Anemia

1. ANEMIA PEDIATRIC
G.ERIC™ MD4

2. Anemia is present when the hemoglobin level is
more than
two standard deviations below the mean for the
child's
age and sex

3. Cutoffs for hemoglobin and hematocrit proposed
by the World Health Organization to define anemia
 Age group HB(g/dl) Hematocrit
%
 Children, 6 mo to 5 yr <11.0 <33
 Children, 5-11 yr <11.5 <34
 Children, 12-13 yr <12.0 <36
 Non-pregnant women <12.0 <36
 Men <13.0 <39

4. Physiological Adaptations
Anemia results in a decrease in the oxygen-carrying
capacity of blood with compensatory physiological adjustments.
When the enhanced release of oxygen from
hemoglobin and increase in blood flow to the tissues is
insufficient to meet requirements, tissue hypoxia develops.
Blood volume is maintained by an increase in plasma
volume and redistribution of blood flow to vital organs
such as brain, muscle and heart. Increase in stroke volume
causes an increase in cardiac output, which increases blood
flow and improves oxygen delivery to tissues

5. Etiology
Causes vary with age and anemia may be
multifactorial. In infants, history should include
that for
maternal infections, anemia or collagen vascular
diseases; prematurity; blood loss; jaundice
(hemolysis due
to ABO or Rh incompatibility, G6PD deficiency,
sepsis)
and presence of hemangiomas or
cephalhematoma.

6. Infants may have physiological anemia at 2-3
months of
age. In infants and young children a dietary
history is
useful, including type and quantity of milk and
intake of
hematinics.

7. other causes include chronic
diarrhea or cow milk allergy. Megaloblastic anemia
may
be nutritional, due to use of goat milk in infants
and a
vegetarian diet in older children. Adolescents are
particularly susceptible due to increased
micronutrient
requirements during the growth spurt, and in girls
menstruation and/ or pregnancy

8. History of pica, blood loss (melena, epistaxis), drug
intake (e.g. anticonvulsants), chronic diarrhea,
prior
surgery, chronic infections, liver or renal disease
and
transfusions should be taken. A family history of
severe
anemia and/ or need for blood transfusions
suggests
thalassemia major

9. History of gallstones and recurrent
jaundice is noted in various types of hemolytic
anemia
(e.g. hereditary spherocytosis). Anemia affecting
only
male members of the family points to an X-linked
disorder
like glucose-6-phosphate dehydrogenase (G6PD)
deficiency. Lack of response to iron supplements
suggests
thalassemia minor.

10. Over 70% of patients with thalassemia major present
with anemia by 6 months of age. Similarly, children
with
Diamond-Blackfan syndrome (pure red cell aplasia)
present at about 3 months of age; diagnosis is based on
persistently low reticulocyte count and absence of
erythroid precursors in the bone marrow.The age at
presentation for Fanconi anemia varies between 3-4 yr
to
adulthood.

11. Clinical Features
The hemoglobin level at which symptoms of anemia
appear, depends on the rate of development of the
anemia. Symptoms occur at higher hemoglobin levels
if anemia develops rapidly, as with hemorrhage.The
most common and earliest symptoms include
lassitude,
and easy fatigability. Alternatively, children may have
anorexia, irritability and poor school performance.
Dyspnea on exertion, tachycardia and palpitations
indicate severe anemia. Other symptoms include
dizziness, headache, tinnitus, lack of concentration
and drowsiness and with severe anemia, clouding of
consciousness.

12. The most prominent and characteristic sign is
pallor,
detected most reliably in nail beds, oral mucous
membranes and conjunctivae.
A mid-systolic 'flow' murmur,
chiefly in the pulmonary area, is appreciated when
the
degree of anemia increases, reflecting increased
blood flow
across heart valves.

13. Systolic bruits and postural hypotension
may be noted with moderate to severe anemia.
Severe anemia is characterized by a high output
state with
an elevated pulse pressure and a 'collapsing'
pulse.

14. Anemia may precipitate heart failure even with
a normal
cardiovascular system. Electrocardiographic
changes,
found in 30% patients with hemoglobin below 6
g/ dl,
include depressed ST segment and flattened or
inverted
T waves.

15. Etiological clues on examination include radial limb
abnormalities (suggest bone marrow failure
syndromes),
splenomegaly (hemolytic anemia, malaria, kala-azar,
tuberculosis or storage diseases) and
lymphadenopathy
and hepatosplenomegaly (malignancies or infections).
Presence of petechiae or purpura indicates
concomitant
thrombocytopenia, while icterus suggests liver disease
or
hemolysis.

16. Investigations
A complete hemogram is required to understand whether
the anemia is isolated or other cell lines are affected.
Changes in the red cell indices provide significant
information on the type of anemia and may precede
lowering of hemoglobin
The mean corpuscular
volume (MCV) denotes the size of the red cells while the
mean corpuscular hemoglobin (MCH) and mean corpuscular
hemoglobin content (MCHC) provide information
on red cell hemoglobinization.

17. Based on the MCV,
anemia is classified as microcytic, normocytic and
Macrocytic
Patients with thalassemia
minor or iron deficiency have low MCV, MCH and MCHC
while those with megaloblastic anemia have elevated
MCV.The red cell distribution width (RDW) provides an
estimate of the size differences in red blood cells.
Examination of the peripheral smear reveals red cell
morphology.The presence of schistocytes, polychromasia
or parasites may help make the diagnosis. count helps
distinguish between anemia caused by red cell
destruction and decreased production

18. Normal blood smear (Wright stain). High-power field
showing normal red cells, a neutrophil, and a few platelets.

19. Severe iron-deficiency anemia. Microcytic and hypochromic
red cells smaller than the nucleus of a lymphocyte associated
with marked variation in size (anisocytosis) and shape (poikilocytosis).

20. Macrocytosis. Red cells are larger than a small lymphocyte
and well hemoglobinized.Often macrocytes are oval shaped
(macro-ovalocytes).

21. Normal
reticulocyte count in newborns is 2-6% and in
children
0.5-2%. However, the reticulocyte count should
be corrected
for the degree of anemia.
CCC= Reticulocyte count x Actualhematocrit
Normal hematocrit

22. where the normal hematocrit is 45%.The corrected
reticulocyte count should be 1-2% in a healthy
individual.
In patients with anemia with increased reticulocyte
count, the Coomb test can help distinguish
between
immune and hereditary hemolytic anemia. When
nutritional anemia is suspected, iron studies and
levels
of vitamin B12 and folic acid are determined.

23. Reticulocyte count in evaluation of anemia
 Low reticulocyte count
 Congenital or acquired,
aplastic or hypoplastic
anemia
 Transient
eythroblastopenia of
childhood
 Pure red cell aplasia
 Parvovirus B19 infection
 Bone marrow infiltration
by malignancy, storage
disorder
 High reticulocyte count
 Hemolysis
 Hemorrhage
 Splenic sequestration
 Recovery from vitamin
Bl2, folic acid or iron
deficiency
 Sepsis
 Peripheral

24. Iron Deficient Anemia
Iron is essential for multiple metabolic processes,
including oxygen transport, DNA synthesis and electron
transport. Iron deficiency anemia occurs when the
decrease
in total iron body content is severe enough to diminish
erythropoiesis and cause anemia. Body iron is regulated
carefully by absorptive cells in the
proximal small intestine, which alter iron absorption to
match
body losses of iron. Iron deficiency results from
diminished
dietary iron absorption in the proximal small intestine or
excessive losses of body iron.

