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HEMOLYTIC ANEMIA
INTRODUCTION
Childhood anemia is a major public health problem worldwide. It is
associated with serious consequences including growth retardation, impaired
motor and cognitive development, and increased morbidity and mortality.1
Anemia is a condition in which the number of red blood cells (and
consequently their oxygen- carrying capacity) is insufficient to meet the body
physiologic needs. Specific physiologic needs vary with a persons age, gender,
residential elevation above sea level (altitude), smoking, behavior and different
stages of pregnancy.2
Hemolysis is defined as the premature destruction of red blood cells
(RBCs). If the rate of destruction exceeds the capacity of the marrow to produce
RBC, anemia results. Normal RBC survival time is 110-120 days. During
hemolysis, RBC survival is shortened and increased marrow activity results in a
heightened reticulocyte percentage and number. Hemolysis should be suspected as
an anemia if an elevated reticulocyte is present. The normal reticulocyte index is
1.0.3
The prevalence of anemia is high in preschool children (47.4%) and in
pregnant women (41.8%), but lower in school age children (25.4%). About 44.5%
of preschool-aged children in Indonesia have anemia. In Indonesia, the reported
anemia prevalence differs in each area and age groups, ranging from 5.4% in well
nourished preschool children to 56.3% in primary school children and 19% to
62.5% in pregnant women. The causes of anemia mostly reported were nutritional
like iron deficiency, abnormal hemoglobin besides other conditions. In Cipto
2
ETIOLOGY
Hemolytic anemia may result from corpuscular or extracorpuscular
abnormalities. One of the types of corpuscular abnormalities is membrane defect.
The diagnosis is sometimes difficult and it may need special hematologic
investigations.6,7,8
1. Intrinsic factor
Usually is inherited: RBC membrane defects, enzyme defects or
haemoglobinopathies.
2. Extrinsic factor
Usually is acquired: immune or RBC fragmentation.
CLASSIFICATION
Acquired Disorders9
1. Immune hemolytic anemia
Immune hemolytic anemia is mediated by antibodies directed against antigens
on the red blood cell surface. Microspherocytes on a peripheral smear and a
positive direct antiglobulin test are the characteristic findings. Immune
hemolytic anemia is classified as autoimmune, alloimmune or drug-induced,
based on the antigen that stimulates antibody or complement-mediated
destruction of red blood cells.
Autoimmune Hemolytic Anemia
Mediated by autoantibodies and further subdivide according to their
maximal binding temperature. Warm hemolysis refers to IgG
autoantibodies, which maximally bind red blood cells at body
3
Infection
Malaria is the classic example of direct red blood cell parasitization.
Plasmodium species, introduced by the Anopheles mosquito, invade red
blood cells and initiate a cycle of cell lysis and further parsitization. Both
the cellular invasion and the metabolic activity of the parasite alter the cell
membrane, leading to splenic sequestration.
Similarly, Babesia microti and Babesia divergens, tick-borne protozoa and
Bartonella bacilliformis, a gram-ngeative bacillus transmitted by the
sandfly, cause extravascular hemolysis by direct red blood cell invasion
and membrane alteration.
Septicemia caused by Clostridium perfringens, which occurs in intra-
abdominal infections and septic abortions, cause hemolysis when the
bacterium releases alpha toxin, a phospholipase that degrades the red
blood cell membrane.
Hereditary Disorders9
The mature red blood cell, while biochemically complex, is a relatively
simple cell that has extruded its nucleus, organelles, and protein-synthesizing
machinery. Defects in any of the remaining components(enzymes, membrane and
hemoglobin) can lead to hemolysis.
5
1. Enzymopathies
The most common enzymopathy causing hemolysis is G6PD deficiency.
G6PD is a critical enzyme in the production of glutathione, which defends
red cell pro- teins (particularly hemoglobin) against oxidative dam- age.
This X-linked disorder predominantly affects men. More than 300 G6PD
variants exist worldwide, but only a minority cause hemolysis.
