Chapter XI.1. Anemia 
Tristan 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 coloring (he has always been fair skinned). On review of symptoms you find that he is an active toddler, with no recent fatigue, exercise intolerance, or increase in sleeping. He has had no blood in his diapers and no black or tarry stools. He is a picky eater, taking small amounts of chicken, pork and some vegetables, but loves milk and drinks six to eight bottles of whole milk per day (approximately 36-48oz per day). Family history reveals a distant aunt who had anemia when she was pregnant but which subsequently resolved. There is no history of splenectomy, gall stones at an early age, or other anemia in the family.

Exam: VS: T 37.5, BP 90/52, P 145, RR 16, 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 as above, 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.

CBC: WBC 6,100, Hgb 6.2 g/dl, Hct 19.8%, Plt 589,000, MCV 54 fL, RDW 21%. Reticulocyte count is 1.8%. The lab reports microcytosis, hypochromia, mild anisocytosis and polychromasia. There is no basophilic stippling.

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 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. His 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 perhaps the most common laboratory abnormality identified in the pediatric population. Within the USA, it is estimated that 20% of the pediatric population will develop anemia; globally, the prevalence is closer to 80%. In particular, iron deficiency anemia accounts for at least 50% of global anemia, though the exact percentage varies from region to region. Anemia is an important condition to diagnose and treat for a multitude of reasons; among the pediatric population, perhaps the most important being its implication in causing poor neurodevelopmental outcomes.

Definitions
Simply put, anemia may be defined as a below-normal number of circulating red blood cells, or concentration of hemoglobin within the blood (though both will typically be present). As in most areas of pediatrics, what truly 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) - A measure 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.
- 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 anemias. MCH can be calculated by dividing hemoglobin by the number of RBCs present in a sample, e.g. MCH = Hgb / RBC.
- Red cell distribution width (RDW) - a measure of how variable the size of the individual RBCs are. Elevated numbers indicate a wider range of red blood cell sizes, and potentially, more than one RBC population.

It is also worth revisiting reticulocytes, and the reticulocyte response. Reticulocytes represent the youngest RBCs; they continue to contain RNA (and can be stained for based on this property). 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 may not be mounting an appropriate response.

Erythropoiesis and the Life Cycle of the Red Blood Cell
Understanding erythropoiesis and the normal RBC ‘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 available, erythropoietin levels fall dramatically to a nadir at 1 month of age, before increasing to reach a maximum at 2 months of age. The net effect of this is a dramatic fall in RBC production, resulting in a physiological anemia that reaches its nadir at 6-9 weeks of age.

Clinical Features of Anemia
A careful history and physical are key factors 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
- Has there been a rapid onset of color change, exercise intolerance, shortness of breath, or fatigue? Or in the infant, irritability and poor intake? A sudden onset of features implies an acute process, while an asymptomatic course implies a more chronic one. Symptoms do not correlate to the severity of anemia, but rather to the speed of the underlying process. A child with a hemoglobin of 4 can appear quite well if a chronic process exists and the change occurred over a long period; a child who quickly drops to a hemoglobin of 4 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, 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 patients may have prolonged, heavy periods, making an accurate menstrual history essential. Severe/chronic epistaxis may also cause/contribute to anemia. Both menorrhagia and epistaxis can point to an underlying coagulopathy. Blood loss may also not be obvious - a history of altered bowel habit 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 important causes of anemia are inherited. Similarly, is there a history of splenomegaly, jaundice, or gallstones? Or a history of splenectomy or cholecystectomy? Such features may indicate a family history of hemolytic anemia, of which many are heritable.
- Along the same lines, what is the child’s ethnic background? Hemoglobinopathies (e.g. thalassemia and sickle cell), G6PD 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 things 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, e.g. 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 / maxillary and malar prominences - thalassemia major, severe hemoglobinopathies
. . . . . Glossitis, angular stomatitis - B12 or iron deficiency
. . . . . Koilonychia (spoon nails) - iron deficiency

Classification of anemia
Anemia can be classified according to two major schemata - physiologic and morphologic. Both are useful, and should be used in conjunction to guide diagnosis.

The morphological approach uses the 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 anemias as due to (a) increased destruction, (b) reduced production, or (c) blood loss.

