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CHAPTER I
INTRODUCTION
Hemolytic anemia is anemia caused by hemolytic process1, while hemolytic
process is a pathological process resulting in shortening of the normal red cell life
span of 120 days, in other words, it means that breakdown of erythrocyte happens
before it must be. Normal adult bone marrow could increase the speed of
erythropoiesis to 6-8 times normal speed.1 So when there is hemolysis on
peripheral blood with erythrocytes’ life span of more than 30 days,2 bone marrow
will give response as an increase of erythropoiesis speed. This condition is called
compensated hemolytic state.1 Hemolytic anemia might occur if erythrocyte life
span is less than 30 days.
Generally, hemolytic anemia is classified into 2 categories: hereditary
hemolytic anemia or congenital hemolytic anemia (CHA) and acquired hemolytic
anemia. CHA is caused by factors inside erythrocyte (intracorpuscular), while
acquired hemolytic anemia is caused by factors outside erythrocyte
(extracorpuscular).1,2
Several disorders included in CHA are: erythrocyte membrane disorder
(membranopathy), erythrocyte metabolism/enzyme disorder (enzimopathy) and
hemoglobin forming disorder (hemoglobinopathy).1 CHA cases are less common
than autoimmune anemia whereas the incidence in India is 0.1 to 0.2 %. The
patient’s age ranging from 2 months to 12 years with the most frequent cases were
between 3-5 years (37.5%).3 It is because only few patients with CHA could
survive until adulthood.1 Although rarely occurred, worse prognosis in CHA needs
to be considered.
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CHAPTER II
CONTENT
2.1 Definition of Congenital Hemolytic Anemia
Hemolytic anemia is caused by hemolytic process in our blood.1 Hemolytic is
a process of disentangling hemoglobin from blood cell into blood plasm, whereas
anemia is a condition of hemoglobin below normal level. Roughly, hemolytic
anemia is a condition of hemoglobin level less from its normal condition because
of the disentangling hemoglobin process.
Male and female have different normal value for hemoglobin level. It is lower
in female due to menstruation once a month. Hemoglobin level in male is 13.5-
17.5g/dl. Female has a normal hemoglobin level of 12-16g/dl.4 Hemolytic anemia
results from shortening life span of red blood cell (RBC) because of increased
RBC hemolytic process, due to failure of bone marrow to compensate hemolytic
process.1,5
Hemolytic anemia is divided into two groups, intracorpuscular hemolytic
anemia and extracorpuscular hemolytic anemia.1 Intracospucular hemolytic
anemia caused by internal factor of erythrocyte itself, e.g.: hereditary factor,
metabolic disorders, and also disorders of hemoglobin formation. While
extracorpuscular hemolytic anemia is caused by external factors, e.g.:
autoimmune, drug induced and infections.
Congenital Hemolytic Anemia (CHA) is caused by hereditary factor or family
genes, resulting from mutation and impairing function of RBC proteins.6 CHA is
divided into three subgroups according to its ethiologies:1 Membranopathy CHA,
Enzymopathy CHA and Hemoglobinopathy CHA.
2.2 Epidemiology
CHA is a very rare disease entity characterized by premature RBC destruction
and anemia due to intrinsic RBC defects.8 Hereditary spherocytosis (HS) is the
most common type of CHA. The estimated prevalence of this membrane disorder
is 1 in 5000 in the white population of Northern Europe. Red blood cell glucose-
6-phosphate-dehydrogenase (G6PD) deficiency is the most common enzyme
2
disorder worldwide, affecting 420 million of the world population.9 While one of
Asian country, Korea has a very low prevalence of CHA. It’s because of HS is
less common in Asians than in Caucasians-with an incidence of 1 in 5000 births.8
According to the results of a recent survey performed from 2007 to 2011 in
Korea, 198 (122 men and 74 women) patients were diagnosed with CHA. The
median age of the patients was 32 months (range: 0–187 months), and there were
127 (64.8%) patients with RBC membranopathies, 39 (19.9%) with
hemoglobinopathies, 26 (13.3%) with RBC enzymopathies, and 3 (1.5%) patients
had CHA of unknown etiology. Data comparison between this study and studies
performed during 1997–2006 and 1981–1990 revealed that the proportion of
hemoglobinopathy and enzymopathy has been gradually increasing. This finding
is probably due to an improvement in the diagnostic techniques for CHA,
especially that of globin gene sequencing and RBC membrane protein and
enzyme analysis, and an increase in multiracial marriages especially with South
East Asians.8
2.3 Etiology
2.3.1 Red cell membrane disorders, example: hereditary spherocytosis, hereditary
elliptocytosis, hereditary stomatocytosis.
