Hemoglobinopathies

Hemoglobinopathies

A genetic point mutation resulting in one nucleotide change and a single amino acid substitution, addition, or deletion in the globin chain (that functionally changes the Hb molecule)

Hemoglobin S

a genetic mutation that results in an amino acid substitution yeilding a hemoglobin that polymerizes under low oxygen tensions changing the shape of the RBCs causing obstruction, hypoxia, and hemolysis

Hemoglobin S etiology

substitution of valine for glutamic acid at the 6th position of the beta chain

+1

change in charge of hemoglobin S

Sickle cell anemia clincial features

symptoms start at 6mo with gamm → beta switch
hand to foot syndrome → weakness/fatigue → pain in extremities → splenomegaly Hemolysis → functional hyposplenism → decreased Ab/opsonization/complement/chemotaxis → increased infections → vaso-occlusive crisis, fever → bone necrosis → osteomyelitis → thrombi → aplastic anemia → leg ulcers
resistance to malaria

UTI

highest causing mortality infection in SCA

sickle cell anemia CBC

anemia
normo/normo
increased PMN and Plt

sickle cell anemia microscopic

sickle cells and target cells
NRBC/poly/retics (increased bone marrow activity)
Schi, HJB

positive

sickle cell anemia solubility test

sickle cell anemia Hb electrophoresis

HbA 0%
HbS >80%
HbF 1-20%
HbA2 2-4.5%

sickle cell anemia treatment

infection prevention
sickle prevention
pain management
crisis management

infection prevention

sickle cell anemia treatment
prophylactic antibiotic
immunizations

sickle prevention

sickle cell anemia treatment
avoid decreased O2 tensions
stay hydrated
hydroxyuria (increases HbF)

pain management

sickle cell anemia treatment
analgesics ongoing (NSAIDS)
opiates during crisis (morphine)

crisis management

sickle cell anemia treatment
opioids for pain
IV fluids vasodilate to clear obstruction
O2 mask to raise oxygen saturation
transfusions
iron chelation

sickle cell anemia prognosis

lifelong pain adn repeated crises
good if carefully managed (most live to middle adulthood)
amniocentesis (DNA) and genetic counseling

Sickle cell trait pathogenesis

normal under stable conditions
can have events during air travel, respiratory infections, anethesia, CHF, heavy exertion
come may have mild symptoms or remain asymptomatic.

sickle cell trait blood smear

normal with few target cells
can have sickle cells during adverse event

positive

sickle cell trait solubility test result

sickle cell trait Hb electrophoresis

HbA 50-60%
HbS 35-45%
HbF <1%
HbA2 2.5-4.5%

Hemoglobin C

amino acid substitution in Hb beta chains resulting in intracellular rod shaped Hb C crystals causing splenic sequestration and hemolytic anemia

Hemoglobin C etiology

point mutation → lysine substituted for a glutamate and the 6th position of the beta chain

+2

charge change of HbC

Hemoglobin C homozygous pathogenesis

lysine for glutamine → structural change → normal O2 tension →oxyHb unstable → HbC hinds → HbC crystals → decreased RBC lifespan → increased splenic sequestration → normo/normo hemolytic anemia 

hemoglobin C homozygous CBC

normo/normo anemia
target cells, NRBC/Retics/poly
HbC crystals

positive

hemoglobin C harlem solubility test result

negative

hemoglobin C solubility test

hemoglobin C homozygous Hb electrophoresis

HbC>90%
HbA 0%
HbF <7%

Hemoglobin C Heterozygous pathogenesis

lysine for glutamate → structural change → oxyhb → rarely becomes unstable (asymptomatic)

Hemoglobin C Heterozygous blood smear

normal Hb (no anemia)
target cells up to 40%

Hemoglobin C Heterozygous Hb electrophoresis

HbA 55-65%
HbC 35-45%
HbA2 2.5%
HbF <1%

hemoglobin E

point mutation resultind in an amino acid substitution yielding a mild anemia

Hemoglobin E etiology

animo acid substitution of lysine for glutamate at the 26th position of the beta chain

+2

charge change in hemoglobin E

Hemoglobin E homozygous pathogenesis

lysine for glutamate → presumes structural change → mild anemia from decreased RBC survival

Hemoglobin E homozygous blood smear

mild anemia, target cells, sometimes microcytes

Hemoglobin E homozygous Hb electrophoresis

HbE 95%
HbA 0%
HbA2 2.5-4%
HbF <1%

Hemoglobin E heterozygous pathogenesis

AA substitution → unstable Hb → decreased RBC survival

Hemoglobin E heterozygous lab tests

CBC = normal
Blood smear = normal with few targets

Hemoglobin E heterozygous Hb electrophoresis

HbA = 70-75%
HbE = 25-30 %
HbA2 = 2.5%
HbF = <1%

Hemoglobin O Arab

amino acid substitution of lysine for glutamic acid in the 121st position of the beta chain

+2

charge change in hemoglobin O arab

hemoglobin O arab clinical manifestions

homozygote = mild anemia
heterozygote = asymptomatic

hemoglobin O arab Hb electrophoresis

migrates with C and E on alkaline electrophoresis

Hemoglobin SC etiology

one HbS and one HbC mutation on each beta gene
considered SCD along with SS and S beta thal

Hemoglobin SC pathogenesis

same clinical issues as HbSS just somewhat less
same frequency as HbSS in African americans
severity between HbSS and HbAS
symptoms start in childhood and increase in teens
crisis less often but some are serious

hemoglobin SC lab testing

CBC = mild to moderate anemia
target cells, sickle cells/HbC crystals or HcSC cells
Hb solubility = posible

Hemoglobin SC Hb electrophoresis

HbS 45%
HbC 45%
HbA 0%
HbA2 2.5 %
HbF 1-7%

Hemoglobin D etiology

point mutation resulting in an amino acid substitution of glutamine for glutamic acid at the 121st position of the beta chain

+1

charge change in hemoglobin D

Hemoglobin D homozygous

very rare
symptoms - virtually no symptoms with no hemolytic anemia
lab testin
Hb solubility = negative
some target cells

Hemoglobin D homozygous Hb electrophoresis

HbD 95%
HbA 0%
HbA2 2.5 %
HbF 2.5%

Hemoglobin D heterozygous

symptoms - asymptomatic
no anemia
normal blood smear

Hemoglobin D heterozygous Hb electrophoresis

HbA 50-60%
HbD 40-50%
HbA2 2.5%
HbF <1%

hemoglobin M etiology

amino acid substitution that causes methemoglobin 

heterozygous

hemoglobin M genetics

hemoglobin M pathogenesis

cyanosis at birth in alpha HbM
cyanosis appears at 4-6 months in beta HbM

Hemoglobin SD etiology

one mutation codes for HbS and one for HbD

Hemoglobin SD pathogenesis

simulates HbSS of Hb electrophoresis, less severe

Hemoglobin SD Hb electrophoresis

indistinguishable from HbSS on alkaline electrophoresis
can be separated on acid electrophoresis

HbC

alkaline electrophoresis
crawl

HbS

alkaline electrophoresis
slow

HbF

alkaline electrophoresis
fast

HbA

alkaline electrophoresis
Accelerate

Hemoglobin S

ɑ₂β₂^6GLU»VAL

Hemoglobin C

ɑ₂β₂^6GLU»LYS

Hemoglobin E

ɑ₂β₂^26GLU»LYS

Hemoglobin O Arab

ɑ₂β₂^121GLU»LYS

Hemoglobin D

ɑ₂β₂^121GLN»GLU