REFERRAL

A referral to a hematologist is generally not required for treatment of iron deficiency unless the diagnosis is uncertain or there are complicating factors to standard treatment.

Thalassemia

GENERAL PRINCIPLES

• The thalassemia syndromes are autosomal recessive disorders characterized by reduced Hgb synthesis associated with mutations in the α- or β-chain of the molecule. They are among the most common genetic abnormalities.⁶
  
• Beta-thalassemia results in a decreased production of β-globin and an excess of α-globin, forming insoluble alpha tetramers, which are toxic to the cell.
  
• Alpha-thalassemia is due to deletion of one or more of the four α-globin genes leading to a β-globin gene excess, which is relatively less toxic.
  
• It is important to differentiate iron deficiency anemia from thalassemia.

Classification

• Beta-thalassemia:
  
  
  
  • Thalassemia minor (trait) occurs with one gene abnormality with variable amounts of β-chain underproduction. Patients are asymptomatic and present with microcytic, hypochromic erythrocytes and Hgb levels typically >10 g/dL.
    
  • Thalassemia intermedia occurs with dysfunction in both β-globin genes, characterized by a later clinical onset and milder anemia, which can require transfusions.
    
  • Thalassemia major (Cooley anemia) is caused by severe abnormalities of both genes and requires lifelong transfusion support unless the patient underwent successful stem cell transplantation in childhood.
  
  
• Alpha-thalassemia:
  
  
  
  • Alpha-thalassemia minima occurs with the deletion of one of four α-globin genes. Patients are not anemic and typically have normal MCV and Hgb electrophoresis.
    
  • Alpha-thalassemia minor clinically resembles beta-thalassemia minor; however, the Hgb electrophoresis pattern is normal.
    
  • Hemoglobin H disease is evident at birth and is characterized by moderate anemia predominantly due to chronic hemolysis, microcytosis, and 5% to 30% hemoglobin H. Oxidant drugs similar to those that exacerbate glucose-6-phosphate dehydrogenase deficiency should be avoided as they may increase hemolysis.

DIAGNOSIS

Clinical Presentation

History

• Mild thalassemia patients are typically asymptomatic and not transfusion dependent.
  
• Patients report a family or personal history of microcytic anemia not responsive to iron therapy.
  
• Patients with severe forms of thalassemia such as Cooley’s anemia, many with thalassemia intermedia, and some with hemoglobin H may develop complications of chronic iron overload (e.g., cardiac, hepatic, or endocrine dysfunction).

Physical Examination

• Signs of hemolysis, including jaundice, hepatosplenomegaly, and leg ulcers, should be noted.
  
• Examine for signs of extramedullary hematopoiesis, (e.g., splenomegaly, mandibular enlargement, and other skeletal deformities).

Diagnostic Testing

• Typically thalassemia trait results in an MCV <75 fL but Hct >30%.
  
• Iron studies including serum ferritin level are obtained to initially evaluate microcytosis as well as periodically check for iron overload in patients with moderate-to-severe disease.
  
• Hemoglobin analysis by electrophoresis or high-pressure liquid chromatography establishes the diagnosis and severity of beta-thalassemia. Analysis will be normal in α-thalassemia because α chains are equally distributed among Hgb A, A2, and F.
  
  
  
  • Normally, Hgb A accounts for 96.5% to 98.5% of hemoglobin, Hgb A2 1.5% to 3.5%, and Hgb F <1.0%.
    
  • In β-thalassemia trait, Hgb A2 and F are increased. Low Hgb A fractions and elevated Hgb F are found in severe disease.
    
  • If α-thalassemia is suspected, α-globin gene deletion testing is confirmatory in the majority of cases.
    
  • Analysis may also reveal abnormal hemoglobin types, such as S, C, or M.
    
  • Ideally, the patient will not have had a blood transfusion in the 3 months before the test. Iron deficiency can falsely lower the Hgb A2 level.

TREATMENT

• Thalassemia trait requires no specific treatment. In patients with severe forms of the disease, red blood cell transfusions to maintain Hgb at 9 to 10 g/dL are needed to prevent the skeletal deformities that result from accelerated erythropoiesis.
  
• Transfusion-dependent anemia often results in iron overload. Chelation therapy with deferasirox 20 to 30 mg/kg PO daily is indicated to prevent hepatic, cardiac, and endocrine damage.⁷ Chelation therapy should be continued with a target ferritin <1,000 mcg/L. Adverse effects of deferasirox include mild-to-moderate GI disturbances and skin rash.

