Disorders of Red Blood Cells

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50 Disorders of Red Blood Cells

Red blood cells (RBC) are non-nucleated cells composed of a cell membrane, complex surface glycoproteins, and hemoglobin (Hb). Hb, the major component of RBCs, facilitates oxygen transport from the lungs to tissue capillaries by reversible binding and releasing oxygen, according to the characteristics of the oxyhemoglobin dissociation curve. As a result, RBC homeostasis is essential to prevent tissue hypoxia and maintain critical organ function.

RBC disorders can be divided into two categories, congenital and acquired disorders. Congenital disorders include membrane defects, thalassemia, hemoglobinopathies, and enzyme defects and aplasia. Acquired disorders include immune destruction, mechanical destruction, anemia of chronic disease, nutritional deficiencies (i.e., deficiency of B12, folate, iron), and aplasia. These disorders have different clinical features and mechanisms of disease, but all result in anemia.

Etiology and Pathogenesis

Congenital Red Blood Cell Disorders

Membrane Defects

Hereditary spherocytosis (HS) is the most common RBC membrane defect, affecting one in 5000 people of Northern European desent. Two-thirds of cases are inherited by autosomal dominant transmission, but de novo mutations can occur. The disorder arises from abnormalities of RBC membrane proteins. Commonly affected membrane proteins include ankyrin, band 3, and spectrin. These abnormalities lead to an unstable RBC membrane that assumes a spherical shape rather than the biconcave disc shape found in normal RBCs. The spherical RBCs have less deformability and cannot circulate freely through narrow capillaries. As a result, they become trapped in the spleen and are engulfed by macrophages, leading to a shortened RBC lifespan.

Hereditary elliptocytosis (HE) is another RBC membrane defect characterized by elliptical or oval-shaped RBCs on the peripheral blood smear. Unlike HS, HE is more common in people of African and Mediterranean ancestry. It is inherited mostly in an autosomal dominant fashion, although there can be spontaneous mutations. Clinical manifestations are usually similar to HS, but different phenotypic variations exist.

Thalassemias

The predominant adult hemoglobin A molecule is a tetramer formed by two α-globin and two β-globin chains. The thalassemias are a heterogeneous group of inherited disorders in which the production of normal Hb is partly or completely suppressed from the defective synthesis of one of the two globin chains (α or β). The type of thalassemia refers to the specific globin chain that is underproduced and is identified as either α- or β-thalassemia. A decrease in the production of either an α- or β-globin chain results in an excess of free globin chains that precipitate in the RBC and cause RBC membrane damage. The end result is anemia from RBC hemolysis and ineffective erythropoiesis in the bone marrow.

Whereas α -thalassemia is more commonly found in Southeast Asia, β-thalassemia is more common in Mediterranean countries. There are two α-globin genes located on chromosome 16. α-Thalassemias are usually the result of large gene deletions, causing a reduction in α-globin production. The severity of disease is directly related to the number of genes involved (Table 50-1).

Table 50-1 α-Thalassemia Gene Deletions

There is one β-globin gene located on chromosome 11. Point mutations are the most common type of genetic mutation in β-thalassemia. The β–thalassemia trait occurs when only one gene is affected, resulting in a mild microcytic anemia. The Hb electrophoresis reveals an increased Hb A2 or Hb F level. In contrast the inheritance of two affected β-globin genes results in a broad spectrum of clinical disease. The severity is determined by the residual amount of β-globin synthesis. The clinical phenotype ranges from transfusion dependence (thalassemia major) to a moderate anemia that does not necessitate chronic transfusions (thalassemia intermedia). Severe β-thalassemia is diagnosed between 6 months and 2 years of age. Laboratory analysis reveals a moderate to severe microcytic anemia and 20% to 100% HbF, 2% to 7% HbA2, and 0% to 80% HbA. Clinically, patients present with pallor, failure to thrive, hepatosplenomegaly, and bone deformities from marrow expansion.

Hemoglobinopathies

The hemoglobinopathies are a group of autosomal recessive inherited disorders characterized by synthesis of abnormal Hb molecules (i.e., S, and C). The most common and severe hemoglobinopathy is sickle cell disease, in which only HbS is produced. Chapter 53 of this book is dedicated to the in-depth discussion of sickle cell disease.

Enzyme Deficiencies

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an x-linked recessive disorder characterized by abnormally low levels of the enzyme G6PD. Worldwide it is the most common enzyme deficiency. G6PD is the rate-limiting enzyme of the pentose phosphate pathway, which is crucial for protecting RBCs from oxidative stress. In G6PD deficiency, damage by oxidant free radicals causes RBCs to hemolyze.

