7. Thaslessemias and Hemoglobinopathies

Question 1

hemoglobin structure

Answer 1

• globular protein (2 alpha and 2 beta chains)
  
  • ea globin contains a heme with 1 iron atom
  • 280,000,000 Hgb per RBC (96% of protein in red cells)
  • tetramer formation alpha2beta2 = hemoglobin A which is most common form in adults
    
    • depends on [proteins] alpha and beta
• with intravascular hemolysis, [Hb] increase too rapidly and depletes HAPTOGLOBIN (binds Hb and preserves it from being broken down and excreted)
  
  • urinary met-Hb is red-brown

Question 2

hemoglobin formation

Answer 2

• 4 alpha genes (chromosome 16) and 2 beta genes (chromosome 11) make equal numbers of globin chains
• heme inserted into globin chains and tetramers are assembled

Question 3

embryonic H, Fetal Hb, HbA, HbA2

Answer 3

embryonic: 2 zeta (chrom 11), 2 epsilon (chrom 16)
fetal: 2 gamma (chrom 11 Ggamma and Agamma), 2 alpha (chrom 16, alpha2 and alpha1)
HbA: 2 beta (chrom 11), 2 alpha (chrom 16, alpha2 and alpha1)
HbA2: 2 delta (chrom 11), 2 alpha (chrom 16, alpha 2 and alpha 1)

Question 4

thalessemias, sickle cell disease, and hemoglobin SC disease are all what kinds of hemoglobin abnormalities?

Answer 4

thalessemias: deficient globin synthesis

sickle cell and hemoglobin SC: abnormal globin structure

Question 5

Thalessemias

Answer 5

Normal globin chains produced in abnormal number. RBC have low Hb content and often are small when unpaired globin chains precipitate and are removed along with membrane.

• severity depends on how many globin genes are affected
• found in similar distribution to malaria
• can lead to anemia, ineffective hematopoiesis, transfusion dependency, iron overload

Question 6

alpha-thalessemia (a*) heterozygote

Answer 6

• Missing one alpha globin gene on one chromosome
  
  • 36% African Americans
    ○ Other 3 alpha globin genes can compensate
    ○ Silent carrier
    Low normal size RBCs (75-85 fL)
    *asymptomatic

Question 7

alpha-thalessemia (a0) heteroxygote

Answer 7

• Missing two alpha globin genes on one chromosome
  
  • Small RBCs (67-77 fL), otherwise normal
  • 5% Southeast Asians
    ○ Loss of 2 could be clinically significant
    ○ Cis, so could have children born with no alpha chains (lethal)
    *asymptomatic

Question 8

alpha thalessemia minor

Answer 8

(also includes α-thalessemia(α0))

- 4% African Americans have only 2 α genes
- RBCs small (67-77 fL) but otherwise normal
- Useful for genetic counseling (trans) * asymptomatic

Question 9

alpha thalessemia major

Answer 9

Alpha Thalessemia major
	- 1/1600 Southeast Asian children conceived have no alpha genes
	- Die in utero of hydrops fetalis
		○ Make hemoglobin H
			§ Beta globin tetramer
		○ Make hemoglobin Barts
			§ Gamma globin tetramer

Question 10

alpha thalessemia intermedia

Answer 10

Hemoglobin H Disease
- Inherit only one alpha gene (lost 3/4)
- Marked anemia and microcytosis
- Make Hemoglobin H
○ Tetramer of Beta globins
○ Unstable, slowly precipitates to form Heinz Bodies
* Moderate to severe hemolytic anemia, modest degree of ineffective erythropoiesis, splenomegaly, variable bone changes

Question 11

beta thalessemia silent trait

Answer 11

partially dysfunctional one beta globin gene

Question 12

beta thalessemia minor

Answer 12

• 4 alpha genes and

Question 13

beta thalessemia intermedia

Answer 13

• Severe (one partially dysf. Beta gene and one completely dysf. Beta gene)
  
  • Present in infancy when HbF production stops and HbA production does not start
  • Jaundice, growth retardation and skeletal deformities possible
    ○ Drive for increased erythropoiesis expands marrow and makes the skull/bones look deformed (“hair on edge” skull)

Question 14

beta thalessemia major

Answer 14

• Treated with folate and RBC transfusion dependent
  
  • Eventually ^^ leads to iron overload
  • Without iron chelation therapy, pts die in their teens of toxic cardiomyopathy or liver failure

Question 15

Sickle Cell Disease - molecular level

Answer 15

adenine substitution to thymine on beta 6 globin gene leads to beta 6 globin glu -> val

• causes a conformational change of deoxyhemoglobin and RBC
  
  • strands assemble to into groups to form fibers and fibers form fascicles which can grow and distort the red cells
  • *****Deoxyhemoglobin-S forms fibers from two strands of molecules held together by the B6 valines

Question 16

conformational change of deoxyhemoglobin and RBC leads to what?