Surgical Management

Splenectomy is indicated when there is a marked increase in transfusion requirements over the course of several months to a year. The benefit is typically transient, and splenectomy confers a higher risk of arterial and venous thrombosis as well as sepsis.

REFERRAL

Patients transitioning from pediatric care to adult care with moderate-to-severe forms of thalassemia should be referred to a hematologist.

PATIENT EDUCATION

• Educate patients that their condition may commonly be mistaken for iron deficiency and to avoid iron replacement therapy, unless the treating physician is aware they also have thalassemia.
  
• Patients should be offered genetic counseling.
  
• Patients may be directed to the Cooley’s Anemia Foundation website, http:\\www.thalassemia.org (last accessed December 22, 2014).

MACROCYTIC ANEMIA

GENERAL PRINCIPLES

• May be an isolated abnormality or may accompany other cytopenias.
  
• The etiology can be determined in almost all cases with a thorough investigation.
  
• Elderly patients with vitamin B₁₂ deficiency may present with subtle symptoms and a mild normocytic anemia.
  
• By definition, the MCV is >100 fL.
  
• An elevated MCV may be classified as megaloblastic, nonmegaloblastic, or false positive.
  
• Megaloblastic anemia is a term used to describe disorders of impaired DNA synthesis in hematopoietic cells that affect all proliferating cells.

Etiology

Megaloblastic

• Folate deficiency arises from a negative folate balance due to malnutrition, malabsorption, or increased requirement secondary to pregnancy or hemolytic anemia.
  
• Patients on long-term diets, alcoholics, elderly, and psychiatric patients are particularly at risk for nutritional folate deficiency.
  
• Pregnancy and lactation require higher (three- to fourfold) daily folate needs and are commonly associated with megaloblastic changes in maternal hematopoietic cells, leading to a dimorphic (combined folate and iron deficiency) anemia.
  
• Folate malabsorption may occur in celiac disease.
  
• Drugs that can interfere with folate absorption include ethanol, trimethoprim, pyrimethamine, diphenylhydantoin, barbiturates, and sulfasalazine.
  
• Patients who are undergoing dialysis require increased folate intake because of folate losses.
  
• Patients with hemolytic anemia, particularly sickle cell anemia, require increased folate for accelerated erythropoiesis and can present with aplastic crisis (rapidly falling erythrocyte counts) with folate deficiency.
  
• Vitamin B₁₂ deficiency occurs insidiously over ≥3 years, due the relatively small daily B₁₂ requirement (1 to 3 mcg) compared with larger total body stores (1 to 3 mg).
  
• In nonvegan adults, vitamin B₁₂ deficiency is almost always due to malabsorption.⁸
  
• Causes of vitamin B₁₂ deficiency include partial gastrectomy (up to 20% of patients within 8 years of surgery) or total gastrectomy and pernicious anemia (PA). Older patients with gastric atrophy may develop a vitamin B₁₂ deficiency due to impaired absorption.
  
• PA occurs in individuals who are >40 years (mean age of onset is 60 years). Up to 30% of patients have a positive family history. PA is associated with other autoimmune disorders (Graves disease [30%], Hashimoto thyroiditis [11%], and Addison disease [5% to 10%]). Of patients with PA, 90% have antiparietal cell IgG antibodies and 60% have anti-intrinsic factor antibodies.
  
• Neurologic complications may occur even in the absence of anemia and may not fully resolve despite adequate treatment.

Nonmegaloblastic

• Reticulocytosis in response to peripheral red blood cell destruction or loss causes nonmegaloblastic macrocytic anemia given that reticulocytes are larger than mature red cells.
  
• Ethanol, medications (antiretrovirals, anticonvulsants, antifolates, chemotherapeutics, metformin, and cholestyramine), myelodysplasia, hypothyroidism, liver disease, hemolysis, hemorrhage, chronic obstructive pulmonary disease (COPD), and splenectomy account for most nonmegaloblastic macrocytosis.
  
• Cold agglutination, severe hyperglycemia, and marked leukocytosis may spuriously elevate the MCV.

DIAGNOSIS

Clinical Presentation

History

• Obtaining a targeted history to identify the abovementioned risk factors and causative agents is critical.
  
• Anemia may be the only overt sign of ethanol abuse and should prompt screening with a validated questionnaire.
  
• Folate-deficient patients present with sleep deprivation, fatigue, and manifestations of depression, irritability, or forgetfulness.
  