25. Iron deficiency in older children
is usually caused by dietary deficiency; the
absorption of
iron is further impaired by dietary constituents that
lower
the absorption of non-heme iron, e.g. phytates,
phosphates
and tannates. Intercurrent infections such as
hookworm
infestation and malaria worsen the problem.

26. Evaluation
A careful dietary history is important, including the type
of milk and weaning foods in infants and the use of
supplements. Pica increases the risks of lead poisoning
and helminthic infections.
Clinical findings are related to the severity and rate of
development of anemia. Irritability and anorexia usually
precede weakness, fatigue, leg cramps, breathlessness and
tachycardia. Congestive cardiac failure and splenomegaly
may occur with severe untreated anemia. Angular
stoma tit is, glossitis, koilonychia and platynychia are
noted
in severe cases.

27. Investigations
The peripheral blood smear reveals microcytic,
hypochromic red cells with anisocytosis and
poikilocytosis and an increased red cell distribution width
(RDW).The MCV and MCHC are reduced.

28. The serum level of iron and ferritin are reduced while
the total iron binding capacity is
Increased.The saturation of transferrin is
reduced to less than 16%.The reduction in serum
ferritin
occurs early and correlates well with the total body iron
stores. Rarely, ferritin may be falsely normal or
elevated
in a sick child since it is an acute phase reactant that
increases in inflammatory conditions. High free
erythroprotoporphyrin
precedes the development of anemia

29. Treatment
The cause of anemia should be identified and
corrected.
Hookworm infestation is the most common cause
of occult
gastrointestinal blood loss Dietary
counseling and treatment of causative factors are
required
to prevent recurrence or failure of therapy. Close
follow
up is required to assess for adequate response.

30. Oral therapy Patients with iron deficiency anemia
should receive 3-6 mg/kg/ day of elemental iron. Ferrous
sulfate, containing 20% elemental iron, is the most effective
and economical oral preparation. Absorption is best when
taken on an empty stomach or in between meals.
Parenteral therapyThe indications of parenteral iron
therapy are: (i) intolerance to oral iron, (ii) malabsorptionand
(iii) ongoing blood loss at a rate where the oral
replacement cannot match iron loss. Intravenous
administration
is preferred over intramuscular route.

31. The total dose of parenteral iron can be calculated by the
following formula:
Iron required (mg) = wt(kg) x 2.3 x (15 - patient
hemoglobin in g/dl) + (500 to 1000 mg)
The total calculated dose is given as divided doses

32. Blood transfusions As iron deficiency anemia is readily
corrected with medication, blood transfusions should
be
avoided in, stable patients. Red cell transfusions are
needed in emergency situations such as acute severe
hemorrhage, severe anemia with congestive cardiac
failure and prior to an invasive procedure. Patients with
very severe anemia and congestive cardiac failure
should
receive transfusions at a very slow rate with
hemodynamic
monitoring and diuretic administration if
necessary.

33. Reasons for non-response to hematinic therapy
for iron deficiency anemia
Poor compliance with therapy
Poorly absorbed iron preparation; e.g. enteric coated
Use of H2 blockers or proton pump inhibitors that cause
achlorhydria
Interaction with food and medications
Associated vitamin B12 or folic acid deficiency
Underlying hemolytic anemia, inflammation or infection
Malabsorption, e.g. celiac disease, giardiasis, H. pylori infection
High rate of ongoing blood loss
Alternative etiology, e.g. sideroblastic anemia

34. Megaloblastic Anemia
Megaloblastic anemia is a distinct type of anemia
characterized by macrocytic red blood cells and
erythroid
precursors that show nuclear d ysmaturity. It is
commonly
caused by deficiency of vitamin B12 (derived from
cobalamin) and/ or folic acid and prevalence varies
with
dietary practices and socioeconomic conditions.

35. Pathophysiology
Megaloblastic anemia is caused by impaired nuclear
maturation, usually due to lack of methyltetrahydrofolate,
a folic acid derivative needed for synthesis of DNA
nucleoproteins.Vitamin B12 is a cofactor in the reaction
necessary for folic acid recycling.The requirement of B12
as a cofactor and its effect on hematopoiesis can be
overcome by large doses of folic acid. Delay in nuclear
progression leads to characteristic RBC morphology and
delayed maturation. Despite active erythropoiesis, there is
premature death of cells before release from the bone
marrow, termed as ineffective erythropoiesis. Megaloblastic
changes affect all hematopoietic cell lines with resultant
anemia, thrombocytopenia and leukopenia

36. Etiology
The two most common causes of megaloblastic
anemia
are vitamin B12 deficiency (cobalamin) and folic
acid
deficiency

37. Folate deficiency can be caused by decreased
intake (infants consuming goat milk or powdered
milk),
increased requirements (infancy, pregnancy, chronic
hemolysis, hyperthyroidism), impaired absorption
(e.g.
celiac disease, malabsorption, anticonvulsants),
concomitant
vitamin B12 deficiency and impaired conversion
to biologically active tetrahydrofolate by
dihydrofolate
reductase (congenital deficiency, inhibition by drugs)

38. Certain drugs inhibit DNA synthesis
to cause megaloblastic anemia.Vitamin
B12 deficiency may be caused by decreased
ingestion,
impaired absorption (e.g. intestinal parasites,
malabsorption,
inherited deficiency of intrinsic factor or
postgastrectomy,
achlorhydria), or impaired utilization (e.g.
congenital enzyme deficiencies).

39. Vitamin B12
deficiency is also described in patients with HIV infection
with or without AIDS. Nutritional deficiency is far more
common in vegans (vegetarian ingesting little or no dairy
products) and those consuming only goat milk. Anemia
in infancy may relate to inadequate body stores due to
maternal deficiency and/or prolonged exclusive
breastfeeding,
since breast milk is a poor source. Helicobacterpylori
infections are implicated in vitamin B12 malabsorption
amongst adults

40.  Drugs that cause megaloblastic anemia
 ImpairedJolie acid absorption: Phenytoin, phenobarbital
 Impaired cobalamin absorption: Proton pump inhibitors
 Interference withJo/ate metabolism: Methotrexate,
trirnethoprirn,
 pyrirnethamine
 Interference with cobalamin metabolism: p-Aminosalicylic
acid,
 metformin, neomycin
 Purine analogs: 6-Mercaptopurine, 6-thioguanine,
azathioprine
 Ribonucleotide reductase inhibitors: Hydroxyurea, cytarabine
 arabinoside
 Pyrimidine analogs: Zidovudine, 5-fluorouracil

41. Metabolic causes of
megaloblastic anemia
Inborn errors of cobalamin
metabolism
Congenital intrinsic factor
deficiency
Deficiency of R-binders of
vitamin B12 and/ or
transcobalamin II
Cobalamin malabsorption due to
defect in intestinal receptor
(Imersliind-Grasbeck syndrome)
Methylmalonic aciduria
Homocystinuria
Inborn errors of folate
metabolism
Congenital folate malabsorption
Dihydrofolate reductase
deficiency
N5-methyl tetrahydrofolate
homocysteine
methyltransferase
deficiency
Other inborn errors
Hereditary orotic aciduria
Lesch Nyhan syndrome
Thiamine responsive
megaloblastic anemia

