Normocytic anemia

Normocytic anemia

• Normocytic anemia is a subset of anemia (ie, low circulating RBC mass or hemoglobin concentration) in which RBCs are of normal size, generally defined in adults as a mean corpuscular volume of 80 to 100 fL
• Associated with heterogeneous causes, generally classified as hyperproliferative (characterized by an appropriate reticulocytosis) or hypoproliferative (characterized by inappropriately low reticulocyte production)
• Hyperproliferative causes include bleeding and hemolysis due to inherited conditions (eg, hemoglobinopathies, RBC membrane defects or enzyme deficiencies) or acquired disease (autoimmune hemolytic anemias, microangiopathies, infectious disease or toxins)
• After reticulocyte count, diagnosis is directed by review of the peripheral smear for RBC morphologic features that suggest specific processes and for presence of immature RBCs and WBCs
• Further testing may include serum chemistries to screen for liver and kidney disease and for indicators of hemolysis (eg, haptoglobin, indirect bilirubin, l-lactate dehydrogenase), iron studies, folate and vitamin B₁₂ levels, direct antiglobulin (Coombs) test, hemoglobin electrophoresis, flow cytometry, or bone marrow biopsy
• Treatment is aimed at the underlying cause; transfusion may be necessary in symptomatic patients or to stabilize those who have lost large blood volumes or have overwhelming hemolysis
• Prevention is not possible in many of the conditions associated with normocytic anemia; avoidance of predictable triggering factors may reduce the incidence in patients with hemolytic disorders

Pitfalls

• Automated blood assays may report normocytic indices based on the mean of a combination of macrocytic and microcytic cells; peripheral smear that does not show a mixture of both macrocytic and microcytic cells and/or RBC distribution width within reference range rule out this artifact
• Normocytic anemia may be multifactorial in origin (eg, chronic inflammation plus iron deficiency)

Normocytic anemia is a subset of anemia (ie, low circulating RBC mass or hemoglobin concentration) in which RBCs are of normal size

Reference values for hemoglobin concentration and RBC mass vary by age, gender, ethnicity, and altitude; common definitions of anemia include a hemoglobin level 2 standard deviations below the mean for age, or less than fifth percentile for age 

WHO defines anemia in adults as hemoglobin level less than 13 g/dL in men and less than 12 g/dL in women (without distinction among ages and ethnicities) 

Tables of pediatric reference ranges are available

RBC size is determined by the mean corpuscular volume, which also varies by age

In adults, the normal range is 80 to 96 fL, and a working definition of normocytic anemia generally uses parameters of 80 to 100 fL 

Tables of pediatric reference ranges are available

Classification

• By duration 
  • Acute
    • Examples include acute blood loss, toxin- or drug-induced hemolysis, and falciparum malaria
  • Chronic
    • Examples include anemia of chronic disease (inflammation), anemia of chronic kidney disease, and myelophthisic disorders
• By mechanism 
  • Loss or destruction of RBCs
    • Examples include hemorrhage or occult bleeding and various causes of congenital and acquired hemolytic disorders
  • Decreased production of RBCs
    • Examples include any causes of ineffective erythropoiesis such as aplastic anemia, bone marrow infiltration, or decreased erythropoietin production (eg, renal disease)
• By regenerative response 
  • Hyperproliferative: robust reticulocytosis (reticulocyte production index greater than 3), implying appropriate erythropoietic response (ie, intact feedback messaging, capable bone marrow, and ample supply of components)
    • Examples include acute blood loss and hemolysis
  • Hypoproliferative: poor reticulocyte response (reticulocyte production index less than 2), implying inability to respond owing to messaging defects, primary bone marrow dysfunction, or lack of components
    • Examples include erythroblastopenia of childhood and anemia of chronic disease (inflammation)

Clinical Presentation

History

• General aspects of presenting features
  • Patients are often asymptomatic at presentation and anemia is discovered through screening (in children) or incidentally during laboratory testing for evaluation of another problem
  • Presence or absence of symptoms may be affected by the severity of anemia and its rate of onset as well as the oxygen delivery needs of the patient
  • Gradual onset of anemia is frequently asymptomatic in young and otherwise healthy patients with good cardiopulmonary reserve and in patients who exert minimal physical activity
• Symptoms related directly to anemia (decreased oxygen delivery) are often nonspecific when present
  • Mild manifestations may include fatigue, generalized weakness, exertional dyspnea, palpitations, lightheadedness, headache, and tinnitus
  • More significant manifestations may include dyspnea at rest, lethargy, and confusion
  • Infants may display irritability and poor feeding
  • Toddlers and older children may not meet development milestones if anemia is longstanding and severe
• Symptoms may be more profound with sudden, severe blood loss or hemolysis
  • May include syncope, altered mental status, and vomiting
  • Red or rust-colored urine and hemoglobinuria may be noted in patients with severe intravascular hemolysis
  • Urine output may be diminished in hemolytic uremic syndrome
• Other symptoms related to the underlying cause may be present; may include:
  • History of an antecedent infection, viral syndrome, or other triggering event may be elicited
  • History of exposures that might be implicated (eg, medications, toxins, travel) may be elicited
  • Fever and weight loss suggest infection-related hemolysis, inflammatory state associated with impaired hematopoiesis, or possible malignancy
  • Unusual ecchymosis may signal internal blood loss (eg, retroperitoneal hematoma)
  • Petechiae or scattered bruising may suggest microangiopathic cause or hematologic malignancy
  • Dyspepsia, change in bowel habits, melena, or gross blood in stool points to gastrointestinal blood loss
  • Recent onset of muscle or joint pain/inflammation may suggest precipitating viral illness (eg, parvovirus); longstanding rheumatologic complaints suggest autoimmune condition and chronic inflammation
  • Unremitting cough may signal ongoing infection (eg, bronchiectasis, tuberculosis) or pulmonary malignancy
  • Bone pain suggests cause associated with marrow infiltration or primary hematologic malignancy
  • Recent or concurrent rash may suggest virus- or drug-induced process
• Patients may present with symptoms related to complications, particularly in patients with underlying comorbidity, such as congestive heart failure or acute coronary syndrome
• History of gallstones at an early age suggests possibility of longstanding hemolytic anemia
• Family history of similar manifestations may raise possibility of a hereditary condition

