis increase as NaCl% decreases?
Because water is increasing and this is what causes hemolysis.
What are 4 circulatory complications of HS that can occur?
1. Obstructive jaundice
2. Splenomegaly
3. Hemolytic crisis
4. Aplastic crisis due to infctn
What is HE?
Hereditary elliptocytosis
How is HE inheredited?
As an autosomal dominant gene.
What is the basic cause of abnormality in HE?
Spectrin association is impaired and it can't recover from the shear force of going through the spleen - remains oval as result.
What are two subcategories of HE?
-Infantile Poikilocytosis
-Southeast Asian Ovaolocytosis
What does infantile poik look like?
a burn patient, but self-fixes in a year. then it's normal heredit. elliptocytosis
what do cells look like in SAO?

what benefit is there to this?
southeast asian ovalocytosis... cells are spoon-shaped discs, w/ double slits.

Band-3 defect confers malaria resistance.
How is Hereditary Pyropoikilocytosis inherited?
As a DOUBLE HETEROZYGOTE - one defect from each parent.
What causes the membrane defect in Hereditary pyropoikilocytosis?
-An excess in spectrin dimers
-Membrane is unstable and lyses at 45 C instead of the normal 49 C.
What does the blood smear look like in hereditary Pyropoik?
LIKE A SEVERE burn patient
What is the prescription for HP?
What causes the membrane defect in hered. acanthocytosis?
Increased surface area because cells can't synthesize Beta-lipoprotein B.
How does the body respond to the increased SA in HAcanth?
By increasing extravascular hemolysis.
What causes acquired acanthocytosis?
Changes in cholesterol levels (plasma).

Increased cholesterol causes RBC membrane projections - fat clumps on the outer phospholipid layer.
What is the membrane defect that causes hered. stomatocytosis?
Defective Na/K pump -> H2O in RBCs increases -> Makes cells plump so only one side is concave.
What test supports herid stomatocytosis finding?
-Increased osmotic fragility
What are 4 things that can cause acquired stomatocytosis?
1. Liver disease
2. Drugs
3. other hematolog. problems
4. Artifact from drying
what the heck is hereditary XEROCYTOSIS?
Condition where RBCs are dehydrated b/c of low potassium levels.
what happens to the hemoglobin in xerocytosis?
it puddles; so you'll see targets and spiculated cells too.
What other lab values are indicative of xerocytosis?
Increased MCHC
Decreased osmotic fragility (cells are more viscous like sickle cells for instance)
what hemoglobinapathy does xerocytosis kinda look like?
Hgb C
What are 3 hemolytic anemias due to METABOLISM DEFECTS?
1. Pyruvate Kinase deficiency
2. G6PD deficiency
3. others
how is pyruvate kinase deficiency inherited?
As an autosomal recessive gene - must have two to express it.
What is the problem in PKD?
What cells are affected?
-Cells can't produce enough ATP.
-Older cells affected.
-Severity can vary
What is the typical morphology seen in PKD?
There isn't any.
Might see acanthocytes if post splenectomy.
What lab value in particular is elevated in PKD?
Total bilirubin - unconjugated bilirubin is increased.
What metabolism pathway is PK deficient in, and what is the result?
Embden-meyerhof glucose pathway; only generates 2 ATP inst. of 3
How does the body respond to decreased o2 transfer in PKD?
Increases 2,3-DPG levels to 2x the normal amount
what tests are used to confirm PKD?
-PK assay
-Family studies
How is g6PD deficiency inherited?
As a sex-linked recessive gene - so only MALES get it.
How is G6PD deficiency expressed
Females have variable activity cuz its sex-linked recessive.
Males have full expression.
Why is G6PD important?
what does its decrease result in?
It protects Hgb from oxidants.

Decrease means oxidant stress.
What type of cells do you see in G6PD?
Heinz bodies
When a patient has a G6PD episode, what 4 symptoms will you see?
(2 patient-related, 2 blood smear related)
-BITE/helmet cells
-Heinz bodies w/ supravital
What induces hemolytic episodes in Mediterraneans with G6PD deficiency?
For G6PD defic, what are
-3 screening tests
-1 confirmatory test
1. Ascorbate Cyanide
2. Florescent spot
3. Heinz Body
Confirmatory: G6PD assay
How is a Heinz body test performed? (2 steps)
1. Expose cells to an oxidizing substance.
2. Stain with Cresyl or methyl violet.
3. Evaluate number of cells w/ Heinz bodies
what is a Normal heinz body test, what is abnormal?
Normal: a FEW cells w/ multiple heinz bodies

Abnormal: MANY w/ them
How is a G6PD assay run?
1. Add G6P and NADP to sample; the G6PD will convert it to 6-phosphogluconate and NADPH which flouresces.
Other than genetic inheritance, how can G6PD deficiency be acquired?
By taking oxidant drugs, and dehydration.
What are 2 other Metabolism defects that cause hemolytic anemias (other than PK and G6PD)
1. Pyrimidine 5 Nucleotidase
2. Embden-Meyerhof pathway enzyme deficiencies
What are the 4 categories of acquired hemolytic anemias?
1. Immune
2. Drug induced
3. Agent-caused
4. PNH
What 3 various "Agents" can cause hemolytic anemia?
1. Physical
2. Chemical
3. Infectious
What are the 2 types of Immune HA?
1. Allo (nonself)
2. Auto (self)
What's actually causing hemolysis in auto-immune HA?
1. Humoral antibody coats cells and complement lysis or RES phagocytosis ensues.
What 2 antibodies are the culprits of cell death in auto HA?
IgM = activates complement

