8/7- Hereditary Hemolytic Anemias Flashcards Preview

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Flashcards in 8/7- Hereditary Hemolytic Anemias Deck (34):
1

What is shown here? 

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Left: reticulocyte

- Excess of membrane which forms tuft (looks like pinched wet clay); this membrane is lost over 24 hr period along with mitochondria, left over RNA, and ribosomes

Right: normal discocyte

2

What determines a RBC's deformability?

Surface area/volume

- Increased in a discocyte

- Decreased in a spherocyte

Membrane pliability

- Unstable in HS and HE

- Oxidation

Increased internal viscosity

- Increased in SS-Hb and xerocytosis

3

Case: Young man with jaundice

- 21 yo referred from GI clinic to hematology after negative workup for jaundice and RUQ pain

- Pts is "lemon yellow", but no N/V

- GI eval: ceruloplasmin, SPEP, hepatitis serology, HIV, ANA, EBV, Sm Mus Ab, and normal liver biopsy

- Hemoglboin: 11.5, HCT 30 (MCHC 38)... Mild anemia

- Reticulocyte count 7% (RPI 3.1)... slightly elevated retics

- Normal PT, PTT

- Normal Hb electrophoresis

- LFTs total bili 4.5 with direct of 1.2

- ALT 63, AST 33, LDH 177

- Mother and maternal grandmother had gallbladder removed at young ages

- Spleen tip palpable on physical exam

What is this? 

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Hereditary Spherocytosis (HS)

- Spherocytic hemolytic anemia seen on PBS

- Family hx of gallbladder removal is indicative of stones due to...?

4

What is the most common hemolytic disease in black people? Caucasians?

Black: sickle cell

Caucasian: Hereditary Spherocytosis

5

Mutations leading to hereditary spherocytosis involve what part of the RBC?

Cytoskeleton

- Problem with vertical interactions (?)

6

What is seen here? 

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Hereditary spherocytosis

- Not completely spherical; this one has a dimple

- These cells have a reduced SA ratio

7

Genetic characteristics of Hereditary Spherocytosis?

- Inheritance

- Prevalence

- Charactersitics

- Autosomal dominant

- Occurs in 1:2000

- 25% of the time, parents are not affected (pt is de novo)

- Variable degrees of anemia

- Reticulocytosis

8

What is the main underlying pathophysiology of HS?

Ankyrin

- Most common

- Gene on 8p; wide deletions with HS, mental retardation, typical facies and hypogonadism

Alpha and Beta Spectrin Mutations

Band 3

- Truncated

- Pincer cells

Protein 4.2 deficiency

- Japanese

- Sphero-elliptocytosis

9

What is this? What causes it?

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Acanthyocytic HS

- Certain beta spectrin mutations

10

What is this? What causes it? 

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"Pincered" HS

- Associated with truncated band 3

11

What is this? 

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Spleen

- Graveyard of the spherocyte

- Small openings between sinusoids of the spleen and veins which carry blood back to circulation act as traps for non-deformable RBCs

- If stuck, consumed by macrophages nearby

- Excess membrane may be removed when cells in HS go through slits, losing bits of lipid bilayer each time, since it's not tethered to the cytoskeleton... thus cells become progressively more spherical in "splenic conditioning"

 

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12

Pathophysiology of HS (figure)

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13

What is seen in HS in regards to osmolarity?

There is increased osmotic fragility in HS

- Physiologic [NaCl] is about 0.9%

- RBCs in hypotonic solutions swell, and can normally deal with this because of the increased SA ratio of cells

- When cell swells beyond the point that the cytoskeleton can hold the membrane together, hemoglobin will escape (osmotic hemolysis)

- In HS, loss of membrane causes hemolysis to occur at higher concentrations (0.7%)

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14

HS Pathophysiology Summarized

- Spectrin Loss (often due to Ankyrin)

- Defects in Vertical Cytoskelton

- Membrane Instability

- Loss of Surface Area

- Spherical RBCs

- Dehydration (increased MCHC)

- Splenic Conditioning and Trapping

15

How may HS be diagnosed?

- Spherocytosis

- Increased MCHC

- Reticulocytosis

- Family History (although parents don't always have it)

- Splenomegaly

- Negative Coomb’s Test (to rule out autoimmunity)

- Increased Osmotic Fragility

- Eosin-5 maleimide (EMI) binding to RBC

16

What is the clinical course of HS?

- Neonatal Jaundice (need phototherapy)

- Splenomegaly

- Hemolytic Crises During Infection

- Aplastic Crises with Parvovirus B19

- Gallstones

- Jaundice with Indirect Hyperbilirubinemia

- Folate Deficiency

- Rarely: pulmonary Hypertension, leg ulcers

17

Treatment of HS?

