HUYẾT HỌC

1. Chapter XI.1. Anemia
Tristan E. Knight, MD
Darryl W. Glaser, MD
November 2014
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A 22 month old boy presents to your office with a chief complaint of pallor. A visiting relative
who has not seen the child for 5 months told his mother that the boy appears pale. The mother
brings him in for a checkup even though she notices no change in his color ("he has always
been fair skinned"). On review of symptoms you find that he is an active toddler, with no
recent fatigue, increase in sleeping, or exercise intolerance. He has had no blood in his diapers
and no black or tarry stools. He is a picky eater, taking only small amounts of chicken, pork,
and some vegetables, but loves milk and drinks six to eight bottles of whole milk daily;
approximately 36 to 48 ounces (1.1 to 1.4 liters) per day. Family history reveals a distant aunt
who had anemia during her pregnancy. There is no history of splenectomy, gall stones at an
early age, or other anemia in the family.
Physical Examination: Vital Signs: Temperature 37.5 degrees C, Blood Pressure 90/52 mmHg,
Pulse 145 beats/minute, Respiration 16 breaths/minute , Height 85.5 cm (50th %ile), Weight
13.2 kg (75th %ile). General appearance: He is a pale appearing, active toddler, holding a
bottle, tearing and eating paper from your exam table. Eyes: No scleral icterus. Pale
conjunctiva. Mouth: Dental caries. Chest: Clear. Heart: Mild tachycardia, grade II/VI systolic
ejection murmur heard best over the upper left sternal border. Abdomen: No
hepatosplenomegaly. Rectal: Dark brown, soft stool, negative for occult blood.
Laboratory: complete blood count (CBC): White blood count (WBC) 6,100, Hemoglobulin
(Hgb) 6.2 g/dL, Hematocrit (Hct) 19.8%, Platelet count 589,000, Mean corpuscular volume
(MCV) 54 fL, RDW 21%. Reticulocyte count is 1.8%. The lab reports microcytosis,
hypochromia, mild anisocytosis, and polychromasia. There is no basophilic stippling.

2. You correctly diagnose iron deficiency anemia, start oral iron and limit his milk intake. You
see him in 3 days to assure compliance and his red cell distribution width (RDW) is 27% and
his reticulocyte count 12%. When you see him back in two weeks his mother is amazed at his
new interest in table foods. Hgb is now 8.5 g/dL, and his MCV 64 fL. Two months later his
hemoglobin has completely normalized, and you continue iron therapy for three more
months.
Introduction
Anemia is one of the most common laboratory abnormalities identified in the pediatric
population. In the U.S., it is estimated that 20% of the pediatric population will develop
anemia; globally, the prevalence is closer to 80% (1). In particular, iron deficiency anemia
accounts for at least 50% of global anemia, though the exact percentage varies from region
to region (1). In the pediatric population, anemia is important to diagnose and treat for a
multitude of reasons such as reducing the risk for poor neurodevelopmental outcomes.
Definitions
Anemia may be defined by a low normal number of circulating red blood cells or a low
hemoglobin concentration of hemoglobin (though both will typically be affected). As in
most areas of pediatrics, what constitutes normal varies substantially with age, and there is
no uniform numerical cut-off. Instead, z-scores are used, with anemia being defined as a
hemoglobin or hematocrit more than two standard deviations below the mean for that age
and sex. Before proceeding, it is worth reviewing several key definitions:
- Hemoglobin (Hgb) - The measures of the amount of hemoglobin present in the blood;
expressed in grams per deciliter (100mL), or g/dL.
- Hematocrit (Hct) - The percentage of whole blood taken up by red blood cells (RBC).
- Mean corpuscular volume (MCV) - Expressed in femtoliters (fL), this is a measure of the
volume of red blood cells and is used in determining whether an anemia is microcytic,
normocytic, or macrocytic.
- Mean Corpuscular Hemoglobin (MCH) - A measure of the average amount of hemoglobin
in each RBC. It is diminished in hypochromic anemia. MCH can be calculated by dividing
hemoglobin by the number of RBCs present in a sample, e.g., MCH = (Hgb / RBC) X 10.
- Red cell distribution width (RDW) - A measure of how variable the sizes of the individual
RBCs are. Elevated number indicates a wider range of red blood cell sizes, and potentially
more than one RBC population.
- Reticulocytes represent the youngest RBCs. They still contain RNA (and can be stained for
this). Reticulocytes are reported as a percentage of total RBCs, and as an absolute number.
Absolute reticulocyte count = RBC/L x percent reticulocytes. The reticulocyte value must be
considered within the context of the severity of the anemia. Since the laboratory-reported
normal range for reticulocytes refers to patients with normal hemoglobin levels, an anemic
patient with a "normal" reticulocyte count is actually abnormal in the sense that the
marrow is not mounting an appropriate response. In other words, the reticulocyte count
should be higher than "normal" if the patient is anemic.

