Thomas Regenbogen and Morey A. Blinder
The internist often evaluates and manages hematologic disorders independently or in concert with a hematologist. This chapter seeks to guide the outpatient physician in the evaluation and management of common conditions. Disorders of coagulation and thrombocytopenia are covered in Chapter 12.
ANEMIA
GENERAL PRINCIPLES
· Anemia always reflects an underlying primary disease. An attempt should be made to diagnose the cause in every case.
· Anemia is defined as a decrease in circulating red blood cell mass: hemoglobin (Hgb) <12 g/dL or hematocrit (Hct) <36% in women and Hgb <14 g/dL or Hct <41% in men.
· Anemia may be classified into three etiologic groups: blood loss (acute or chronic), decreased red cell production, and increased red cell destruction.
· The morphologic classification has diagnostic utility for many presentations. The mean cellular volume (MCV) is used to classify anemia as microcytic (<80 fL), normocytic (80 to 100 fL), and macrocytic (>100 fL).
DIAGNOSIS
Clinical Presentation
· Patients may be asymptomatic or have only minor complaints, especially with longer chronicity and slower decline in Hgb. Clinical findings will be present in most individuals at Hgb <7.0 g/dL.
· Symptoms and signs are generally due to tissue hypoxia. These include fatigue, pallor, dizziness, headaches, poor concentration, and weakness. Tachycardia and dyspnea on exertion are seen in severe anemia. High-output heart failure and shock may develop in the most severe cases.
· The history and physical examination in conjunction with basic laboratory data will either be diagnostic or narrow the differential diagnosis dramatically. As such, it is critical to address the following as part of the initial evaluation:
o Gastrointestinal (GI) hemorrhage
o Obstetric and menstrual history
o Evidence of hemolysis or predisposition to hemolysis
o Comorbidities such as gastrointestinal disease or resection, malabsorption, renal disease, rheumatologic disease, etc.
o Comorbidities that may be exacerbated by anemia, such as cardiovascular disease
o Personal or family history of anemia and prior treatments
o Prescribed and over-the-counter medications, alcohol consumption, diet, ethnic background, and religious beliefs pertaining to blood transfusion
o Clinical evidence of other cytopenias (e.g., infections or easy bruising)
Diagnostic Testing
· The evaluation should begin with a complete blood count (CBC) including red cell indices and reticulocyte count. Findings in the H&P help guide further evaluation. If iron deficiency is suspected, obtain an iron panel and ferritin level. If hemolysis is suspected, obtain a hepatic function panel, urinalysis, haptoglobin, and peripheral smear. Obtain serum vitamin B12 and serum folate levels with macrocytosis.
· The relative reticulocyte count measures the percentage of immature red cells in the blood. The absolute reticulocyte count (relative reticulocyte count multiplied by the red cell count) may be reported by some labs. The normal range for absolute reticulocyte count is 50,000 to 75,000 per μL.
o The reticulocyte index (RI) = relative reticulocyte count × (patient Hct/normal Hct). RI is an indication of whether the bone marrow (BM) is responding appropriately based on the degree of anemia.
o Individuals with normal erythrocyte proliferation will have an RI >3% to compensate for bleeding or hemolysis; however, an RI <3% with anemia indicates decreased production of erythrocytes (hypoproliferative anemia).
· A BM biopsy may be indicated in cases of normocytic anemia with a low reticulocyte count (e.g., to confirm iron deficiency in the setting of chronic disease states). It is also typically indicated in the evaluation of pancytopenia.
MICROCYTIC ANEMIA
Iron Deficiency Anemia
GENERAL PRINCIPLES
· Iron deficiency is the most common cause of anemia in the ambulatory setting.1
· GI bleeding is the most common etiology of iron deficiency in men and postmenopausal women in the developed world.
· Menstrual blood loss and pregnancy are common etiologies in premenopausal women; however, the clinician should not overlook GI bleeding in premenopausal women.
· The differential diagnosis of microcytic anemia includes iron deficiency, thalassemia, anemia of chronic inflammation (occasionally microcytic), sideroblastic, and occasionally myelodysplastic syndrome (MDS).
· Functional iron deficiency refers to adequate iron stores but inadequate mobilization for erythropoiesis, as is seen in patients with end-stage renal disease.
DIAGNOSIS
Clinical Presentation
History
· A careful history of both physiologic and abnormal hemorrhage must be obtained.
· Pica is an abnormal change in dietary habits (e.g., eating ice, clay, or starch) and is associated with iron deficiency anemia.
· Diseases of the stomach and proximal small intestine (e.g., Helicobacter pylori infection, achlorhydria, celiac disease, and bariatric surgery) often lead to impaired iron absorption.
Physical Examination
· The physical exam may be unremarkable as the classic signs are typically present only in severe iron deficiency.