The severity of disease is based on the baseline G6PD level. The majority of individuals with G6PD have a moderate deficiency (10% normal activity), and at a steady state, they are hematologically normal. But with exposure to an oxidative stressor, they can develop acute hemolysis with resultant anemia, reticulocytosis, and hyperbilirubinemia or jaundice. Patients with a severe G6PD deficiency (i.e., Mediterranean variant) can have baseline mild anemia and reticulocytosis. Drugs that are oxidative stressors and should be avoided in patients with G6PD include antimalarials, sulfonamides and sulfones, quinolones, aspirin, methylene blue, and rasburicase. Other categories of oxidative stressors to avoid include fava beans and naphthalene mothballs. The degree of hemolysis varies with the drug’s antioxidant effect, the amount ingested, and the severity of the enzyme deficiency in the patient. The highest prevalence of disease is among persons of African, Asian, and Mediterranean descent.

Pyruvate kinase (PK) deficiency is an inherited metabolic disorder of the enzyme PK, which catalyzes the rate-limiting step in the glycolysis pathway. A deficiency of the enzyme PK compromises RBC adenosine triphosphate production and metabolic energy demand, leading to hemolysis. The inheritance pattern is usually autosomal recessive. Clinically, patients have a moderate to severe hemolytic anemia, reticulocytosis (may be 40%-70%), jaundice, and splenomegaly. Symptoms caused by hemolysis range from mild to severe.

Diamond-Blackfan Anemia

Diamond Blackfan anemia (DBA) is a congenital, lifelong pure RBC aplasia characterized by anemia, reticulocytopenia, and normocellular bone marrow with a paucity of erythroid precursors. The white blood cell count and platelets are usually normal. The anemia can be mildly macrocytic or normocytic and usually manifests after birth or in the first few months of life. DBA is associated with various congenital abnormalities, most commonly short stature, craniofacial abnormalities, and thumb abnormalities (classically triphalangeal thumbs). It is also associated with an increased predisposition to cancer. Inheritance patterns vary, since dominant, recessive, and sporadic mutations can all cause DBA. Approximately 50% of patients with DBA have a single mutation in a gene encoding for a ribosomal protein.

Congenital Bone Marrow Failure Syndromes

Inherited bone marrow failure syndromes include Fanconi anemia, dyskeratosis congenita, Schwachman-Diamond syndrome, Pearson syndrome, and amegakaryocytic thrombocytopenia. In contrast to DBA, these disorders affect multiple cell lines. These disorders are rare. Presentation can occur at a young age with symptoms of pancytopenia and congenital malformations, which differ by syndrome.

Acquired Red Blood Cell Disorders

Mechanical Red Blood Cell Destruction

The previous congenital RBC disorders are caused by abnormalities inherent to RBCs. In contrast, mechanical destruction involves hemolysis caused by extrinsic factors unrelated to the RBCs. Examples of mechanical RBC destruction include vascular lesions (i.e., AVMs), cardiac valvular defects, and microangiopathic damage (i.e., hemolytic uremic syndrome or thrombotic thrombocytopenic purpura). RBCs can also be destroyed by infections, drugs, toxins, and heat (with severe burns).

Autoimmune Hemolytic Anemia

The most common immune-mediated extrinsic anemia is autoimmune hemolytic anemia (AIHA), in which circulating antibodies are directed against the patient’s RBCs. AIHA can be primary or secondary to infection, drugs, or an underlying disease process such as lymphoma, systemic lupus erythematosus, or immunodeficiency. Primary AIHA occurs in the majority of children and often occurs after a viral illness. The specific autoantibodies can be either IgG in warm-reactive antibodies or IgM in cold-agglutinin disease. Patients with AIHA require close monitoring because brisk hemolysis can result in a sudden decrease in Hb that can be life threatening.

Anemia of Chronic Disease

Anemia of chronic disease occurs with a wide range of chronic inflammatory, malignant, autoimmune, and infectious conditions. The theorized primary mechanism involves proinflammatory cytokines disrupting iron homeostasis. An influx of cytokines causes iron sequestration within reticuloendothelial cells, making less iron available in the circulation for erythroid progenitor cells. Anemia of chronic disease is characterized by inadequate RBC production in the setting of low serum iron and low iron-binding capacity. The RBCs are usually normocytic and normochromic, but they also can be mildly hypochromic and microcytic.