3. Erythropoiesis and the Life Cycle of the Red Blood Cell
Understanding erythropoiesis and the normal RBC's life cycle is key to understanding
anemia. Fetal erythropoiesis begins in the yolk sac, before moving to the primitive liver at 6
weeks gestation. The liver remains the primary organ of hematopoiesis until the bone
marrow takes over at approximately the 6th month of gestation. After birth, due to the
dramatic increase in oxygen availability, erythropoietin levels fall dramatically to a
minimum at 1 month of age, before increasing at 2 months of age. The net effect is a
dramatic fall in RBC production, resulting in a physiological anemia that reaches its lowest
point at 6 to 9 weeks of age.
Clinical Features of Anemia
A careful history and physical exam are essential in evaluating the anemic patient. The
differential diagnosis can be substantially narrowed through these means, sparing the
patient unnecessary, time consuming, and expensive investigations. Anemia of any source
tends to present with similar findings; the astute clinician can use an effective history to
better elucidate the mechanism.
History taking
Critical questions to review include:
- Has there been a rapid onset of color change, exercise intolerance, shortness of breath, or
fatigue? Or for the infant, is there any irritability or poor intake? A sudden onset of
symptoms implies an acute process, while an asymptomatic course implies a more gradual
or chronic one. Symptoms do not correlate to the severity of anemia, but rather to the
speed of the underlying process. A child with Hgb 4 g/dL can appear quite well if a chronic
process exists and the change occurred over a long period; a child who quickly drops to
Hgb 4 g/dL from the normal range would be quite symptomatic.
- Questions regarding diet can provide key clues. The volume of cow's milk, age it was
introduced, type of formula, and presence of iron-fortified cereals in the diet should all be
assessed. Though less common, Vitamin B12 and folate deficiencies can also be determined
via careful dietary history. The presence of pica (the eating of unusual things, in particular
ice or dirt) can indicate iron deficiency or lead poisoning. Cow's milk is poor in bio-
available iron and causes microscopic damage to the intestinal lining, leading to occult
blood loss. For these reasons, excess cow's milk ingestion is a common cause of iron
deficiency in preschool age children.
- Is there a history of blood loss? Teenage female patients may have prolonged, heavy
menustrual periods, making an accurate menstrual history essential. Severe or chronic
epistaxis may also cause or contribute to anemia. Both menorrhagia and epistaxis can point
to an underlying coagulopathy. A history of altered bowel habits or changes in stool color
may point to GI blood loss.
- Is there a family history of anemia, low blood counts, or prescribed iron? Many significant

4. causes of anemia are inherited. Similarly, is there a history of splenomegaly, jaundice,
gallstones, splenectomy, or cholecystectomy? Such features may indicate a family history of
hemolytic anemia, of which many are inherited.
- What is the child's ethnic background? Hemoglobinopathies (e.g., thalassemia and sickle
cell anemia), G6PD (glucose-6-phosphate dehydrogenase) deficiency, and certain
membrane defects are more common in certain ethnic groups.
- Is there a history of jaundice, icterus, or changes in urine color, particularly associated
with features of anemia? Such presentations may indicate a hemolytic anemia.
- Are prior CBC's available for comparison? A chronic history of relatively low hemoglobins
may indicate a chronic, inherited process, while a sudden drop in hemoglobin from
previously normal levels (or from previous normal levels for that patient) may indicate an
acute process.
Physical Examination
- Pallor is a key feature of anemia, but can be difficult to detect. Pallor is more readily
determinable at the sites of capillary beds, by examining the conjunctiva, palmar creases,
and nail beds. Pallor here is predictive of relatively severe anemia.
- Hemolytic anemia may feature scleral icterus, jaundice, and hepatosplenomegaly.
- Other signs may correlate more closely to specific anemia etiologies, for instance:
. . . Cavernous hemangioma: microangiopathic hemolytic anemia
. . . Lower extremity ulcers: sickle cell disease
. . . Frontal bossing or maxillary and malar prominences: thalassemia major, severe
hemoglobinopathies
. . . Glossitis, angular stomatitis: vitamin B12 or iron deficiency
. . . Koilonychia (spoon nails): iron deficiency
Classification of anemia
Anemia can be classified according to two major schemata: morphologic and physiologic.
Both are useful, and should be used in conjunction to guide the evaluation to a diagnosis.
The morphological approach uses MCV to classify anemia as microcytic, normocytic, or
macrocytic. This is an over-simplification, and many anemias do not fall so neatly into a
particular category. Anemia of chronic disease, for instance, may be either normocytic or
microcytic.
The physiologic approach uses the underlying mechanism to classify anemia as due to a)
reduced production, b) increased destruction, or c) blood loss.