· A digital rectal exam should be performed to examine for a mass and to test for occult blood.
Diagnostic Testing
· The MCV correlates with the degree of anemia; therefore, early mild iron deficiency may present as a normal or only slightly decreased MCV.
· Serum iron (SI) concentration is typically low, while total iron-binding capacity (TIBC) is typically elevated but can be low/normal with comorbid liver disease or inflammatory states. Transferrin increases linearly to approximately 400 mg/dL once patients are in negative iron balance, so that transferrin saturation (SI/TIBC) falls below 16% only when iron stores are exhausted. Pregnancy and oral contraceptive pills (OCP) use increase serum transferrin. Serum iron and TIBC have poor sensitivity and specificity for iron deficiency anemia.
· Ferritin is the primary storage form for iron in the reticuloendothelium and is the most accurate noninvasive marker of iron stores.
o A ferritin level of <10 ng/mL in women or 20 ng/mL in men is a specific marker of low iron stores.
o Ferritin is an acute-phase reactant, so normal levels may be seen in inflammatory states despite low iron stores. A serum ferritin of >200 ng/mL generally excludes an iron deficiency. However, in renal dialysis patients, a functional iron deficiency may be seen with a ferritin level of 500 to 1,200 ng/mL.2
· If the diagnosis of iron deficiency remains uncertain in the setting of normal renal function, a trial of oral iron repletion with repeat monitoring of Hgb/Hct 2 to 4 weeks after initiation is a reasonable diagnostic approach.
· A BM aspiration with special staining for iron is the definitive test for establishing iron deficiency but is rarely required due to improved serologic testing.
TREATMENT
· Evaluate and treat the underlying cause while treating the iron deficiency, if possible.
· If the anemia is severe (Hgb <7 g/dL) or if the patient is symptomatic with Hgb <10 g/dL, consider admission for transfusion and monitoring and to expedite evaluation if it is a new finding.3
· The majority of ambulatory patients may be treated with oral iron preparations (Table 13-1). We recommend ferrous sulfate, 325 mg PO, three times/day, 1 hour before meals and 2 hours from antacids. Each pill contains approximately 65 mg of elemental iron, of which 5 to 20 mg (about 10% to 30%) may be absorbed depending on patient-specific factors such as degree of anemia.
· In elderly adults, lower doses may be tolerated better yet equally effective over several months. Consider using 5- to 10-mL iron sulfate elixir in a quarter glass of orange juice before breakfast. Dental staining is a common adverse effect and may be avoided by using a straw.4
· Iron is best absorbed in the duodenum and proximal jejunum; therefore, delayed-release formulations will result in suboptimal absorption. Dosing with meals will also decrease absorption. A mildly acidic medium enhances absorption; thus, 250 mg of ascorbic acid may be given with the supplement.
· Common adverse effects are constipation, abdominal discomfort, or diarrhea. This is managed by decreasing frequency to BID, taking with meals, adding stool softeners, or reducing the elemental iron dose to <40 mg. A longer duration of therapy may be necessary.
· Serum ferritin should be monitored every 2 months during therapy, and normalization indicates repletion of iron stores. The Hgb/Hct typically increases after 1 to 2 weeks of therapy, but is variable depending on the cause of anemia and tolerability of treatment.
· If the underlying cause has resolved, therapy is discontinued once iron stores are replete. However, some patients will require long-term iron replacement.
· Occasionally, intravenous iron preparations may be required in the setting of bowel inflammation, rapid gastrointestinal transit, or malabsorption. In select severe cases, medication noncompliance is an indication for intravenous repletion. Treatment of anemia in the setting of CKD is discussed in Chapter 24.
· Iron dextran is commonly used, but newer formulations are available (Table 13-1):
o The iron deficit may be calculated with a readily available formula; however, the typical requirement is 1,000 to 3,000 mg of elemental iron to replenish stores in the adult.
o IV iron dextran therapy (INFeD, Dexferrum) can be complicated by serious side effects including anaphylaxis; therefore, an IV test dose of 25 mg in 50 mL of normal saline should be administered over 5 to 10 minutes. Methylprednisolone, diphenhydramine, and 1:1,000 epinephrine 1-mg ampule (for subcutaneous administration) should be immediately available at all times during the infusion.
o Delayed reactions to IV iron, such as arthralgia, myalgia, fever, pruritus, and lymphadenopathy may be seen within 3 days of therapy and usually resolve spontaneously or with nonsteroidal anti-inflammatory drugs. Newer parenteral formulations are associated with fewer anaphylactic reactions; however, many clinicians recommend test doses, especially if the patient has had a reaction to dextran or has other drug allergies.5
TABLE 13-1 Pharmacologic Iron Supplementation
aBrands are listed for reference but are not comprehensive; consult your local pharmacy or formulary for available brands and cost.
bSeveral dosage strengths may be available. For parenteral preparations, the common unit vial volume is shown.
cAlways confirm elemental iron content when prescribing iron supplementation. Enteral absorption is typically 10%–30% of elemental iron.
dDose iron based on the content of elemental iron. Typical enteral repletion dose is 150–300 mg elemental iron per day.
eParenteral iron dosage should be calculated based on estimated iron deficiency, common single doses shown. See package insert for administration instructions.