42. Peripheral smear of a 12-yr-old girl with megaloblastic
anemia showing hypersegmented polymorphonuclear cell. Note that
the nucleus has more than 5 lobes

43. Clinical Manifestations
A careful dietary history is essential to the diagnosis of
megaloblastic anemia. History should include that for
malabsorption, infestations and for intake of medications.
Folate deficiency can occur during prolonged parenteral
nutrition and through losses during hemodialysis. Patients
with pernicious anemia may have history of autoimmune
disorders.
Anemia, anorexia, irritability and easy fatigability are
clinical features common to other causes of anemia.
Features characteristically found in megaloblastic anemia
include glossitis, stoma ti tis and hyperpigmentation of the
skin on knuckles and terminal phalanges, enlargement of
liver and spleen

44. Neurologic signs
may precede the onset of anemia. Petechiae and
hemorrhagic manifestations are reported in one-fourth
cases.The child should be evaluated for signs of
malabsorption such as weight loss, abdominal distention,
diarrhea and steatorrhea. Abdominal scars from ileal
resections may be present.
Neurologic examination is mandatory.The earliest
neurologic signs include loss of position and vibratory
sensation; other posterior and lateral column deficits may
appear later. Memory loss, confusion and neuropsychiatric
symptoms may occur. Neurological signs may persist
despite correction of deficiency.

45. Laboratory Evaluation
Complete hemogram with red cell indices reveals
macrocytic red cells (usually >110 fl) and cytopenias.
Hypersegmented neutrophils (nucleus with 6 or
more
lobes) may be seen.
The reticulocyte count is
useful. If available, serum B12 and folate levels
should be assayed. Investigations are performed if
a specific
underlying cause is suspected.

46. Schilling test involves
administration of vitamin B12 (1 mg of unlabeled B12 by
intramuscular route to saturate hepatic receptors and 1 μg
of radiolabeled crystalline B12 orally) followed by
collection of 24-hr urine collection; adequate absorption
is suggested by detection of >7% of administered
radioactivity in the urine. Repeating the test with
coadministration
of intrinsic factor helps differentiate
between pernicious anemia and malabsorption, the latter
being more common in children.

47. Any child with more than
one abnormal hematological cell line should undergo
bone
marrow aspiration.This helps to rule out leukemia,
myelodysplasia and aplastic anemia. In megaloblastic
anemia the bone marrow is cellular and shows
nuclearcytoplasmic
asynchrony in red blood cell precursors.
Granulocyte precursors may also be abnormal. Serum
chemistry may reveal elevated lactic dehydrogenase
(LDH) and indirect bilirubin

48. Differential Diagnosis
Other causes of macrocytosis to be considered in the
differential diagnosis of megaloblastic anemia include
aplastic anemia, other marrow failure syndromes (pure
red cell aplasia, Fanconi anemia, transient
erythroblastopenia
of childhood), congenital dyserythropoietic
anemia, chronic liver disease, hypothyroidism, cold
agglutinin
disease, neoplasms, myelodysplastic syndromes and
HIV infection

49. Treatment
Treatment depends on the underlying cause.While
evaluating for cause, therapeutic doses of folate
should be administered along with vitamin B12.
While folate
therapy corrects anemia, it does not correct
neurological
changes induced by cobalamin deficiency and
results in
the progression of neuropsychiatric symptoms.

50. Folate
deficiency due to dietary insufficiency or increased
demands is best treated with supplements, while that
induced by use of anti-folate medications requires reducing
or discontinuing the administration of the implicating
drug and addition of supplements. Folate is available as 5
mg tablet and overdose is not associated with any adverse
effects; a dose of 1-5 mg daily is advocated for 3--4 weeks.
Vitamin B12 is administered at a dose of 250-1000 μg by
intramuscular route; young children should receive lower
doses (250-500 μg) since tremors and extrapyramidal
toxicity are reported.

51. Therapy is given daily for 1-2 weeks
and then weekly until the hematocrit is normal. Patients
with pernicious anemia and malabsorption require
monthly supplementation for life. Patients with neurological
complications should receive 1000 μg daily for 2
weeks, then every 2 weeks for 6 months and monthly for
life.The absorption of oral supplements is variable and
may be insufficient in patients with malabsorption.
Patients with dietary insufficiency should receive nutritional
counseling; if diet cannot be altered due to social
and cultural reasons, lifelong vitamin B12 supplementation
is required, either as oral supplements daily or
parenteral doses every 3-12 months.

52. Hemolytic Anemia
The term hemolytic anemia refers to conditions in which
the rate of red cell destruction is accelerated and the ability
of the bone marrow to respond to anemia is unimpaired.
Hemolytic disorders may be divided into
inherited and acquired varieties.
This
classification has a pathogenetic significance because the
nature of hereditary lesions differs from that of acquired.
Most intrinsic defects are inherited and the extrinsic are
acquired. An exception is paroxysmal nocturnal
hemoglobinuria, an acquired disorder characterized by
an intrinsic red cell defect.

53. Clinical Features
In acute hemolysis, symptoms are related to the
rate of
fall of hemoglobin; patients with rapid
hemolysis have an acute and severe
presentation. Anemia is suggested
by weakness, pallor and fatigue. Jaundice is a
prominent
finding of some hemolytic anemias.

54. Jaundice is a prominent
finding of some hemolytic anemias. Red urine
suggests
hemoglobinuria in intravascular hemolysis.
Splenomegaly
is seen in autoimmune and several congenital
causes of
hemolytic anemias.

55. Other useful clues to etiology are the
presence of gallstones (spherocytosis),
hemolytic or
thalassemic facies and leg ulcers (sickle cell
anemia); however laboratory tests are still
required to
confirm the cau

56. Causes of hemolytic anemia
Acquired
Mechanical: Macroangiopathic. (Artificial
heart valves, march
hemoglobinuria); microangiopathic (
disseminated intra vascular
coagulation, hemolytic uremic syndrome,
thrombotic
thrombocytopenic purpura)
Infections, e.g. malaria, kala-azar,
Clostridium welchii
Antibody mediated: Autoimmune hemolytic
anemia (warm and
cold types)
Transfusion reactions: Immediate and
delayed
Hemolytic disease of the newborn
Drugs:Cefotetan, ceftriaxone
Hypersplenism
Cryopathy, e.g. cold agglutinin disease,
paroxysmal cold
hemoglobinuria
Physical injury, e.g. bums
Chemical injury, e.g. snake bite, lead and
arsenic toxicity
Inherited
Hemoglobinopathies, e.g. thalassemia,
sickle cell disease
Red cell membrane defect, e.g. glucose-6-
phosphate dehydrogenase
deficiency
Disorders of the cytoskeletal membrane,
e.g. hereditary
spherocytosis
Unstable hemoglobins
Lipid membrane defects, e.g.
abetalipoproteinemia
Porphyria

57. Child with hemolytic anemia, showing hemolytic facies
and icterus

58. Laboratory Findings
The reticulocyte count is useful in determining the rate of
red cell destruction.The normal reticulocyte count value
in the newborn is 3.2±1.4% and in children 1.2±0.7%.
in the newborn is 3.2±1.4% and in children 1.2±0.7%.
Laboratory test findings in hemolytic anemia can be
divided into three groups:
1. Increase in erythrocyte destruction
ii. Compensatory increase in the rate of erythropoiesis
(Table 12.10) and
iii. Features specific to particular etiologies of hemolytic
anemia.