Nutritional Deficiencies

Deficiencies of vitamin B12 (cobalamin) and folate can cause a megaloblastic anemia resulting from inhibition of DNA synthesis during RBC production. The anemia is macrocytic and can be accompanied by leukopenia and thrombocytopenia. Dietary deficiencies of these vitamins are somewhat rare in the pediatric population. Animal products, such as meat and dairy, are the only dietary sources of cobalamin. Even in severely limited diets, vitamin B12 deficiency takes many years to develop because of its long half-life. Folate is more widespread in the human diet and is found in cereal, fruits, vegetables, and meat. Other causes of vitamin B12 deficiency include defective B12 absorption from a failure to secrete intrinsic factor, a failure to absorb B12 in the small intestine, and congenital deficiencies in vitamin B12 transport or metabolism. Other causes of folate deficiency include malabsorption, increased folate requirements in chronic hemolytic anemias, or congenital disorders of folic acid metabolism. Of note, certain drugs (i.e., methotrexate) interfere with folic acid metabolism and can cause folate deficiency.

Iron deficiency is the most common cause of anemia in the pediatric population, affecting approximately 5% to 10% of toddlers and adolescent girls. The prompt diagnosis and treatment of this condition is important because clinical manifestations include poor academic achievement, reduced attention span, and growth retardation. Iron deficiency occurs when an insufficient amount of iron is available to meet the body’s requirements. In pediatric patients, it is usually caused by inadequate dietary intake, chronic blood loss (gastrointestinal or menstrual bleeding) or malabsorption (celiac disease or inflammatory bowel disease). High-risk groups include premature infants (who receive less iron from the mother in the third trimester) and infants consuming large amounts of cow’s milk (specifically, >24 oz/d) and menstruating women. In children older than 2 years of age, dietary causes of iron deficiency is less likely, and chronic blood loss (heavy menses) or malabsorption (celiac disease or inflammatory bowel disease) need to be considered. Iron-deficiency anemia is microcytic and hypochromic, with a low serum iron and ferritin and an elevated total iron-binding capacity.

Transient Erythroblastopenia of Childhood

Transient erythroblastopenia of childhood (TEC) is a disorder characterized by the temporary cessation of RBC production in previously healthy children. Despite the severity of anemia, patients usually present with slowly developing pallor without other symptoms. Laboratory workup reveals anemia and reticulocytopenia; typically, no other cell lines are affected, but the neutrophil count may be decreased. In TEC, the anemia is transient (unlike DBA). The mean age at diagnosis is 26 months; fewer than 10% are older than 3 years at diagnosis. The cause remains unknown, but a viral cause has been proposed.

Transient Red Blood Cell Aplasia from Parvovirus B19

Infection with parvovirus causes a reticulocytopenia for approximately 7 to 10 days. Patients with congenital RBC disorders with increased RBC turnover and decreased RBC life span are at risk for developing a significant anemia during the period of acquired reticulocytopenia (see Chapter 53). Clinically, patients can present with pallor, headache, and a marked decrease in Hb level. The hallmark is a low reticulocyte count, indicating suppression of bone marrow activity. Blood transfusion is indicated in patients with significant anemia who are symptomatic.

Clinical Presentation and Differential Diagnosis

The clinical presentation of anemia varies greatly depending on the severity of anemia and the time span in which it develops. Frequently, in a process that develops chronically over weeks to months, children will be asymptomatic and may come to medical attention because of an abnormal screening complete blood count (CBC). On the other end of the spectrum, patients with an acute onset of anemia can present with cardiovascular compromise and shock because the body does not have time to compensate for the decreased oxygen-carrying capacity. Compared with adults, children have a large physiologic reserve and can function quite well with chronically low Hb levels.

A patient with mild anemia may only feel slightly fatigued and reveal pallor at sites where capillary beds are visible through the mucosa (conjunctivae, palms, and nail beds). Clinically, anemia can be appreciated when the Hb concentration is below 8 to 9 g/dL, although the complexion of the child and the rapidity of onset may influence this value. In moderate anemia, the body begins to attempt to compensate for decreased oxygen delivery by increasing cardiac output; therefore, tachycardia and a systolic murmur may be present. A systolic flow murmur is often heard if the Hb level is below 8 g/dL. Symptoms at this time may include headache, excessive sleeping (especially in infants), poor feeding, and syncope. In severe anemia, the body’s end-organ hypoxia increases, and the patient shows signs of decreased perfusion. Signs of severe anemia include tachypnea, altered mental status, and exertional dyspnea. Left untreated, anemia can progress to cardiovascular collapse.

