Hemolytic Anemia in

newborn and children

Bidasari Lubis

Child Health Departement Medical Faculty

University of Sumatera Utara

1
 Introduction
Premature destruction of red blood cells (RBCs) from the
circulation before their normal life span of 120 days
(half life 55-60 days)

Corpuscular abnormalities
(membrane, enzymes, hemoglobin )
Extracorpuscular abnormalities (immune ,nonimmune)

HEMOLYSIS ANEMIA
2
 Severity of this anemia

How long RBC live before destroyed by the

spleen
How quickly bone marrow can replace RBC

3
 Classification of Hemolytic
Anemia
Site of haemolysis
1.Extravascular haemolytic disorders:
macrophages of the RES
2.Intravascular haemolytic disorders: within the
circulatory system
3.Combination extra and intravascular
haemolysis.

4
 Alur pemeriksaan
Hitung Anemia Neonatal
Retikulosit

Pemeriksaan Antiglobulin
Retikulosit Retikulosit Direk / Indirek
Rendah Normal / Meningkat
Aplasia kongenital /
anemia hipoplasia
Anemia aplastik didaoat
Ggn endokrin Negatif Positif
Racun Anemia hemolitik imun
Peny. Kronik
Infeksi
Defisiensi besi
MCV
Ggn sumsum

Rendah Meningkat
Thalassemia

Slide darah tepi

Normal Abnormal
Defisiensi enzim sel eritrosit Hemoglobinopati
Kehilangan darah Mikroangiopatik hemolitik
Infeksi Gangguan dinding sel eritrosit
5 Sekuesterasi Splenik Defisiensi G6PD
Hemolisis mekanis
 Classification of HA

Extravascular haemolysis

Red cell destruction

usually occurs in the
cell of the RES.

6
 Classification of HA

Intravascular hemolysis

Liberation of free Hb
Filtered through the kidney
Appear in urine as
haemoglobinuria

7
 Classification of HA

Site of defect
Intrinsic defect (intracorpuscular)

structural or functional defect within the red cell.

Extrinsic defect (extracorpuscular)
an abnormality in the red cell environment.

Inherited or acquired:
Inherited Hemolytic
Anemia are usually intrinsic defect
Acquired Hemolytic
Anemia extrinsic defect

8
Approach to the
diagnosis of hemolytic
anemia
Patient history
Clinical features

Laboratory: hematologic

9
 Clinical features as results of

1. Increased destruction:
Anemia, enlargement of the spleen,
gallstones
2. Increased compensatory production of red
cells:
Increased erythropoiesis, increased
reticulocyte, bone abnormalities

10
 Clinical features
Pallor
Jaundice
Splenomegaly
Dark urine
Pigment gall stones.
Ulcers around the ankle
Aplastic crisis may
complicate viral infections.
Hypertrophic skeletal
changes
Fatigue
Light headedness /dizzy
feeling
Breathing problems
when exercise
Irregular heartbeat
Enlargement spleen/liver
Growth retardation
11
 Laboratory findings

1. Features of increased red cell breakdown.

2. Features of increased red cell production.
3. Damaged red cells.

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 ...Laboratory

Features of increased red cell breakdown:

Serum bilirubin , unconjugated and bound
to albumin.
Urobilinogen

Faecal stercobilinogen

Serum haptoglobins ( - )

13
 ...Laboratory

Haemoglobinuria

Notice the dark

colour of urine
compared to the
normal colour in the
other container.
This is a sign of
intravascular
haemolysis.

14
 ...Laboratory

Features of increased red cell production:

Reticulocytosis
Bone marrow erythroid hyperplasia.