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:
o 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.
o Thalassemia intermedia occurs with dysfunction in both β-globin genes, characterized by a later clinical onset and milder anemia, which can require transfusions.
o 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:
o 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.
o Alpha-thalassemia minor clinically resembles beta-thalassemia minor; however, the Hgb electrophoresis pattern is normal.
o 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.
o Normally, Hgb A accounts for 96.5% to 98.5% of hemoglobin, Hgb A2 1.5% to 3.5%, and Hgb F <1.0%.
o In β-thalassemia trait, Hgb A2 and F are increased. Low Hgb A fractions and elevated Hgb F are found in severe disease.
o If α-thalassemia is suspected, α-globin gene deletion testing is confirmatory in the majority of cases.
o Analysis may also reveal abnormal hemoglobin types, such as S, C, or M.
o 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 B12deficiency 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
o The vitamin B12 level is <100 pg/mL, there is vitamin B12 deficiency.
o 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
o 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
o 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.
o Oral tablets or syrup, 50 to 1,000 mcg/day, may be given for maintenance indefinitely depending on the underlying cause.
o 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:
o Refractory anemia
o Refractory anemia with ringed sideroblasts
o Refractory anemia with excess blasts
o 5q− syndrome
o 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:
o Scheduled or unscheduled transfusions of red blood cells or platelets.
o Vaccinate for pneumococcal pneumonia, Haemophilus influenzae serotype b, seasonal influenza, and pertussis.
o Providers should have an elevated index of suspicion for infections and pursue early treatment.
· Chemotherapeutics:
o 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.
o Referral to an academic center for clinical trial enrollment is encouraged, especially in those with refractory or recurrent disease.
· Hematopoietic stem cell transplantation:
o 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.
o 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:
o This group often has many comorbidities and poor prognostic indicators and may not be candidates for intensive therapy.
o 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:
o Asymptomatic patients with Hgb <7 g/dL
o Stable coronary artery disease with Hgb <8 g/dL
o 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:
o Acute or chronic
o Immune versus non–immune mediated
o 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 spherocytessuggest 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 may present with a stable anemia and reticulocytosis. In fulminant cases with an erythrocyte life span of <5 days, the anemia can be severe and the compensatory erythropoiesis inadequate. Patients may present with rapidly declining Hgb, fever, chest pain, and dyspnea. Jaundice, icterus, and dark urine reflect elevated indirect bilirubin from Hgb degradation.
· CAIHA may be characterized by severe acute hemolysis triggered by exposure to cold temperatures. Cyanosis can be seen in the extremities or other exposed areas. Chronic cold agglutinin disease is otherwise generally characterized by mild anemia with intermittent exacerbations.
Diagnostic Testing
· Laboratory evaluation of WAIHA shows a positive DAT for IgG, with 80% of patients also having antibodies detectable in the serum (positive indirect Coombs test). Plasma haptoglobin is decreased, LDH is increased, and the peripheral smear shows spherocytes.
· In CAIHA, IgM and C3 are present on the erythrocyte, but the DAT identifies only the presence of C3. IgG is negative on the DAT. The anemia is often mild and stable because serum complement inhibitors (C3 inactivator) limit complement activation on the erythrocyte membrane, which is temperature dependent.
TREATMENT
· Therapy for WAIHA is directed at identifying and treating any underlying cause.
· Steroid therapy (prednisone 1 to 2 mg/kg/day), splenectomy, and rituximab for patients with refractory disease are used to decrease the immune clearance of erythrocytes.
· Transfusion should not be delayed in situations of severe anemia or hemodynamic compromise. Fully typed and crossmatched red cells may be delayed due to the presence of antibodies; therefore, O-negative blood should be given in emergent situations. Hemolysis of transfused red cells will occur at the same rate as the patient’s own blood, but will not exacerbate the disease. The use of a blood warmer may be of marginal benefit.
· Cold avoidance and evaluation to identify underlying malignancy are important for CAIHA. Plasmapheresis may be helpful in the acute setting. Transfused blood must be prewarmed.
· Steroids and splenectomy are not effective in the treatment of IgM-mediated disease.23
Drug-Induced Hemolytic Anemia
· Drug-induced hemolytic anemia occurs by several mechanisms and is treated by identifying and withdrawing the causative agent. It presents similarly to WAIHA. The DAT may be positive or negative for IgG. It may also become negative soon after withdrawal of the offending agent.