2. Membranopathies
Hereditary spherocytosis is an autosomal dominant disorder caused by
mutations in the red blood cell membrane skeleton protein genes. With a
weakened protein backbone anchoring its lipid bilayer, the membrane
undergoes a progressive deterioration in structure, resulting in a
spherocyte, the characteristic abnormality seen on peripheral smear.
3. Hemoglobinopathies
Chronic hemolysis can be a characteristic of disorders of hemoglobin
synthesis, including sickle cell anemia and thalassemias.
The thalassemias are a heterogeneous group of inherited multifactorial
anemias characterized by defects in the synthesis of the alpha or beta
subunit of the hemoglobin tetramer (22). The deficiency in one globin
chain leads to an overall decrease in hemoglobin and the intracellular
precipitation of the excess chain, which damages the membrane and leads
to clinically evident hemolysis in the severe forms of alpha thalassemia
(hemoglobin H disease) and beta thalassemia (intermedia and major).
Beta thalassemia can be diagnosed by hemoglobin electrophoresis, which
shows elevated levels of hemoglobins A2 and F, while diagnosis of alpha
thalassemia requires genetic stud- ies. Thalassemias are characterized by
hypochromia and microcytosis; target cells frequently are seen on the
peripheral smear.
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RISK FACTOR11
Drug use Primaquine, sulfamethoxazole, and nitrofurantoin
(Furadantin) can lead to hemolysis; this is more
pronounced in patients with G6PD deficiency but can
occur in any patient; phenytoin (Dilantin) can cause
megaloblastic anemia
Ethnicity African ancestry in sickle cell disease; Mediterranean,
Asian, or African ancestry in thalassemia; Sephardic
Jewish, Filipino, Greek, Sardinian, or Kurdish ancestry in
G6PD deficiency
Family history Thalassemia, spherocytosis, and sickle cell disease;
family history may include gallstones and jaundice in
addition to anemia
Mechanical heart valves Mechanical destruction by the valve can cause hemolysis
Sex G6PD deficiency and pyruvate kinase deficiency are X-
linked and therefore more common in males
Splenomegaly Sequestration and increased destruction of RBCs can
cause hemolysis
Infection Infection can precipitate immune-mediated hemolytic
anemia or cause hemolytic crises in patients with\
inherited enzyme defects and sickle cell disease; can
cause RBC aplasia (as in parvovirus B19 infection) or
result in transient erythroblastopenia of childhood
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Hereditary Disorders3
Enzymopathies:
Symptom:
Pallor, jaundice, fatigue and exercise intolerance.
Laboratory Findings:
Reticulocytosis and indirect hyperbilirubinemia. Mean corpuscular
hemoglobin concentration is increased.
Blood smear:
Polychromatophilic reticulocytes and spherocytes. The spherocytes are
smaller in diameter and on the blood film are hyperchromic.
Hemoglobinopathies
Sickle cell Anemia
Symptoms and signs:
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Thalasemias
Symptoms and signs:
Poor appetite, letargy, cachexia, hepatosplenomegaly, pallor,
hemisiderosis, jaundice
TREATMENT
Autoimmune Hemolytic Anemia
Corticosteroid
Prednisone dosage 2 mg/kg/day. If hemolytic process decreased, and
hemoglobin concentration increased, corticosteroid dosage can be tapered
off slowly.
Intravenous gammaglobulin
Dosage 2 g/kg body weight. Therapy with immunoglobulins might be
considered in acute life-threatening situations in order to reduce
breakdown of patients or donor erythrocytes.
Transfusion
Erythrocyte transfusion can be considered if hemoglobin concentration is
low and there are signs of congestive heart failure, 5 mL/kg body weight
for 3-4 hours.
Splenectomy
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Membranopathies
Splenectomy eliminates most of the hemolysis associated with this
disorder. After splenectomy, osmotic fragility often improves because of
diminished splenic conditioning and less RBC membrane loss, and the
anemia, reticulocytosis, and hyperbilirubinemia resolve.
Folic acid,1 mg/24 hr should be administered to prevent secondary folic
acid deficiency.