Physical examination

• Pallor
  • May be visible; often most noticeable in the face, conjunctivae, nail beds, and palmar creases
• Jaundice
  • May be noted in patients with significant hemolysis
  • Observed in the scleral icterus and yellow discoloration of mucus membranes and skin
• Tachycardia and/or hypotension
  • May be present with severe anemia or sudden onset of anemia
  • Often exacerbated by orthostatic maneuvers (postural change from supine to sitting to standing)
  • May be associated with bounding pulse
• Systolic flow murmur
  • Sometimes appreciated on auscultation
• General appearance
  • May appear profoundly ill in acute severe hemolysis or hemorrhage
  • Mental status changes (eg, confusion, delirium) may be present in patients with microangiopathic syndromes (eg, thrombotic thrombocytopenia), severe malaria, or Clostridium perfringens bacteremia
• Other signs related to the underlying cause may be noted with careful physical examination
  • Perform a thorough physical examination in effort to discover sometimes subtle clues; some examples include:
    • Splenomegaly in patients with hemolysis, chronic infection, or myelofibrosis
    • Petechiae in microangiopathic syndrome or possible malignancy
    • Acrocyanosis in cold agglutinin disease
    • Evident or occult source of bleeding (eg, retroperitoneal hematoma, ruptured spleen)

Causes

• Hyperproliferative causes; associated with brisk reticulocytosis (reticulocyte production index greater than 3)
  • Acute blood loss
    • Hemorrhage
  • Hemolysis
    • Congenital hemolytic disorders
      • Hemoglobinopathies due to genetic defects resulting in abnormal erythrocytes (eg, sickle cell disease, sickle cell hemoglobin C disease) (Related: Sickle cell disease)
      • Disorders of RBC membranes resulting in erythrocyte fragility (eg, hereditary spherocytosis, hereditary elliptocytosis)
      • RBC enzyme deficiencies (eg, glucose-6-phosphate dehydrogenase deficiency, pyruvate kinase deficiency) (Related: Glucose-6-phosphate dehydrogenase deficiency)
        • Hemolysis in patients with glucose-6-phosphate dehydrogenase deficiency may be triggered by certain dietary items (eg, fava beans) or medications (eg, sulfonamides, nitrofurantoin, phenazopyridine, primaquine)
    • Acquired hemolytic disorders
      • Immune-mediated hemolytic anemias resulting in the destruction of RBCs
        • Autoimmune classified into warm, cold, and mixed forms based on the thermal characteristics of the autoantibody (Related: Autoimmune hemolytic anemia)
        • May also be drug induced; possible drugs include:
          • Methyldopa
          • Penicillins
          • Cephalosporins
          • Erythromycin
          • Acetaminophen
          • Procainamide
        • Hemolytic disease of the newborn
      • Mechanical injury
        • Microangiopathic
          • A number of life-threatening disorders involve mechanically induced hemolysis in the microvasculature of the bone marrow; these syndromes are often associated with disordered coagulation, thrombosis, consumptive thrombocytopenia, bleeding, and multiorgan failure
          • Examples include thrombotic thrombocytopenic purpura, disseminated intravascular coagulopathy, and hemolytic uremic syndrome (Related: Thrombotic thrombocytopenic purpura)
          • Triggers may include infection, malignancy, toxins, and pregnancy; in many cases, a precipitating factor is not identified
        • Prosthetic heart valves (Waring blender syndrome)
      • Paroxysmal nocturnal hemoglobinuria
        • Caused by a spontaneous mutation resulting in loss of RBC protective mechanism; permits occurrence of complement-mediated cell lysis
      • Infections in which the pathogen destroys circulating RBCs (Related: Malaria)
        • Examples include malaria, babesiosis, and Clostridium perfringens
      • Direct toxin effect
        • Examples include bee and wasp stings, spider bites, and snake venom
        • May also represent the mechanism for some drug-induced anemias
• Hypoproliferative causes; associated with little or no reticulocytosis (reticulocyte production index less than 2)
  • Primary
    • Bone marrow abnormalities that result in bone marrow failure
      • Examples include myelodysplastic syndromes, myelofibrosis, aplastic anemia, pure red cell aplasia, hematologic malignancies (ie, leukemia, lymphoma, and multiple myeloma), or infiltration by malignancy
    • Certain viral or other infections
      • May destroy erythropoietic cells directly (eg, HIV, parvovirus B19) or may trigger immune-mediated destruction of RBCs precursors (eg, transient erythroblastopenia of childhood)
    • Acute or remote exposure to toxins may impair hematopoietic capability
      • Examples include chemotherapeutic agents and radiation
  • Secondary
    • Inadequate delivery of iron to bone marrow and utilization of iron by bone marrow
      • Occurs in inflammatory states or malignancy and is associated with resistance to erythropoietin resulting in impaired erythropoiesis (ie, anemia of chronic disease, also known as anemia of inflammation); anemia of critical illness is a variant
        • Anemia of chronic disease (or inflammation) is most common cause of normocytic anemia worldwide 
    • Decreased production of erythropoietin
      • Chronic kidney disease
      • Chronic liver disease
      • Endocrine deficiency (eg, hypothyroidism, adrenal or pituitary insufficiency)
      • Inflammation
    • Nutritional deficiencies
      • May be associated with normocytosis early in course of deficiency
      • Eventually associated with microcytosis (iron deficiency) or macrocytosis (vitamin B₁₂ and/or folate deficiency)
• Overexpansion of plasma volume relative to RBC mass may result in apparent anemia
  • Examples of such physiologic states include pregnancy and overhydration

Risk factors and/or associations

Age

• Age at presentation varies with the cause
  • Hereditary conditions are present at birth but may not be clinically apparent
  • Acquired conditions tend to occur in middle age or later, with several exceptions:
    • Parvovirus B19
      • Common disease in early childhood and is associated with viral destruction of erythrocyte precursors
      • Causes only mild transient anemia in healthy children but may cause aplastic crises in children with preexisting hemolytic anemia
    • Transient erythroblastopenia of childhood 
      • Occurs after infection or toxin exposure in children aged 6 months to 3 years; cause is often undetermined