• When anemia due to vitamin B₁₂ deficiency is clinically present, neurologic manifestations including peripheral neuropathy, paresthesias, lethargy, hypotonia, and seizures are also likely.

Physical Examination

• Physical examination may reveal poor nutrition, pigmentation of skin creases and nail beds, or glossitis.
  
• Jaundice or splenomegaly may indicate ineffective and extramedullary hematopoiesis.
  
• Vitamin B₁₂ deficiency may cause decreased vibratory and positional sense, ataxia, paresthesias, confusion, and dementia.

Diagnostic Testing

• The initial workup includes CBC, reticulocyte index, peripheral smear, and vitamin B₁₂ level.
  
• MCV >110 fL is more specific for megaloblastic anemia, but may be found in MDS as it reflects disordered hematopoiesis.
  
• The peripheral smear may show megaloblastic changes such as anisocytosis, poikilocytosis, and macroovalocytes; hypersegmented neutrophils (containing ≥5 nuclear lobes) are common. Dimorphic red cells indicate combined microcytic and macrocytic processes.
  
• If the peripheral smear is normal, consider adding thyroid and hepatic function panels to the initial laboratory work up.
  
• If the reticulocyte index is elevated, investigate for hemolysis.
  
• If the reticulocyte index is not elevated and
  
  
  
  • The vitamin B₁₂ level is <100 pg/mL, there is vitamin B₁₂ deficiency.
    
  • The vitamin B₁₂ level is between 100 and 400 pg/mL, order serum methylmalonic acid (MMA) and homocysteine levels.
    
    
    
    • If the MMA is elevated, vitamin B₁₂ deficiency is present.
      
    • If the MMA level is normal but homocysteine is elevated, folate deficiency is present.⁹
    
    
  • The vitamin B₁₂ level is >400 pg/mL, check serum folate concentration. If folate is low, folate deficiency is present.
  
  
• BM biopsy may be necessary in the case of normal MMA, homocysteine, and folate levels to rule out an MDS.

TREATMENT

• Potassium monitoring and supplementation may be necessary when treatment is initiated to avoid complications of hypokalemia induced by enhanced hematopoiesis.
  
• Reticulocytosis should begin within 1 week of therapy, followed by a rising Hgb over 6 to 8 weeks.
  
• In one-third of patients, coexisting iron deficiency is present at diagnosis or develops during therapy and is a common cause for an incomplete response to repletion.¹⁰
  
• Folic acid, 1 mg PO daily, is given until the deficiency is corrected. High doses of folic acid (up to 5 mg PO daily) may be needed in patients with malabsorption syndromes.
  
• Vitamin B₁₂ deficiency is corrected by administering cyanocobalamin. High-dose enteral replacement may be considered in highly motivated patients; however, the risk of relapse is higher than with parenteral therapy if treatment is discontinued prematurely.¹¹
  
  
  
  • IM replacement is given daily for 1 week, then 1 mg/week for 4 weeks and then 1 mg/month for life. Monthly IM administration is approximately as cost-effective as enteral replacement.
    
  • Oral tablets or syrup, 50 to 1,000 mcg/day, may be given for maintenance indefinitely depending on the underlying cause.
    
  • Cyanocobalamin nasal spray (i.e., Nascobal) is approved for patients who have been repleted with intramuscular injections and have no nervous system involvement. It may be suitable for maintenance in those with malabsorption.
  
  
• Monitoring of red cell indices may confirm the diagnosis of vitamin B₁₂ deficiency if there is a complete response.

MYELODYSPLASTIC SYNDROME

GENERAL PRINCIPLES

• Myelodysplastic syndrome (MDS) is a heterogeneous group of acquired, clonal disorders characterized by disordered hematopoiesis and potential transformation to acute myelogenous leukemia (AML) or pancytopenia.
  
• The natural history is variable, and mortality secondary to bone marrow failure is higher than with AML.¹²
  
• MDS should be strongly considered in the differential diagnosis of anemia in the elderly.

Classification

• There are several classifications; however, the most commonly used is the WHO, which lists the following subgroups based on cytopenia, percentage of bone marrow blasts, and cytogenetics:
  
  
  
  • Refractory anemia
    
  • Refractory anemia with ringed sideroblasts
    
  • Refractory anemia with excess blasts
    
  • 5q− syndrome
    
  • Chronic myelomonocytic leukemia¹³
  
  
• The International Prognostic Scoring System (IPSS) and its revision (IPSS-R) are most commonly used to stratify patients based on survival and risk of transformation to AML.¹⁴

Epidemiology

• The incidence of MDS increases from approximately 1:100,000 persons between 45 and 49 years old to 49.7 cases per 100,000 persons over the age of 85.¹⁵ The vast majority of cases occur in individuals over the age of 60.
  
