Transcript Hemolytic Anemias – the Hemoglobinopathies

HEMOLYTIC ANEMIAS –
THE
HEMOGLOBINOPATHIES
Part 1
HEMOLYTIC ANEMIAS – THE
HEMOGLOBINOPATHIES
 Hemolytic
anemias are a heterogenous
group of normochromic, normocytic
anemias (except for the thalassemias) in
which the RBC survival time is decreased.
 The premature destruction may result
from intrinsic abnormalities of the RBCs
or abnormalities extrinsic to the RBC.
 Reticulocytosis is a constant feature.
HEMOLYTIC ANEMIAS – THE
HEMOGLOBINOPATHIES
 Remember
that the life span of the RBC
can decrease to about 18 days before
increased erythropoiesis in the bone
marrow is unable to compensate.
 Hemoglobinopathies are a type of
intracorpuscular defect leading to the
production of an abnormal hemoglobin or
to an aberration of hemoglobin synthesis
 Abnormal hemoglobins

Most are clinically insignificant with no
physiologic consequence
HEMOLYTIC ANEMIAS – THE
HEMOGLOBINOPATHIES
Most abnormalities occur in the beta chain with
abnormalities in this chain more likely to cause
disease because we have only two genes that encode
the beta chains, but we have four genes that encode
the alpha chains.
 Most variants arise from the substitution of a single
amino acid in the  globin chain.

HEMOLYTIC ANEMIAS – THE
HEMOGLOBINOPATHIES



Changes may also arise from multiple
substitutions, insertions or deletions, frame
shift mutations, cross-overs, and fusions of
subunits.
If an individual is homozygous for a structural
gene in the beta chain, the individual is said to
have the disease or anemia
If the individual is heterozygous, they are said
to have the trait, and 50% or less of the
hemoglobin will be abnormal.

The % of abnormal hemoglobin is usually less than
50% because the  chain will preferentially bind with
the normal  chains.
HEMOLYTIC ANEMIAS – THE
HEMOGLOBINOPATHIES

Sickle cell disease
Hemoglobin S – position 6 on the  chain has a valine
(nonpolar) substituted for the normal glutamic acid
(polar)
 Carriers of the gene in Africa may be as high as 2040% because when parasitized by Plasmodium
(causes malaria), cells containing hgbS will sickle
quickly, either killing the parasite or causing RBCs to
be sequestered in the spleen and destroyed.
Therefore, having the gene provides a certain
protection against malaria.
 It is usually only in the homozygous state that the
disease is so devastating
 8-10 % of African Americans are carriers in the U.S.,
with .3-1.3 % being homozygous

HEMOGLOBIN S
HEMOLYTIC ANEMIAS – THE
HEMOGLOBINOPATHIES

Pathophysiology of the disease
 When oxygenated, Hgb S is soluble
 When oxygen tension decreases, hgb S in the
deoxyhemoglobin state polymerizes into insoluble
aggregates leading to sickled cells
 This leads to increased blood viscosity which leads to
decreased circulation and increased exposure to low
oxygen. This, in turn, leads to more sickling
 The small microvasculature may become clogged with the
rigid sickle cells leading to hypoxia and infarction of
organs and a “sickle cell crisis”.
SICKLE CELLS
HEMOLYTIC ANEMIAS – THE
HEMOGLOBINOPATHIES
Upon reoxygenation, the RBC may return to its original
shape
 However, repeated sickling damages the permeability of
the RBC membrane leading to premature death of the
cell
 In addition, after repeated sickling events, the cells
become irreversibly sickled and are removed by the
spleen
 Early in childhood, the spleen loses its function due to
splenic atrophy and necrosis from repeated ischemic
(blood supply decreased due to blockage of the small
vasculature) crises.
 Thus, these young patients are more prone to
infections, especially from encapsulated
microorganisms.
 The liver and bone marrow then take over destruction
of abnormal cells.

HEMOLYTIC ANEMIAS – THE
HEMOGLOBINOPATHIES


Hgb S has a decreased affinity for oxygen, leading to a
shift to the right in the oxygen dissociation curve. This,
however, creates more deoxyhemoglobin, and hence,
more sickling
Clinical findings
The disease is diagnosed early at about 6 months of age
when hemoglobin F is replaced with hgb S rather than
hgb A.
 Homozygous individuals frequently do not live beyond
middle age (improved healthcare has increased the life
expectancy of these individuals)
 Chronic hemolytic anemia – due to extravascular
hemolysis.
 RBC survival may decrease to 14 days
 Increased bilirubin turnover leads to gallstones

HEMOLYTIC ANEMIAS – THE
HEMOGLOBINOPATHIES
Compensation mechanisms lead to cardiac
hypertrophy and enlargement and eventual failure
 The hyperplastic bone marrow leads to thinning of the
bones
 Hematologic complications that may occur are called
crises. Three types of crisis may occur
 Aplastic – usually associated with infection and
results in temporary marrow aplasia due to overwork
 Hemolytic crisis – sudden acute anemia – in young
children this may be due to splenic pooling
 Vaso-occlusive or painful – plugs of rigid sickle cells in
the capillaries cause tissue damage and necrosis and
lead to organ dysfunction. This is the “hallmark” of
sickle cell disease.