5. All anemias can be classified using both morphologic and physiologic approaches, and the
use of both systems concordantly may allow the differential to be narrowed. An overview
of the classification schema is provided below:
I. CLASSIFICATION BASED ON MORPHOLOGICAL APPROACH
. . . A. Microcytic
. . . . . . 1. Iron deficiency anemia
. . . . . . 2. Anemia of chronic disease*
. . . . . . 3. Thalassemias (see Chapter XI.2)
. . . . . . 4. Sideroblastic anemia
. . . . . . 5. Lead Poisoning
. . . B. Normocytic
. . . . . .1. Acute blood loss
. . . . . . 2. TEC (transient erythroblastopenia of childhood)
. . . . . . 3. Sicke cell disease (see Chapter X1.3)
. . . . . . 4. Renal disease (reduced erythropoietin)*
. . . . . . 5. Mixed macrocytic and microcytic anemia occurring together
. . . C. Macrocytic
. . . . . . 1. Bone marrow failure
. . . . . . . . . a. DBA (Diamond Blackfan Anemia)
. . . . . . . . . b. Aplastic anemia
. . . . . . . . . c. CDA (Congenital dyserythropoietic anemia)
. . . . . . 2. Folate deficiency
. . . . . . 3. B12 deficiency
. . . . . . 4. Liver disease
. . . . . . 5. Hypothyroidism
. . . . . . 6. Use of DNA replication-impairing drugs
*Anemia of chronic disease and anemia due to renal disease may be microcytic or
normocytic.
II. CLASSIFICATION BASED ON PHYSIOLOGIC APPROACH
. . . A. Decreased Production
. . . . . . 1. DBA (Diamond Blackfan Anemia)
. . . . . . 2. CDA (Congenital dyserythropoietic anemia)
. . . . . . 3. TEC (transient erythroblastopenia of childhood)
. . . . . . 4. Aplastic Anemia
. . . . . . 5. Deficiencies, including iron, vitamin B12, folate
. . . . . . 6. Lead toxicity
. . . . . . 7. Thalassemia
. . . . . . 8. Anemia of chronic disease
. . . . . . 9. Hypothyroidism
. . . . . . 10. Sideroblastic anemia (production of ringed sideroblasts)
. . . B. Hemolysis
. . . . . . 1. Intrinsic to red blood cells
. . . . . . . . . a. Hemoglobinopathies

6. . . . . . . . . . b. Enzymatic defects - G6PD, pyruvate kinase deficiency
. . . . . . . . . c. Membranous defects - elliptocytosis, spherocytosis
. . . . . . 2. Extrinsic to red blood cells
. . . . . . . . . a. Immune hemolytic disease
. . . . . . . . . . . 1) Autoimmune (warm / cold)
. . . . . . . . . . . 2) Alloimmune (e.g., of newborn)
. . . . . . . . . b. Microangiopathic (HUS, DIC, TTP)**
. . . . . . . . . c. Hypersplenism
. . . . . . . . . d. Paroxysmal nocturnal hemoglobinuria
. . . C. Acute Blood Loss or Hemostasis related- Hemorragic
**HUS (hemolytic uremic syndrome), DIC (disseminated intravascular coagulation), TTP
(thrombotic thrombocytopenic purpura)
The following sections provide an overview of some of the major types of anemia discussed
above.
1. Iron Deficiency Anemia
Iron deficiency is the commonest cause of anemia in childhood worldwide, with up to a
quarter of the world's population affected. In the U.S., approximately 10% of toddlers are
iron deficient, with 3% being anemic (2). These rates slowly decline until adolescence, at
which point 16% of females develop iron deficiency, and 4% become anemic (2).
Tỉ lệ: 10- 40 % TG
Nguy cơ cao: < 2yr
Fe metabolism:
 Absorption: Mè, đậu nành, thịt, trứng (Sữa mẹ và sữa bò rất ít)
Chất ức chế: trà, đồ chát (chứa fi-tát)
Bình thường, chỉ hấp thu 1mg/d, nếu trẻ; 1,5 -2 mg/d, kinh nguyệt: 5 mg, thai 7mg.
Iron serum= 100- 150 y%, Transferrin saturation = 30%
 Distribution:
Normal, 4.5 gr / người lớn 5000ml máu
 2.5 gr in hemoglobin (Giả sử, RBC life= 100d => 1% Hb destruction => 25 mg Fe
releasing per day)
 1.5 gr in ferritin
 0.5 enzyme, myoglobin
Comment [md1]: Bất đồng nhóm màu mẹ
con