All anemias can be classified using both physiological and morphological approaches, and the use of both systems concordantly may allow the differential to be narrowed. An overview of the classification schema is provided below:

1. Classification based on morphological approach
. . . . .a. Microcytic
. . . . . . . . . . i. Iron deficiency anemia
. . . . . . . . . . ii. Anemia of chronic disease*
. . . . . . . . . . iii. Thalassemias
. . . . . . . . . . iv. Sideroblastic anemia
. . . . . . . . . . v. Lead Poisoning\
. . . . .b. Normocytic
. . . . . . . . . . i. Acute blood loss
. . . . . . . . . . ii. TEC (transient erythroblastopenia of childhood)
. . . . . . . . . . iii. Sickle cell disease
. . . . . . . . . . iv. Renal disease (e.g. reduced erythropoietin) *
. . . . . . . . . . v. Mixed macrocytic and microcytic anemia occurring together
. . . . .c. Macrocytic
. . . . . . . . . . i. Bone marrow failure
. . . . . . . . . . . . . . .1. DBA (Diamond Blackfan Anemia)
. . . . . . . . . . . . . . .2. Aplastic anemia
. . . . . . . . . . . . . . .3. CDA (Congenital dyserythropoietic anemia)
. . . . . . . . . . ii. Folate deficiency
. . . . . . . . . . iii. B12 deficiency
. . . . . . . . . . iv. Liver disease
. . . . . . . . . . v. Hypothyroidism
. . . . . . . . . . vi. Use of DNA replication-impairing

*Anemia of chronic disease and anemia due to renal disease may be microcytic or normocytic.

2. Classification based on physiologic mechanism
. . . . .a. Decreased Production
. . . . . . . . . . i. DBA (Diamond Blackfan Anemia)
. . . . . . . . . . ii. CDA (Congenital dyserythropoietic anemia)
. . . . . . . . . . iii. TEC (transient erythroblastopenia of childhood)
. . . . . . . . . . iv. Aplastic Anemia
. . . . . . . . . . v. Deficiencies, including Iron, B12, Folate
. . . . . . . . . . vi. Lead toxicity
. . . . . . . . . . vii. Thalassemia
. . . . . . . . . . viii. Anemia of chronic disease
. . . . . . . . . . ix. Hypothyroidism
. . . . . . . . . . x. Sideroblastic anemia
. . . . .b. Hemolysis
. . . . . . . . . . i. Intrinsic to red blood cells
. . . . . . . . . . . . . . .1. Hemoglobinopathies
. . . . . . . . . . . . . . .2. Enzymatic defects - G6PD, Pyruvate Kinase deficiency
. . . . . . . . . . . . . . .3. Membranous defects - Elliptocytosis, spherocytosis
. . . . . . . . . . ii. Extrinsic
. . . . . . . . . . . . . . .1. Immune hemolytic disease
. . . . . . . . . . . . . . . . . . .a. Autoimmune (warm / cold)
. . . . . . . . . . . . . . . . . . .b. Alloimmune (e.g. of newborn)
. . . . . . . . . . . . . . .2. Microangiopathic (HUS, DIC, TTP)
. . . . . . . . . . . . . . .3. Hypersplenism
. . . . . . . . . . . . . . .4. Paroxysmal nocturnal hemoglobinuria
. . . . .c. Acute Loss

The following sections provide an overview of some of the major types of anemia discussed above

Iron Deficiency Anemia
This is the commonest cause of anemia in childhood, and world wide, with up to a quarter of the world’s population affected; in the US, approximately 10% of toddlers are iron deficient , with 3% being frankly anemic. These rates slowly decline until adolescence, at which point 16% of adolescent females develop iron deficiency, and 4% become anemic. In the US, children from lower socioeconomic groups are at an increased risk; 16%, 13%, 14%, and 10% of children living below the poverty line have iron deficiency anemia at ages 12, 18, 24, and 36 months, respectively.

75% of the body’s iron 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. The majority of the body’s iron is recycled via the reticuloendothelial system; in adults, 5% of the daily iron need is met via dietary absorption, equaling that which is lost. In the pediatric population however, due to rapid growth, 30% of the daily iron requirement must come from the diet.