VASO-OCCLUSIVE CRISIS
HEMOLYTIC ANEMIAS – THE
HEMOGLOBINOPATHIES

Lab findings
 Normochromic, normocytic anemia
 10-20% reticulocytes
 6-10 g/dl hgb
 During crisis – marked anisoctyosis and poikilocytosis
with target cells, fragmented cells, nucleated RBCs,
and sickle cells
 Basophilic stippling, Howell Jolly bodies and
siderocytes due to splenic hypofunction
 Bone marrow – normoblastic hyperplasia
 Diagnosis – by a peripheral smear, hgb
electrophoresis, solubility tests, sodium metabisulfite
will cause the cells to sickle by deoxygenating the
blood (seen under the microscope)
SICKLE CELL DISEASE
HEMOGLOBIN ELECTROPHORESIS
HEMOLYTIC ANEMIAS – THE
HEMOGLOBINOPATHIES


Therapy
 No known effective long term therapy
 Drug companies are working on drugs to inhibit hgb S
polymerization
 Bone marrow transplant
 Gene therapy
Sickle cell trait – heterozygous for hgb S
Usually the patient has no problems because >50% of
their hemoglobin is hgb A
 There may be occasional problems upon exposure to
severe hypoxia
 Diagnosis is by hgb electrophoresis or sodium
metabisulfite treatment

HEMOLYTIC ANEMIAS – THE
HEMOGLOBINOPATHIES

Hemoglobin C disease
Lysine is substituted for glutamic acid at position 6 on the 
chain.
 Hgb C has decreased solubility and in the deoxyhemoglobin
state, the RBCs form intracellular crystals leading to a rigid
RBC with a decreased survival time (33-35 days).
 The disease is usually asymptomatic although patients may
have joint or abdominal pain.
 This disease is common in Africa.

HEMOGLOBIN C
HEMOLYTIC ANEMIAS – THE
HEMOGLOBINOPATHIES
Lab findings
 Slight reticulocytosis
 Hgb C crystals
 Target cells
 RBCs may look folded
 Microspherocytes
 Fragmented cells
 Diagnosis by hgb electrophoresis

HEMOGLOBIN C DISEASE
HEMOLYTIC ANEMIAS – THE
HEMOGLOBINOPATHIES


Hgb C trait – is symptomless
S/C disease
Both  chains are abnormal
 Therefore, hgb A is absent and the disease is almost
as severe as in hgb S disease
 Clinical symptoms are similar to those of mild sickle
cell anemia
 The patient may develop a vaso-occlusive crisis
 Differential diagnosis of S/C from hgb S disease may
be made on the finding of prominent splenomegaly in
S/C disease. Why is this not seen in hgb S disease?

HEMOLYTIC ANEMIAS – THE
HEMOGLOBINOPATHIES
Lab findings
 Normochromic, normocytic mild to moderate anemia
 Many target cells, folded cells, cells with hgb C crystals,
and occasional sickle cells
 Slight to marked anisocytosis and poikilocytosis
 Diagnosis using hgb electrophoresis

S/C DISEASE
HEMOLYTIC ANEMIAS – THE
HEMOGLOBINOPATHIES

Hgb D disease and trait
A glutamine replaces glutamic acid at position 121 on the 
chain
 Both homozygous and heterozygous states are
asymptomatic
 When combined with S to form D/S, D potentiates the
polymerization of deoxyhemoglobin leading to sickling and
mild anemia.


Hgb E disease and trait
HEMOLYTIC ANEMIAS – THE
HEMOGLOBINOPATHIES
A glutamic acid replaces lysine at position 26 on the  chain
leading to a slightly unstable hemoglobin with oxidant
stress.
 Hgb E has a decreased affinity for oxygen leading to a shift
to the right in the oxygen dissociation curve
 This is found mainly in individuals from the Orient
 Homozygous individuals have a mild microcytic anemia
with decreased RBC survival, target cells and increased
osmotic fragility
 Heterozygous individuals are symptomless


Unstable hemoglobin disorders
Contain amino acid changes in internal portions of he hgb
chains leading to decreased stability
 They are characterized by precipitation of the abnormal hgb
as Heinz bodies which leads to increased cell rigidity,
membrane damage, and RBC hemolysis.

HEMOLYTIC ANEMIAS – THE
HEMOGLOBINOPATHIES
These hgb disorders are known collectively as congenital
Heinz body hemolytic anemias
 They are only found in the heterozygous state since the
homozygous state is incompatible with life


Hemoglobin variants with altered oxygen affinity
HEMOLYTIC ANEMIAS – THE
HEMOGLOBINOPATHIES
Amino acid substitutions in the globin chains close to the
heme pocket may affect the ability of the hemoglobin to
carry oxygen
 This also occurs with substitutions near the 2, 3 DPG
binding site
 Decreased hgb affinity for oxygen leads to the shift to the
right in the oxygen dissociation curve
 Increased oxygen affinity leads to a shift to the left in the
oxygen dissociation curve and to polycythemia
 Hgb M variants
 Are characterized by permanent methemoglobin
formation because iron is stabilized in the Fe +3 state

HEMOGLOBINS WITH ALTERED
AFFINITY FOR OXYGEN