7. The majority of the body's iron (75%) is bound up in hemoglobin and myoglobin. Ferritin
and hemosiderin (both storage proteins) account for 22%, with a small amount (3%)
bound in enzymatic reactions.
Bioavailability of iron also plays a role. After 4 months, iron supplementation should be
started until sufficient intake of iron-rich cereals has begun.
Preterm infants, lacking iron stores. Oral iron supplementation is correlated with improved
growth, improved neurodevelopment, and reduced risk of infections.
Causes:
Risk factors: Sinh nhiều con/ lần, sinh nhiều lần, SDD bào thai, Xh trong khi sinh.
Giảm cung:
Cung ko đúng, sữa bò (avoided < 12mo, limit < 600ml/ d for 1- 5 yr; intestinal mucosa
damage, low biovaiability) , sau 4 tháng…Jack Hayern Luzet.
The reasons for limitation to cow's milk intake are: 1) cow's milk is directly toxic to the
intestinal mucosa, causing microscopic bleeding, 2) cow's milk has low iron bioavailability,
and 3) cow's milk has a high fat content and reduces appetite for other, potentially iron rich
foods.
Blood loss
- Giun móc
- Blood loss is also an important cause of iron deficiency, particularly occult blood loss in
the urine, feces, or via menorrhagia.. Further, hemolytic anemias do not result in iron
deficiency, as the body is a ble to effectively reuse free iron.
In the presence of a hypochromic (low MCHC), microcytic (low MCV) anemia with an
inadequate reticulocyte count, iron deficiency should be suspected. An elevated platelet
count is often seen. RDW may be elevated due to the presence of both microcytic and
normocytic cells. Serum iron is low, total iron binding capacity (TIBC) is elevated, and the
percentage of iron saturation is low. Low serum ferritin is diagnostic; however, ferritin is
an acute phase reactant and can be falsely elevated in inflammation, so should be
interpreted with caution.
The normal range for ferritin is frequently published to be very wide (e.g., 15 to 300)
making it difficult to confirm iron deficiency at its lower limit. An iron stain of the bone
marrow is the most accurate test for iron deficiency, but it is too painful and invasive to be
routinely used.
Comment [md2]: Sinh non: 0.6 lúc < 6mo,
1.2 lúc > 6 mo.
Comment [md3]: Children with
appropriate diet and iron deficiency anemia
must be investigated for a source of blood
loss

8. Clinical features:
Tích tụ MAO: trẻ quấy khóc, vật vã, chán ăn, hay buồn ngủ, kèm minh mẫn.
Tóc dễ gãy rụng, spoon nail.S
Lách to ở newborn.
Investigation
- Thiếu máu: HgB giảm, MCV giảm nhiều +/-, MCH reduced
- Sắt:
 Fe serum < 100 ug%
 Ferritin < 12ng/mL
 Transferrin saturation reduced
- Soi phân tìm giun móc (Ancylostoma)
Treatment
1. IRON supplement:
Oral iron therapy at 3 mg/kg (for mild anemia) or 6 mg/kg (for severe anemia) of
elemental iron should be initiated and not taken with milk, tea, coffee, ngũ cốc.
IM, IV ferous less used.
12- 24h: Giảm triệu chứng LS
48- 72h: increase Reticulocytes, max in day 7th.
Increase HgB 0.5 g%/d if Adequate response.
Once the hemoglobin has normalized, therapy should be continued for an additional 2 to 3
months (to replace iron stores).
Patients receiving adequate supplementation but with an inadequate response after 4
weeks, should be investigated further.
2. Transfusion: Hb < 4g/dL,
3. Điều trị nguyên nhân: Dinh dưỡng, sổ giun.