· The role of steroids is not well defined, but they are often used due to diagnostic uncertainty. Common precipitants include cephalosporins (most commonly cefotetan and ceftriaxone), sulfamethoxazole/trimethoprim, dapsone, fluoroquinolones, NSAIDs, methyldopa, nitrofurantoin, and penicillin.
Microangiopathic Hemolytic Anemia
· Microangiopathic hemolytic anemia (MAHA) is a morphologic classification in which fragmented erythrocytes (schistocytes) are seen on peripheral blood smear.
· Processes that cause erythrocyte fragmentation and hemolysis include disseminated intravascular coagulation (DIC), thrombotic thrombocytopenic purpura (TTP), hemolytic-uremic syndrome (HUS), malignant hypertension, the preeclampsia/eclampsia syndromes, vasculitis, adenocarcinoma, and malfunctioning heart valves. DIC, TTP, and HUS are discussed in Chapter 12.
Sickle Cell Disease
GENERAL PRINCIPLES
· The sickle cell diseases are a group of hereditary Hgb disorders in which Hgb undergoes sickle shape transformation under conditions of deoxygenation.
· The most common are homozygous sickle cell anemia (Hgb SS) or other heterozygous conditions (Hgb SC, Hgb S-beta-thalassemia). Newborn screening programs for hemoglobinopathies now identify most patients in infancy.
· Sickle cell trait is present in 2.5 million people in the United States, occurring in 8% of African Americans.
· No abnormal hematologic findings are associated with sickle cell trait, which is a benign hereditary condition. Nevertheless, some risks have been reported. High-altitude hypoxia may lead to splenic infarction or cerebrovascular complications. Basic military training and competitive sports, particularly basketball and football, are associated with increased incidence of sudden death related to extreme exertion and dehydration.
· The National Institutes of Health provide useful guidelines for sickle cell disease (http://www.nhlbi.nih.gov/health-pro/guidelines/sickle-cell-disease-guidelines, last accessed December 22, 2014).24
· Sickle cell trait guidelines differ, but organizations such as the National Collegiate Athletic Association (NCAA) and military publish specific guidelines.
DIAGNOSIS
Clinical Presentation
· Clinical manifestations are variable but generally relate to complications from chronic hemolysis and/or vascular occlusion. Patients often have one syndrome that predominates.
o Vasoocclusive complications include pain crises, avascular necrosis, priapism, and acute chest syndrome.
o Chronic hemolysis complications include pulmonary hypertension, cholelithiasis, and leg ulcers.
o Strokes, renal medullary infarctions, and priapism are complications of both forms.
· Acute intermittent complications account for much of the care provided to these patients and include the following:
o Acute painful episodes (so-called sickle cell crisis):
§ Vasoocclusive pain crises are the most common manifestation of sickle cell disease. Pain is typically in the extremities, back, chest, and abdomen and lasts for 2 to 6 days. These crises may be idiopathic or precipitated by stress, dehydration, or infection.
§ Some patients with higher Hgb F levels have mild disease with few painful episodes and rarely require medical attention. Nevertheless, these patients are still at risk of all of the complications of the disease.
o Acute chest syndrome occurs when hypoxia (<90% oxygen saturation) leads to increased intravascular sickling and irreversible occlusion of the microvasculature (predominantly pulmonary) circulation. Smokers and patients with lung pathology, such as pneumonia, are particularly at risk.25
o Aplastic crisis presents with a sudden decrease in Hgb level. The RI is inappropriately low, reflecting suppression of erythropoiesis. The most common etiology in pediatric patients is infection with parvovirus B19. Folate deficiency should also be considered because of the chronic increased requirements for erythropoiesis.
o Cerebrovascular events: stroke may occur at any age but is most common in children <10 years of age and is usually caused by large-vessel occlusion (i.e., middle cerebral artery).26
o Infections in adults typically occur in tissues that are susceptible to vasoocclusive infarcts (bone, kidney, lung). Staphylococcus spp., Salmonella spp., and enteric organisms are the most common pathogens. Pneumonia is most likely to be caused by Mycoplasma pneumoniae, Staphylococcus aureus, or Haemophilus influenzae and must be distinguished from acute chest syndrome.
o Renal medullary infarction results in chronic polyuria due to isosthenuria, leading to a chronic risk of dehydration.
o Renal tubular defects caused by sickling in the anoxic hyperosmolar environment of the renal medulla may lead to isosthenuria and hematuria in both sickle cell trait and disease. These conditions predispose patients to dehydration, which increases the risk of vasoocclusive events.
o Cholelithiasis is present in >80% of patients, primarily due to bilirubin stones.
o Avascular necrosis (AVN) of the femoral heads occurs in up to 50% of patients and is a cause of severe pain in adults.
o Leg ulceration occurring at the ankle is often chronic and recurring.
o Pregnancy in a sickle cell patient should be considered high risk and is associated with increased spontaneous abortions or premature delivery, along with increased vasoocclusive crises.
