Normocytic anemias

Causes of hemoglobinopathies

1. A single AA substitution in (usually) the beta chain → Sickle Cell anemia

2. Abnormal synthesis of one of the AA chains→ Thalassemias

3. Fusion of Hemoglobin chains→ HGB Lepore (δβ)

4. Extension of AA chain → Hgb Constant spring (α chain)

Sickle cell anemia genetics

β chain substitutions on chromosome 11

• Autosomal codominant abnormality (both alleles expressed simultaneously instead of one masking the other)

• Occurs 1:375 of African Americans

  • Predominant in malaria areas: Central & West Africa, parts of Mediterranean, Asia, India

  • Trait: 8-10% of African Americans

  • Anemia: 0.3-1.3% African Americans

• 4 haplotypes, depending on amount of HgbF (higher HgbF= less severe S/S):

  • Asian

  • Senegal

  • Benin

  • Bantu

Sickling gene

• Glutamate substituted by Valine at position 6 from the N Terminus (total 146 AAs)

• Glu is hydrophilic and Val is hydrophobic

  • Creates sticky patch that cause Hgb to stiffen

Sickle cell shape

• HgbS forms liquid tactoids (elongated)/ stiff rod fibers beneath membrane

• Stiffens RBCs in low O2 areas: spleen, liver, kidney, joints, extremities

• Sickle/ boat shape obstruct small blood vessels, adheres to vascular endothelium

• Less O2 delivered to tissues

• pH decreases

• Sickling induced by: hypoxia, acidosis, dehydration, fever, cold exposure

• Repetitive sickling→ RBC life is 10-20 days

Sickle cell S/S

Basic S/S:

1. Chronic hemolytic anemia

2. Recurrent painful attacks

3. Bacterial infections

4. Deterioration of tissues/ organ fxn

5. Shortened life expectancy

Dactylitis also present (sickle cells in microvasculature→ swollen hands and feet)

Diagnosed between 6-24 months

• Protected with high levels of Hgb before then

Sickle cell indices and peripheral smear

• normocytic, normochromic anemia

• Hgb 6-8 g/dL (normal: 12-16M 10-14F)

• Decreased: RBC count, hematocrit

• Decreased Hpt: indicates extravascular hemolysis

• Increased Bilirubin, LDH

• Increased Reticulocytes→ mildly elevated MCV

• HgbS precipitates→ Positive sickle solubility test in high-molarity buffered phosphate solutions

• HgbS also present in hgb electrophoresis

Sickle cell trait + population

• Heterozygous

• 60% HgbA, 40% HgbS

• US: 2.5M people

• Africa: 25-30% where Malaria is endemic

• Circumstances that cause crisis: unpressurized cabin, high altitudes, low oxygen

HgbC disease gene + population

Substitution from the 6th position of the N-Terminal of the beta chain where glutamic acid is substituted by Lysine

Considered a sickling disorder

HgbC Disease: two abnormal genes

HgbC trait: one abnormal gene (asymptomatic)

• Heterozygous: HgbAC: 60% HgbA, 40% HgbC

Population:

17-28% in West Africa (or Northern Ghana)

2-3% African Americans have the trait

• 0.02% have the disease

HgbC indices

• normochromic, normocytic

• MCHC mildly elevated due to dense HgbC

• RBC lifespan 38 days

HgbC peripheral smear

C for crystal/ “Bars of gold”

• obstructs microvasculature, melts in spleen

Codocytes predominant: 50-90%

Electrophoresis has wide band of HgbC in same position as HgbA2

Hgb electrophoresis

HgbC and HgbA2 on same level

Based on charge as they move from diff charges

HgbSC

• Heterozygous combination of HgbC and HgbS

• RBC lifespan: 28days

• Less severe than homo HgbS but more severe than homo HgbC

• Considered a sickle disease

• Electrophoresis reveal 50% HgbS and 50% HgbC (according to Dr. Nocera)

• But according to The Blood Project, it’s 50% HgbS and 45% HgbC

HgbSC indices/ peripheral smear

Increased MCHC

normocytic, normochromic

Hct >25%

Some Hgb off-center

Codocytes and sickle cells present

HgbD

Punjab and LA variants

• but high incidence in Britain

β121 Glu→ Gln mutation

Migrates with HgbS in electrophoresis

Does not sickle and has normal solubility

Could exist hetero with HgbS

• Produces aggregates

HgbE

2nd most prevalent hemoglobinopathy worldwide

• Mostly in SEA

• Nearly 50% in Thailand

  • Cambodia and Laos also have high numbers

β26 Glu→ Lys

Unstable under oxidant stress

Oxygen dissociation shifted to right (less affinity)

Hypochromic, microcytic but asymptomatic

Hgb-Phila

Occurs in those of African descent

α68 Asn→ Lys

HgbO Arab

β121 Glu→ Lys

Rare in African Americans