9. Tái khám: L1: 2 tuần
Lần sau: mỗi tháng
Theo dõi: màu da, phết máu, hồng cầu lưới, ferritin.
2. Thalassemia
3. Anemia of Chronic Disease
Anemia of chronic disease is seen in a wide variety of pathological states, including
malignancy, inflammation, and infection.
Anemia of chronic disease tends to be microcytic (though it may be normocytic) with an
inappropriately low reticulocyte response and erythropoietin levels. In addition, ferritin
levels are normal or elevated. This is in contrast to iron deficiency anemia in which ferritin
is low. Multiple factors contribute, including iron sequestration within the
reticuloendothelial system, reduced bone marrow or erythroid precursor response to
erythropoietin, and reduced RBC life span. Severe cases may be treated with erythropoietin
(EPO) and iron supplementation, though generally the best course is to treat or control the
underlying condition if possible.
4. Sideroblastic Anemia
This is an anemia arising from a disorder of heme synthesis or processing, resulting in
granular deposition of iron in the perinuclear mitochondria, producing a ring which at least
partially surrounds the nucleus of the developing red blood cells. In sideroblastic anemia,
adequate iron is present, but the red blood cells are unable to effectively utilize it. Multiple
forms exist, the discussion of which are beyond the scope of this chapter. Sideroblastic
anemia is most commonly a microcytic, hypochromic anemia. A wide RDW is seen,
reflecting the variation in RBC size.
The key diagnostic feature is the presence of ring sideroblasts in the bone marrow. The
more mature, enucleated form of sideroblasts, the siderocyte, may be seen in the
peripheral blood, which is a hypochromic RBC with coarse basophilic granules which stain
positive for iron. Transferrin is elevated, as are ferritin and serum iron. Iron overload is a
common and serious complication, and may require chelation.
5. Lead Poisoning
Following the removal of lead from gasoline and paint, the average lead level found in
children fell from 16 mcg/dL to less than 3 mcg/dL (6). Children under 6 years of age are
most vulnerable to lead toxicity for two reasons: 1) they are more likely to engage in
behaviors that increase their exposure, and 2) their blood brain barrier is less developed,
allowing entry into the CNS more easily.
Chronic exposure to lead causes a variety of effects, including behavioral or developmental
abnormalities, kidney injury, GI symptoms, and anemia. The anemia seen in lead poisoning
is microcytic, hypochromic, and reticulocytopenic due to interference of lead with enzymes

10. within the heme synthesis pathway. At higher levels, lead also has a directly hemolytic
effect. Other features include basophilic stippling of peripheral RBCs and an elevated
erythrocyte protoporphyrin. A diagnosis is made once a lead level of greater than 5 mcg/dL
is found by venous blood sample.
Management of lead poisoning depends upon the level present:
. . . 70 mcg/dL or greater: In severe intoxication or with encephalopathy (emesis, altered
mental status, headache, seizures), chelation therapy with combined dimercaprol and
EDTA (ethylenediaminetetraacetic acid) is indicated.
. . . 45 to 69 mcg/dL: This is moderate lead intoxication that can be treated with oral
succimer (also known as dimercaptosuccinic acid, DMSA) chelation therapy.
. . . 10 to 44 mcg/dL: This is mild lead intoxication. Chelation therapy is not indicated, but
one should obtain a detailed history to identify and remove the lead exposure source
followed by close clinical follow up and repeat lead levels.
6. Transient erythroblastopenia of childhood (TEC)
TEC is a transient, self-limited anemia due to a temporary cessation in erythrocyte
production 1- 2 months. The etiology is unknown, but TEC is the most common cause of
decreased RBC production. Suspect TEC in an otherwise healthy child with a normocytic
anemia with reticulocytopenia. Mild neutropenia is also seen in approximately half of the
cases. Seen usually in patients aged 1 month to 6 years, and unlike DBA, TEC patients do
not have congenital abnormalities.
7. Diamond-Blackfan Anemia (DBA)
DBA is a production failure anemia, a congenital erythroid aplasia that typically presents in
infancy or early childhood and is secondary to mutations affecting ribosome synthesis. A
rare condition with an incidence of approximately 1 in 200,000, suspect DBA in patients
under a year of age with severe macrocytic anemia, low reticulocyte counts, and normal
marrow cellularity with markedly decreased or absent RBC precursors. The platelet count
and WBC count may be increased, decreased, or normal. Fifty percent of patients will have
other congenital abnormalities. Treatment is initially corticosteroids or ongoing
transfusion in steroid non-responders.
8. Congenital dyserythropoietic anemia (CDA)
This is actually a group of four disorders. CDA is a due to ineffective erythropoiesis with
multinuclear erythroblasts seen. Specific genetic abnormalities have been identified for all
four conditions, all of which share pathognomonic cytopathologic nuclear abnormalities in
the bone marrow erythroid precursors. CDA should be suspected in a patient with
binucleated normoblasts on peripheral smear who has a congenital hemolytic anemia with
inappropriately low reticulocyte counts.