Sex

• Glucose-6-phosphate dehydrogenase deficiency is X linked; in general, males may exhibit severe phenotype and females experience less severe phenotype (depending on degree of X inactivation) or are carriers 

Genetics

• Some specific causes are associated with genetic factors:
  • Inherited
    • Sickle cell disease
      • Mutation in the HBB gene results in sickle hemoglobin; autosomal recessive trait with homozygosity resulting in sickle cell disease (OMIM #603903)
    • Hereditary spherocytosis
      • Associated with a heterogeneous group of mutations resulting in abnormalities of various structural proteins (OMIM #182900, #616649, #270970, #612653, #612690, others); some are autosomal dominant and others autosomal recessive 
    • Hereditary elliptocytosis
      • Heterogeneous group of mutations resulting in fragile ovoid RBCs subject to hemolysis; usually inherited in an autosomal dominant pattern (OMIM #611804,  #130600, #617948, #166900)
    • Glucose-6-phosphate dehydrogenase deficiency
      • Associated with any of numerous mutations in the gene coding for the enzyme, located on the X chromosome (OMIM *305900) 
    • Pyruvate kinase deficiency
      • Associated with an inherited (autosomal dominant) somatic mutation of PKLR gene (OMIM #266200)
  • Acquired
    • Paroxysmal nocturnal hemoglobinuria
      • Acquired as the result of a spontaneous somatic mutation in the PIGA gene on the X chromosome (OMIM #300818) 
    • Myelodysplastic syndrome
      • At least 4 mutations (involving genes SF3B1, GATA2, TET2, ASXL1) have been associated with myelodysplastic syndrome (OMIM #614286) and with a propensity for transformation to acute myeloid leukemia
    • Myelofibrosis
      • Mutations at several loci (MPL, JAK2, CALR) have been associated with myelofibrosis (OMIM #254450) 
    • Aplastic anemia
      • Several mutations (involving genes SBDS, NBN, PRF1, and IFNG) have been identified in association with aplastic anemia (OMIM #609135) 

Ethnicity/race

• Some causes are associated with certain ethnicities
  • Sickle-cell disease is more common in persons of African and middle Eastern descent
  • Hereditary spherocytosis is more common in persons of northern European and Japanese descent 
  • One form of hereditary elliptocytosis (type 4, or Southeast Asian ovalocytosis) is more common in persons from Malaysia, Indonesia, the Philippines, and Papua New Guinea; other variants are associated with African and Mediterranean ancestry 
  • Glucose-6-phosphate dehydrogenase deficiency is more common in African, Middle Eastern, Mediterranean, and Asian populations 

Other risk factors/associations

• Acquired autoimmune hemolytic anemias are often associated with underlying or precipitating disease 
  • Warm autoimmune hemolytic anemia may occur in the setting of lymphoproliferative diseases, systemic lupus erythematosus or other autoimmune diseases, or HIV infection
  • Cold autoimmune hemolytic anemia may follow infection (eg, mycoplasma, Epstein-Barr virus, cytomegalovirus) or may be associated with malignancies (especially chronic lymphocytic leukemia and lymphomas)

• Detailed history and thorough physical examination may provide information suggesting cause of anemia as well as physiologic impact
• Preliminary diagnosis of normocytic anemia is based on the results of a CBC revealing a hemoglobin level 2 standard deviations below the mean for age (or less than the 5th percentile for age) with a mean corpuscular volume within the reference range
  • Check that RBC distribution width is within reference range to assure that the measured RBC volume is accurate and not an artifact of mixed macrocytic and microcytic cells
  • Associated thrombocytopenia suggests microangiopathy or primary bone marrow disorder
  • Associated leucopenia suggests primary marrow disorder or, rarely, overwhelming infection
• Obtain a reticulocyte count and peripheral smear in all patients
  • Reticulocyte count and reticulocyte production index 
    • Reticulocyte production index is calculated as (reticulocyte percentage ÷ reticulocyte maturation time [days]) × (hematocrit ÷ 0.45)

Hematocrit	Reticulocyte maturation time (days)
35	1.5
30	1.75
25	2
20	2.25
15	2.5

Citation: Data from Chernecky CC et al: R. In: Chernecky CC et al, eds: Laboratory Tests and Diagnostic Procedures. 6th ed. Philadelphia, PA: Elsevier; 2013:953-93.

• • Normal or decreased reticulocyte count and/or reticulocyte production index is less than 2 
    • Consider the possibility of renal insufficiency, endocrinopathy, other chronic diseases, acute infection, primary marrow disorders, transient erythroblastopenia of childhood, early nutritional deficiency (eg, iron, folate, vitamin B₁₂), and acute blood loss (soon after blood loss, before appropriate marrow response can be mounted)
    • Test for nutritional deficiencies: serum iron, total iron binding capacity, ferritin, vitamin B₁₂/methylmalonic acid, and folate levels
    • Perform further testing as clinically indicated (eg, creatinine and liver enzyme levels, thyroid studies, adrenal function)
  • Elevated reticulocyte count and/or reticulocyte production index is greater than 2 
    • Consider hemolytic anemia or hemorrhage
    • Obtain serum levels of haptoglobin, l-lactate dehydrogenase, and indirect bilirubin for evidence of hemolysis
      • Hemolysis is suggested with low haptoglobin, elevated l-lactate dehydrogenase, and increased indirect bilirubin levels; peripheral smear result may suggest a cause
    • External (eg, gastrointestinal bleeding, uterine bleeding) or internal (eg, retroperitoneal hematoma) blood loss is likely if hemolysis is not suggested by laboratory evaluation
• Further studies may be indicated based on clinical presentation and results of preliminary testing (eg, viral studies, rheumatologic testing, imaging)
• In urgent cases that require transfusion before work-up, it is important to draw and hold blood for later testing because transfusion can alter results