59. An elevated corrected reticulocyte count may be the
only manifestation of mild hemolytic anemia in a well
compensated child. Hemoglobin and heme released
from
red cells following intravascular hemolysis bind to the
proteins haptoglobin and hemopexin.These protein
complexes are removed from circulation. Hence,
haptoglobin and hemopexin levels are low in patients
with intravascular hemolytic anemia.

60. A peripheral smear is useful in evaluation of hemolytic
anemias. It may show malarial parasites; presence of
bite
cells may suggest glucose 6 phosphate dehydrogenase
enzyme (G6PD) deficiency. Spherocytes are seen in
hereditary spherocytosis, but may also be seen post
transfusion. Microcytosis with many fragmented red
cells
may suggest thalassemia and thromb schistocytosis
(fragmented red cells) can be seen in
disseminated intravascular coagulopathy or hemolytic
uremic syndrome. ocytopenia with

61. The Coombs test is the most important
initial test to perform to define the etiology of
hemolysis.
A positive direct antiglobin (direct Coombs) test means
that the erythrocyte is coated with IgG or C3
component
of complement, and is positive in most cases of
immune
hemolytic anemia. However, the test may be falsely
negative in 2-5% cases

62. Hallmarks of intravascular and extravascular
hemolysis.
Following intra vascular hemolysis, hemoglobin is
released
into the plasma (hemoglobinemia).A part of the
circulating
free hemoglobin is converted to methemoglobin,
which binds with albumin to form methemalbumin that
confers a brown color to plasma for several days
following
the hemolytic event.When the amount of hemoglobin
exceeds the haptoglobin binding capacity it is excreted
in
the urine (hemoglobinuria).

63. Some of this hemoglobin is
reabsorbed in the proximal renal tubules; the loss
of
hemeladen tubular cells is seen as hemosiderinuria.
Similar to intravascular hemolysis, unconjugated
bilirubin, lactate dehydrogenase and reticulocyte
count
are elevated in extravascular hemolysis and
haptoglobulin
may be decreased.

64. However, in extravascular destruction
of red cells, there is no free hemoglobin or
methemoglobin
in the plasma; hence, hemoglobinemia,
hemoglobinuria
and hemosiderinuria are absent.
Specific tests such as hemoglobin electrophoresis,
osmotic fragility, enzyme assays for G6PD and
pyruvate
kinase deficiency and assay for CDSS/59 for
paroxysmal
nocturnal hemoglobinuria are based on the etiology
suspected (

65. Management
It is important to maintain fluid balance and renal output
during and after acute hemolysis. Shock is managed by
appropriate measures. However, blood transfusions,
Considered useful in acute anemia of other types, should
be used cautiously when managing patients with
acquired
hemolytic anemias. Even with careful blood matching,
transfused blood cells may undergo hemolysis, leading
to an increase in the burden on excretory organs and,
sometimes, thromboses.

66. Acute autoimmune hemolytic anemia is treated
with
corticosteroids (prednisone 1-2 mg/kg/day), which
are
tapered gradually over several months after
ongoing
hemolysis has resolved. Patients with chronic
hemolysis
require thorough investigation for etiology and
treatment
specific to cause.

67. Laboratory signs of accelerated erythrocyte
destruction
Fall in blood hemoglobin level at> 1.0 g/ dl per week
Increased serum level of unconjugated bilirubin
Increased urinary urobilinogen excretion
Increased serum lactate dehydrogenase
Reduced haptoglobin and hemopexin
Reduced glycosylated hemoglobin
Decreased erythrocyte life span (labeled with radioisotope
s1cr)

68.  Laboratory signs of
accelerated
erythropoiesis
Peripheral blood
Polychromasia or
reticulocytosis
Macrocytosis
Increase in nucleated
red cells
Bone marrow
Erythroid hyperplasia
Iron kinetic studies
Increased plasma iron
turnover
Increased erythrocyte
iron turnover

69. Hereditary Spherocytosis
Patients with hereditary spherocytosis may have one of
several membrane protein defects. Many of these result
in instability of spectrin and ankyrin, the major skeletal
membrane proteins.The degree of skeletal membrane protein
deficiency correlates with the degree of hemolysis.
Membrane protein deficiency leads to structural changes
including membrane instability, loss of surface area,
abnormal membrane permeability and reduced red cell
deformability.These defects are accentuated during
depletion of metabolites, demonstrated as an increase in
osmotic fragility after 24-hr incubation of blood cells at
37°C. Non-deformable erythrocytes are destroyed during
passage through spleen.

70. Laboratory findings. Patients with hereditary
spherocytosis
may have a mild to moderate chronic hemolytic
anemia.
The red cell distribution width (RDW) is increased
due to
the presence of spherocytes and increased
reticulocytes.
The MCV is decreased and MCHC increased due to
cellular dehydration.

71. Presentation.The age of presentation ranges
from early
childhood to adulthood. Patients chiefly
present with
jaundice of varying intensity. Splenomegaly is
found in
75% patients. Gallstones are frequent,
particularly in older
patients and represent pigment calculi.

72. Management. Patients require lifelong folic acid
supplementation
of 1-5 mg daily to prevent folate deficient due
to the high turnover of red cells and accelerated
erythropoeisis.
While splenectomy does not cure the hemolytic
disorder, it may reduce the degree of hemolysis. It is
the
treatment of choice in patients with severe
hemolysis and
high transfusion requirement. Splenectomy is
delayed or
avoided in patients with mild hemolysis.

73. Splenectomy
may diminish the risk of traumatic splenic rupture in
children with splenomegaly. Splenectomy is usually
performed beyond 6 yr of age following immunizations
against Haemophilus influenzae type B, Streptococcal
pneumoniae and Neisseria meningitidis. Post
splenectomy,
patients should receive penicillin prophylaxis, to
prevent
sepsis, usually up to early adulthood.

74. As with other hemolytic anemias, patients with
hereditary
spherocytosis are also susceptible to aplastic crisis
with human parvovirus B19.This organism
selectively
invades erythroid progenitor cells and causes
transient
arrest in red cell production. Patients usually
recover in
4-6 weeks.

75. Abnorma/lties in Red Cell
Glycofysis
Glucose is the primary metabolic substrate for
erythrocytes.
Since mature red cells do not contain
mitochondria,
glucose is metabolized by anerobic pathways;
the two
main metabolic pathways are Embden
Meyerhof pump
(EMP) and the hexose monophosphate shunt.

76. The Embden
Meyerhof pump pathway accounts for 90% of glucose
utilization.The inability to maintain adenosine
triphosphate
impairs cellular functions, including deformability,
membrane lipid turnover and membrane permeability,
leading to shortened red cell life.The hexose
monophosphate
shunt is responsible for 10% of glucose metabolism.

77. This pathway generates substrates that protect red
cells
from oxidant injury. A defect in this shunt causes
collection of oxidized hemoglobin (Heinz bodies), lipids
and membrane proteins in red cells, which result in
hemolysis.The reticulocyte count is raised and bone
marrow shows erythroid hyperplasia. Demonstration
of
autohemolysis is a useful screening test; diagnosis
requires
specific enzyme assays.