15
 ...Laboratory

Damaged red cells:

Morphology: microspherocytes, elliptocytes,
fragments, etc
Special tests: Osmotic fragility autohaemolysis
Red cell survival is shortened; this is best shown by
51Cr labelling

16
 ...Laboratory

Poikilocytosis 17
 ...Laboratory

Target cell 18
 ...Laboratory

Reticulocytosis is a
feature of increased
red cell production.
New methylene blue
is used to stain the
reticulocytes

19
 ...Laboratory

Fragmented cells,
and bitten cells are
sings of damaged
cells occurring in
haemolysis

20
 ...Laboratory

Reticulocyte count
Reticulocyte Production Index

Increased serum bilirubin

Increased lactic dehydrogenase

Decrease serum haptoglobin

21
 HISTORY
Recent infection, exposure to drugs, presence of known illness, dark urine, pallor,
fatigability, anorexia

PHYSICAL EXAMINATION
Pallor, jaundice, tachycardia, tachypnea, splenomegaly

ROUTINE LABORATORY TESTS

Peripheral blood smear, red cell agglutination, spherocytosis, red cell fragmentation,
polychromatophilia, erythrophagocytosis, Reticulocyte smear: increase in reticulocytes

IMMUNOLOGIC EVALUATION

RED CELL AGGLUTINATION DIRECT ANTIGLOBULIN

REACTION &
Room temperature or 4C ANTICOMPLEMENT
Positive for cold agglutination BIPHASIC HEMOLYSIS (immediate & incubated)
Blood clotted in cold
then incubated at 37C;
Lysis: biphasic antibody
NEGATIVE POSITIVE
Immune hemolytic Other
mechanism hemolytic
disease
22
Main types of inherited hemolytic
anemias

1. Hemoglobinopathies
2. Thalassemias
3. Enzyme defects
4. Membrane defects

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 Acquired hemolytic anemia
1. Immune hemolytic 2. Non-immunologic
anemias: 1. Mechanical trauma ,
microangiopathic
1. Autoimmune hemolytic
( TTP,HUS,DIC)
anemia (AIHA)
2. Severe
2. Hemolytic Disease of the hypophosphatemia
newborn (HDN) 3. Wilson disease
3. Drug induce 4. Cooper poisoning
immunehemolytic anemia 5. Oxydative drugs
4. Paroxysmal Nocturnal 6. Severe burns
Hemoglobinuria 7. Venoms
8. Infections

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Autoimmune Hemolytic Anemia
(AIHA)

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 Autoimmune Hemolytic Anemia
(AIHA)
Autoantibodies against red cell
destruction of
antibody-coated red cells.
Hallmark :
positive Direct Antiglobulin Test (DAT) /
Coombs test detects a coating of
immunoglobulin or components of
complement on the RBC surface
26
 ..AIHA

Antibody or complement on the surface of the

patients erythrocyte (DAT).
Antibodies in the patients serum (Indirect
antiglobulin or Coombs test).

Hemolysis in AIHA : extravascular, involves

IgG, primarily in the liver and spleen.

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 ..AIHA
AIHA associated Warm Antibodies

Clinical features
Severe : Abdominal pain
live threatening condition Low grade fever
Enlarged spleen & liver
Sudden onset :
palor, jaundice,dark urine

Lethargy

28
 ..AIHA

Laboratory studies for AIHA

Hb: very low, normocytic normochromic

Reticulocytosis

Peripheral smear: spherocytosis, schistocytes,

poikilocytes, anisocytes, polychromasia, nucleated
RBC

Direct Coombs test : positive

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 ..AIHA

Autoimmune Hemolytic Anemia

30
 ..AIHA

Diagnosis of AIHA

Clinical finding

Laboratory:
peripheral blood smear
Direct Antiglobulin test (DAT)
Eluate studies
Indirect antiglobulin test
Semin Hematol 2005;42:131-136
31
 ..AIHA

Treatment of AIHA
1. Corticosteroid therapy:
1. Hydrocortisone 8 40 mg/kg/day
2. Prednisone 2 10 mg/Kg/24 hr
2. Splenectomy
3. Immunosuppression
4. Danazol
5. IVGG (IV Gammaglobulin)
6. High Dose Cyclophosphamide therapy
7. Rituximab: monoclonal anti-CD20 ab
8. Plasmapheresis
9. Blood transfusion : AIHA with fulminant hemolysis
Semin Hematol 2005;42:131-136

