Hemoglobinopathies

Question 1

Hemoglobin electrophoresis: cellulose acetate vs citrate gel

Answer 1

Cellulose acetate - hemoglobins migrate together; cannot differentiate between S,D, or G
Citrate gel - separates better

Question 2

Which hemoglobins should NOT be seen?

Answer 2

HbH, Hb Bart

Question 3

Newborn screening of hemoglobinopathies

Answer 3

Part of routine newborn care
Normal is hemoglobin F and A
Sickle cell trait: F>A>S
Sickle cell disease: F>S>A

Question 4

Disease pathology of thalassemias

Answer 4

1. Decreased globin production, imbalance of globin production, or excess globin precipitates
2. ineffective blood cell formation, or hemolysis
3. anemia, bone marrow expansion, extramedullary hematopoiesis, increased iron absorption

Question 5

alpha-thalassemia

Answer 5

deficiency of alpha Hb

deletions

Question 6

Barts/Hydrops Fetalis

• what is it
• treatment

Answer 6

complete absense of alpha Hb (alpha thalassemia)
incompatible with life
High levels of HbH and HbBarts

Intrauterine transfusions with postnatal chronic transfusions and SCT being utilized

Question 7

alpha thalassemia silent carrier

Answer 7

small DNA deletion, removes 1 alpha gene

2 variants: rightward and leftward crossover

Question 8

alpha thalassemia trait

Answer 8

loss of 2 alpha genes - either cis or trans
–> if parents are cis (meaning one chromosome completely missing), 25% chance of nonviable fetus
mild anemia, hypochromia, microcytosis
Often mistaken for iron deficiency anemia

Question 9

HbH disease

Answer 9

loss of 3 alpha genes
phenotype: thalassemia intermedia. Moderate anemia and microcytosis
Excess Hb Barts (neonatal) and HbH (older)
Unstable hemoglobin –> hemolytic

Question 10

Hb Constant Spring

Answer 10

HbH variant
Phenotype: Intermedia
Mutation in stop codon

Question 11

Beta Globin Mutations

Answer 11

mostly point mutations
B+ - make some B globin
B0 - make none

Question 12

Beta thalassemia trait

Answer 12

B/B0 or B/B+
asymptomatic
mild anemia, hypochromia, and microcytosis

Increased HbF and HbA2 (alpha to delta binding)
Often misdiagnosed as iron deficiency

can be diagnosed on Hb electrophoresis

Question 13

Beta thal intermedia

Answer 13

mild to moderately severe anemia
Microcytosis, hypochromia
Increased HbF and HbA2
Hepatosplenomegaly possible
wide clinical spectrum
***affected by alpha globin gene mutations***

Question 14

Beta thal major

Answer 14

B0/B0
severe anemia develops in year 1
Severe microcytosis and hypochromia
Organomegaly, growth failure
Transfusion dependent
Bone marrow transplant needed for cure
Hemachromatosis due to excess iron absorption and transfusions

clinical features: frontal bossing - prominent forehead

Question 15

Thalassemia Major Management: chronic hypertransfusion therapy

Answer 15

chronic hypertransfusion therapy every 2-4 weeks

alleviates anemia, improve growth and development, suppress inefficient erythropoiesis

Greater survival rates

Question 16

Thalassemia Major Management: Pharmacological

Answer 16

Hydroxyurea
augment HbF production
Response varies between patients

Side effects: cytopenias, hyperpigmentation, weight gain, azoospermia

Thal major cases: reduce need for transfusions

Question 17

Allogenic Hematopoietic stem cell transplant

Answer 17

can be done at any age but is better when young
Sibling best; matched unrelated donor next best

Myeloablative conditioning needed to wipe out preexisting marrow

Immunosuppresive therapy
GVHD prophylaxis

Question 18

Gene therapy for hemoglobinopathies

Answer 18

introduce stable, functional globin genes into patient’s HSCTs

Question 19

Sickle cell disease

Answer 19

Point mutation in B globin chain
AR
RBC’s become very stiff
most common inherited blood disorder in the US
~8% of African Americans are SCD carriers

Question 20

Sickle Cell disease pathophysiology

Answer 20

RBC’s stick to blood vessel walls –> hemolysis –> iron shift, cells dry out
Scavenging and depletion of nitric oxide
Increased adhesion and recruitment of neutrophils
Activation of coagulation system

Question 21

HbSS disease

Answer 21

Sickle cell anemia
most common sickle cell disease
severe or moderately severe phenotype
shortest survival

Question 22

Clinical presentation of sickle cell disease

Answer 22

Diagnosed on newborn screen
asymptomatic until 6 mo

Fetal hemoglobin starts to drop –> sickle starts to come out

Puffy hands

Question 23

Vaso-occlusive pain crisis (VOC)

Answer 23

most common complication of SCD

Block blood supply to bones

Question 24

SCD management

Answer 24

Analgesia within 30 minutes
use SC route when IV access difficult
Opioids
NSAIDS as adjuant

*Meperidine not recommended due to neurological side effects and delirium

Question 25

SCD CNS complications

Answer 25

stroke
aneurysm
hemorrhagic stroke
ischemic or infarctive stroke
moyamoya
silent cerebral infarct
Transient ischemic attack

Question 26

SCD pulmonary complications

Answer 26

Asthma - same incidence as general pop

Restrictive lung disease

Pulmonary hypertension

Question 27

Acute Chest syndrome

Answer 27

second most common cause of hospitilization

Most common cause of death

Question 28

Hydroxyurea

Answer 28

SCD therapeutic option
Ribonucleotide reductase inhibitor
used to treat myeloproliferative disorders
Acts on S phase of cell cycle

Used in malignancies:

• myosuppression
• increase HgF production

Question 29

Novel agents

Answer 29

Anti-inflamamtory: Crizanlizumab

Hemoglobin modifiers: Voxelator

Question 30

Sickle Cell trait - symptoms?

Answer 30

Asymptomatic and well
Increased risk of:
- renal disease
- exertional heart illness
- pulmonary embolism
- glaucoma after hyphema

Question 31

Hemoglobin C

Answer 31

Less soluble, crystallizes
Mild chronic hemolytic anemia
Intermittent jaundice
splenomegaly
intra and extracellular crystal formation
Target cells, microcytosis