10 Hemoglobinopathies

Question 0

Electrophoresis

Answer 0

HbA isoelectric point is 6.8
In alkaline buffers moves toward anode(+) (mvmt dep on charge only)
In acidic buffers moves toward Cathode (-) (mvmt dep. on charge and meda interactions[cellulose media])

Question 1

Hemoglobinopathy diagnostic techniques

Answer 1

• Electrophoresis (Gel or capillary)
• HPLC
• Advanced techniques
  
  • Isoelectric focusing
  • Globin chain electrophoresis
  • Gene mutation analysis

Question 2

HPLC

Answer 2

Lysate absorbed to resin,
Hb Eluted off with changing buffer concentration
A at 2.46 minutes, S at 4.43 minutes (almost twice as long), C >5 ins

Question 3

Sickle cell disease

Answer 3

1: 600 AA
* Beta chain Glutamic acid (Glu) 6 Valine (Val) causes polymerization and sickling
* Sickling initially reversable but accumulate membrane DMG
* 20 day RBC Lifespan
* 10-12 week manifestatin 2/2 decline in HbF

Heterozygous protects against malaria

Question 4

Factors increasing sickling

Answer 4

Dec. O2, longer transit within low O2 regions(spleen and BM have long transit, Increased [HbS], Dehydration, Acidosis, Cold temp (vasoconstriction), infections.

Question 5

Clinical SS manifestations

Answer 5

• Severe Anemia
• Acute pain crises- especially in bone marrow
• Autosplenectomy(and increased risk of infection by encapsulated bacteria
• Acute chest syndrome - Bacteria, infarct and emboli from infarcted marrow- inflammation causes sluggish flow and more sickling
• Stroke- 11% risk by age 20
• Aplastic crises-ParvovirusB19
• Splenic sequestration
• infection, Liver dmg, Folate consumption and MEGALOBLASTIC anemia, growth retardation, bone abnormalities, renal dysfunction, leg ulcers, cholelythiasis

Question 6

Lab findings for sickle cells

Answer 6

Chronic anemia 5-11g/dl Hb
Increased Bilirubin
Increased reticulocytes
Sickled cells, target cells, polychromasia
Normal MCV
Post splenectomy changes in adult

Question 7

Hb SC

Answer 7

Beta Glu 6 Lys (acidic to basic) - no polymerization but dehydration of cells and still sickling

Hb 10-12 mg/dL

Question 8

HbS/Bthal

Answer 8

Variable pathogenesis based on amount of normal B chain

Labs: HbS>HbA

Question 9

HbSS Treatment

Answer 9

Newborn screening
Infection prophylaxis
Supportive care
Hydroxyurea- Block cell cycle and increases HbF
(decreases pain crises, transfusions, admissions, Acute chest incidence)
RBC transfusion
Allogenic stem cell transplant: Only curative therapy

Question 10

HbSS prognosis

Answer 10

M- 42 year life expectancy, F-48
No real changes in adult outcomes (improved child mortality/morbidity)
Death in adults
-Liver dysfunction
-PHTN
-Stroke
-Vaso-occlusive crisis
-Acute chest

Question 11

S- trait

Answer 11

Carriers of HbS (40%)

Generally normal, but may have subclinical renal damage with microhematuria and dilute urine

Question 12

HbC

Answer 12

Beta glu 6 Lys
*Mild to moderate- often assymptomatic disease with occasional splenomegaly and abdominal pain
30-35 RBC life span HEMOLYTIC ANEMIA
Hb 8-12
TARGET CELLS, microcytic, occasional C CRYSTALS, spherocytes

Question 13

Thalassemias

Answer 13

*Decreased production of alpha or beta hemoglobin chains
Beta: Mediterranian, middle east, india/pakistan, southeast asia
Alpha: Africa, Medeterranian, Mid-east, Southeast Asia

Question 14

Thalassemia histo

Answer 14

Problem with cytoplasmic maturation causes hypochromia and microcytosis

Question 15

Beta thalassemia Major

Answer 15

• Severe B chain decrease = Alpha precipitates in RBC precursors, MEDULLARY hemolysis (in BM)
• presents as HbF declines
• Hb 2-3g/dL

Transfusion dependent- Syndrome dependent on transfusion and chelation

Histo: Hypochromic, target cells, nucleated RBC in PB

Question 16

B-Thal Major with inadequate transfusion

Answer 16

DEATH IN CHILDHOOD
Stunted growth 
Frontal bossing with "mongoloid facies"
Skin hyperpigmentation
Bony abnormalities
Fever
Wasting
Hyperuricemia
Spontaneous fracture
Hepatosplenomegaly
Infection
folate deficitency

Question 17

B-thal Major with adequate transfusion

Answer 17

Normal early devo
Slight cardiac disease and endocrine disorder

• Without adequate chelation
  
  • Absence of pubertal growth/menarche
  • Endocrine disease (DM, adrenal insufficiency)
• Hemosidarosis and cardiac death at 20-30 YO

Question 18

B-Thal minor

Answer 18

Heterozygous beta chan production
Asymptomatic carriers
Common in Mediterranian and asian, 1.5% AA

Labs: Hb Normal (usually no anemia or slight decr. 10)
Microcytosis
Mild anisopoikilocytosis
Basophilic stippling
**3.5-7% HbA2**

Question 19

Alpha thal

Answer 19

4 genes, 4 clinical subtypes

• Silent carrier- 1 gene
• Alpha thal trait-2 genes-> Mild assymptomatic microcytic anemia
• Hemoglobin H- 3 deletions–> Mild to moderate hemolytic anemia
  
  • HbH Beta tetremers- Precipitation and late hemolysis
• Hydrops fetalis 4 deletions- Only tetremers- still born or die shortly after birth.