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.

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.

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 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.

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
. . . . . . . . . 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

**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.

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). In the U.S., 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 (2).

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. The bulk 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 to 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 to 1 mg per liter of iron, but has a 50% bioavailability, compared to formula which has a higher iron content (12mg per liter) but a 5% bioavailability. Full term infants should receive 1 mg/kg/day of iron. For the first 4 months, this is met with breastfeeding alone. But after 4 months, iron supplementation should be started until sufficient intake of iron-rich cereals has begun. Preterm infants, lacking iron stores, should receive higher amounts of iron supplementation of 2 to 4 mg/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 12 months of age. Intake should be limited to 20 ounces (600 mL) per day in children 1 to 5 years of age. 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 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.

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.

Treatment with 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. In adequate responders, hemoglobin should rise by more than 1 g/dL in 4 weeks. 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.

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.

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.

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 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.

Transient erythroblastopenia of childhood (TEC)
TEC is a transient, self-limited anemia due to a temporary cessation in erythrocyte production. 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. Clinically, these patients tend to do well with an anemia lasting 1 to 2 months, followed by a spontaneous recovery. Transfusions are only required for more severe cases.

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.

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.

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 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 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 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.

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 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.