Answer 16

intravascular hemolysis, functional asplenia, renal injury, bone infarction, pulmonary infarction, brain infarction, and other manifestations (hand/foot syndrome, ulcers, priapism)

Question 17

sickle cell and intravascular hemolysis

Answer 17

§ Chronic hemolytic anemia
§ Sickled RBCs only survive 10 days
□ Free Hb injures endothelium and scavenges NO, causing pulm hypertension
§ High rates of marrow turnover leads to folate deficiency
§ Parvovirus B-19 causes aplastic crisis
□ Affects progenitor red stem cells (bone marrow)

Question 18

sickle cell and functional asplenia

Answer 18

§ Deoxygenation of RBC in splenic sinusoids leads to sequestration and infarction
□ More susceptible to bacterial infections
® Pneumococcal pneumonia and salmonella osteomyelitis are more common!
(target red cells seen in asplenia, HbC, liver disease, and thalessemia = HALT said the hunter to his target)

Question 19

sickle cell and renal injury

Answer 19

§ Papillary infarction and sloughing can lead to obstruction and chronic blood loss
§ Loss of renal [ ] ability -> systematic hyperosmolarity and more frequent sickling episodes

Question 20

sickle cell and bone infarct

Answer 20

§ Rigid BVs in bone obstruct easily
§ Marrow infarcts cause painful episodes and loss of productive marrow
§ Femoral and humeral head and other large bone infarcts can lead to orthopedic disability

Question 21

sickle cell and pulm infarct

Answer 21

§ Pneumonia can lead to lung hypoxia and lung vessel infarction
□ Areas of necrotic lung more susceptible to infection
§ Vicious cycle of infection and infarction leading to shunting and global hypoxia is the most common cause of death

Question 22

sickle cell and brain infarct

Answer 22

§ BVs injury from sickle cells leads to BV thickening and increased susceptibility to stroke
§ Pts w/hx of stroke at at increased risk for future stroke
§ Stroke is second most common cause of death and the most important cause of dsiability
(** LITERATURE SAYS TRANSFUSIONS REALLY HELP PREVENT THIS*)

Question 23

sickle cell and “other manifestations”

Answer 23

§ Hand/foot syndrome in infants leads to the loss of digits and limbs
§ Skin ulcers, esp pretibial, are frequent and can lead to osteomyelitis
§ Priapism occurs in teenage males, loss of erectile function if not treated early

Penile infarction

Question 24

Drivers of sickle cell formation

Answer 24

○ Lose water, so cell edges come closer together
- Low pH -> low O2 tension
○ Low O2, cells sickle more
- Decreased transit times through vascular beds
○ Normally slow in spleen and bone marrow
○ Setting of inflammation
§ Difficult cycle to break

Question 25

what % of HbF prevents signs/sxs of sickle cell anemia?

Answer 25

> 30

Question 26

treatment of sickle cell anemia

Answer 26

Hydroxyurea
- Only drug approved
- Increases HbF levels
- Reduces frequency of painful episodes
- Works in ~40% of all HbSS patients
Other Treatments:
- Immunize for pneumococcus and neisseria (to prevent problems)
- Keep hydrated
- Treat painful episodes (problem with assuming drug seeking)
- Transfuse for nonresolving and critical crises like chest crisis and stroke
- Attempt tx with hydroxyurea to induce production of HbF
- Bone marrow transplant if HLA matched sibling with normal Hb exists

Question 27

lab tests for sickle cell anemia

Answer 27

cellulose acetate (pH8.2) and  citrate agar (pH6.4) separate out F, A, S, and C
quantification by gel screening to really see despite overlap

Question 28

HbAS

Answer 28

benign- causes hematuria (genetic counseling for patient when cause found to be AS)- can cause splenic infarction (rare)
- rare infarction in ortho surgery with tourniquets
Rare deaths in military recruits

Question 29

HbSC

Answer 29

□ Touch on this only briefly, may see in clinic
□ HbC (glu to lys in B6 globin)
□ HbSC is milder than HbSS

Question 30

causes of aplastic anemia?

Answer 30

idiopathic, drug related (iatrogenic), viral infections (hep, epstein barr, etc), inherited (fanconi anemia, telomerase defects)