Laboratory

• CBC
  • Confirms a diagnosis of anemia when hemoglobin falls below defined reference range for age, usually 2 standard deviations or more below the mean 
    • Tables of pediatric reference ranges are available
    • WHO defines anemia in adults as a hemoglobin level less than 13 g/dL in men and less than 12 g/dL in women (without distinction between age and ethnicity) 
    • Some confounding variables may alter interpretation of hemoglobin levels with respect to conventional reference range
      • African Americans have an average hemoglobin value of 0.5 to 0.73 below those of white Americans 
      • Lifestyle issues that may mask presence of underlying anemia
        • High-altitude living skews hemoglobin values higher than sea-level living
        • People who smoke or are exposed to significant amounts of secondhand smoke or carbon monoxide may develop erythrocytosis
      • High prevalence of chronic disease may skew acceptable reference range lower for a given population; confounding issues may include malnutrition, infection (eg, malaria), and congenital blood dyscrasias (eg, sickle cell, thalassemia)
      • Anemia in certain groups may be difficult to interpret owing to a number of potential and often coexistent causes
        • Endurance athletes, owing to dilution, iron deficiency, intravascular (mechanical) hemolysis, and use of erythropoietin, androgen, and other hormone analogues 
        • Anemia in older adults, owing to nutritional deficiencies, chronic renal disease, chronic disease in general, myelodysplasia, and other causes
  • Provides indices (ie, mean corpuscular volume, mean corpuscular hemoglobin concentration, and random distribution width) to categorize anemia and direct work-up
    • Mean corpuscular volume 
      • Value reflects average volume of RBCs
      • In adults, the normal range for mean corpuscular volume is 80 to 96 fL; a working definition of normocytic anemia generally uses parameters of 80 to 100 fL
      • Tables of pediatric reference ranges are available
    • Random distribution width 
      • Reflects variation in RBC size (ie, degree of anisocytosis as noted on peripheral smear)
      • Random distribution width within the reference range indicates that RBCs are of uniform size (ie, not a mixture of microcytes and macrocytes)
      • Presence of anisocytosis may suggest multiple processes (eg, iron deficiency plus vitamin B₁₂ or folate deficiency)
    • Mean corpuscular hemoglobin concentration
      • Elevated in conditions associated with intravascular hemolysis (eg, hereditary spherocytosis, sickle cell disease) 
      • Value reflects the average RBC hemoglobin concentration
  • Degree of anemia varies with cause
    • Hemorrhage may result in profound anemia but may not be evident on blood count results until volume has been replaced
    • Anemia of chronic disease (inflammation) usually does not by itself account for a hemoglobin level less than 8 g/dL 
    • Anemia associated with renal failure (decreased erythropoietin production) may be profound, especially at serum creatinine levels greater than 3 mg/dL 
• Peripheral smear 
  • RBC morphology often provides clues to diagnosis and direction of further testing
  • Abnormal WBC differential count or morphology and presence of immature RBCs or WBCs may suggest hematologic malignancy or marrow infiltration
• Reticulocyte count
  • Number of reticulocytes per 1000 erythrocytes, expressed as a percentage of erythrocytes; reference values vary with age 
  • Reticulocyte production index is a calculated value that corrects for changes in hematocrit and erythrocyte kinetics that occur with anemia; the reference value is 1 
    • In the setting of anemia, a value of 2 or more indicates an appropriate bone marrow response, whereas a value of less than 2 indicates inadequate erythropoietic response 
  • Very low reticulocyte count in the context of severe anemia suggests aplastic anemia or pure red cell aplasia and need for bone marrow biopsy 
• Indicators of hemolysis
  • Low levels of haptoglobin are consistent with hemolysis
  • Serum levels of l-lactate dehydrogenase and indirect bilirubin may be elevated in hemolysis
  • In combination, elevated l-lactate dehydrogenase level and low haptoglobin level are 90% sensitive for the diagnosis of hemolysis 
• Urinalysis
  • Positive urine dipstick reaction for heme in the absence of RBCs suggests hemolysis; presence of RBCs may indicate iron deficiency due to blood loss and should prompt work-up of hematuria 
• Direct antiglobulin test (Coombs) 
  • Demonstrates presence of antibodies or complement on the surface of RBCs that is the hallmark of autoimmune hemolysis
    • Positive test result is indicated by binding of anti-IgG or anti-C3 antibodies to patient’s antibody- or complement-coated RBCs
    • 3 principal patterns of RBC sensitization may be detected, reflecting the likely type of autoimmune hemolytic anemia:
      • Anti-IgG–positive direct antiglobulin test result
        • Warm antibody autoimmune hemolytic anemia
        • Drug-induced hemolytic anemia
      • Anti-C3–positive direct antiglobulin test result
        • Cold agglutinin syndrome
        • Drug-induced hemolytic anemia
      • Anti-IgG plus anti-C3–positive direct antiglobulin test result
        • Mixed warm and cold antibody autoimmune hemolytic anemia
        • Warm antibody autoimmune hemolytic anemia
        • Drug-induced hemolytic anemia
• Hemoglobin electrophoresis
  • Used to confirm hemoglobinopathy; in normocytic anemias, most commonly sickle cell disease (homozygous) or a heterozygous combination of 2 abnormal genes (eg, hemoglobin sickle cell disease) 
• RBC enzyme levels
  • Assays are available for glucose-6-phosphate dehydrogenase and pyruvate kinase activity
  • Best time to test for enzyme defects is outside a period of active hemolysis
    • Enzyme production is greatest early in the life span of the cell, so it will be maximal in the setting of robust reticulocytosis (ie, after an episode of hemolysis); therefore, a so-called normal level in that context may not be a true reflection of patient’s steady state production 
• Osmotic fragility
  • Demonstrates increased susceptibility of RBCs to lysis in mildly hypotonic fluid; previously considered the gold standard for diagnosing hereditary spherocytosis 
• Flow cytometry
  • Used to detect specific cell parameters that have been associated with certain conditions (eg, hereditary spherocytosis, paroxysmal nocturnal hemoglobinuria, some primary bone marrow conditions)
• Iron studies 
  • Iron deficiency anemia: serum iron levels are low, ferritin level is low, and total iron binding capacity is high
  • Anemia of chronic disease (inflammation): serum iron is low, ferritin level is normal or elevated (greater than 12 ng/mL) and total iron binding capacity is normal or low
  • When iron deficiency occurs in the setting of an inflammatory state, serum ferritin levels may be misleadingly high, as ferritin is an acute phase reactant
• Folate and vitamin B₁₂/methylmalonic acid levels
  • Low levels are generally associated with macrocytic anemia, but anemia resulting from these deficiencies may be normocytic early in the course