Diagnostic Testing
· Hgb analysis by electrophoresis or high-pressure liquid chromatography is used to diagnose hemoglobinopathies and distinguishes homozygous sickle cell disease (Hgb SS) from other abnormal hemoglobin.
· The mean Hgb in Hgb SS disease is about 8 g/dL (range 5 to 10 g/dL). The MCV may be slightly elevated because of reticulocytosis but is low in Hgb S-β-thalassemia.
· Leukocytosis (10,000 to 20,000/mm3) and thrombocytosis (>450,000/mm3) are common due to enhanced stimulation of the marrow compartment and autosplenectomy.
· Peripheral smear shows sickle-shaped erythrocytes, target cells (particularly in Hgb SC and Hgb S-β-thalassemia), and Howell-Jolly bodies, indicative of functional asplenism.
· The degree of anemia and reticulocytosis is generally milder in Hgb SC disease.
TREATMENT
· Outpatient management of acute painful episodes consists of rehydration (oral fluids, 3 to 4 L/day), evaluation for and management of infections, analgesia, and, if needed, antipyretic and empiric antibiotic therapy.
o Morphine (0.3 to 0.6 mg/kg PO every 4 hours PRN) is the drug of choice for moderate-to-severe pain.
o Pain management is a complex problem that may require multidisciplinary approaches, including social services, psychiatric consultation, and pain service to optimize the use of opiate medications.
o Transfusion should only be used for severe symptomatic anemia in uncomplicated vasoocclusive crises.
o Indications for hospitalization include inability to ingest adequate oral fluids, requirement for parenteral opioids or antibiotics, a declining Hgb level associated with inadequate erythropoiesis, or hypoxia.
o Hydroxyurea therapy (15 to 35 mg/kg PO daily) has been shown to increase levels of Hgb F and significantly decreases the frequency of vasoocclusive crises and acute chest syndrome in adults with sickle cell disease. It should be considered in most patients (nonpregnant) with Hgb SS or S β-thalassemia.27
· Individuals with suspected acute chest syndrome require immediate hospitalization and aggressive transfusion therapy, including red cell exchange. The presentation of acute chest syndrome is clinically indistinguishable from pneumonia; thus, empiric broad-spectrum antibiotics should be administered.
· Priapism is initially treated with hydration and analgesia. Persistent erections for >24 hours may require transfusion therapy or surgical drainage.
· General prevention and maintenance treatments include the following:
o Dehydration and hypoxia should be avoided because they may precipitate or exacerbate irreversible sickling.
o Folic acid, 1 mg PO daily, is generally administered to all patients with sickle cell disease because of chronic hemolysis.
o Pneumococcal vaccine is administered due to the risk of asplenism.
o Ophthalmologic examinations are recommended yearly for adults due to the high incidence of proliferative retinopathy leading to vitreous hemorrhage and retinal detachment.
o Local and regional anesthesia can be used without special precautions. Measures to avoid volume depletion, hypoxia, and hypernatremia are crucial.
o For general anesthesia, red blood cell transfusion to increase the Hgb concentration to 10 g/dL is strongly suggested and seems to be as effective as more aggressive regimens.29
COMPLICATIONS
· Patients with suspected aplastic crisis require hospitalization. Therapy includes folic acid, 5 mg/day, as well as red blood cell transfusions.
· Cholelithiasis may lead to acute cholecystitis or biliary colic. Acute cholecystitis should be treated medically with antibiotics, and cholecystectomy should be performed when the attack subsides. Elective cholecystectomy for asymptomatic gallstones is controversial; however, persistent abdominal complaints may suggest cholelithiasis as the cause.
· Treatment of AVN consists of local heat, analgesics, and avoidance of weight bearing. Hip and shoulder arthroplasty are usually effective in decreasing symptoms and improving function.
· In those with a history of stroke, the pediatric literature suggests transfusions to maintain the Hgb S concentration at <50% for at least 5 years to reduce the incidence of recurrent stroke.30
· Leg ulcers are treated with rest, leg elevation, and intensive local care. Referral to a wound care clinic or dermatologist is helpful.
Red Cell Enzyme Deficiencies
GENERAL PRINCIPLES
The most common hereditary enzyme deficiency is glucose-6-phosphate dehydrogenase deficiency, a sex-linked disorder that typically affects men. Erythrocytes that are deficient in this enzyme are more susceptible to hemolysis via oxidant stress, triggered by infections or drug exposure, leading to chronic or episodic hemolysis.
DIAGNOSIS
Clinical Presentation
· A mild form of the disease is seen in approximately 10% of African American men with anemia often precipitated by infection, fever, or medications such as sulfa, dapsone, antiretrovirals, and hydroxychloroquine.31
· A more severe form is the Mediterranean variant, in which hemolysis occurs when susceptible individuals ingest fava beans and present with fatigue, jaundice, and bilirubinuria.