32
 ..AIHA

Transfusion therapy in AIHA

1. Patient stable, responding to therapy transfusion (-)

2. Reticulocytopenia: early need for transfussion support
3. Incompatible blood
4. Neurologic sign such confusion: transfusion is urgently
5. Leukocyte reduced donor RBC

Semin Hematol 2005;42:131-136

33
 ..AIHA

AIHA Associated with COLD Antibodies

RBC Antibodies more active at low temperatures

<37C agglutinate RBC Cold antibodies.

Primarily of the IgM class and require complement for

activity

The range of temperature associated with RBC

agglutination Thermal amplitude

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 ..AIHA

AIHA Associated with COLD Antibodies

When very titers of cold antibodies are present &

active near body temperature severe intravascular
hemolysis with hemoglobinemia & hemoglobinuria

Cold agglutinin disease intravascular complement

lysis or be destroyed in both the liver & spleen

35
 ..AIHA
Treatment of AIHA Associated with
COLD Antibodies

1. Control underlying disorders

2. Severe anemia:
Transfusion
Cytotoxic drug
3. Plasmapheresis
4. Avoid exposure to cold
5. Corticosteroid and splenectomy : not efeective

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Glucose 6 Phospate
Dehydrogenase
(G6PD)
Deficiency

37
 Glucose 6 Phospate Dehydrogenase

(G6PD) Deficiency
X-linked enzyme deficiency

More than 100 distinct enzyme variants of G6PD are

associated with a wide spectrum of hemolytic disease

Responsible for 2 clinical syndromes :

episodic hemolytic anemia
spontaneous chronic nonspherocytic hemolytic anemia

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 .. (G6PD) Deficiency

Maternal IgG antibodies againts fetal RBC antigen

cross placenta to fetal circulation during gestation
RBC destruction, complication before birth. Anemia &
hyperbilirubinemia after birth

Severe: hydrops fetalis, hepatospenomegaly, heart

failure

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.. (G6PD) Deficiency

40
 .. (G6PD) Deficiency

Clinical Manifestations

Symptoms develop 24-48 hr after ingested a substance

that has oxidant properties

The degree of hemolysis varies with the inciting agent,

the amount ingested, and the severity of the enzyme
deficiency

In severe cases : hemoglobinuria and jaundice, Hb

concentration may fall precipitously and be life
threatening

41
 .. (G6PD) Deficiency

Diagnosis

Can be suspected when the G6PD activity is within the

low normal range in the presence of a high reticulocyte
count

Treatment
Avoid oxidant stress to RBCs
Transfusion : acute anemia & symptomatic

42
 .. (G6PD) Deficiency

Agents precipitating Hemolysis in G6PD

Deficiency
MEDICATIONS
Antibacterials o Antimalarials : Primaquine,
Sulfonamide Pamaquine ,Chloroquine, Quinacrine
Trimetoprim-sulfamethoxazole Others
Nalidixic acid o Phenacetine
Chloramphenicol
o Vitamin K Analogs
Nitrofurantoin
o Methylene blue
Probenecid
Phenazopyridine o Acetylsalycilic acid

CHEMICALS
- Phenylhydrazine
- Benzene
- Naphtalene

ILLNESS : - Diabetic acidosis

- Hepatitis 43
- 1
Hemolytic Disease

of the Newborn
( HDN )
44
 Hemolytic Disease of the
Newborn (HDN)

Synonymous:Rh D allo-immunisation
Neonatal emergency
Severe Rh D disease
Rapidly developing or severe or prolonged
hyperbilirubinemia

Maternal antenatal antibody screening: (+)

Direct Anti-globulin Test (DAT) : (+)
Hemolysis detected on blood film examination
45
 .HDN

