Hemoglobinopathies and Thalassemias

List the embryonic hemoglobins along with their globin chain composition

• Gower 1 = S2E3

• Gower 2 = A2E2

• Portland = S2Y2

state normal newborn and adult hemoglobins including globin chain composition

Newborn

• F = A2Y2

Adult

• A = A2B2

• A2 = A2S2

identify the percentage of each hemoglobin type present in normal newborns and normal adults

• Birth 

  • 60-90% F

  • 10-40% A

• Adult 

  • <1-2% F

  • >95% A

  • <3.5% A2

define hemoglobinopathy and thalassemia and differentiate between the two

• Hemoglobinopathies 

  • abnormal globin chain synthesis 

  • qualitative

  • structural defects

• Thalassemias

  • quantitative 

  • affects amount of globin chain produced

Discuss diagnosis of hemoglobinopathies and thalassemias including importance of clinical history, physical exam,  CBC, and blood smear. 

identify diagnostic tests used to classify varient hemoglobins

• electrophoresis

• HPLC

• solubility

• isoelectric focusing

Discuss the principle, clinical significance, quality control, and possible limitations of the following tests

• cellulose electrophoresis: list the order in which the hemoglobins migrate 

• Citrate electrophoresis: list the order in which the hemoglobins migrate

• capillary electrophoresis 

• high performance liquid chromatography 

• isoelectric focusing

Describe the physiological effects caused by

• hemoglobin variants with increased O2 affinity

• hemoglobin variants with decreased O2 affinity 

• methemoglobinemia 

• unstable hemoglobins

Identify the globin chain substitution for Hgb S and Hgb C, Hgb SC, Hgb E, and Hgb D-punjab

• S

  • Valine for glutamic acid

  • 6th position

• C

  • Lysine for glutamic acid

  • 6th position

• SC

  • valine for glutamic acid (B1)

  • lysine for glutamic acid (B2)

• E

  • Lysine for glutamic acid

  • 26th position

• D-punjab

  • glutamine for glutamic acid 

  • 121st position

List the geographic distribution of Hgb S, Hgb C, Hgb E, and alpha- and beta- thalassemias, and discuss why it may be prevalent in those areas 

• S

  • X

• C

  • west Africa

  • south America

  • central America

  • Caribbean

  • North America

• E

  • Thailand

  • Cambodia

  • Laos

  • Malaysia

  • Indonesia

• Alpha thal/beta thal

  • “thalassemia belt”

    • Eastern Mediterranean through middle east and India to Southwast Asia and Northern Africa

  • Alpha = Cyprus, Eastern Saudi Arabia, Nepal, India, Thailand, and Papua New Guinea

  • Beta = Cyprus, Greece, India, Thailand, and Indonesia

Discuss the pathophysiology and clinical presentation of Hgb SA, as well as characteristic RBC morphs

• Sickle cell trait (heterozygous)

• Pathophysiology

  • individual produces both Hgb A and Hgb S

    • Approx 60% Hgb A and 40% Hgb S

  • decreased Hgb S % can indicate iron deficiency or alpha thal

• RBC Morph

  • few target cells 

  • usually normal

• Solubility 

  • turbid = pos

• Presentation

  • usually asymptomatic, occasional sickling

Discuss the pathophysiology and clinical presentation of Hgb SS, as well as characteristic RBC morphs

• Sickle cell disease (homozygous)

• Pathophysiology

  • dont produce Hgb A, only Hgb S

• Symptoms

  • usually symptom free until 6 months of age

  • crises

• Inheritance

  • parents need to be AA or AS

• RBC morphs

  • sickle cells

  • Target cells

  • nRBCs

  • polychromasia

  • howell jolly bodies

Discuss the pathophysiology and clinical presentation of Hgb CC, as well as characteristic RBC morphs

• Pathophysiology

Discuss the pathophysiology and clinical presentation of Hgb AC, as well as characteristic RBC morphs

Discuss the pathophysiology and clinical presentation of Hgb SC, as well as characteristic RBC morphs

Discuss the pathophysiology and clinical presentation of Hgb EE, as well as characteristic RBC morphs.

Interpret citrate agar and cellulose acetate gel electrophoresis patterns for the following hemoglobinopathies

• Hgb SS

• Hgb AS

• Hgb AC

• Hgb CC

• Hgb SC

• Hgb EE

• D-Punjab

Explain why multiple laboratory methods are necessary for proper diagnosis of hemoglobinopathies 

categorize the type of hemoglobinopathy or thalassemia by interpreting patient history, chemistry and hematology results, red cell morphology, and electrophoresis results

Discuss the pathophysiology of thalassemia

• Decreased or absent globin chain synthesis leads to 

  • decreased production of hemoglobin

  • imbalance in alpha/beta ratio

    • unaffected gene produces globin chains at a normal level 

    • unpaired normal globin chains will accumulate in the red cell causing damage and premature cell death

describe the pathophysiology of hereditary persistence of fetal hemoglobin and hemoglobin Lepore

State the genotype(s) and describe the physical characteristics, clinical course, and laboratory findings including red cell morphologies or any special stains for beta-thalassemia major

State the genotype(s) and describe the physical characteristics, clinical course, and laboratory findings including red cell morphologies or any special stains for beta-thalassemia minor

State the genotype(s) and describe the physical characteristics, clinical course, and laboratory findings including red cell morphologies or any special stains for betal-thalassemia intermedia

State the genotype(s) and describe the physical characteristics, clinical course, and laboratory findings including red cell morphologies or any special stains for silent carrier of alpha-thalassemia

State the genotype(s) and describe the physical characteristics, clinical course, and laboratory findings including red cell morphologies or any special stains for alpha- thalassemia minor

State the genotype(s) and describe the physical characteristics, clinical course, and laboratory findings including red cell morphologies or any special stains for hemoglobin H disease

State the genotype(s) and describe the physical characteristics, clinical course, and laboratory findings including red cell morphologies or any special stains for hemoglobin Bart hydrops fetalis syndrome

Name the globin chain composition of the following

• Hgb Bart

• Hgb H

• Hgb Lepore

• HPFH (hereditary persistence of fetal hemoglobin) 

**how does 12d manifest?*

Differentiate the following haplotypes based on globin chain production

• B0

• B+

• Bsilent

• a0

• a+

• aT

Identify and discuss treatment options for sickle cell anemia and beta-thalassemia major