Diagnostic Testing
· The peripheral smear classically shows bite cells.
· Diagnosis is made by demonstrating reduced levels of the enzyme. Because older senescent cells with lower enzyme levels hemolyze first during an acute hemolytic episode, a younger population of erythrocytes may result in a falsely elevated (normal) enzyme level; thus, the test should be repeated at least 6 weeks after the hemolytic event.
TREATMENT
Acute hemolytic episodes are largely intravascular and self-limited. Therapy is supportive and includes hydration and transfusion in addition to identifying and removing oxidant stresses such as drugs.
Polycythemia
GENERAL PRINCIPLES
· Polycythemia, defined as an abnormally elevated Hgb, Hct, or red cell mass, may be absolute or relative to plasma volume.
· It is most important to differentiate polycythemia vera (PV) from secondary and relative polycythemia because the treatment differs.32
DIAGNOSIS
Clinical Presentation
History
· Elicit either a history of lung disease or symptoms suggestive of such.
· Inquire about possible exposure to carbon monoxide, tobacco smoke, or high-altitude locations.
· Determine whether dehydration may be present such as with diuretic use.
· Symptoms suggestive of obstructive sleep apnea may be helpful in establishing the etiology.
· Testosterone replacement may increase the Hgb level by approximately 1 g/dL.
Physical Examination
· Examine for cyanosis, abnormal heart sounds suggestive of shunt, and lung sounds suggestive of obstructive disease.
· Splenomegaly is seen with PV and is typically not present in secondary or relative polycythemia.
Differential Diagnosis
Dehydration causes a relative polycythemia. Chronic hypoxemia, obstructive sleep apnea, and carbon monoxide poisoning may cause secondary polycythemia. PV is a myeloproliferative neoplasm (MPN).
Diagnostic Testing
· Repeat the CBC to confirm polycythemia.
· The next step is to rule out PV by checking JAK2 V617F mutation status and EPO level. JAK2 mutations are present in 94% of PV cases, and EPO may be low.33 In cases of diagnostic uncertainty, red blood cell mass is used to differentiate absolute polycythemia from a relative reduction in plasma volume; however, this test is not widely available, and it will not differentiate PV from secondary polycythemia.
· Workup of secondary polycythemia is patient specific. Consider sleep study, echocardiogram, pulse oximetry, and carboxyhemoglobin.
TREATMENT
· PV may be initially treated with phlebotomy followed by maintenance therapy with continued phlebotomy or hydroxyurea to keep the Hct <45%.34
· Aspirin 81 mg daily reduces the high incidence of thrombotic events in PV.35
· Treatment of secondary polycythemia is dependent on the cause, and phlebotomy is rarely indicated. Aspirin is often used due to comorbid conditions but is not specifically indicated.
Thrombocytosis
GENERAL PRINCIPLES
· Secondary thrombocytosis may occur in response to recovery from bleeding or thrombocytopenia, postsplenectomy, iron deficiency, chronic infectious or inflammatory states, and malignancies.
· Essential thrombocythemia (ET) is a chronic MPN.
· Progression to myelofibrosis or acute myeloid leukemia occurs in a minority of ET patients.36
· Arterial thrombosis, including transient ischemic attacks and stroke, is common in ET. The risk of thrombosis increases with age, prior thrombosis, duration of disease, other comorbidities, and platelet count.37
DIAGNOSIS
Clinical Presentation
· Patients with secondary thrombocytosis generally do not have an increased risk of bleeding or thrombosis. However, patients postsplenectomy may have an increased risk of portal vein thrombosis. Platelet normalization occurs after improvement of the underlying disorder.
· ET may present asymptomatically with laboratory abnormalities or present with a thrombotic or hemorrhagic event.
· Erythromelalgia, due to microvascular occlusive platelet thrombi, presents as intense burning or throbbing of the extremities, typically involving the feet. Cold exposure usually relieves symptoms. Typical signs of erythromelalgia include erythema and warmth of affected digits.
· Approximately 50% of ET patients develop mild splenomegaly.
Diagnostic Testing
· The diagnosis of ET is currently based on the 2008 World Health Organization revised criteria.13
· The general practitioner can evaluate for a sustained platelet count of >450 × 109/L, presence of JAK2 V617F mutation, and no cause for reactive thrombocytosis if the JAK2 mutation is absent.
· The hematologist may perform a BM aspirate and biopsy to evaluate for increased mature megakaryocytes and rule out myelofibrosis or other MPN.
TREATMENT
· Aspirin 81 mg daily is indicated unless there is history of significant hemorrhage.