2.3.2 Red cell enzymopathies, example: G6PD and Pyruvate Kinase deficiencies.
2.3.3 Abnormal Hb, example: thalassemias and sickle cell disease.10
2.4 Pathophysiology
2.4.1. Red cell membrane disorders
a. Hereditary spherocytosis
- Hereditary Spherocytosis is usually caused by defects in the proteins
involved in the vertical interactions between the membrane skeleton
and the lipid bilayer of the red cell. The loss of membrane may be
caused by the release of parts of the lipid bilayer that are not supported
by the skeleton. In hereditary spherocytosis, the marrow produces red
cells of normal biconcave shape but these lose membrane and become
increasingly spherical (loss of surface area relative to volume) as they
circulate through the spleen and the rest of the RE system.11
3
- The 3 protein defect that caused HS, Spectrin, Ankyrin and Band 3
which in turn cause the destabilization of lipid bilayer. The
destabilization of membrane can affect the deformability. Ultimately,
the spherocytes are unable to pass through the splenic microcirculation
where they die prematurely. The anemia may be compensated by an
increase in the production of new RBCs.12
b. Hereditary elliptocytosis
- Hereditary elliptocytosis (HE) is associated with an autosomal
dominant inheritance pattern and is not associated with anemia in most
cases. HE results from defects in RBC structural proteins that mediate
horizontal interaction in the RBC cytoskeleton.
- The RBCs in HE fail to regain their normal discoid shape. This failure
eventually produces the fixed characteristic morphology of elliptocytes
with a decreased surface-to-volume ratio. These elliptocytes are not as
deformable as normal RBCs and are eventually trapped and removed
by the spleen. This process of premature destruction (ie, cells surviving
< 120 d) is the basis of the extravascular hemolysis that clinically
defines these disorders.12
c. Hereditary stomatocytosis
- Hereditary stomatocytosis (also known as hereditary hydrocytosis, or
overhydrated stomatocytosis) refers to a heterogeneous group of
autosomal dominant hemolytic anemias caused by increase in
intracellular sodium and water content with a mild decrease in
intracellular potassium as a result of a sodium influx into the red blood
4
Picture 1. Pathophysiology process of hereditary spherocytosis12
cells. Despite a marked compensatory increase in active transport of
sodium (Na) and potassium by the Na+/K+-ATPase (which normally
maintains the low sodium and high potassium concentrations in the
cells), the pump hyperactivity is unable to compensate for the vastly
increased sodium leak. The cell then lyses and a haemolytic
anemia occurs.12
2.4.2 Red cell enzymopathies
a. G6PD deficiency
- G6PD, a pivotal enzyme in the hexose monophosphate shunt, mediates
the generation of reduced nicotinamide adenine dinucleotide phosphate
(NADPH). As red cells age, the activity of G6PD declines. The normal
enzyme (G6PD B) has an in vivo half-life of 62 days, which in turn
reduces glutathione.
- Reduced glutathione is a major free radical scavenger in the RBC.
Despite this loss of enzyme activity, normal old red blood cells contain
sufficient G6PD activity to generate NADPH and thereby sustain
Glutahione levels in the face of oxidant stress.
- In contrast, the G6PD variants are unstable and have much shorter
half-lives. The activity of G6PD A- in reticulocytes is normal, but it
declines rapidly thereafter with a half-life of only 13 days. The clinical
correlation of this age-related enzyme instability is that hemolysis in
patients with G6PD A- generally is mild.
- G6PD deficiency may result in acute hemolysis when the RBC is
exposed to oxidant stress. G6PD-deficient erythrocytes exposed to
oxidants (infection, drugs, fava beans) become depleted of
Glutathione.
- This reaction is central to the cell injury in this disorder since once
Glutathione is depleted, there is further oxidation of other RBC
sulfhydryl-containing proteins. Oxidation of the sulfhydryl groups on
hemoglobin leads to the formation of denatured globin or
sulfhemoglobin.
5
- Then sulfhemoglobin become insoluble masses that attach to the red
cell membrane by disulfide bridges, and these are known as Heinz
bodies.