IgG = activates RES
How does IgM and IgG action differ, and which is immediate or delayed?
IgM = immediate; causes INTRAVASC hemolysis by activating complement.
IgG = delayed; causes EXTRAVASC hemolysis by coating cells for RES phagocytosis.
What test determines if allo-immune HA is IgM of IgG mediated? How?
DAT - determines if Ab and Complement are coating cells (polyspecific). If positive, do monoclonal to find out which.
What happens in a DAT test?
1. Add Anti-IgG/complement antibody to sample.
2. Add Antibody to previous reagent
3. If IgG/complement are on RBCs, agglutination. test further to see which.
What 2 major things will cause an alloimmune reaction HA?
1. transfusion reaction
2. HDN hemolytic disease of newborn.
What are 2 categories of HDN, and which is more severe?
ABO group - shows spherocytes
Rh group - nRBCs b/c reaction is stronger.
How is AUTO-immune HA classified? (2 types)

Which is more common?
by temperature:
Warm (hemolysis at 37)
Cold (hemolysis at 4)
-Warm is more common.
What antibody type is active in WAIHA?
What triggers this to happen?
IgG; triggered by virus infection.
What 3 lab findings characterize WAIHA?
-DAT can be pos or false neg.
What antibody type is active in CAIHA?
IgM and Complement
What lab findings do you NOT see in CAIHA that are in WAIHA?
spherocytes and nRBCs.
What causes CAIHA, and in whom?
it's idiopathic, generally in old people w/ infections and malignant disease.
mycoplasma pneumonia (contaminant on brian/haley's cultures?)
How will DAT vary for CAIHA and WAIHA?
If monoclonal is added, will show C' and IgM for CAIHA versus only IgG for WAIHA.
what type of hemolysis occurs in CAIHA?
extra AND intravascular
what is a very big hint on the PBS and indices that a patient has CAIHA?
very high MCHC and agglutinated cells - autoagglut. occurs below room temp.
What is PCH?
What population is it seen in?
What antibody causes it?
-Paroxysmal cold hemoglobinurea
-Biphasic IgG Donath Landsteiner
How does IgG cause PCH?
It binds RBCs after exposure to cold and then binds complement for MAC attack when it warms up. Hb then spills into urine.
What characterizes PCH?

What likely triggers it?
Dark urine - hemoglobinurea.

Assoc. with respiratory viral infections.
What drugs induce HA?
(2 actual drugs, one sideeffect)
-Immune Complexes activate C' and cause intravasc. hemolysis
What are 7 immune complexes that can cause HA?
1. Babesiosis
2. Bartonella
3. Clostridium
4. Leishmania
5. Malaria
6. Toxoplasma
7. Trypanosoma
What do chemicals that cause HA do to red cells?
1. Oxidize/denature Hb
2. Cause Heinz bodies
3. Cause bite cells
What Wisconsin bug causes Venom-induced HA?
-what type of hemolysis?
-morphology seen?
-Brown recluse spider
-intravascular hemolysis
What are 4 physical agents that cause HA?
1. Heat (burns)
2. Marching/Running
3. Prosthetic devices
4. Microangiopathy
What is the pathologic process that causes MAHA?

What type of hemolysis?
Microangiopathic HA -->
Fibrin in vessels tears up RBCs.

Intravasc AND Extravascular
What are some cuases of MAHA?
1. Hypertension
2. Disseminated carcinoma
3. Hemolytic Uremic Syndrome (from ecoli)
4. Thromb. Thrombocytopenia Purpura (Herriod's daughter)
what is "PNH"?

What is pretty unique about it?
Paroxysmal Nocturnal Hemoglobinurea

-an ACQUIRED membrane defect
How can a membrane defect (in formation) be acquired?
By damage to stem cells in the bone marrow at a previous time.
What cells are affect in PNH?
Stem cells -> so everything down stream: RBCs, WBCs, plts.
What causes the hemolysis in PNH?
cells are susceptible to complement lysis.
what are patients with PNH mostly suffering from
waking up every morning with rust colored urine.
what kind of blood picture and lab findings do you see in PNH?
-Increased retics/polychromasia
-Incr. bilirubin, decr. haptogbn
-Hbemia, Hburia, Hmsiderinurea
What 3 tests are used to diagnose PNH?
1. Sucrose hemoysis test (screening test)
2. Ham's test
3. CD59 w/ flow cytometry
What's the basic principle of the Sucrose hemolysis test?
Cells are susc. to complement; adding complement in sugar water will causes >5% lysis in 30 min.
What's the difference betwen the Sucr. hemolysis test and Ham's?
Ham's is acidified - cells are even more C' susceptible in acid.
what is CD 59?
a complement regulating protein that is missing on PNH cells; unregulated complement lyses RBCs.
What's the only visible morphology in PNH?
polychromasia; that's it.
what patient popln is PNH most seen in?
older people.

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