• Approximately 10% of anemia cases in the elderly are proven to be MDS, and it is the suspected diagnosis in as many as 16%.¹⁶

Risk Factors

• Most cases of MDS are idiopathic.
  
• Risk factors include some congenital diseases, ionizing radiation, prior chemotherapy, and exposure to benzene, which is commonly found in cigarette smoke.¹⁵

DIAGNOSIS

Clinical Presentation

• MDS may be asymptomatic and detected on laboratory analysis. Fatigue, easy bruising, or recurrent infections are common presenting complaints. Obtain a history of blood product transfusions and episodes of bleeding.
  
• Examining the skin may yield signs of thrombocytopenia and infection. Dermatosis (Sweet syndrome) or chloromas (dermal extramedullary leukemic cell accumulations) should prompt timely referral as they may signal malignant transformation.
  
• Scleral icterus may indicate hemolysis.

Diagnostic Testing

Laboratories

• CBC with reticulocyte count and peripheral smear. Anemia is usually present, and the MCV is typically elevated but may be normal or even low. The reticulocyte count is inappropriately low. Some patients present with leukopenia or thrombocytopenia or both. Rarely, thrombocytosis is present, and the hematologist may test for a JAK2 mutation. The peripheral smear may reveal dysplastic neutrophils, macrocytic erythrocytes, evidence of dysfunctional erythropoiesis, and normal platelets. The CBC may be initially repeated monthly to evaluate the progression of disease and less frequently thereafter.
  
• HIV serology, vitamin B₁₂ profiles, serum folate, copper, ferritin, and iron studies are part of the routine initial evaluation of all patients. The hematologist may request HLA typing if the patient has had many transfusions or is a candidate for stem cell transplant.

Diagnostic Procedures

BM biopsy and aspirate are performed by the hematologist to diagnose and classify MDS.

TREATMENT

• Supportive treatment:
  
  
  
  • Scheduled or unscheduled transfusions of red blood cells or platelets.
    
  • Vaccinate for pneumococcal pneumonia, Haemophilus influenzae serotype b, seasonal influenza, and pertussis.
    
  • Providers should have an elevated index of suspicion for infections and pursue early treatment.
  
  
• Chemotherapeutics:
  
  
  
  • Treatment options include DNA hypomethylating agents (i.e., azacitidine), immunosuppressants, and lenalidomide. Lenalidomide is approved for 5q− syndrome and has about a 50% chance of inducing transfusion independence.¹⁷ The hematologist may also use granulocyte colony–stimulating factors. Younger patients with otherwise good health may benefit from higher-intensity regimens including stem cell transplant.
    
  • Referral to an academic center for clinical trial enrollment is encouraged, especially in those with refractory or recurrent disease.
  
  
• Hematopoietic stem cell transplantation:
  
  
  
  • This is the only treatment capable of cure and requires careful discussion between the patient, primary care physician, and hematologist. Comorbidities, goals of care, support structure, age of the patient, and the high morbidity and mortality of the procedure play important roles in this discussion.
    
  • Early referral to a tertiary center with a stem cell transplant program is ideal because the preliminary evaluation for transplant can be time consuming.
  
  
• Treatment of the elderly:
  
  
  
  • This group often has many comorbidities and poor prognostic indicators and may not be candidates for intensive therapy.
    
  • Trials of dose-reduced oral agents have found improved outcomes with a favorable toxicity profile in this demographic.¹⁸

REFERRAL

Referral to a hematologist once the diagnosis is suspected is recommended for definitive diagnosis, risk stratification, and treatment. If there are intermediate- or high-risk features, early referral for hematopoietic stem cell transplantation evaluation is appropriate.

PATIENT EDUCATION

Patients may be directed to the MDS Foundation, http:\\www.MDS-Foundation.org (last accessed December 22, 2014).

NORMOCYTIC ANEMIA

The causes of normocytic anemia include acute blood loss; malignancy (Chapter 35); BM infiltration; anemia of chronic disease (ACD), rheumatologic conditions, and chronic infection; and anemia of chronic renal insufficiency (Chapter 24).

Anemia of Chronic Disease

GENERAL PRINCIPLES

• Develops in patients with chronic inflammation due to malignancy, autoimmune disorders, and chronic infection.
  