11. 9. Aplastic Anemia
•
Treatment: Eliminate causative agent, bone marrow transplant,
GM-CSF
4 Không: không sốt, không sụt cân, không đau xương, gan lách ko to.
Folate deficiency and B12 deficiency
Both folate deficiency and vitamin B12 deficiency are rarely seen in children. Both cause a
macrocytic anemia, sometimes associated with thrombocytopenia and granulocytopenia.
Both are diagnosed directly via blood levels. Suspect folate deficiency in children who are
fed goat's milk. Vitamin B12 deficiency may be suspected based on the presence of hyper-
segmented neutrophils on peripheral smear. Its diagnosis requires further work up in the
form of the Schilling test, as B12 deficiency may be due to poor absorption or intrinsic

12. factor deficiency (pernicious anemia). Recall that intrinsic factor is required for B12
absorption in the ileum. The Schilling test determines whether the B12 deficiency is due to
intrinsic factor deficiency, ileal malabsorption, or dietary deficiency.
Reduced Erythropoietin Production
Erythropoietin (EPO) is the growth factor which stimulates RBC production. EPO is a renal
product, but influenced by a wide range of metabolic factors. It is produced in response to
hypoxemia to increase circulating RBCs. In children with renal disease, erythropoietin
levels are reduced, causing a normocytic anemia which can be treated by exogenous EPO
administration. Hypothyroidism or injury to the pituitary-hypothalamic axis also impairs
EPO production, and can therefore cause anemia.
Hemolytic Anemias
In states of health, the average RBC will survive 100 to 120 days in circulation.
Approximately 1% of RBC are destroyed each day, and replaced with reticulocytes. In
hemolytic anemia, the red cell survival is shortened, and the RBC intracellular contents are
released into the blood and can be measured. A history of dark urine might be present.
Positive exam findings might include jaundice, scleral icterus, splenomegaly, and pallor.
Elevated levels of LDH (lactate dehydrogenase) and bilirubin may be seen. Chronic
hemolysis increases the risk for pigmented gallstones during childhood. For this reason,
the presence of incidental or symptomatic gallstones in pediatric patients should trigger
further investigations. Serum haptoglobin forms a complex with free hemoglobin and is
cleared by the liver. As such, low or absent haptoglobin levels are seen in hemolytic states.
Congenital haptoglobin deficiencies do exist and may also be a cause of low serum
haptoglobin, but are rare. Serum free hemoglobin is increased. Reticulocytosis in a patient
without documented blood loss may also be indicative of hemolysis, though it may also
reflect recovery from TEC or response to treatment in a production deficiency anemia.
Special isotope studies that directly measure RBC survival are also available, but not
routinely performed.
Hemolytic anemias may be classified according to the mechanism of RBC destruction.
Intrinsic hemolytic anemias are due to a defect within the RBC itself, and include
hemoglobinopathies, membrane defects, or enzymatic defects. Extrinsic
hemoglobinopathies are due to an external abnormality acting on an otherwise normal
RBC.
Intrinsic Hemolytic Anemia: Hemoglobinopathies, Thalassemias, and Sickle cell
disease
Both thalassemia and sickle cell disease are inherited anemias secondary to impaired or
altered hemoglobin synthesis. Both increased destruction and reduced production
contribute to the anemias seen in these conditions. They are discussed fully in other
chapters.
Intrinsic Hemolytic Anemia, Enzymatic defects: G6PD deficiency, and Pyruvate
Kinase deficiency
G6PD (glucose-6-phosphate dehydrogenase) deficiency can cause a hemolytic anemia