78. Glucose-6-phosphate dehydrogenase deficiency
Glucose-6- phosphate dehydrogenase (G6PD)
deficiency
is the most common red cell enzyme deficiency.
It is an Xlinked
recessive disease with full expression in affected
males. Many variants are identified based on
differences
in antioxidant reserve and enzyme levels.

79. After an oxidant
exposure, hemoglobin is oxidized to methemoglobin and
denatured to form intracellular inclusions also known as
Heinz bodies.These Heinz bodies get attached to the red
cell membrane and aggregate intrinsic membrane
proteins
such as band 3. Reticuloendothelial cells detect these
membrane changes as antigenic sites and ingest a part
of
the red cell.This partly phagocytosed cell, called 'bite'
cell, has a shortened half-life.

80. The child may present with jaundice in neonatal period.
Findings during a hemolytic crisis are pallor, icterus,
hemoglobinemia, hemoglobinuria and splenomegaly.
Plasma haptoglobin and hemopexin are low.The
peripheral blood smear shows fragmented bite cells and
polychromasia. Special stains demonstrate Heinz bodies
during the initial few days of hemolysis. Diagnosis of
G6PD deficiency is suggested by family history, clinical
findings, laboratory features and exposure to oxidants
prior to the hemolytic event

81. Confirmation
of the diagnosis requires quantitative enzyme
assay or
molecular gene analysis.
Management consists of supportive care during the
acute crisis (hydration, monitoring and transfusions
if
needed) along with folic acid supplementation.
Counseling
to avoid intake of oxidant drugs is
imperative.

82. Pyruvate kinase deficiencyThis is the most common
enzyme defect in the Embden Meyerhof pump and is
inherited in an autosomal recessive manner. Homozygotes
present with splenomegaly, icterus and hemolytic
anemia, but the clinical spectrum is variable. Folic acid
supplementation is required to prevent megaloblastic
complications due to relative folate deficiency.
Splenectomy
is considered a therapeutic option in patients with
pyruvate kinase deficiency, it does not stop the hemolytic
process.The reticulocyte count increases dramatically after
splenectomy.

83.  Drugs that cause oxidant stress and hemolysis in
 patients with glucose-6-phosphate
dehydrogenase deficiency
 Sulfonamides: Sulfamethoxazole
 Antimalarials: Primaquine, quinine
 Analgesics: Aspirin, non-steroidal anti-inflammatory
drugs,
 phenazopyridine (pyridium)
 Others: Nitrofurantoin, dapsone, methylene blue,
rasburicase,
 toluidine blue, nalidixic acid, furazolidine, quinidine

84. Autoimmune Hemolytic Anemia
An autoimmune phenomenon targeting the red cells
may
occur in isolation, or arise as a complication of an
infection
(viral hepatitis B, upper respiratory tract viral
infections,
mononucleosis and cytomegalovirus infection),
systemic
lupus erythematosus (SLE) or other autoimmune
syndromes, immunodeficiency states or malignancies.

85. Clinical featuresThe disease usually has an acute
onset,
manifested by weakness, pallor, fatigue and
dark urine.
Jaundice is a prominent finding and
splenomegaly is
common. Some cases are chronic. Clinical
features may
suggest an underlying disease (e.g. SLE or HIV).

86. Laboratory findingsThe anemia is normochromic and
normocytic and may vary from mild to severe.The
reticulocyte count is usually increased. Spherocytes and
nucleated red cells may be seen on the peripheral blood
smear. Other features suggesting hemolysis include
increased levels of lactic dehydrogenase, indirect and total
bilirubin, aspartate aminotransferase and urinary urobilinogen.
Intravascular hemolysis is indicated by hemoglobinemia
or hemoglobinuria. Serologic studies help
define pathophysiology, plan therapeutic strategies and
assess prognosis.The direct antiglobulin test is positive
in almost all cases. Further evaluation allows distinction
into one of three syndromes.

87. Autoimmune hemolytic anemia due to warm reactive autoantibodies is
caused by IgG antibodies against the patient's
red blood cells, with specificity for Rh-like antigen.These
antibodies have maximal in vitro antibody activity at 37°C
and do not require complement for activity.The condition
can occur in isolation (primary), associated with immune
disorders (e.g. SLE, lymphoproliferative disease,
immunodeficiency),
or with use of certain drugs (e.g. penicillin,
cephalosporins) due to the 'hapten' mechanism (tight
binding of drug to the red cell membrane is followed by
immune destruction of cells by newly formed or preexisting
antibodies to the drug). Extra vascular destruction
of the red cells by reticuloendothelial system occurs,
resulting in splenomegaly.

88. In contrast, patients with cold reactive autoimmune
hemolytic anemia have antibodies, primarily of the IgM
class, that require complement for their activity, have
optimal reactivity in vitro at 4°C, and are specific to the
i
or I antigen on red cells. Detection of complement
alone
on red blood cells help make a diagnosis.While the
condition is usually seen in adults, children may
develop
Donath Landsteiner hemolytic anemia, which is
associated
with an acute viral syndrome and is mediated by cold

89. hemolysis. Paroxysmal cold hemoglobinuria is a related
condition, usually identical to cold autoimmune hemolytic
anemia, except for antigen specificity to P antigen and the
evidence of in vitro hemolysis.Children may develop cold
agglutinins following infections, such as mycoplasma,
Epstein-Barr virus (EBV) and cytomegalovirus (CMV), in
association with intravascular hemolysis.
IgG and complement associated autoimmune hemolytic
anemia may occasionally occur due to warm antibody or,
very rarely, due to drug associated autoimmune hemolytic
anemia.

90. Management
Most patients with warm autoimmune
hemolytic anemia respond to prednisone 1 mg/
kg, given daily for 4 weeks or till hemoglobin is
stable.
After initial treatment, corticosteroids may be
tapered
slowly over 4-6 months. While use of intravenous
immune
globulin (!VIG) (1 g/kg/day for 2 days) may induce
remission, the response is not sustained.

91. In severe cases
unresponsive to conventional therapy,
immunosuppressive
agents such as cyclophosphamide, azathioprine and
cyclosporine may be tried alone or in combination with
corticosteroids. Danazol is effective in 50-60% of cases
of
chronic hemolytic anemia. Refractory cases may
respond
to rituximab (monoclonal antibody to B cell CD20) or to
hematopoietic stem cell transplantation.

92. Patients with cold autoimmune hemolytic anemia and
paroxysmal cold hemoglobinuria are less likely to
respond
to corticosteroids or intravenous immunoglobulin (IVIG).
When associated with infections, these syndromes have
an acute, self-limited course and supportive care is all
that
is necessary. Plasma exchange is effective in severe cold
autoimmune (IgM) hemolytic anemia and may be helpful
in severe cases because the offending antibody has an
intravascular distribution.

93. Transfusion may be necessary because of the
complication of severe anemia but should be
monitored
closely. In most patients, cross-match compatible
blood
will not be found and the least incompatible unit
should
be identified by the blood bank.Transfusions must
be
conducted carefully, beginning with a test dose.