Hemoglobinopathies
Sickle Cell
All children who have sickle cell disease should be immunized with
the conjugate pneumococcal vaccine and all other routine vaccines for
children. At the age of 2 mo all children should begin penicillin
prophylaxis with 125 mg twice daily.
Drug therapy with hydroxyurea has successfully elevate fetal
hemoglobin levels and reduced morbidity in adults, dosage15
mg/kg/24 hr and if tolerated, the dose is increased to a maximum of
less than 30 mg/kg/24 hr. Complete blood counts,liver function test,
and fetal hemoglobin levels should be monitored at leats monthly as
long as patients are on this medication.
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Bone marrow transplantation is the only cure for sickle cell disease,
but it is only an option for children younger than 16 yr of age who
have an HLA-matched sibling.
Thalasemias
Transfusion, blood products are leukoreduced and phenotypically
matched for the Rh and Kell antigens are required.
If there is the possibility of a bone marrow transplant, the blood should
be negative for cytomegalovirus and irradiated.
A post-transfusion hemoglobin level of 9.5 g/dL is the goal.
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CASE REPORT
Name : RB
Age : 3 years and 3 months old
Sex : Male
Date of Admission : July, 30th 2014
History:
It was realized by his parents four days before admitted to hospital. The
history of pale (-). History of spontaneous bleeding (-), nosebleed (-), hematoma (-
), melena (-).
Yellow found in the entire body around three days before admitted to
hospital. First, it was seen only in the eyes but then throughout the entire body.
History of tea-like appearance urine was not found, history of colorless defecation
was not found.
History of vomitting was found around 3 days ago, the frequency of 5
times per day, the volume was cup of aqua, the content was what is eaten and
drunk. Within this 2 days, the event of vomit is not found.
Fever was happened since five months ago before admitted hospital, the
fever was not very high, the fever was intermittent fever, the temperature was
decreased when drugs was given to him. Seizures was not found, Chills was not
found. The patient was taken to the clinics and were given antipyretic syrup and
antibiotic syrup by the doctor. Current fever is not found.
Cough is not found, cold is not found, micturition is normal and defecation
is normal
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History of previous illness : The patient was reffered from PTPN II Tj. Morawa
Hospital by the Paediatrician with the diagnosis of suspect sepsis+icterus+severe
anemia+hyperbilirubinemia.
History of drugs : Ceftriaxone inj., Ondansetron inj., Ranitidine inj.,
Ampicillin inj., Novalgin inj., Paracetamol.
Pregnant History
There is no history of fever, hypertension, diabetic mellitus, and consumed herbal
medicine.
Birth History
Spontaneous; attended by midwives; BW 3300 gram; BL 42 cm, cyanotic (-).
Immunization History
Not complete, only Hep-B and DPT
Feeding History
From birth to 6 months : Breast milk
From 6 to 12 months : Breast milk + rice porridge
From 12 months until now : daily menu
History of Growth and Development
Sitting : 5 months
Crawling : 8 months
Standing : 14 months
Walking : 14 months
Physical Examination
Generalized status
Body weight: 12 kg, Body length: 99 cm
Body weight according to age WHO 2006 : -2 < Z-scrore < 0
Body lenght according to age WHO 2006 : 0 < Z-scrore < 2
Body weight according to body length WHO 2006 : -3 < Z-score < -2
Interpretation : undernutrition
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Presens status
Consciousness: GCS : 15 (E4V5M6), Blood pressure 90/60 mmHg, HR: 112 bpm,
RR: 26 bpm, body temperature: 36,8oC, body weight : 12 kg, body length : 99 cm,
Head circumference : 44 cm
Anemic (+), Icteric (+), Cyanosis (-), Edema (-), Dyspnea (-).
Localized status
Head :
Large Fontanella closed. Head circumference: 44 cm, black hair, normal.
Eye: Isochoric pupil (3mm/3mm), light reflex (+/+), inferior palpebra
conjunctiva pale (+/+), icteric sclera (+/+).
Nose and Ear were within normal limit
Mouth: Lips mucosa pale (+).
Neck :
TVJ R-2 cmH2O, Lymph node enlargement (-).