In healthy infants, the daily iron requirement is 0.5 - 0.8 mg/day. However, only a small fraction of dietary iron is absorbed, making the required actual intake much higher. Bioavailability of iron also plays a role; breastmilk contains 0.3 - 1mg / L of iron, but has a 50% bioavailability, compared to formula which has a high iron content (12mg/L) but a low bioavailability (5%). Full term infants should receive 1mg/kg/day of iron. This is met for the first 4 months by breastfeeding (provided the mother has adequate iron stores of her own), but after 4 months, iron supplementation should be started until sufficient intake of iron-rich cereals are being taken. Preterm infants, lacking iron stores, should receive higher amounts of iron supplementation; 2-4mg/kg/day. Oral iron supplementation is correlated with improved growth, improved neurodevelopment, and reduced risk of infections.

Cow’s milk intake is an important cause of iron deficiency anemia, and should be avoided entirely in children under 1 year of age. Intake should be limited to 20oz (600mL) per day in children 1-5 years of age. This is for three reasons. First, cow’s milk is directly toxic to the intestinal mucosa, causing microscopic bleeding. Second, cow’s milk has low bioavailability, and third, it has a high fat content and reduces appetite for other, potentially iron rich foods. Blood loss is also an important cause of iron deficiency, particularly occult blood loss in the urine, feces, or via menorrhagia; children with appropriate diet and iron deficiency anemia must be investigated for a source of blood loss. Further, hemolytic anemias do not result in iron deficiency, as the body is able to effectively reuse free iron.

Suspect iron deficiency in the presence of a hypochromic (low MCHC), microcytic (low MCV) anemia with an inadequate reticulocyte count. An elevated platelet count also 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 % 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.

To treat, oral iron therapy at 3mg/kg (for mild anemia) or 6mg/kg (for severe anemia) of elemental iron should be initiated, and not taken with milk. In adequate responders, hemoglobin should rise by more than 1 g/dL in 4 weeks; once Hgb has normalized, therapy should be continued for an additional 2-3 months (to replace iron stores). In patients receiving adequate supplementation but with inadequate response after 4 weeks, further investigation should be performed.

Anemia of Chronic Disease
This anemia 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 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 they are low. Multiple factors contribute, including iron sequestration within the reticuloendothelial system, reduced bone marrow/erythroid precursor response to erythropoietin, and reduced RBC life span. Severe cases may be treated with EPO and iron supplementation, though generally the best course is to treat or control the underlying condition if possible.

Sideroblastic Anemia
An anemia arising from disorder heme synthesis / 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 cell. 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, and 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.

Lead Poisoning
Following the removal of lead from gasoline and paint, the average lead level in children fell from 16mcg/dL to <3mcg/dL. Children under 6 years of age are most vulnerable to lead toxicity for two reasons - they are more likely to engage in behaviors that increase their exposure, and 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/developmental abnormalities, kidney injury, GI symptoms, and anemia. The anemia seen in lead poisoning is microcytic, hypochromic, and reticulocytopenic; it is due to interference of lead with enzymes 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 level of >5mcg/dL is found by venous blood sample.

Management of lead poisoning depends upon the level present:
. . . . . 70mcg/dL or greater - severe intoxication - or with encephalopathy (emesis, altered mental status, headache, seizures). Chelation therapy with combined dimercaprol and EDTA.
. . . . . 45-69mcg/dL - moderate lead intoxication - chelation with DMSA.
. . . . . 10-44 mcg/dL - mild lead intoxication - chelation not indicated; detailed history required to identify and remove lead exposure, with close follow up and repeat lead levels.

Folate deficiency and B12 deficiency
Both folate deficiency and B12 deficiency are rarely seen in children. Both cause a macrocytic anemia, and potentially also thrombocytopenia and granulocytopenia. Both are diagnosed directly via blood levels. 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 factor deficiency (pernicious anemia).

Diamond-Blackfan Anemia (DBA)
DBA is a production failure anemia. It is a congenital erythroid aplasia that typically presents in infancy or early childhood, and is secondary to mutations affecting ribosome synthesis. It is a rare condition, with an incidence of approximately 1 / 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. Platelet / WBC count may be increased, decreased, or normal. 50% of patients will also have congenital abnormalities. Treatment is initially via steroids, or via ongoing transfusion in steroid non-responders.