94. Transfusion may be necessary because of the
complication of severe anemia but should be
monitored
closely. In most patients, cross-match compatible
blood
will not be found and the least incompatible unit
should
be identified by the blood bank.Transfusions must
be
conducted carefully, beginning with a test dose.

95. Prognosis In general, children with warm autoimmune
hemolytic anemia are at greater risk for more severe
and
chronic disease with higher morbidity and mortality
rates.
Hemolysis and positivity of antiglobulin tests may
continue for months or years. Patients with cold
autoimmune
hemolytic anemia or paroxysmal cold hemoglobinuria
have acute self-limited disease.

96. Thalassemias
The word thalassemia is a Greek term derived from
thalassa, which means 'the sea' (referring to the Mediterranean
sea) and emia, which means 'related to blood'.
The disease is more common in populations in the
geographic belt from SoutheastAsia to Africa.Thalassemias,
caused by defects in the globin gene, are the most
common monogenic disease. More than 200 mutations
are described and the defects are inherited in an autosomal
recessive manner.The carrier rates for p thalassemia
in north Indians are reported to vary from 3-17%
in different ethnic groups

97. Pathophysiology
The major hemoglobin in humans, called HbA,
constitutes
approximately 90% of total hemoglobin in children
beyond one year of age. A minor component, HbA2,
accounts for 2-3% of hemoglobin.The main
hemoglobin
in fetal life is HbF, of which only traces remain after one
year. Each of these hemoglobins has two a chains that
are
associated with two p globin chains in HbA, o chains in
HbA2 and y globin chains in HbF.

98. Thalassemias are inherited disorders of
hemoglobin
synthesis that result from an alteration in the rate
of globin
chain production. A decrease in the rate of
production of
globins (a, p, o, y) impedes hemoglobin synthesis
and
creates an imbalance with normally produced
globin
chains.

99. Because two types of chains (a and non-a) pair
with each other at a ratio close to 1:1 to form normal
hemoglobin, an excess of the normally produced type is
present and accumulates in the cell as an unstable
product, leading to early the destruction of the red cell.
The type of thalassemia usually carries the name of the
chain or chains that is not produced.The reduction may
vary from a slight decrease to a complete absence.When
p chains are produced at a lower rate, the thalassemia is
termed P+, whereas p0 thalassemia indicates a complete
absence of production of P chains from the involved
allele.

100. Presentation
Thalassemia should be considered in the
differential
diagnosis of any child with hypochromic,
microcytic
anemia that does not respond to iron
supplementation.

101. Children with p thalassemia major usually
demonstrate
no symptoms until about 3-6 months of age, when
p chains
are needed to pair with a chains to form HbA, since
y
chains production is turned off. However, in some
cases,
the condition may not be recognized till 3-5 yr of
age due
to a delay in cessation of HbF production.

102. Severe pallor and hepatosplenomegaly are almost
always present. Icterus is usually absent, but mild to
moderate jaundice may occur due to liver dysfunction
from iron overload and chronic hepatitis. Symptoms of
severe anemia such as intolerance to exercise, irritability,
heart murmur or even signs of frank heart failure may be
present. Bony abnormalities, such as frontal bossing,
prominent facial bones and dental malocclusion are
usually present (Fig 12.6). Ineffective erythropoiesis
leads
to a hypermetabolic state associated with fever and
failure
to thrive. Hyperuricemia may be encountered.

103. LaboratoryStudies
Complete blood count and peripheral blood film
examination are usually sufficient to suspect the diagnosis.
In thalassemias major and intermedia, the hemoglobin level
ranges from 2-8 g/dl, MCV and MCH are significantly
low, reticulocyte count is elevated to 5-8% and
leukocytosis is usually present. A shift to the left reflects
the hemolytic process.The platelet count is usually normal
unless the spleen is markedly enlarged, causing
hypersplenism. Peripheral blood film examination reveals
marked hypochromasia and rnicrocytosis, polychromatophilic
cells, nucleated red blood cells, basophilic stippling
and occasional immature leukocytes

104. High performance liquid chromatography (HPLC) for
hemoglobin must be sent prior to the first b lood
transfusion.The test confirms the diagnosis of 􀁊
thalassemia.
Absence of HbA and elevation of HbF suggest
thalassernia major; the level of HbA2 is not important
for
diagnosis.The presence of elevated HbA2 alone
suggests
the diagnosis of thalassemia trait.

105. Management
Patients with thalassemia major require medical
supervision to monitor for complications and
transfusion
therapy. Blood transfusion should be initiated at an
early
age when the child is asymptomatic and attempts
should
be made to keep pretransfusion hemoglobin 9-10
g/ dl
(to promote growth and prevent deformity).

106. Chelation
therapy to deal with the accumulated iron overload is
vital
to prevent iron overload and organ dysfunction. A
normal
diet is recommended, with supplements of folic acid
and
small doses of vitamins C and E. Iron supplements
should
not be given. Drinking tea with meals has been shown
to
decrease absorption of iron in the gut.

107. Iron overload. Iron overload is the major causes of
morbidity and organ toxicity.The excessive load of iron
is due to increased gastrointestinal iron absorption as
well
as repeated transfusions. Hence, avoidance of
transfusions
alone will not eliminate the iron overload problem.
Patients with signs of iron overload demonstrate signs of
endocrinopathy caused by iron deposits,
includingdiabetes, hypothyroidism,
hypoparathyroidism, decreased
growth and lack of sexual maturation. diabetes,
hypothyroidism, hypoparathyroidism, decreased
growth and lack of sexual maturation.

108. Chelation therapy.The introduction of chelating agents
capable of removing excess iron from the body has
dramatically increased life expectancy.The cost, however,
has resulted in poor compliance and inadequate dosing
of iron chelators in many Indian patients.The optimal time
to initiate chelation therapy is dictated by the amount of
accumulated iron.This usually occurs after 1-2 yr of
transfusions when ferritin level is about 1000-1500 μg/1.
The standard till now has been deferoxamine which must
be administered parenterally because of its short half-life.
Prolonged subcutaneous infusion is the most effective
route. A total dose of 40-60 mg/kg/ day is infused over
8-12 hours during the night for 5-6 days a week by a
mechanical pump. Patients should be warned about
orange discoloration of urine due to the excretion of irondeferoxamine
complex (ferrioxamine). Higher doses of
deferoxamine (6-10 g) may be administered intravenously,
as inpatient when serious iron overload such
as cardiac failure occurs

109. Sickle Cell Anemia
Sickle cell anemia is an autosomal recessive
disease that
results from the substitution of valine for
glutamic acid at
position 6 of the beta-globin gene. Patients
who are homozygous
for the HbS gene have sickle cell disease.
Patients
who are heterozygous for the HbS gene have
sickle trait

110. Clinical Features
Patients with sickle cell anemia can present with serious
and varied manifestations.
Pain is the most common presentation of vaso-occlusive
crisis. Presentation with pain suggests acute chest syndrome
if pleuritic in nature and arthritis or osteomyelitis if joint or
bone are involved. Painful crises tend to recur, precipitated
by triggers such as dehydration or fever. Shortness of breath
or dyspnea suggests an acute chest syndrome, while unilateral
weakness, aphasia, paresthesias, visual symptoms
may suggest stroke or infarct.