Procedures

Bone marrow aspiration and biopsy

General explanation

• Usually performed under conscious (moderate) sedation and/or local anesthesia
• Hollow cutting needle is used to remove a core of bone containing bone marrow (for core biopsy) or to remove bone marrow fluid (for aspiration biopsy)
  • Aspiration and biopsy are usually performed at the same time
  • Aspiration provides sample of marrow cells
  • Biopsy provides marrow cells and cellular framework of marrow
• Typically performed on the iliac crest in adults (or rarely, the sternum) and the iliac crest, femur, or anterior tibia in children

Indication 

• Immature WBCs (blasts) or nucleated RBCs seen on peripheral smear
• Severe pancytopenia
• Very low reticulocyte count (less than 0.1%)
• Unexplained severe anemia
• Clinical concern for marrow infiltration

Contraindications

• Uncorrected coagulopathy
• Skin infection or recent radiation at or near puncture site
• Child weight less than 10 kg

Differential Diagnosis

Most common

• Because normocytic anemia is defined by laboratory parameters, differential diagnosis includes laboratory artifacts resulting in similar values
  • Multifactorial anemia
    • A combination of factors leading to both microcytic and macrocytic cells may result in a normal value on automated measurement of mean corpuscular volume
    • Reasons might include mixed causes (eg, deficiency of iron and folate) or microcytic anemia with robust reticulocytosis
    • High RBC distribution width provides a clue; microscopic examination of a peripheral blood smear can confirm disparity in cell size
  • Dilution
    • Large plasma volume relative to RBC mass may result in the appearance of anemia with normocytic indices
    • May occur in scenarios such as volume overload and pregnancy
    • Distinguished on the basis of clinical circumstances

Treatment Goals

• Restore reference hemoglobin levels and RBC mass
• Correct underlying cause if possible
• Prevent recurrence

Disposition

Admission criteria

Acute anemia due to severe blood loss requires admission to control bleeding and transfuse blood

Symptomatic anemia may require admission for transfusion and stabilization of complications (eg, heart failure)

Criteria for ICU admission

• Severe anemia precipitating cardiac ischemia or overwhelming hemolysis resulting in acute kidney failure may require ICU admission
• Patients with suspected or proven microangiopathic syndromes (eg, thrombotic thrombocytopenic purpura, hemolytic uremic syndrome)

Recommendations for specialist referral

• Consult a hematologist in the following situations:
  • Diagnosis is unclear
  • Bone marrow biopsy is indicated
  • Microangiopathic syndrome is suspected
  • To help manage chronic conditions (eg, hemoglobinopathies, enzyme defects, primary bone marrow disorders)
• Consult an infectious disease specialist to treat precipitating infections (eg, malaria, babesiosis, Clostridium perfringens)
• Consult the appropriate specialist for aid in ongoing management (eg, rheumatologist, nephrologist) for patients whose anemia is secondary to underlying systemic disorder

Treatment Options

General treatment principles

• Address the underlying cause, where possible, and provide supportive care 
• In symptomatic patients
  • Transfusion may be required regardless of underlying cause of anemia
  • Urgent transfusion may be required for patients with active bleeding, very brisk hemolysis, or an aplastic event
• In patients with obvious or occult bleeding
  • Identify and address source of bleeding to stem further loss and stabilize patient

Congenital hemolytic conditions

• Treatment focuses on avoidance of predictable triggers and provision of supportive measures; in some cases, more specific measures are available 
• Splenectomy may be considered in patients with severe anemia and/or symptomatic splenomegaly; disease-specific recommendations are available
  • Splenectomy is associated with lifelong increase in susceptibility to certain infections
  • It is preferable to postpone splenectomy until after age 6 years if clinically tolerable 
• Glucose-6-phosphatase dehydrogenase deficiency
  • A variety of drugs and foods can precipitate hemolysis, and avoidance of triggers is advised; lists of known triggers are available 
  • Of note, genetic heterogeneity of this enzyme deficiency results in different degrees of reaction to potential triggers (eg, ingestion of fava beans can cause severe hemolysis in some, but minimal or no reaction in others)
  • Supplemental folate is routinely given during periods of hemolysis 
• Sickle cell anemia
  • Hydroxyurea reduces the need for transfusions; stem cell transplant may be curative 

Acquired hemolysis

• Immune-mediated 
  • Warm autoimmune hemolytic anemia
    • Mainstay of treatment is suppression of immune response with corticosteroids or biologic agents (most commonly, rituximab)
      • Corticosteroids achieve a response in about 75% to 80% of patients, but duration of response is limited after discontinuation; follow-up maintenance doses or additional therapies are needed in most cases
      • Rituximab is associated with response rates of about 70% to 80%, and effect has lasted up to several years in some cases
      • Splenectomy may be appropriate if other measures are inadequate
        • Effective in about 70% of patients, with very long-standing results in a significant number of patients
      • Azathioprine, cyclophosphamide, or cyclosporine may be used as last resort
  • Cold autoimmune hemolytic anemia
    • Cold agglutinin disease caused by infection (eg, mycoplasma, Epstein-Barr virus) usually remits spontaneously
    • Cold agglutinin disease due to other conditions often requires only avoidance of cold temperatures; rituximab is pharmacotherapy of choice when indicated (eg, acrocyanosis, transfusion dependence)
• Microangiopathy
  • Treatment is complex and varies with the specific diagnosis; treatable precipitating causes should be addressed and appropriate specialty consultation urgently sought for definitive management 
    • Thrombotic thrombocytopenic purpura
    • Hemolytic uremic syndrome: intensive supportive care including transfusions, careful management of fluids and blood pressure, and hemodialysis if necessary (Related: Acute kidney injury)
    • Disseminated intravascular coagulation: transfusion of platelets and clotting factors as needed
• Paroxysmal nocturnal hemoglobinuria
  • Eculizumab (a monoclonal antibody that blocks the complement-mediated hemolysis in paroxysmal nocturnal hemoglobinuria) has been effective in reducing hemolysis, stabilizing hemoglobin, and reducing thrombotic events 
• Other causes of acquired hemolysis
  • Require condition-specific treatment (eg, parasitic or bacterial infections, toxins)