• The etiology is multifactorial: defective iron mobilization due to increased levels of hepcidin, inflammatory cytokine-mediated suppression of erythropoiesis, and impaired endogenous erythropoietin (EPO) production.¹⁹
  
• Iron may inadequately mobilize in times of brisk of hematopoiesis in response to exogenous EPO.
  
• Anemia is thought to be a marker of the severity of the provocative disease.

DIAGNOSIS

• Measurement of serum hepcidin may become a diagnostic tool; however, this test is not yet widely available.²⁰
  
• Mild-to-moderate normocytic, normochromic anemia is typical in ACD, but may be severe (Hgb <8 g/dL).
  
• Iron studies may reveal a low serum iron and low TIBC.
  
• Ferritin level <30 ng/dL indicates coexisting iron deficiency. If the ferritin is indeterminate, measuring soluble transferrin receptor (sTfR) can aid in identifying iron deficiency in the setting of ACD.

TREATMENT

• Treatment of the underlying disease process will improve ACD.
  
• Assess for iron deficiency and treat with intravenous iron. IV iron is preferred to enteral iron in ACD because of the poor enteral absorption during inflammatory states. Note that IV iron should not be given if active infection is suspected.
  
• Consider using an erythropoietin-stimulating agent (ESA) if the above strategies do not improve the anemia. Hgb should not be treated to levels >12 g/dL with ESA therapy due to the risk of cardiovascular events.²¹
  
• If there is a suboptimal (<1 g/dL) increase in hemoglobin 2 weeks after administration of ESA, reevaluate iron stores.
  
• Transfusion guidelines are patient specific:
  
  
  
  • Asymptomatic patients with Hgb <7 g/dL
    
  • Stable coronary artery disease with Hgb <8 g/dL
    
  • Symptomatic patients with Hgb <10 g/dL³

Aplastic Anemia

Aplastic anemia (AA) is an acquired immune-mediated disorder of hematopoietic stem cells, presenting in people of all ages as pancytopenia. Most cases are idiopathic in adults. AA must be differentiated from B₁₂ deficiency, MDS, or other BM failure syndromes. Initial therapy is supportive, with early referral to a tertiary care center for immunosuppressive therapy and/or stem cell transplantation. Transfusions should be minimized and, when administered, should be leukodepleted and from nonfamily members. Patients with a history of AA are at an increased lifetime risk for developing paroxysmal nocturnal hemoglobinuria.²²

Hemolytic Anemia

• Hemolytic anemia may be characterized as:
  
  
  
  • Acute or chronic
    
  • Immune versus non–immune mediated
    
  • Inherited or acquired
  
  
• The only abnormal laboratory values in acute hemolysis may be decreased Hgb and Hct. Internal hemorrhage can present with similar laboratory findings to hemolytic anemia.
  
• Maximal reticulocyte response occurs in 3 to 5 days. Lactate dehydrogenase (LDH) and bilirubin are increased in most patients reflecting an increase in red cell turnover. Serum haptoglobin is a sensitive early marker and is decreased by clearance of intravascular Hgb. The direct Coombs test (direct antibody test or DAT) identifies the presence of IgG or C3 bound to red cells; the indirect Coombs test indicates the presence of antibodies to red cells in the serum.
  
• Examination of the peripheral smear confirms hemolysis and may help identify the cause. Intravascular hemolysis may reveal red cell fragmentation (schistocytes, helmet cells), whereas spherocytes suggest extravascular, immune-mediated hemolysis. Polychromasia and nucleated erythrocytes can be seen with intense hemolysis and increased erythropoiesis.

Autoimmune Hemolytic Anemia

GENERAL PRINCIPLES

• Autoimmune hemolytic anemia (AIHA) is caused by antibodies to erythrocytes, leading to a shortened cell lifespan.
  
• Warm-antibody AIHA (WAIHA) is caused by IgG antibodies ± complement (C3) that react best at 37°C. It may be idiopathic or associated with an underlying malignancy (lymphoma, chronic lymphocytic leukemia [CLL], collagen vascular disorder) or drug induced.
  
• Cold-antibody AIHA (CAIHA or cold agglutinin disease) is less common than WAIHA and is caused by antibodies (usually IgM) and C3, which are most reactive with erythrocytes at lower temperatures. It may be chronic and associated with a B-cell neoplasm (lymphoma, CLL, Waldenström macroglobulinemia) or acute when caused by an infection (Mycoplasma spp., mononucleosis).

DIAGNOSIS

Clinical Presentation

• Mild cases of WAIHA
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