Folate Supplementation

Splenectomy

- Not done in children until 8 or 9 yo

- Not done as often because of possible post-splenectomy issues (sepsis with encapsulated organisms, DVT post abdominal surgery, long term risk for DVT, pulmonary HTN, increased risk for CVD and stroke)

18

What is this? 

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Hereditary Elliptocytosis

- Problem with horizontal interactions

- Shear stress elongates the cell; normally flips back when it gets into wider venous circulation, but here, they don't go back

19

What is this? 

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Hereditary Elliptocytosis

- More than 50% of the RBCs should be elliptical

- Some of the cells resemble the ovalocytes you see in B12 deficiency

- The elliptocytes are not typically macrocytic

20

What is this? 

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Hereditary Elliptocytosis

- When heated, the elliptocyte spectrin is typically unstable

- Spectrin precipitates from the membrane and blebs of lipid form

21

What is this? What causes it? Epidemiology? 

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A form of HE/Ovalocytosis in which RBC has a transverse ridge (characteristic triangular shape)

- Abnormal band 3 proteins

- Appear to be resistant to malarial invasion (band 3 is a malarial receptor); protective

- Found in SE Asia and the South Pacific (Malaysia, New Guinea, Indonesia, Philippines)

22

Genetic characteristics of HE?

- Inheritance

- Characteristics

- Epidemiology

- Autosomal dominant

- More severe disorders are usually double heterozygotes

- Bizarre blebbing and microspherocytes: HPP (hereditary pyropoikilocytosis); can have incredibly small MCV (like a mouse)

- Southeast Asian ovalocytosis is associated with resistance to malaria

23

What are the membrane protein defects associated with HE?

Spectrin

- Self-association sites (key feature!)

- Spectrin alpha(LELY)

Protein 4.1

Glycophorin C deficiency

- Leach phenotype 7 kb deletion

- GPC deficiency with elliptocytosis

24

Case) A Day Laborer with Anemia

- 25 yo man employed in plumbing supply store on weekends as day laborer

- Spent a day cleaning chemical storage plants down by the ship channel (Saturday)

- 3 days later, doesn't feel well; mild dyspnea

- Examination unremarkable

- Lab: Hct 37.8, Hb 13.2, WBC 14.8... so slightly anemic with a little WBC elevation

- Next day had fatigue and yellow eyes

- Lab: Hct 25.6, Hb 9.1 MCV 96, WBC 21.3... so more severe anemia and lymphocytosis

- UA: moderate blood, 4+ bili, no red cells

- Total bilirubin 10.6, direct 2.3

- LDH: 2.3

- Coombs D/I both negative

- Reticulocyte count 6.5%... relatively increased

- Haptoglobin 6 

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Oxidant hemolysis

- All factors of intravascular hemolysis present

- Blister cells: precipitates of hemoglobin that are so dense they won't take up dye in the Wright's stain (although can use Heinz body stain) 

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25

What is this? 

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Blister cells stained with Heinz body stain

26

Process of oxidant hemolysis (flowchart)?

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27

What is this? 

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Heinz bodies

- May occur from hemoglobinopathy or from metabolic disorder (not producing NADP)

28

G6PD Variants?

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29

Benefit of G6PD mutation?

Possibly malaria resistant (metabolically defunct cell can't handle the load?)

30

Epidemiology of GP6D?

About 10% of American black men are G6PD deficient

31

What are some compounds associated with oxidant hemolysis in G6PD?

Antimalarials

- Primaquine, Quinacrine

Sulfonamides, Sulfones

- Sulfamethoxazole, Sulfanilamide

- Diaphenylsulfone (Dapsone)

Nitrofurans

- Nitrofurantoin

Misc

- Methylene blue

- Naphthalene (Moth balls)

- Rasburicase

32

Review of G6P Deficiency

- Hundreds of variants

- X-linked inheritance

- A- present in 12 % of black American men

- Neonatal hyperbilirubinemia

- Mediterranean: may hemolyze with fava beans—divicine; may have chronic hemolysis

- Blister and bite cells during hemolysis

- Heinz bodies Crystal violet supravital stain

33

Pathophysiology of pyruvate kinase deficiency

- Autosomal recessive, but most affected are double heterozygotes

- Red blood cell enzyme is deficient and there is little generation of ATP

- Most of the circulating cells are reticulocytes because they retain a few mitochondria

- Before splenectomy: 5-15 %, after splenectomy 70 % reticulocytes

- The morphology of the cell is that of a run down energy depleted red blood cell—mostly echinocytosis with extreme polychromatophilia from the resistant population of reticulocytes.

34

What is this? 

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PK Deficiency

- In PK deficiency not enough ATP is generated so all of the membrane pumps run down such that the RBC cannot maintain it’s Na K gradient or the integrety of its lipids—echinocytes form. The only cells that are truly happy are very young reticuloyctes they can make ATP with their mitochrondria.