Primary hypoproliferative (bone marrow) disorders

• General treatment of anemia due to these conditions requires both:
  • Disease-specific therapy (often guided by presence of certain biomarkers), and
  • Supportive measures (eg, nutritional supplementation to assure adequate stores for hematopoiesis, transfusion when other measures are ineffective and patient is symptomatic)
• Transient erythroblastopenia of childhood
  • Usually resolves spontaneously within a few weeks without transfusion; there is no specific therapy 

Secondary hypoproliferative anemias

• Anemia of inflammation (characterized by relative resistance to erythropoietin) 
  • Effective treatment of the underlying disease often allows gradual resolution of anemia
  • Direct treatment for symptomatic anemia may be necessary when underlying clinical condition is not reversible
    • Treatment may include transfusions or erythropoietin-stimulating agents (used off label) with or without iron supplementation 
• Secondary anemia (characterized by inadequate production of erythropoietin [eg, hypothyroidism, adrenal or pituitary insufficiency, chronic liver or kidney disease])
  • Treatment hinges on optimal therapy of the underlying condition
  • Guidelines for these diseases do not specifically address management of anemia, with the exception of chronic kidney disease
• Anemia in chronic kidney disease
  • Several organizations offer guidelines for management
    • KDIGO guidelines (Kidney Disease: Improving Global Outcomes) suggest initiating erythropoietin-stimulating agents when hemoglobin level is between 9 and 10 g/dL to maintain maintenance goal hemoglobin of 10 to 11.5 g/dL (11 to 12 g/dL in pediatric patients) 
    • National Institute for Health and Care Excellence guidelines recommend erythropoietin-stimulating agents to keep hemoglobin levels between 10 and 12 g/dL (9.5 and 11.5 g/dL for children younger than 2 years) 
    • Both recommend ensuring adequate iron stores 
    • A Cochrane review supports use of erythropoietin-stimulating agents in predialysis (as well as dialysis) patients, finding evidence that these agents correct anemia, reduce transfusion needs, and improve exercise capacity and quality of life 