A complete physical examination is important to establish the cause of anemia. Growth parameters should be obtained in all anemic patients. Failure to thrive suggests a more chronic anemia. Jaundice or darkened urine signifies a significant hemolytic process.

Hepatosplenomegaly is an important finding present in extramedullary hematopoiesis (in chronic hemolytic diseases such as thalassemia) or infiltrative disorders. Frontal bossing is another sign suggestive of extramedullary hematopoiesis.

The differential diagnosis of anemia is diverse. Physiologically, anemia can be divided into three categories: decreased or ineffective RBC production, premature RBC destruction, and blood loss. Causes of anemia can be further subdivided based on a morphologic approach using the reticulocyte index (see Diagnostic Approach) and the mean corpuscular volume (MCV) (Figure 50-1).

Figure 50-1 Diagnostic approach to anemia.

Diagnostic Approach

Through the combination of a thorough history, physical examination, and a few simple laboratory tests, the cause of anemia can usually be determined. The initial laboratory workup should include a CBC with differential and reticulocyte count. All three cell lines on the CBC need to be analyzed to determine whether the process causing the anemia is limited to erythroids or if other cells lines are affected.

Anemia is defined as a decrease in the Hb concentration more than 2 standard deviations below the mean for age (Table 50-2). The MCV and reticulocyte count are helpful measurements in categorizing anemia. The MCV provides a quick, accurate, and readily available method of distinguishing the microcytic anemias (iron deficiency, thalassemia syndromes) from the normocytic (membrane disorders, enzyme deficiencies, AIHA, most hemoglobinopathies) or macrocytic (bone marrow or stem cell failure, disorders of vitamin B12, and folic acid absorption or metabolism) anemias. The MCV varies with age, necessitating the use of age-adjusted normal values (see Table 50-2).

Table 50-2 Normal Hematologic Values for Age

The reticulocyte count should be performed and distinguishes anemias caused by impaired RBC production from those caused by increased RBC destruction. The reticulocyte count is expressed as a percent of total RBCs; it must be corrected for the degree of the anemia. A normal reticulocyte count is 1%. The easiest way to make this correction is to calculate the reticulocyte index (RI) by multiplying the reticulocyte count by the reported hematocrit divided by a normal hematocrit. For example, a reticulocyte count of 5% in a child with severe iron-deficiency anemia and a hematocrit of 7% is not elevated when corrected for the degree of anemia (5% × 7%/33% = 1%).

After the cause of the anemia has been further categorized into broad disease categories, specific tests can be drawn. Table 50-3 lists specific diagnostic tests and their associated conditions.

Table 50-3 Diagnostic Tests for Evaluating Anemia

Diagnostic Test	Disease
DAT or Coombs test	AIHA
Hemoglobin electrophoresis	Sickle cell disease
Hemoglobin electrophoresis	Thalassemia
RBC enzyme assays	G6PD deficiency
RBC enzyme assays	PK deficiency
Osmotic fragility test	Hereditary spherocytosis
Iron studies	Iron-deficiency anemia
Folate, vitamin B12	Macrocytic or megaloblastic anemia
Bone marrow aspiration and biopsy	Myelodysplastic syndrome
	Aplastic anemia
	Malignancy
	Diamond-Blackfan anemia
ADAMTS13 activity and inhibitor level	TTP
Chromosomal breakage analysis	Fanconi’s anemia

AIHA, autoimmune hemolytic anemia; DAT, direct antiglobulin; G6PD, glucose-6-phosphate dehydrogenase; PK, pyruvate kinase; RBC, red blood cell; TTP, thrombotic thrombocytopenic purpura.

Management and Therapy

Congenital Disorders

Therapy for patients with congenital RBC disorders is disease specific. In hereditary spherocytosis, splenectomy is curative but is associated with surgical and postsplenectomy infectious risks. There is also a possible increased risk for pulmonary hypertension after splenectomy. The procedure is reserved for severe cases and is usually deferred until at least 5 years of age because of the increased risk of infection with encapsulated organisms. Patients should be immunized against Haemophilus influenzae, Streptococcus pneumoniae, and Neisseria meningitides before surgery and require lifelong penicillin prophylaxis after surgery. Indications for splenectomy include severe anemia (Hb < 8 g/dL), poor growth, chronic fatigue, or recurrent hemolytic episodes requiring frequent RBC transfusions.

The best management strategy in G6PD deficiency is educating patients about avoidance of oxidative stressors that can trigger hemolysis. They should be instructed to avoid exposure to certain drugs, naphthalene (found in mothballs), and fava beans to prevent hemolytic crises. Management of an acute hemolytic crisis is supportive. Some patients may require an RBC transfusion if they develop severe symptomatic anemia.

