sp hemato b6 jos fix (1)

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

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- 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.

7

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

8

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

9

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


Blood transfusions might be indicated if the anemia is severe.20


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


There is no definitive therapy for hereditary elliptocytosis.

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2.7.3 Hereditary Stomatocytosis


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


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


Anemia should be treated with appropriate measures. Treatment of

hyperbilirubinemia in G6PD-deficient neonates, when indicated, is with

phototherapy and exchange transfusions.22


Patients with chronic hemolysis or non-spherocytic anemia should be

placed on daily folic acid supplements.22


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


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

11

most older patients when anemia becomes severe during infectious

episodes, aplastic crisis, or pregnancy.24


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


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


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


Supplemental folic acid help to prevent megaloblastic crisis. For surgical

care, consider splenectomy could be perform when there was

splenomegaly and hyperspenism.18


Definitive therapy with stem cell transplantation can be curative to

manage thalassemia beta.18

2.7.7 Thalassemia Alpha


Transfusions might be needed periodically or in periods of severe

anemia.26

12


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


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


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


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


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

http://emedicine.medscape.com/article/1014514-overview

http://emedicine.medscape.com/article/1014514-overview

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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sp hemato b6 jos fix (1)

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