· Platelet reduction therapy is indicated in patients >60 years old or with a prior thrombosis or hemorrhage, hypertension, diabetes, smoking, or hyperlipidemia. The majority of thrombotic complications occur at modest platelet count elevations. Treatment typically targets a platelet count of <400 × 109/L. Platelet-lowering drugs include hydroxyurea, anagrelide, or interferon-α in pregnant patients or women in their childbearing years.38 Hydroxyurea and anagrelide provide equivalent platelet count control, but anagrelide is associated with more adverse effects.39
· There is some evidence that plateletpheresis is beneficial in acute arterial thrombosis such as stroke or myocardial infarction.40
WHITE BLOOD CELL DISORDERS
Leukocytosis
GENERAL PRINCIPLES
· Leukocytosis is an elevation in the absolute WBC count (>10,000/mm3).
· Neutrophilia is not often further evaluated until >20,000/mm3.
· An elevated WBC count typically reflects the normal response of BM to an infectious or inflammatory process, steroid use, β-agonist or lithium therapy, splenectomy, stress, or smoking.
· Occasionally, leukocytosis is due to a primary BM abnormality in WBC production, maturation, or death (apoptosis) related to leukemia or MPN and can affect any cell in the leukocyte lineage.
· A WBC count >50,000/mm3 may be termed a leukemoid reaction and must be interpreted in the clinical context with a high degree of suspicion for malignancy. Some infections such as Clostridium difficile colitis may evoke this type of response.
· Lymphocytosis is less common and is associated with viral infections, medication effect, or leukemia.
· Eosinophilia (>1,000/mm3) has a limited differential. The most common cause worldwide is helminthic infections, while in developed nations, it is atopy. Other causes include malignancy, Addison disease, and collagen vascular disease.41
DIAGNOSIS
Clinical Presentation
History
· For mild neutrophilia, signs and symptoms of infection should be elicited. Cigarette smokers should be identified, and weight loss in this population may suggest malignancy. Recent corticosteroid use may produce a mild-to-moderate neutrophilia.
· Features of acute leukemia include bone pain, fatigue, night sweats, fever, or bleeding. Furthermore, neurologic deficiencies or cardiopulmonary distress are rare but suggestive of leukostasis secondary to leukemia.
Physical Examination
· Lymphocytosis secondary to CLL occasionally presents with splenomegaly and lymphadenopathy.
· Patients with chronic myelogenous leukemia (CML) present with leukocytosis and splenomegaly; they will rarely present with lymphadenopathy. The skin should be examined for chloromas.
Diagnostic Testing
· Repeat the CBC with differential and examine the peripheral smear.
· The presence of blasts on a peripheral smear is concerning for an acute leukemia and requires prompt evaluation. Acute leukemia may also have an associated elevation in LDH and uric acid due to rapid cell turnover.
· Unexplained lymphocytosis should also be assessed with peripheral flow cytometry and BCR-abl molecular studies.
TREATMENT
· Mild neutrophilia prompts a review of the patient’s comorbidities and appropriate infectious disease workup. It often does not warrant evaluation by a hematologist. If there are clinical features concerning for acute leukemia, such as circulating blasts or other cytopenias, contact a specialist directly or admit to a hospital as the acuity dictates.
· Chronic leukemias may be relatively asymptomatic and are typically evaluated and treated in an outpatient specialist setting.
Leukopenia
· Leukopenia is an abnormally low WBC count (<3,500 cells/mm3) and may occur in response to infection, inflammation, malignancy, or vitamin deficiencies.
· Drug-induced neutropenia due to chemotherapeutic or immunosuppressive drugs is usually dose dependent.
· Idiosyncratic leukopenia may be caused by a broad range of medications and should be suspected when developing shortly after starting a new agent. Common classes are antiepileptics, antibiotics, NSAIDs, and some antipsychotics.42
· Severe neutropenia (absolute neutrophil count [ANC] <500/mm3) increases the risk of a life-threatening bacterial infection. Neutropenic fever requires emergent evaluation, admission, panculture, and empiric broad-spectrum antibiotics.
· Unexplained pancytopenia with symptoms concerning for leukemia warrants immediate specialist evaluation.
· Chronic benign neutropenia is common in African Americans and is not clinically significant as their response to infection is normal.
· HIV infection may cause lymphopenia, while most other viral infections cause lymphocytosis.
· Growth factor support, such as G-CSF, should be considered in patients with chronic neutropenia and ongoing infections. An agent commonly used in the outpatient setting is filgrastim 5 mcg/kg (typically either 240 mcg or 480 mcg per dose) injected subcutaneously.
Monoclonal Gammopathies
An elevated total protein may be polyclonal or monoclonal. Common reasons for polyclonal gammopathy are chronic infection, inflammation, or liver disease. Monoclonal gammopathies are discussed individually below.