- The end result of these changes is the production of rigid,
nondeformable erythrocytes that are susceptible to stagnation and
destruction by macrophages in the spleen and liver. Both extravascular
and intravascular hemolysis occurs in G6PD-deficient individuals.12,13
b. Pyruvate Kinase Deficiency
- In pyruvate kinase deficiency, an erythrocyte enzymopathy, a blockage
of metabolic process created in the Embden-Meyerhof pathway at the
level of the deficient enzyme. Intermediate byproducts and various
glycolytic metabolites proximal to the metabolic block accumulate in
the erythrocyte, while the erythrocyte becomes depleted of the distal
products in the pathway, such as lactate and ATP.
- The lack of ATP disturbs the cation gradient accross the erythrocytic
cell membrane, causing the loss of potassium and water, which results
in cell dehydration, contraction, and crenation (echinocytes) and leads
to premature destruction of the erythrocyte.12
2.4.3 Abnormal Hb
a.Thalassemia
- The thalassemias are inherited disorders of Hb synthesis that result
from an alteration in the rate of globin chain production. A decrease in
the rate of production of a certain globin chain or chains (α, β, γ, δ)
impedes Hb synthesis and creates an imbalance with the other,
normally produced globin chains.
- α, β, γ, δ chains that accumulate in the RBC precursors are insoluble,
precipitate in the cell, interact with the membrane (causing significant
damage), and interfere with cell division. This leads to excessive
intramedullary destruction of the RBC precursors. In addition, the
surviving cells that arrive in the peripheral blood with intracellular
inclusion bodies (excess chains) are subject to hemolysis; this means
6
that both hemolysis and ineffective erythropoiesis cause anemia in the
person with α, β, γ, δ thalassemia.14
b.Sickle cell
- Hemolysis is a constant finding in sickle cell syndromes resulted from
the mutation of one codon in β globin gene that resulting in mutated
hemoglobin which is HbS. Approximately one third of RBCs undergo
intravascular hemolysis, possibly due to loss of membrane filaments
during oxygenation and deoxygenation. Sickle shape of erythrocyte
itself adhere to macrophages. This property may contribute to
erythrophagocytosis and the hemolytic process. While, the unability to
bind oxygen resulted in increase ROS are the causes of hemolytic in
sickle cell disease. 1,15
- The remainder hemolyze by erythrophagocytosis by macrophages.
This process can be partially modified by Fc (crystallizable fragment)
blockade, suggesting that the process can be mediated by immune
mechanisms.15
2.5 CHA Diagnosis
2.5.1 History Taking
Sacred seven:
a. Onset
b. Location
c. Quality
d. Quantity
e. Chronology
f. Modifying factors
g. Other symptom
Demography data, such as age is important to be considered because CHA
could be found in children and infant. There are several characteristics of CHA
that could be identified by history taking or anamnesis. Patient with CHA has
low level of hemoglobin. At the first attack the condition is not bad but
gradually the condition might get worse.
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Basic Four:
a. Past history
b. Family history
c. Social
d. Present condition
Family history is also very important to find the probability for the patient
to have the disease. If there is other family suffering from CHA, there is higher
probability of the patient to suffer from CHA.
2.5.2 Physical Examination
a. Splenomegaly
Spleen is the organ where erythrocyte is destroyed because it contains
macrophage. In hemolytic anemia spleen will overwork in destructing
RBC thus resulting in splenomegaly.2
b. Hepatomegaly
Hepatomegaly occurs because of liver overwork in destructing RBC.1
c. Hb <7 g/dl
CHA is one of the worse conditions of anemia where the level of
hemoglobin is lower than 7 g/dl. This condition occur gradually.16
d. Hemoglobinuria1
e. Hemosiderinuria
Prussian Blue will demonstrate heme in urine. The normal value is 0.1
mg/day and in CHA could increase to 3-11 mg/day.1
2.5.3 Supporting Examination
a. Blood smear
There is microspherocyte with dark color and smaller size compared to
normal erythrocyte. We will also find spherocyte, erythrocyte looks
rounder and lost its central pallor. There is high amount of immature
blood cells or new blood cells, caused by increased erythropoiesis
suggesting the sign of CHA caused by membrane defect. The other cells
might be found in blood smear are sickle cell and target cell, and lien
atrophy might also be found as a sign of CHA.2
b. Bone marrow examination
From bone marrow examination we will find signs increased
erythropoiesis such as hyperplasia normoblastict.16
c. Fragility osmotic
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In the laboratory, red blood cells are tested with a solution that makes
them swelling in order to determine how fragile they are. It is used to
measure erythrocyte resistance to hemolysis while being exposed to
varying levels of dilution of a saline solution. In CHA the erythrocyte
would lyse easier than the normal cells.1
d. Coomb’s test
In Coomb’s test of CHA patient show negative result, suggesting that
there is no autoimmune activity.1
e. Electrophoresis test
This test is to differentiate hemoglobin and myoglobin in the urine. If
hemoglobin is found in urine, it is suggestive of CHA.1
2.6 Differential diagnosis
2.6.1 Acute Bleeding Anemia
The difference between CHA and acute bleeding anemia is that in acute
bleeding anemia we would not find icterus. After getting some treatment,
hemoglobin level will increase to the normal while in CHA it would take
longer time and could be long life.