Nutritional deficiencies

• Replace deficiencies of iron, folate, and/or vitamin B₁₂ when indicated

Drug therapy

• Corticosteroids
  • For autoimmune hemolytic anemia
    • Prednisone Oral tablet; Adults: Titrate to response. Usual starting dose 1 mg/kg PO once daily. 
• Ribonucleotide reductase inhibitor
  • For sickle cell disease:
  • Hydroxyurea
    • Siklos formulation (tablet)
      • Hydroxyurea Oral tablet; Children and Adolescents 2 to 17 years: 20 mg/kg/dose PO once daily initially; increase by 5 mg/kg/day every 8 weeks or if a painful crisis occurs until a maximum tolerated dose or 35 mg/kg/day is reached. Use actual or ideal body weight (whichever is less) and calculate the rounded dose to the nearest 50- or 100-mg strength. Therapy interruption, dosage reduction, or discontinuation may be necessary in patients who develop myelosuppression. Prophylactic administration of folic acid is recommended.
    • Droxia formulation (capsule)
      • Hydroxyurea Oral capsule; Adults: 15 mg/kg/dose PO once daily initially; increase by 5 mg/kg/day every 12 weeks until a maximum tolerated dose or 35 mg/kg/day is reached. Use actual or ideal body weight (whichever is less) for dosing. Therapy interruption, dosage reduction, or discontinuation may be necessary in patients who develop myelosuppression. Prophylactic administration of folic acid is recommended.
• Monoclonal antibodies
  • For autoimmune hemolytic anemia:
    • Rituximab
      • Rituximab (Murine) Solution for injection; Adults: 375 mg/m2 IV weekly x4 weeks produced a response rate of 71%.
  • For paroxysmal nocturnal hemoglobinuria:
    • Eculizumab
      • Eculizumab Solution for injection; Adults: 600 mg IV infusion every 7 days for 4 weeks; give 900 mg IV infusion 7 days after fourth dose; then give 900 mg IV infusion every 14 days. Studies of up to 64 weeks in duration indicate a stabilization of hemoglobin and reduction in blood transfusions. If not already vaccinated, vaccinate against N. meningitidis at least 2 weeks prior to treatment initiation.
• Erythropoietin-stimulating agents
  • For anemia of chronic kidney disease:
  • Epoetin alfa
    • Epoetin Alfa (Hamster) Solution for injection; Infants, Children, and Adolescents 1 month to 16 years: 50 units/kg/dose IV or subcutaneously 3 times weekly; use IV for patients on dialysis. Initiate treatment when hemoglobin (Hgb) is less than 10 g/dL; if Hgb approaches or exceeds 12 g/dL, reduce or interrupt the dose. If Hgb rises more than 1 g/dL in any 2-week period, reduce dose by 25% or more as needed to reduce rapid response. If Hgb has not increased more than 1 g/dL after 4 weeks, increase dose by 25%. Do not increase the dose more frequently than once every 4 weeks; decreases can occur more frequently.
    • Epoetin Alfa (Hamster) Solution for injection; Adolescents 17 years: 50 to 100 units/kg/dose IV or subcutaneously 3 times weekly; use IV for patients on dialysis. For patients on dialysis, initiate when hemoglobin (Hgb) is less than 10 g/dL; if Hgb approaches or exceeds 11 g/dL, reduce or interrupt the dose. For patients not on dialysis, consider initiating only when Hgb is less than 10 g/dL and rate of Hgb decline indicates likelihood of requiring RBC transfusion and reducing risk of alloimmunization and/or other RBC transfusion-related risks is a goal. If Hgb is more than 10 g/dL, reduce or interrupt treatment; use lowest dose sufficient to reduce need for RBC transfusions. If Hgb rises more than 1 g/dL in any 2-week period, reduce dose by 25% or more as needed to reduce rapid response. If Hgb has not increased more than 1 g/dL after 4 weeks, increase dose by 25%. Do not increase the dose more frequently than once every 4 weeks; decreases can occur more frequently.
    • Epoetin Alfa (Hamster) Solution for injection; Adults: 50 to 100 units/kg/dose IV or subcutaneously 3 times weekly; use IV for patients on dialysis. For patients on dialysis, initiate when hemoglobin (Hgb) is less than 10 g/dL; if Hgb approaches or exceeds 11 g/dL, reduce or interrupt the dose. For patients not on dialysis, consider initiating only when Hgb is less than 10 g/dL and rate of Hgb decline indicates likelihood of requiring RBC transfusion and reducing risk of alloimmunization and/or other RBC transfusion-related risks is a goal. If Hgb more than 10 g/dL, reduce or interrupt treatment; use lowest dose sufficient to reduce need for RBC transfusions. If Hgb rises more than 1 g/dL in any 2-week period, reduce dose by 25% or more as needed to reduce rapid response. If Hgb has not increased more than 1 g/dL after 4 weeks, increase dose by 25%. Do not increase the dose more frequently than once every 4 weeks; decreases can occur more frequently.
  • Darbepoetin alfa
    • For patients on hemodialysis
      • Darbepoetin Alfa (Hamster) Solution for injection; Children and Adolescents on hemodialysis: Initially, 0.45 mcg/kg/week subcutaneously or IV; IV route is recommended with hemodialysis. Initiate when Hgb is less than 10 g/dL. If Hgb concentration approaches or exceeds 12 g/dL, reduce or interrupt treatment. If the Hgb rises more than 1 g/dL in any 2-week period, reduce dose by 25% or more as needed to reduce rapid responses. If the Hgb has not increased more than 1 g/dL after 4 weeks, increase dose by 25%. Use lowest dose that will maintain Hgb concentration sufficient to reduce need for RBC transfusions.
      • Darbepoetin Alfa (Hamster) Solution for injection; Adults on hemodialysis: Initially, 0.45 mcg/kg/week subcutaneously or IV or 0.75 mcg/kg IV or subcutaneously once every 2 weeks as appropriate; IV route is recommended with hemodialysis. Initiate when Hgb is less than 10 g/dL. If Hgb concentration approaches or exceeds 11 g/dL, reduce or interrupt treatment. If the Hgb rises more than 1 g/dL in any 2-week period, reduce dose by 25% or more as needed to reduce rapid responses. If the Hgb has not increased more than 1 g/dL after 4 weeks, increase dose by 25%. Use lowest dose that will maintain Hgb concentration sufficient to reduce need for RBC transfusions.
    • For Patients not on hemodialysis
      • Darbepoetin Alfa (Hamster) Solution for injection; Children and Adolescents not on hemodialysis: Initially, 0.45 mcg/kg/week subcutaneously or IV or 0.75 mcg/kg subcutaneously or IV once every 2 weeks as appropriate. Initiate when Hgb is less than 10 g/dL. If Hgb concentration approaches or exceeds 12 g/dL, reduce or interrupt treatment. If the Hgb rises more than 1 g/dL in any 2-week period, reduce dose by 25% or more as needed to reduce rapid responses. If the Hgb has not increased more than 1 g/dL after 4 weeks, increase dose by 25%. Use lowest dose that will maintain Hgb concentration sufficient to reduce need for RBC transfusions.
      • Darbepoetin Alfa (Hamster) Solution for injection; Adults not on hemodialysis: Initially, 0.45 mcg/kg IV or subcutaneously once every 4 weeks as appropriate. Consider initiating only when Hgb is less than 10 g/dL and the rate of Hgb decline indicates the likelihood of requiring a RBC transfusion and reducing the risk of alloimmunization and/or other RBC transfusion-related risks is a goal. If Hgb is more than 10 g/dL, reduce or interrupt treatment, and use the lowest dose sufficient to reduce the need for RBC transfusions. If Hgb rises more than 1 g/dL in any 2-week period, reduce dose by 25% or more as needed to reduce rapid responses. If Hgb has not increased more than 1 g/dL after 4 weeks, increase dose by 25%. Use lowest dose that will maintain Hgb concentration sufficient to reduce the need for RBC transfusions.
• Hematinic agents
  • Iron
    • Oral
    • Iron Oral solution; Term Neonates, Infants, and Children: 3 to 6 mg elemental iron/kg/day PO (divided into 1 to 3 doses/day) for 4 weeks; 60 mg/day PO has been recommended for school aged children. Repeat anemia screening; an increase in hemoglobin of 1 g/dL or more or an increase in hematocrit of 3% or more confirms the diagnosis. If diagnosis is confirmed, continue treatment for 2 to 3 more months then repeat anemia screening. Smaller dosages may be used but correction will occur at a slower rate.
    • Iron Oral tablet; Adults and Adolescents: 60 mg elemental iron PO 1 to 3 times daily for 4 weeks. Repeat anemia screening; an increase in hemoglobin of 1 g/dL or more or an increase in hematocrit of 3% or more confirms the diagnosis. If diagnosis is confirmed, continue treatment for 2 to 3 more months then repeat anemia screening. Smaller dosages may be used, but correction will occur at a slower rate.
    • Parenteral
      • For the treatment of iron-deficiency anemia in patients with chronic kidney disease
      • Iron Sucrose Solution for injection; Children and Adolescents 2 to 17 years: Dosing for iron replacement treatment not established. For iron maintenance treatment, 0.5 mg/kg/dose IV every 4 weeks (Max: 100 mg/dose) for 12 weeks. Administer by slow IV injection (undiluted) over 5 minutes or diluted in 0.9% Sodium Chloride Injection at a concentration of 1 to 2 mg/mL and administered over 5 to 60 minutes. Repeat if necessary.
      • Iron Sucrose Solution for injection; Adults: 200 mg IV undiluted by slow injection over 2 to 5 minutes or diluted in up to 100 mL of 0.9% Sodium Chloride Injection over 15 minutes, given 5 times within 2 weeks (total dose: 1,000 mg). Limited experience with 500 mg in 250 mL of 0.9% Sodium Chloride Injection given as an IV infusion over 3.5 to 4 hours on day 1 and day 14; also has been administered as 500 mg by IV infusion over 3 hours on 2 consecutive days. May repeat if iron deficiency recurs.
  • Folate
    • Folic Acid Oral tablet; Adults, Adolescents, and Children > = 11 years: 1 mg PO, subcutaneously, or IM once daily. The maintenance dose is 0.4 mg PO once daily.
  • Vitamin B₁₂
    • Vitamin B12 (Cyanocobalamin) Solution for injection; Adults: 1,000 mcg IM given daily or every other day for 1 week, then weekly for 4 to 8 weeks, then monthly until recovery is usual dosage; FDA-approved dosage is 100 mcg IM/subcutaneously once daily for 6 or 7 days; after clinical improvement and if reticulocyte response seen, give 100 mcg IM/subcutaneously on alternate days for 7 doses, then every 3 to 4 days for another 2 to 3 weeks, then 100 mcg IM/subcutaneously monthly. Administer with folic acid, if needed.