Monoclonal Gammopathy of Unknown Significance
· Monoclonal gammopathy of unknown significance (MGUS) refers to the presence of a monoclonal protein (M protein) totaling <3 g/dL in the absence of related organ failure (e.g., anemia, hypercalcemia, renal insufficiency, lytic bone lesions) or known underlying lymphoproliferative disorder.
· The incidence of MGUS increases with age; 3% of persons >50 years of age are affected, and people of African descent are twice as likely as Caucasians to have MGUS.
· Initial laboratory data should include CBC; basic metabolic panel including serum calcium, urinalysis, serum protein electrophoresis and immunofixation; and serum free light-chain assay. Normal urinalysis does not rule out proteinuria; thus, 24-hour urine collection for protein electrophoresis and immunofixation is needed to detect and quantify immunoglobulin light chains.
· A skeletal survey is important to document the absence of bone lesions. Advanced imaging and/or biopsy may be necessary to characterize suspicious lesions.
· MGUS evolves into a more serious lymphoproliferative malignancy at a rate of about 1% per year. Non-IgG MGUS may progress to multiple myeloma. IgM MGUS may transform to Waldenström macroglobulinemia or chronic lymphocytic leukemia.
· Three risk factors for progression have been identified: non-IgG gammopathy (IgM or IgA), abnormal serum free light-chain ratio (κ/λ ratio), and initial gammopathy concentration of >1.5 g/dL each increase the risk of progressing, and the presence of all three confers the highest risk of 58% at 20 years.43
· Referral is indicated for BM biopsy in patients at moderate to high risk of disease progression. Patients with MGUS should be monitored with CBC, electrolytes, renal function and serum protein electrophoresis (SPEP) every 6 to 12 months indefinitely due to the risk of malignant transformation.
Multiple Myeloma
· Multiple myeloma (MM) is a lymphoproliferative disorder that may present with unexpected skeletal fracture (long bone or vertebral body), renal failure (due to light chain proteinuria), cytopenia, hypercalcemia, or a combination of these. Fatigue and anemia may be the only presenting features particularly in older patients. A subset with hypogammaglobulinemia will present with recurrent bacterial infection such as pneumococcal pneumonia.
· The diagnosis is usually established by a BM examination with the presence of plasma cells >30% in the marrow or biopsy proven plasmacytoma.
· Initial treatment of hypercalcemia includes intravenous fluids and a bisphosphonate such as zoledronic acid 4 mg IV.
· Treatment of MM is rapidly changing and has become quite effective in controlling the disease. Care should be coordinated with a specialist and may include corticosteroids in combination with chemotherapy (melphalan, thalidomide, lenalidomide, or bortezomib). Palliative radiotherapy may be indicated for bone lesions, and orthopedic surgery may be necessary for impending fracture. The role of stem cell transplant is evolving as chemotherapy becomes more effective. Currently, it provides modest survival benefit and is typically indicated in those with poor-risk features.44
· The Multiple Myeloma Research Foundation website (http://www.themmrf.org, last accessed December 22, 2014) is an excellent online resource for clinicians and patients.
Amyloidosis
· Primary (amyloid light chain [AL]) amyloidosis is an infiltrative disorder due to monoclonal light-chain deposition in various tissues most often involving the kidney (renal failure, nephrotic syndrome), heart (nonischemic cardiomyopathy), peripheral nervous system (neuropathy), and GI tract/liver (macroglossia, diarrhea, nausea, vomiting). Unexplained findings in any of these organ systems should prompt evaluation for amyloidosis.45
· An M protein discovered by serum or urine protein electrophoresis or serum free light-chain assay is found in >95% of patients with AL amyloidosis. Biopsy of an affected organ, BM, or fat pad may also be helpful.
· Treatment options include chemotherapeutics similar to those used in MM; thus, specialty consultation is recommended.
THE BONE MARROW BIOPSY
Patients referred to a hematologist often undergo this procedure as part of the initial diagnostic workup and occasionally require repeated examinations. Patients may have preconceived ideas about this so it is helpful to counsel your patient since it is often not as painful as expected. Patients may experience localized pain that resolves over a few days. It has been shown that <1% of procedures are associated with an adverse event.46 Of these, bleeding is the most common while infection is extremely unlikely. The provider may indicate a preference in terms of systemic anticoagulation management periprocedurally.
COUNSELING THE POTENTIAL STEM CELL DONOR
Unfortunately, misconceptions regarding stem cell donation and transplant have hindered enrollment. Counter to images of surgeons “scraping the bone marrow,” the patient does not routinely undergo a surgical procedure for either donation or transplant of stem cells. Stem cell donation involves a SQ injection of G-CSF followed a few days later by a pheresis procedure. This has been shown to be safe with no long-term adverse effects.47 Stem cell transplant is by intravenous infusion following bone marrow ablative therapy with chemotherapeutics and sometimes total body irradiation. All transplant recipients require central venous access.
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