111. Sudden increase in pallor,
syncope or sudden pain or fullness in the left
side of the
abdomen mass may indicate a splenic
sequestration crisis

112. The usual presentations in a young child are
icterus due
to elevated unconjugated bilirubin, pallor and
mild
splenomegaly.The disease may manifest as a
febrile illness
since these children are prone to pneumococcal,
Salmonella
and other bacterial infections

113. Tachypnea suggests
pneumonia, congestive heart failure, or acute chest
syndrome, while hypoxia is common with acute chest
syndrome. Children with a plastic crisis may present
with
congestive heart failure (CHF) due to severe anemia.
Hypotension and tachycardia are signs of septic shock
or
sequestration crisis. Growth retardation and gallstones
are
common in children with sickle cell anemia.

114. Types of Crisis
Vasa-occlusive crisis. A vaso-occlusive crisis
occurs when
the microcirculation is obstructed by sickled red
blood
cells resulting in ischemic injury.The major
complaint is
pain, usually affecting bones such as femur,
tibia and
lower vertebrae.

115. Alternatively, vaso-occlusion may
present as dactylitis, hand and foot syndrome (painful
and
swollen hands and/ or feet), or an acute abdomen.The
spleen may undergo auto-infarction and is often not
palpable beyond 6 yr of age. Involvement of the kidney
results in papillary necrosis leading to inability to
concentrate urine (isosthenuria).Other presentations
include acute chest syndrome, retinal hemorrhages,
priapism, avascular necrosis of the femoral head and
cerebrovascular accidents.

116. Acute chest syndrome. This is a type of vaso-occulsive
crisis
that affects the lung and presents with chest pain,
cough,
tachypnea, dyspnea, hypoxemia, fever or a new
pulmonary
infiltrate.This requires urgent admission; oxygen
support, antibiotics (also should cover for mycoplasma
and chlamydia), intravenous fluids, bronchodilators
and
use of steroids may be of benefit

117. Sequestration crisis.This is due to sickled cells
that block
splenic outflow, leading to the pooling of
peripheral blood
in the engorged spleen resulting in splenic
sequestration

118. Aplastic crisis. Aplastic crises can occur when the bone
marrow stops producing red blood cells.This is most
commonly seen in patients with infection or folate
deficiency.This is usually self-limited and may follow
viral infections of which parvovirus B19 is the most
commonly implicated. Usually only supportive care
and
occasionally packed red blood cell transfusions are
required.

119. Infections
Affected children have increased susceptibility to
encapsulated organisms (e.g. Haemophilus
influenzae, Streptococcus pneumoniae).They are
also at risk of other
common infectious organisms such as
Salmonella,
Mycoplasma pneun10niae, St aphylococcus aureus
and
Escherichia coli.

120. Laboratory Studies
Anemia and thrombocytosis are commonly found.
Leukocytosis occurs in patients with sickle cell
anemia.
However, a rise in the white blood cell count (i.e.
>20,000
per mm3) with a left shift is indicative of infection.
In the
peripheral smear, sickle-shaped red blood cells are
found
along with target cells.

121. Presence of Howell-Jolly bodies
indicates that the patient is functionally
asplenic.The
baseline indirect bilirubin level may be elevated
because
of chronic hemolysis.

122. If the diagnosis of sickle cell anemia has not been
made,
a sickling test will establish the presence of sickle
hemoglobin. Hemoglobin electrophoresis is the test
that
can differentiate between individuals who are
homozygous
or heterozygous. Hemoglobin in a homozygous patient
will chiefly (80-90%) be hemoglobin SS (HbSS), while
carriers will have 35-40% as HbSS.This needs to be
checked prior to blood transfusions.

123. Assessment During Acute Illness
In a sick child, a type and cross-match is required for
probable transfusion.A chest X-ray and X-rays of bones
may be indicated in pain crisis. Blood culture should be
sent. Monitoring of oxygen saturation and arterial blood
gases should be ordered in patients with respiratory
distress.A major drop in hemoglobin (more than 2 g/dl)
from baseline indicates a splenic sequestration or aplastic
crisis. Reticulocyte count and examination of spleen size
will help to differentiate between these two conditions.
An electrocardiogram must be performed if symptoms of
chest pain and/or pulse irregularities are noted.

124. Inpatient Management
Hydration and analgesia are the mainstays of
treatment
in a pain crisis. Narcotic analgesia is most
frequently used.
Hydration is corrected orally if the patient is not
vomiting
and can tolerate oral fluids. In severe dehydration,
intravenous fluids are required. Care is taken not to
overload the patient and accurate intake-output
monitoring should be ensured.

125.  Blood transfusion is useful
 in patients in aplastic crisis and acute
sequestration crisis.

126. Oxygen supplementation is of benefit if the patient has
hypoxia. Intubation and mechanical ventilation may be
required in children in whom cerebrovascular accidents
have occurred, or with acute chest syndrome.
Exchange
blood transfusions are indicated in cases of
cerebrovascular
accidents and acute chest syndrome.This involves
replacing
the patient's red blood cells by normal donor red blood
cells, decreasing HbSS to less than 30%.

127. They may be
performed in patients with acute sequestration
crisis or in priapism that does not resolve
after adequate hydration
and analgesia.

128. Preventive Care
All children require prophylaxis with penicillin or
I amoxicillin, at least until 5 yr of age and
should receive
immunizations with pneumococcal,
meningococcal and
Haemophilus influenzae B vaccines.They should
receive life
long folate supplementation.

129. Hydroxyurea is a cytotoxic
agent which can increase HbF and reduce episodes
of pain
crises and acute chest syndrome and may be useful
beyond
5 yr of age. Parents need to learn how to identify
complications
and be informed for necessity and indications for
admission. Patients need to be screened regularly
for
development of gallstones. Genetic counseling and
testing
should be offered to the family.

130. Aplastic Anemia
Aplastic anemia comprises a group of disorders
of the
hematopoietic stem cells resulting in the
suppression of
one or more of erythroid, myeloid and
megakaryocytic
cell lines.The condition may be inherited or
acquired

131. Etiopathogenesis
Hematopoietic stem cells may be deficient due to (i) an
acquired injury from viruses, toxins or chemicals;
(ii) abnormal marrow microenvironment; (iii)
immunologic
suppression of hematopoiesis (mediated by
antibodies or cytotoxicT cells); and (iv) mutations in
genes
controlling hematopoiesis resulting in inherited bone
marrow failure syndromes

132. Clinical Features
Physical examination in case of severe anemia
reveals
pallor and/or signs of congestive heart failure.
Ecchymoses, petechiae, gum bleeding and nose
bleeds are
associated with thrombocytopenia

133. Fever, pneumonia or
sepsis may occur due to neutropenia. Inherited bone
marrow
failure syndromes, usually diagnosed in childhood
or as young adults, may be associated with
characteristic
congenital physical anomalies, positive family history
or
neonatal thrombocytopenia.The child should be
evaluated for the stigmata of congenital bone marrow
failure syndromes

134. However, Fanconi anemia may be present even
without
any abnormal phenotypic features. History of
exposure to toxins, drugs like
chloramphenicol, environmental
hazards and viral infections, e.g. hepatitis B or
C, suggest
an acquired aplasia.