13. secondary to reduced membrane G6PD activity. G6PD enzyme protects erythrocytes from
oxidant stress, meaning that in deficient states, oxidant metabolites cause damage and
hemolyze RBCs. Acute hemolytic crises occur with exposure to oxidant drugs (e.g., aspirin,
sulfonamides, nitrofurantoin, phenazopyridine, quinolones, chloramphenicol, etc.), foods
(e.g., fava beans), or infections. Periodic episodes of jaundice may occur, as well as
prolonged neonatal jaundice. The G6PD gene is inherited on the X chromosome, so that
males are affected most often, although females may rarely be affected (homozygous).
G6PD deficiency causes a normocytic anemia with blood smears showing bite or blister
cells. Heinz bodies, which are comprised of denatured hemoglobin, may be present. A
depressed level of G6PD activity is diagnostic.
Pyruvate kinase (PK) is an enzyme active in erythrocyte glycolysis. In PK deficiency,
erythrocytes are unable to synthesize ATP effectively. A broad range of phenotypes exist,
but all have some degree of hemolytic anemia, ranging from compensated states to severe
anemia.
Intrinsic Hemolytic Anemia, Membrane defects: Spherocytosis and Elliptocytosis
Hereditary spherocytosis (HS) is due to an abnormality in the erythrocyte structural
protein spectrin. This defect causes the erythrocyte cellular membrane to lose surface area,
without a corresponding loss in cellular volume, forcing RBCs to adopt a spherical shape.
Spherical cells are rigid and fragile, and become sequestered and destroyed in the spleen.
Investigations show an elevated reticulocyte count, normal MCV, and elevated MCHC. This
is relatively specific to hereditary spherocytosis. The osmotic fragility assay and flow
cytometry are diagnostic tests. HS is a common cause of hemolytic anemia. It is inherited in
an autosomal dominant fashion. Patients can present with jaundice, splenomegaly, and
anemia. Alternatively, patients can present in serious aplastic crises, in which parvovirus
B19 causes a temporary cessation of RBC production. When combined with ongoing
hemolysis, this can cause a precipitous drop in hemoglobin. Hyperhemolytic crises can also
occur, in which there is an accelerated rate of hemolysis, presenting with increased
jaundice, pallor, and signs/symptoms of anemia. Splenectomy is clinically curative, causing
resolution of jaundice, and reticulocytosis. However, this procedure should be deferred
until the age of at least 5 years, as splenic function is vital in young children to prevent
sepsis due to encapsulated organisms. Folic acid, blood transfusion, and/or erythropoietin
therapy should be utilized until splenectomy is performed. Severe disease, symptomatic
anemia, or frequent crises are indications for earlier splenectomy.
Hereditary elliptocytosis is an autosomal dominant inherited condition in which large
numbers of elliptical erythrocytes are produced. The precise etiology is unknown. Most
patients are asymptomatic, but approximately 10% have clear evidence of hemolysis that
often proceed to have more serious anemia, jaundice, and splenomegaly, as well as a
tendency toward gall stones.
Extrinsic Hemolytic Anemia: Autoimmune hemolytic anemia
Autoimmune hemolytic anemia (AIHA) involves the production of antibodies to
components or antigens of the erythrocyte cellular membrane, which damage the
erythrocyte and cause hemolysis. The direct Coombs test is positive, indicating that

14. immunoglobulin or complement is bound to the erythrocyte surface. AIHA can be triggered
by malignancy, autoimmune disorders (systemic lupus erythematosus in particular),
infections (especially Epstein-Barr virus and mycoplasma), or drugs (most commonly
cephalosporins and penicillins).
Extrinsic Hemolytic Anemia: Alloimmune hemolytic anemia
In particular, this form of anemia affects fetuses and neonates. In cases in which the mother
and infant are of different blood types, and a sensitizing exposure has occurred, maternal
antibodies cross the placenta and cause hemolysis, which vary from relatively mild
hyperbilirubinemia and jaundice to hydrops fetalis and fetal demise. This topic is fully
explored in the newborn hematology chapter XI.5.
Extrinsic Hemolytic Anemia: Microangiopathic
In some conditions, mechanical injury causes hemolysis of red blood cells within the
vasculature itself. Hemolytic uremic syndrome (HUS), thrombotic thrombocytopenic
purpura (TTP), and disseminated intravascular coagulation (DIC) all feature some element
of microangiopathic hemolysis where shear stress is exerted on the RBCs by fibrin strands
and clots. This damages the RBC membrane and causes hemolysis, leading to anemia and
formation of schistocytes, fragmented pieces of RBCs in circulation. Transfusion is a
temporizing measure, as the donor RBCs are hemolyzed just as rapidly as the patient's.
Questions
1. What two classification schemes can be used to narrow down the differential diagnosis
of anemia in children?
2. What laboratory finding suggests that an anemia is due to a decreased production of red
blood cells?
3. What elements of the history, physical exam, and laboratory evaluation suggest
increased red cell destruction as the cause of anemia?
4. What are some of the ways in which iron deficiency can be diagnosed?
5. True/False: Cow's milk exerts a direct toxic effect on the intestinal mucosa of some
infants, leading to microscopic blood loss and iron deficiency anemia.
6. True/False: Children with iron deficiency anemia caused by excessive cow's milk intake
sometimes have a history of black or tarry stools.
7. True/False: The iron content of cow's milk is zero or very close to zero.