Thorax:
Symmetrical fusiformis, Chest retraction(-), HR : 112 bpm, reguler, murmur (-),
RR: 26 x/i, regular, rales (-).
Abdomen:
Rapid turgor. Normoperistaltic. Liver was enlargement 3cm BAC, spleen and
renal unpalpable..
Extremities:
Pulse 112 bpm, regular, adequate pressure and volume, warm acral, CRT < 3,
Blood Pressure 90/60 mmHg
Urogenital:
Male, within normal limit.
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Result : E/B/Nseg/Nbat/L/M : 0 / 1 / 42 / 20 / 29 / 8
Erythrocyte : Hypochromic Microcytic, Target cell (+), spherocytosis (+),
Blast (-)
Differential Diagnosis:
Hemolytic Anemia ec dd/ - suspect Thalasemia + Malnutrition
- Autoimmune
- G6PD Deficiency
- Malaria
- Hepatitis Virus
Working Diagnosis:
Hemolytic Anemia ec suspect Thalasemia + Malnutrition
Management:
- Bed Rest
- IVFD D5% NaCl 0,45% 35 gtt/I micro
- Ceftriaxone injection 600mg/12 hours/IV skin test
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- PRC Transfusion
Need : (11-4,2)x4x12 = 326cc
Allowance : 5cc/kgBB = 5x12 = 60cc/12jam
- Diet daily menu 1350 kkal + 24 gram protein
Diagnostic Planning:
- Hb Electrophoresis, Comb Test, Reticulocyte count, Iron Profile, G6PD
- Septic Work Up (CRP, Procalcitonin, Blood Culture, and Sensitivity test)
- Complete blood count post transfusion
- Urin&fecal analysis, urine culture
- Consoult Pediatric Hemato-Oncology division
- Consoult Nutrition & Metabolic disease division
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FOLLOW UP
Diagnostic Planning :
Waiting Hb Electrophoresis Result
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Discussion
RB 3 years 3 months, male, was admitted to RSUP HAM at July 30th 2014
diagnosed with Hemolytic Anemia. This diagnosis was made based on clinical
findings found in the patient such as pale that last for around 4 days with no
evidence of spontaneous bleeding and yellowish in his entire body included eyes
that last for three days.
The others symptom on this patient were vomiting and fever. Fever was
happened this 5 months, the fever was up and down but the fever was not too
high. From the physical examination we found conjunctiva palpebral inferior pale,
sclera icteric, jaundice and hepatomegaly. In the theory of hemolytic anemia, the
main symptom is fever, pale with lethargy, icterus, jaundice and maybe found
hepatosplenomegaly.
From laboratory finding in this patient we found Hb 4,2g% before PRC
transfusion and Hb 14,1g% after PRC transfusion. Reticulocyte count also
increased 4-5 times from normal which is 8,54. In the theory of hemolytic anemia,
we can found low hemoglobin, low RBC, and increased of reticulocyte cound due
to hemolytic anemia. The result of negative coombs test can exclude the diagnosis
of autoimmune and we can suspect of others hemolytic anemia.
We also found Hypochromic Microcytic, Target cell and spherocytosis in
the thin blood smear and no plasmodium appearance in thick blood smear. In the
theory, we can find other shape of erythrocyte than normal in hemolytic anemia
such as Spherocytes, polychromasy, polychilocytosis, sickle red cells,
hypochromic, hyperchromic and Howell-Jolly Bodies.
In these patients, no such treatment is needed beside blood transfusion
until the cause of hemolytic anemia is found. As we see, given a blood transfusion
increased the hemoglobin and reduced the pale and jaundice. We also give
antibiotic Ceftriaxone for the prophylaxis of infection due to high leucocytes.
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Conclusions
The conclusion of this paper is a boy, 3 years and 3 months old, diagnosed with
Hemolytic Anemia ec suspect Thalasemia. The patient received :
- Bed Rest
- IVFD D5% NaCl 0,45% 35 gtt/I micro
- Ceftriaxone injection 600mg/12 hours/IV
- PRC Transfusion 326cc
- Diet daily menu 1350 kkal + 24 gram protein
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REFERENCES