UK 1970: routine postnatal prophylactic anti-D

immunoglobulin for Rh D negative women

ABO incompatibility more common caused by

Hemolytic Disease of the Newborn (HDN) and
less severe than Rh incompatibility

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 .HDN

Clinical Features of HDN

Result of the rate of red cell destruction and the degree
of compensatory erithrocyte production by the fetus

Jaundice, Immune hemolysis & anemia,

Encephalopathy (kernicterus), Purpura, Hypoglycemia

47
 .HDN

Laboratory Evaluation of HDN

Peripheral Blood

Anemia, reticulocytosis, normoblastosis, polychromasia,and anisocytosis

48
 .HDN

Laboratory Evaluation of HDN

Bone marrow : Erythroid hyperplasia

Immunologic evaluation :
Rh HDN autoimmune hemolytic disease mediated
by IgG Ab.

Diagnosis: red cells from Rh-positive infant born to an

Rh-negative mother direct antiglobulin test (DAT)/
Coombs test : positive

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 .HDN

Therapy of HDN

Prevention of Rh isosensitization
Treatment of the affected infant

Prevention of intrauterine fetal death

Prevention of bilirubin encephalopathy

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 .HDN

Acute-management HDN

1. Phototherapy
2. High-dose IVIG
3. Exchange transfusion

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 .HDN
Intravenous immunoglobulin (IVIG)
for HDN

Treatment for severe life threatening

Not recommended for routine treatment acute or
chronic AIHA
(Transfusion Med.rev.;21:2:S3-S8,2007)
HD IVIG reduces the need exchange transfusion in
isoimmune hemolytic jaundice.

Low dose(0.5g/Kg) , reducing the duration of

phototherapy in Rh-isoimmunized neonates
(Indian Pediatrics.2008:;45:633-659)

52
 .HDN

Intravenous immunoglobulin (IVIG)

for HDN
AAP Guidelines : IVIG in hyperbilirubinemia
secondary to hemolytic disease
avoid exchange transfusion
Multiple doses IVIG reduction exchange
transfusion
(Irish Med J 2008:101:2:46-48.)
(Arch Dis Child Fetal Neonatal Ed 2003:88:f6-f10.)

HD IVIG reduction exchange transfusion and

phototherapy
(J Trop.Ped 2002:48:116-117)

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 .HDN

Exchange transfusion

Severe anemia < 10 g/dl at birth

Severe hyperbilirubinemia in the first 48 h of
life or rapidly increasing hyperbilirubinaemia

54
 .HDN

Preventing HDN

1. Determine Rh status mother

2. Rh-D negative mother injection anti-D Ig
about 28 , 34 week gestation, after baby
delivered

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 Drug Induced
Immune Hemolytic Anemia
(DIIHA)

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Drug Induced Immune
Hemolytic anemia
Amphotericin B Ceftazidime
Ampicillin Ceftriaxone
Benzylpenicillin Cefalotin
Carbenicillin Chlorpromazine
Cefazolin Cladribine
Cefotaxime Erythromycin
Cefotetan Fludarabine
Cefoxitin Furosemide

57
 DIIHA
Drug Induced Immune
Hemolytic anemia
Hydralazine Methadone Probenecid Tetracycline
Hydrochorothiazide Methicillin Procainamide Ticarcillin
Ibuprofen Methotrexate Quinidine Tolbutamide
Insulin Methyldopa Ranitidine
Interferon Paracetamol Rifampicin
Interleukin-2 Phenacetin Sulfonamide
Isoniazid Phenytoin Sulindac
Mefloquine Piperacillin

Garraty G..Immunohematol 2004;20:138-46.

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 Conclusion
Good history taking is essential in guiding the
physician towards the correct diagnosis.
Clinical findings seldom are sufficient to enable a
definitive diagnosis of a particular haemolytic
condition to be made.
Lab investigations play a central role in the
accurate diagnosis of haemolysis.

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 Thank You for
60
Your Attention