15. 8. The lab reports a patient's hemoglobin as 7 g/dL, and the reticulocyte count as 1%. The
published normal value for the reticulocyte count is 0.7% to 2.0%, so the reticulocyte count
is within the laboratory's normal range. How would you interpret this reticulocyte count?
References
1. World Health Organization. Worldwide prevalence of anemia 1993-2005: WHO global
database on anemia. Edited by Bruno de Benoist, Erin McLean, Ines Egli and Mary Cogswell,
Geneva, 2008. Available at:
http://apps.who.int/iris/bitstream/10665/43894/1/9789241596657_eng.pdf
2. Brotanek JM Gosz J, Weitzman M, Flores G. Secular trends in the prevalence of iron
deficiency among US toddlers, 1976-2002. Arch Pediatr Adolesc Med. 2008; 162(4):374
3. Abdelrazik N, Al-Haggar M, Al-Marsafawy H, Adel-Hadi H, Al-Baz R, Mostafa AH. Impact
of long term iron supplementation in breast-fed infants. Indian J Pediatr. 2007;74(8):739.
4. Steinmacher J, Pohlandt F, Bode H, Sander S, Kron M,Franz AR. Randomized trial of early
versus late enteral iron supplementation in infants with a birth weight of less than 1301g:
neurocognitive development at 5.3 years of age. Pediatrics. 2007;120(3):538
5. Fleming MD. Congenital sideroblastic anemias: iron and heme lost in mitochondrial
translation. Hematology Am Soc Hematol Educ Program 2011;2011:525.
6. Blood Lead Levels - United States 199-2002. Centers for Disease Control and Prevention
(CDC). MMWR Morb Mortal Wkly Rep. 2005;54(20):513.
7. Robert JR, Reigart JR. Medical Assessment and Intervention. In: Managing Elevated Blood
Lead Levels Among Young Children: Recommendations from the Advisory Committee on
Childhood Lead Poisoning Prevention, Centers for Disease Control and Prevention, Atlanta
2002.
8. Bellinger D, Rappaport L. Developmental Assessment and Interventions. In: Managing
Elevated Blood Lead Levels Among Young Children: Recommendations from the Advisory
Committee on Childhood Lead Poisoning Prevention, Centers for Disease Control and
Prevention, Atlanta 2002.
9. Dobrozsi SD, Flood VH, Panepinto J, Scott P, Brandow A. Vitamin B12 deficiency: The
great masquerader. Pediatric Blood and Cancer. 2014;61(4):753-755.
10. Vlachos A, Ball S, Dahl N, et al. Diagnosing and treating Diamond-Blackfan anemia:
results of an international clinical consensus conference. Br J Haematol. 2008; 142:859

16. 11. Jaako P, Flygare J, Olsson K, et al. Mice with ribosomal protein S19 deficiency develop
bone marrow failure and symptoms like patients with Diamond Blackfan anemia. Blood
2011; 118:6087
12. Shaw J, Meeder R. Transient erythroblastopenia of childhood in siblings: case report
and review of the literature. J Pediatr Hematol Oncol. 2007;29:659
13. Shimada E, Odagiri M, Chaiwong K, et al. Detection of Hpdel among Thais, a deleted
allele of the haptoglobin gene that causes congenital haptoglobin deficiency. Transfusion,
2007;47: 2315-2321.
14. Wickramasinghe SN, Wood WG. Advances in the understanding of the congenital
dyserythropoietic anemias. Br J Haematol. 2005;131:431
Answers to questions
1. Classification by physiologic mechanism (decreased production, increased destruction,
and blood loss) and classification by morphologic approach based on red blood cell size
(microcytic, normocytic, and macrocytic anemias)
2. Low reticulocyte count.
3. History of dark urine. Physical exam of jaundice, scleral icterus, splenomegaly. Lab
results of elevated LDH, elevated bilirubin, elevated serum free hemoglobin, decreased
serum haptoglobin, high reticulocyte count, and positive direct antibody test (DAT, also
known as Coombs test).
4. Bone marrow stain for iron has the highest positive predictive value and specificity, but
it is too invasive in most instances. Low serum ferritin is indicative of iron deficiency, but
its wide range of normal values and its fluctuation with acute inflammation may make its
interpretation difficult. Serum iron coupled with TIBC and percent iron saturation are
satisfactory, but these tests are subject to some laboratory fluctuation as well. Response to
a therapeutic trial of iron is also acceptable as proof of iron deficiency.
5. True
6. True
7. False. There is iron in cow's milk, but it has very poor bioavailability.
8. This reticulocyte count value is normal for a patient with a normal hemoglobin, but for a
severely anemic patient, the reticulocyte count should be higher. Thus, in view of this
patient's severe anemia, this patient's reticulocyte count is actually low and indicative of a
condition in which RBCs are not being produced.

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