135. Laboratory Studies
Hematological features of bone marrow failure include
pancytopenia or bilineage involvement, noted in aplastic
anemia, single cytopenia as seen in pure red cell aplasia
and amegakaryocytic thrombocytopenic purpura. Single
lineage cytopenias should be differentiated from
transient
erythroblastopenia of childhood. Peripheral blood smear
reveals anemia, occasionally with macrocytosis (<llO fl),
thrombocytopenia and agranulocytosis. Bone marrow
aspirate and biopsy are essential for evaluation of
bone marrow cellularity Usually, the marrow contains
very few hematopoietic
cells and is replaced with fat cells and lymphocytes.

136. Specific testsThe sucrose hemolysis test or Ham's test
may be positive in patient with underlying paroxysmal
nocturnal hemoglobinuria (PNH), in which red cells are
lysed by patient's acidified sera, and in congenital
dyserythropoeitic anemia type II, where red cells are
lysed
by other acidified sera but not patient's sera. Recent
transfusion with packed red blood cells may give false
negative results.

137. A more specific test for PNH is the assay
for two complement regulatory proteins present on red
blood cells, CD55 (decay accelerating factor, DAF) and
CD59 (membrane inhibitor of reactive lysis, MIRL).The
peripheral blood cells in Fanconi anemia show a
characteristic
hypersensitivity towards chromosomal breakage when
incubated with DNA cross-linking agents such as
mitomycin C. Chromosomal fragility is noted even in
patients who lack the characteristic physical stigmata
of
Fanconi anemia.

138. Treatment
Supportive care should be instituted with packed red cells
for severe anemia, platelets transfusions for severe
thrombocytopenia and antibiotics for management of
infections. Hematopoietic stem cell transplant (HSCT) is
the only definitive therapy. Criteria for referral for HSCT
include: (i) young age; (ii) severe aplastic anemia; and
(iii) availability of matched sibling. Patients with severe
acquired aplastic anemia who cannot undergo HSCT may
benefit from infusions of antithymocyte globulin (ATC)
or antilymphocyte globulin (ALG) along with oral
cyclosporine. Patients with neutropenia with infection
should receive a trial of granulocyte colony stimulating
factor (G-CSF). However, G-CSF should be discontinued
after seven days even if neutrophil count does not
improve, since its prolonged use carries the risk of
malignant transformation.

139. Immunosuppressive therapy is contraindicated i n
children w i t h Fanconi anemia. I n these patients,
hematopoietic stem cell transplantation is the
only cure.
However, these children continue to be at risk of
malignancies in the future. Oral androgens have
been used
as palliative therapy in such patients.

140. Prognosis
The severity and extent of cytopenias determine
prognosis.
Patients with severe aplasia are at risk of high output
cardiac
failure due to anemia, bacterial and fungal infections
due to
neutropenia and severe bleeding due to
thrombocytopenia.
With current transplantation regimens, longterm
survival in patients with severe aplastic anemia is 60-
70%, with
survival rates exceeding 80% in favorable subgroups.

141. Child with Fanconi anemia. The child had hyperpigmentation,
microcephaly and microphthalmia. She also had radial
ray defects and growth retardation

142. Radial ray defects present in a wide spectrum and include
absent or hypoplastic thumbs. Thenar hypoplasia may be
missed
unless carefully examined

143. DISORDERS OF HEMOSTASIS AND THROMBOSIS
Approach to a Bleeding Child Bleeding may
occur due to defects in platelets coagulation
disorders or
dysfunctional fibrinolysis. Clinical assessment, of
type of
bleeding, history of antecedent events and
screening tests
can help identify the cause, so that specific
management
can be initiated.

144. Pathogenesis
The process of hemostasis involves platelets, vessel wall
and plasma proteins in a fine balance between blood flow
and local responses to vascular injury (clotting).The
plasma proteins involved in hemostasis perform three
processes: (i) a multiple-step zymogen pathway leading
to thrombin generation; (ii) thrombin-induced formation
of fibrin clot; and (iii) complex fibrinolytic mechanisms
that limit clot propagation.The result of these processes
is the generation of insoluble fibrin and activation of
platelets to form a hemostatic plug.This process is controlled by
multiple pro- and anticoagulant pathways,
platelet number and function, vascular factors and other
metabolic processes.

145. The coagulation cascade is often
depicted as involving two pathways, intrinsic and
extrinsic
The extrinsic pathway is the primary initiating
pathway for coagulation and is measured by
prothrombin
time, while the intrinsic system works as a regulatory
amplification loop, measured by activated partial
thromboplastin time

146.  Causes of thrombocytopenia
 Idiopathic thrombocytopenic
purpura
 Infections: Disseminated
intravascular coagulation, malaria,
 kala-azar, dengue hemorrhagic
fever, hepatitis B and C, HIV,
 congenital (TORCH) infections,
infection associated
 hemophagocytosis syndrome
 Medications:Valproate, penicillins,
heparin, quinine, digoxin
 Thrombotic microangiopatlzy:
Thrombotic thrombocytopenic
 purpura; hemolytic uremic
syndrome
 Malignancies: Leukemia,
lymphoma, neuroblastoma
 Autoimmune or related disorders:
Systemic lupus erythematoses,
 Evans syndrome, antiphospholipid
syndrome, neonatal
 immune thrombocytopenia
 Immunodeficiency:Wiskott Aldrich
syndrome, HIV/ AIDS
 Bone marrow failure:
Thrombocytopenia with absent
radii,
 Fanconi anemia, Shwachman-
Diamond syndrome
 Marrow replacement:
Osteopetrosis, Gaucher disease
 Others: Hypersplenism, Kasabach
Merritt syndrome

147.  Common coagulation
disorders
 Inherited disorders
 Hemophilia A and B
 vonWillebrand disease
 Specific factor
deficiencies
 FactorVII, X, XIll
deficiency
 Afibrinogenemia
 Acquired disorders
 Liver disease
 Vitamin K deficiency
 W arfarin overdose
 Disseminated
intravascular
coagulation

148. Clinical Evaluation
In case of recent onset bleeding, history of
antecedent infections, rash (Henoch-Schonlein
purpura,
varicella), icterus (liver failure); and prodromal
diarrhea
or associated renal failure (hemolytic uremic
syndrome)
are important. Medications associated with bleeding
include anticonvulsants, penicillins, warfarin, aspirin,
non-steroidal anti-inflammatory medications and
heparin.

149. History of blood transfusions helps in assessing the
severity of the illness. Family history is important.The
sex of affected family members and details of bleeding
manifestations should be noted; a disorder affecting
only
boys suggests an X-linked disorder such as hemophilia,
while girls may have bleeding disorders in autosomal
dominant conditions like von Willebrand disease. Poor
wound healing and prolonged bleeding from the
umbilical
stump suggests factor XIII deficiency

150. Examination is done for the presence of ecchymoses
petechia, vascular malformations (hemangioma,
telangiectasia) and rashes.The presence of
splenomegaly
suggests the presence of infections, malignancy,
collagen
vascular disorders or hypersplenism rather than a
primary
bleeding defect. Rashes may be seen following drug
exposure, due to infections, collagen vascular
disorders,
Langerhans cell histiocytosis and Wiskott-Aldrich
syndrome.

151. Large ecchymotic patch on the upper limb of a young girl
with von Willebrand disease

152. Laboratory Investigations
 A complete hemogram is done for platelet
count, morphology
 of platelets and red cells and evidence of
rnicroangiopathic
 hemolysis