For patients with β-thalassemia, the clinical phenotype ranges from transfusion dependence (thalassemia major) to a moderate anemia that does not necessitate chronic transfusions (thalassemia intermedia). The recommended treatment for β-thalassemia major involves regular blood transfusions every 2 to 5 weeks to maintain a nadir Hb of 9 to 10 g/dL. With regular blood transfusions, patients will develop iron overload, and if left untreated, it is fatal. At this time, patients with iron overload are treated with medications that bind iron known as chelators. The chelators currently in use in the United States include deferoxamine (Desferal), which is typically given as a 12-hour infusion intravenously or subcutaneously, and deferasirox (Exjade), an oral medication given once daily.

Therapy for patients with DBA includes an initial therapeutic regimen of chronic RBC transfusions followed by a corticosteroid trial. Forty percent of patients fail to respond to corticosteroid therapy. Those that do respond may remain steroid dependent. For an unknown reason, 20% of patients will go into remission. Allogenic bone marrow transplant is the only curative treatment.

Acquired Disorders

Therapy of patients with acquired RBC disorders involves correcting the underlying abnormality. In nutritional deficiencies, for example, treatment focuses on addressing the root cause and concurrently administering nutritional supplementation. The cause of iron deficiency needs to be determined for each patient. At the same time, the patient is given supplementation with 6 mg/kg/d of elemental iron divided two or three times per day. To fully replete the iron stores, the iron replacement should continue for 3 to 4 months until the CBC normalizes (including the MCV and RBC distribution width). With anemia of chronic disease, the treatment is focused on treating the underlying cause (i.e., oncologic process, rheumatoid arthritis).

AIHA can cause brisk, severe hemolysis and patients require close monitoring. Treatment of primary AIHA includes methylprednisone 1 to 2 mg/kg/d intravenously every 6 hours. After the Hb stabilizes, the patient can be switched to 1 to 2 mg/kg/d of oral prednisone. Steroids are then gradually tapered over a period of weeks to months. In cases of cardiovascular compromise, an RBC transfusion should be considered. However, because antibodies against RBCs cause AIHA, the patients’ antibodies may also hemolyze the transfused blood. Extreme caution should be taken when transfusing these patients. Second-line therapy for AIHA includes intravenous immunoglobulin, and patients with refractory disease can be treated with exchange transfusion; plasma pheresis; or other immunomodulators, including rituximab, danazol, vincristine, or cyclophosphamide.

Treatment of patients with TEC or an aplastic crisis from parvovirus requires regular monitoring of CBCs until the anemia normalizes. Blood transfusion may be required if the patient is severely anemic with cardiovascular compromise. No other treatment is necessary, and patients undergo spontaneous resolution.

Future Directions

A new diagnostic test for hereditary spherocytosis is available. The test uses flow cytometry and is based on the fluorescence of RBCs after incubation with the dye eosin-5-malimide. The novel test has many advantages over the standard osmotic fragility test, including necessitating only a small amount of blood (100 microliters) and higher sensitivity and specificity (92% and 99%, respectively). Results of the flow cytometry test are available in 2 hours. Comparatively, the osmotic fragility test requires 3 mL of blood, and the sensitivity is only 80% (mild cases are not detected). Also, the specificity is lower in the osmotic fragility test because it can be falsely abnormal in other disease processes that result in spherocytes (e.g., AIHA).

Bone marrow transplant (BMT) is a treatment modality for patients with β-thalassemia major. BMT is reserved for only the most severe cases because of the risks and long-term side effects.

A novel treatment modality based on globin gene expression for β-thalassemia is currently in the experimental phase. Scientists have successfully manipulated globin gene expression in murine models but have not developed a specific targeting vector in humans yet. This potential target for gene therapy involves the insertion of normal β-globin gene into the patient’s stem cells. If the treatment is developed successfully, it has the potential to cure β-thalassemia.

Suggested Readings

Brugnara C, Oski FA, Nathan DG. Diagnostic approach to the anemic patient. In: Orkin SH, Nathan DG, Ginsburg D, et al, editors. Hematology of Infancy and Childhood. Philadelphia: Saunders; 2009:455-466.

Rund D, Rachmilewitz E. β-Thalassemia. N Engl J Med. 2005;353(11):1135-1145.

Segel GB. Anemia. Pediatr Rev. 1988;10(3):77-88.

Shah S, Vega R. Hereditary spherocytosis. Pediatr Rev. 2004;25(5):168-172.

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