Transient erythroblastopenia of childhood (TEC)
TEC is a transient, self-limited anemia due to a temporary cessation in erythrocyte production. Its etiology is unknown, but it 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 cases. It is usually seen in patients aged one month to 6 years, and unlike DBA, TEC patients do not have congenital abnormalities. Clinically, these patients tend to do well with an anemia lasting 1-2 months, followed by a spontaneous recovery. Transfusions are required for more severe cases only.

Congenital dyserythropoietic anemia (CDA)
Actually a group of 4 disorders, CDA is a due to ineffective erythropoiesis with multinuclear erythroblasts seen. Specific genetic abnormalities have been identified for all 4 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.

Reduced Erythropoietin Production
Erythropoietin 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 via 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 100-120 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. Elevated levels of LDH and bilirubin are seen, and the chronically hemolytic patient may develop pigmented gallstones during childhood; for this reason, the presence of incidental or symptomatic gallstones 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; congenital haptoglobin deficiencies do exist and may also be a cause of low serum haptoglobin, but are rare. 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 - sickle cell disease and the thalassemias
Both thalassemia and sickle cell disease are inherited anemias secondary to impaired/altered hemoglobin synthesis. Both increased destruction and reduced production contribute to the anemias seen in these conditions. They are discussed in full in separate chapters.

Intrinsic Hemolytic Anemia - Membrane defects - Elliptocytosis, spherocytosis
Hereditary spherocytosis (HS) is due to an abnormality in the erythrocyte structural protein spectrin. This defect causes the erythrocyte cellular membrane to loose 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/destroyed in the spleen. Investigations show an elevated reticulocyte count, normal MCV, and elevated MCHC; this is relatively specific to hereditary spherocytosis. It can be diagnosed by the osmotic fragility assay, or via flow cytometry. HS is the most common cause of hemolytic anemia, and is inherited in an autosomal dominant fashion. Patients 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; 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 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 used 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; these patients often go on to have more serious anemia, jaundice, and splenomegaly, as well as a tendency toward gall stones.

Intrinsic Hemolytic Anemia - Enzymatic defects - G6PD deficiency, Pyruvate Kinase deficiency
G6PD (glucose-6-phosphate dehydrogenase) deficiency can cause a hemolytic anemia secondary to reduced G6PD activity; this enzyme protects erythrocytes from oxidant stress, meaning that in deficient states, oxidant metabolites cause damage and hemolysis of RBCs. Acute hemolytic crises occur with exposure to oxidant drugs, foods, or infections. Periodic episodes of jaundice may occur, as well as prolonged neonatal jaundice. The G6PD gene is inherited on the X chromosome, meaning that males are affected most often, although - females may rarely be affected.G6PD deficiency causes a normocytic anemia with blood smears showing bite cells. Heinz bodies, which are comprised of denatured hemoglobin, are present. A depressed level of G6PD activity is diagnostic.

Pyruvate kinase is an enzyme active in erythrocyte glycolysis. In Pyruvate kinase 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.

Extrinsic Hemolytic Anemia - Autoimmune hemolytic anemia
Autoimmune hemolytic anemia (AIHA) involves the production of antibodies to components/antigens of the erythrocyte cellular membrane, which damage the erythrocyte and cause hemolysis. The direct Coombs test - which detects immunoglobulins / complement bound to the erythrocyte surface - is positive. AIHA can be triggered by malignancy, autoimmune disorders (SLE in particular), infections (EBV and mycoplasma especially), or drugs (cephalosporins and penicillin, most commonly).

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.

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; 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 patients’.


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, 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 often 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.

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

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 red blood cell size (microcytic, normocytic, and macrocytic anemias) and classification by mechanism (decreased production, increased destruction, and blood loss).

2. Low reticulocyte count.

3. History: dark urine. Physical exam: jaundice, scleral icterus, splenomegaly. Lab: elevated LDH, AST, indirect bilirubin; decreased serum haptoglobin; positive direct antibody test (DAT, also known as Coombs test), high reticulocyte count.

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 diagnostic of iron deficiency, but its wide range of normal values and its fluctuation with acute inflammation may make interpretation difficult. Serum iron coupled with TIBC and % iron saturation are satisfactory, but this test is 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 high. 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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