2.6.2 Erythropoiesis Anemia
Erythropoiesis anemia is similar to CHA because there are icterus and
hyperplasia normoblastic in bone marrow. But in erythropoiesis anemia,
the reticulocyte is not increased as found in CHA.
2.6.3 Icterus without Anemia
Icterus would also be seen in Gilbert Syndrome or other catabolism
abnormality. It is different with CHA because there is no abnormality of
erythrocyte morphology.
2.6.4 Myoglobinuria
It happened in severe muscle damage or crush syndrome. There are
some similarities between myoglobinuria and hemoglobinuria, such as
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urine with black or brown color. But they could be differentiated by
electrophoresis.1
2.7 Management
2.7.1 Hereditary Spherocytosis
a. Emergency therapy
Neonates with severe hyperbilirubinemia caused by hereditary
spherocytosis (HS) should be treated with phototherapy and/or exchange
transfusion as clinically indicated. Aplastic crises occasionally can cause
the hemoglobin level to fall, RBC transfusions often are necessary in
these cases.17
b. Supportive-symptomatic therapy
Splenectomy is curative but is typically recomended only in patient with
severe anemia. Partial splenectomies are increasingly used in pediatric
patients. Splenectomy ideally should not be performed in child under 5
years because of the increased incidence of postsplenectomy infections
with encapsulated organisms such as S pneumoniae and H influenzae in
young children.18 Lifelong folic acid supplementation is recommended for
patients with HS because of their low levels of chronic hemolysis that
indicated to prevent megaloblastic crisis.19
c. Definitive therapy
There is no definitive therapy for hereditary spherocytosis
2.7.2 Hereditary Elliptocytosis
a. Emergency therapy
Blood transfusions might be indicated if the anemia is severe.20
b. Supportive-symptomatic therapy
A diet rich in folic acid or folic acid supplementation is recommended to
avoid consequences of folate deficiency in a hemolytic state.20
Splenectomy markedly improves anemia for patients with clinically
significant hemolysis and reduces hemolysis that results from HE.18
c. Definitive therapy
There is no definitive therapy for hereditary elliptocytosis.
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2.7.3 Hereditary Stomatocytosis
a. Emergency therapy
In a few severe cases, erythrocyte hypertransfusion has been beneficial.
Neonates with stomatocytosis have required phototherapy and red cell
transfusion for treatment of anemia and hyperbilirubinemia.21
b. Supportive-symptomatic therapy
The patients should receive folate supplementation and be monitored for
complications of hemolysis. Splenectomy should be carefully considered
in patients with hereditary stomatocytosis.21
c.Definitive therapy
There is no definitive therapy for hereditary stomatocytosis.
2.7.4 Glucose-6-Phospate Dehydrogenase Deficiency
a. Emergency therapy
Anemia should be treated with appropriate measures. Treatment of
hyperbilirubinemia in G6PD-deficient neonates, when indicated, is with
phototherapy and exchange transfusions.22
b. Supportive-symptomatic therapy
Patients with chronic hemolysis or non-spherocytic anemia should be
placed on daily folic acid supplements.22
c. Definitive therapy
Most individuals with G6PD should be taught to avoid drugs and
chemical exposures that can cause oxidant stress.23
2.7.5 Pyruvate Kinase Deficiency
a. Emergency therapy
Intrauterine transfusion required in most patients with extremely severe
fetal anemia associated with hydrops fetalis. Phototherapy or exchange
transfusion required for most newborns with severe hyperbilirubinemia.