Nondrug and supportive care

Transfusion

• Indications are highly individualized based on age, symptom severity, and comorbidities 
• In general, transfusion can be considered at a hemoglobin level of 7 g/dL or less, with a posttransfusion goal of 7 to 9 g/dL 
• In patients with cardiac disease, especially if they are experiencing cardiac symptoms (eg, chest pain, congestive heart failure, tachycardia or hypotension despite fluid replacement), transfusion should be considered at a threshold of 8 g/dL 
• Conversely, otherwise healthy patients who are relatively asymptomatic may not require transfusion at a threshold of 7 g/dL if the underlying cause can be addressed promptly
• Use of leukocyte-depleted RBCs is preferred in patients with autoimmune hemolytic anemia 

Procedures

Splenectomy

General explanation

• Surgical removal of spleen; typically performed laparoscopically
• Decision to remove spleen must be balanced with increased risk of thrombosis and bacterial infection leading to sepsis

Indication

• Hemolytic anemia refractory to other measures and associated with symptomatic hemolytic events, transfusion dependence, or marked splenic enlargement

Contraindications

• Uncontrollable coagulopathy

Complications

• Lifelong increase in susceptibility to certain infections; immunization against pneumococcal, Haemophilus species, and meningococcal infections is recommended (preferably preoperatively) with booster doses as recommended by guidelines 
• Increased risk for thrombosis, especially in the splenic and portal veins; there are no uniform recommendations for prophylactic anticoagulation or ultrasonographic surveillance 

Comorbidities

• Preexisting cardiovascular conditions (eg, heart failure, coronary heart disease, hypertension, stroke) are exacerbated by anemia; higher transfusion thresholds are recommended 

Monitoring

• KDIGO guidelines recommend the following schedule for monitoring hemoglobin levels in anemic patients with chronic kidney disease: 
  • For patients with anemia who are not being treated with an erythropoietin-stimulating agent:
    • Every 3 months for stages 3 to 5 chronic kidney disease not treated by dialysis and stage 5 disease treated with peritoneal dialysis
    • Monthly levels are recommended for patients with stage 5 disease treated with hemodialysis
  • For patients treated with an erythropoietin stimulating agent:
    • Monthly during initiation
    • Thereafter, every 3 months for nondialysis patients and monthly for dialysis recipients
• Specific monitoring schedules have not been defined for other conditions

Complications

• Potential complications are wide ranging depending on the underlying causes
  • Acute blood loss anemia may result in multiorgan damage owing to poor perfusion
  • High output congestive heart failure
    • May result from moderately severe anemia in patients with impaired cardiac compensatory mechanisms (eg, coronary artery disease) and markedly severe anemia in otherwise healthy patients (eg, children)
    • Secondary events such as acute coronary syndrome and arrhythmia may occur
  • Hemolytic anemias
    • Increased thrombosis risk in some hemolytic anemias (especially paroxysmal hemoglobinuria); splenectomy further increases risk
    • Gallstones are a common complication of hemolytic anemias
    • Paroxysmal nocturnal hemoglobinopathy may progress to (or be associated with) bone marrow failure
    • Microangiopathic syndromes (eg, thrombotic thrombocytopenic purpura, hemolytic uremic syndrome) may have catastrophic complications, including acute kidney failure, hemorrhage, and death
  • Primary hypoproliferative disorders
    • Possible complications
      • Permanent loss of hematopoietic ability (eg, transfusion dependence)
      • Effects of cytopenias in other cell lines (eg, coagulopathy due to thrombocytopenia, increased risk of infection due to leucopenia)
      • Malignant transformation

Prognosis

• Prognosis varies widely depending on cause
• In older adults, normocytic anemia is associated with loss of independence and a trend to lower survival; in hospitalized patients, it is a risk factor for hospital readmission and higher 3-month mortality 
• In general, untreated anemia of any type (not limited to normocytic indices) may increase morbidity and mortality for older adults and those with chronic disease (eg, heart failure, chronic kidney disease)

Screening

At-risk populations

• Neonates
  • Screening for sickle cell disease is recommended for all neonates in the United States 
• Children
  • American Academy of Pediatrics recommends screening at age 12 months, with additional screening earlier (eg, age 4 months) or later as clinically indicated for children at high risk for anemia 
• Patients with chronic kidney disease
  • KDIGO guidelines recommend screening for anemia; frequency depends on stage of disease and whether patient is on dialysis 

Screening tests

• Newborn screening programs screen for sickle cell hemoglobin with isoelectric focusing or high-performance liquid chromatography, and a positive result is confirmed by a second complementary technique (Related: Sickle cell disease)
• Serum hemoglobin level is the recommended test to screen for anemia 

Prevention

• Hemolytic disease of the newborn
  • Can be prevented by prenatal ABO and Rh blood typing with isoimmune antibody testing; then, if indicated, administer Rho(D) immunoglobulin
• Hemolytic disease 
  • Hemolytic events and resulting anemia may be preventable when triggers can be identified and avoided

Sources

Kujovich JL: Evaluation of anemia. Obstet Gynecol Clin North Am. 43(2):247-64, 2016 Reference