Simple blood transfusion administered for anemia during early childhood
and, occasionally, into adulthood. Sporadic blood transfusions required in
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most older patients when anemia becomes severe during infectious
episodes, aplastic crisis, or pregnancy.24
b. Supportive-symptomatic therapy
Supplemental folic acid and other B vitamins help to prevent deficiencies
from increased erythrocyte production.24 For surgical care, consider
splenectomy or partial splenectomy, although both failure and success
have been reported in patients with pyruvate kinase deficiency.18
c. Definitive therapy
Large doses of salicylates should be avoided in patients with severe
anemia, because these inhibit oxidative phosphorylation, thereby causing
further ATP depletion. Therapeutic intervention with agents that can
stimulate pyruvate kinase or circumvent the deficiency defect remains
experimental.24
2.7.6 Thalassemia Beta
a. Emergency therapy
Some pregnant patients with the beta thalassemia trait may develop
concurrent iron deficiency and severe anemia; they may require
transfusional support if they are not responsive to iron repletion
modalities.25
b. Supportive-symptomatic therapy
Supplemental folic acid help to prevent megaloblastic crisis. For surgical
care, consider splenectomy could be perform when there was
splenomegaly and hyperspenism.18
c. Definitive therapy
Definitive therapy with stem cell transplantation can be curative to
manage thalassemia beta.18
2.7.7 Thalassemia Alpha
a. Emergency therapy
Transfusions might be needed periodically or in periods of severe
anemia.26
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b. Supportive-symptomatic therapy
In patients with elevated ferritin levels, the diet should be low in iron and
chelation therapy with deferoxamine or deferasirox should be considered.
Folic acid supplementation may be beneficial in patients with elevated
reticulocyte counts, indicating increased utilization resulting from the
hemolytic process and the high bone marrow turnover rate. Splenectomy
might be beneficial for some patients with HbH disease. Orthopedic or
orthodontic surgery might be necessary to correct skeletal abnormalities
due to erythroid hyperplasia.26
c. Definitive therapy
In very severe cases, allogeneic hematopoietic stem cell
transplantation may be considered. This measure is curative because the
hematopoietic system of the patient is replaced by that of the donor.18
2.7.8 Si c kle Cell Anemia
a. Emergency therapy
Serious forms of vascular occlusian (eg. Stroke, acute chest syndrome,
sequestration crisis, priapism) are often treated with exchange
transfusion. Chronic RBC transfusion is also recommended in children at
high risk for stroke as defined by transcranial doppler ultrasound.6
b. Supportive-symptomatic therapy
Treatment for patients with sickle cell anemia is largerly supportive.
Hydration and pain medication are used to treat acute painful crisis.6 In
some patients, supplementation of folic acid might be useful.
Hydroxyurea, an inhibitor of ribonucleotide reductase, has been shown to
increase HbF levels and is approved for the treatment of patients with
frequent painful crisis.18
c. Definitive therapy
In individuals with severe clinical disease, allogeneic stem cell
transplantation can be curative to manage sikle cell anemia.18 The drugs
used in treatment of sickle cell disease (SCD) include antimetabolites,
analgesics, antibiotics, and vaccines.27
13
2.8 Prognosis of Congenital Hemolytic Anemia
The outcome of congenital hemolytic anemia depends on the type and
causes of hemolytic anemia. Usually severe anemia could result in
worsening of heart disease, lung disease or cerebrovascular disease
worse. Outcome of late anemia leads to antibody persistence for weeks
and causes continued hemolysis which is break down of blood and also
causes anemia as late as age 6 months especially among infants who had
received Intrauterine transfusions. Erythropoietin treatment will help
preventing severe anemia and further transfusions. The most common
problem for neurological outcome is sensorineural problem such as
hearing loss.28,29
CHAPTER III
SUMMARY
Congenital hemolytic anemia (CHA) is the type of hemolytic anemia caused
by hereditary or familial genes as the result of mutation impairing function of red
blood cell proteins. The hemolysis itself is caused by the mature breakdown (<120
days) of erythrocyte due to three general causes.
14
There are several disorders classified into CHA depending on its etiologies;
1) erythrocyte membrane disorder (membranopathy) such as hereditary
spherocytosis, hereditary elliptocytosis, and hereditary stomatocytosis; 2)
erythrocyte metabolism or enzyme disorder (enzimopathy) such as G6PD and
Pyruvate Kinase Deficiencies; and 3) hemoglobin forming disorder
(hemoglobinopathy) such as Thalassemia and Sickle Cell Disease.
The diagnosis is established by history taking and physical examination of
spleen, icterus, urine, and hemoglobin level. There are also other studies required
to diagnose CHA such as blood smear, bone marrow examination, fragility
osmotic, Coomb’s test, and electrophoresis. Management of patients with CHA is
based on its etiology.
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