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How to Interpret and Pursue an Abnormal Complete Blood Cell Count in Adults

      A complete blood cell count (CBC) is one of the most common laboratory tests in medicine. For example, at our institution alone, approximately 1800 CBCs are ordered every day, and 10% to 20% of results are reported as abnormal. Therefore, it is in every clinician's interest to have some understanding of the specific test basics as well as a structured action plan when confronted with abnormal CBC results. In this article, we provide practical diagnostic algorithms that address frequently encountered conditions associated with CBC abnormalities including anemia, thrombocytopenia, leukopenia, polycythemia, thrombocytosis, and leukocytosis. The objective is to help the nonhematologist recognize when a subspecialty consultation is reasonable and when it may be circumvented, thus allowing a cost-effective and intellectually rewarding practice.
      ACD (anemia of chronic disease), ANC (absolute neutrophil count), CBC (complete blood cell count), CML (chronic myeloid leukemia), ET (essential thrombocythemia), FISH (fluorescence in situ hybridization), Hct (hematocrit), HES (hypereosinophilic syndrome), Hgb (hemoglobin), HIV (human immunodeficiency virus), IDA (iron deficiency anemia), ITP (idiopathic thrombocytopenic purpura), LDH (lactate dehydrogenase), LGL (large granular lymphocyte), MCV (mean corpuscular volume), MDS (myelodysplastic syndrome), PA (pernicious anemia), PBS (peripheral blood smear), PT (primary thrombocytosis), PV (polycythemia vera), RBC (red blood cell), RCM (RBC mass), RT (reactive thrombocytosis), TCR (T-cell receptor), TTP/HUS (thrombotic thrombocytopenic purpura/hemolytic uremic syndrome), WBC (white blood cell)
      Circulating blood cells, including red blood cells (RBCs), white blood cells (WBCs), and platelets, are counted and sized electronically by modern instruments.
      • Rappaport ES
      • Helbert B
      • Beissner RS
      • Trowbridge A
      Automated hematology: where we stand.
      • Gulati GL
      • Hyun BH
      The automated CBC: a current perspective.
      One such instrument, the Coulter counter, generates an electrical pulse when a blood cell passes through a small aperture surrounded by electrodes. Each electrical pulse represents an individual cell, and the pulse height indicates the cell volume. Therefore, the electronic counter not only registers the total cell count but also estimates the average cell volume and the variation in cell size. In the context of RBCs, for example, these measurements are referred to as the mean corpuscular volume (MCV) and the RBC distribution width, respectively. Modern electronic counters are also capable of multimodal assessment of cell size and content, thus providing additional information about the various categories of WBCs including neutrophils, lymphocytes, monocytes, eosinophils, and basophils (ie, 5-part differential).
      Two other “measured variables” of the complete blood cell count (CBC) are hemoglobin (Hgb) and hematocrit (Hct). Both provide equivalent information, approximately conveyed by the RBC count, and are interchangeable.
      • Behrens JA
      • Brown WP
      • Gibson DF
      • Detter JC
      Whole-blood hemoglobin determinations: a comparison of methodologies.
      • Keen ML
      Hemoglobin and hematocrit: an analysis of clinical accuracy: case study of the anemic patient.
      The Hgb is computed by a spectrophotometer after RBCs are lysed in a given volume of blood and the Hgb is chemically converted into a stable pigment. The Hct is determined by a microhematocrit centrifuge and represents the percentage of a given volume of whole blood that is occupied by packed RBCs.
      • Penn D
      • Williams PR
      • Dutcher TF
      • Adair RM
      Comparison of hematocrit determinations by microhematocrit and electronic particle counter.
      • Bull BS
      • Fujimoto K
      • Houwen B
      • ICSH Expert Panel on Cytometry
      • et al.
      International Council for Standardization in Haematology (ICSH) recommendations for “surrogate reference” method for the packed cell volume.
      However, Hct also can be calculated by multiplying the RBC count and the MCV. Other “calculated” variables in the CBC include the mean corpuscular Hgb content (Hgb × 1/RBC count) and mean corpuscular Hgb concentration (Hgb × 1/Hct); these 2 calculated values are rarely used in routine clinical practice.
      For practical purposes, the variables to focus on when examining the CBC are Hgb (as a general indicator of anemia or polycythemia), MCV (a key parameter for the classification of anemias), RBC distribution width (a relatively useful parameter in the differential diagnosis of anemia), RBC count (an increased RBC count associated with anemia is characteristic in the thalassemia trait), platelet count (to detect either thrombocytopenia or thrombocythemia), and WBC count with differential (usually gives important clues for the diagnosis of acute leukemia and chronic lymphoid or myeloid disorders as well as for the presence of leukopenia and neutropenia). Furthermore, in patients with an abnormal WBC count, the clinician should immediately ask which WBC type is affected: neutrophils, lymphocytes, monocytes, eosinophils, or basophils. In this regard, the machine-derived 5-part differential should be confirmed by the human eye (ie, peripheral blood smear [PBS] examination) before it is acted on.
      Finally, an “abnormal” CBC should be interpreted within the context of an individual's baseline value because up to 5% of the general population without disease may display laboratory values outside the statistically assigned “normal” reference range
      • Korvin CC
      • Pearce RH
      Laboratory screening: a critical survey: II.
      (Table 1
      • Bain BJ
      Ethnic and sex differences in the total and differential white cell count and platelet count.
      Hematological and nutritional biochemistry reference data for persons 6 months-74 years of age: United States, 1976-80.
      ). Likewise, an individual may display a substantial change from his or her baseline (ie, personal normal) without violating the “normal” reference range. Similarly, differences in the CBC based on race and sex should be considered when interpreting results. In general, RBC-associated measurements are lower and platelet counts are higher in women compared with men, and persons of African ancestry display significantly lower Hgb, WBC, neutrophil, and platelet counts than white persons.
      • Bain BJ
      Ethnic and sex differences in the total and differential white cell count and platelet count.
      Hematological and nutritional biochemistry reference data for persons 6 months-74 years of age: United States, 1976-80.
      TABLE 1Reference Ranges of Complete Blood Cell Count in Adult White Persons and Persons of African Ancestry
      * Abstracted from population-based studies from Bain
      • Bain BJ
      Ethnic and sex differences in the total and differential white cell count and platelet count.
      and NHANES-II.
      Hematological and nutritional biochemistry reference data for persons 6 months-74 years of age: United States, 1976-80.
      Mayo Clinic normal values, based primarily on white subjects, are in parentheses for comparison. RBC = red blood cell; WBC = white blood cell.
      WhiteAfrican
      VariableMaleFemaleMaleFemale
      Hemoglobin
      Hematological and nutritional biochemistry reference data for persons 6 months-74 years of age: United States, 1976-80.
      (g/dL)
      12.7-17.0 (13.5-17.5)11.6-15.6 (12.0-15.5)11.3–16.410.5–14.7
      RBCs
      Hematological and nutritional biochemistry reference data for persons 6 months-74 years of age: United States, 1976-80.
      (× 1012/L)
      4.0-5.6 (4.3-5.7)3.8-5.2 (3.9-5.0)3.8–5.73.6–5.2
      • Mean corpuscular volume
        Hematological and nutritional biochemistry reference data for persons 6 months-74 years of age: United States, 1976-80.
        (fL)
      81.2-101.4 (81.2-95.1)81.1-99.8 (81.6-98.3)77.4–103.774.2–100.9
      RBC distribution width (%)(11.8-15.6)(11.9-15.5)
      Platelets
      • Bain BJ
      Ethnic and sex differences in the total and differential white cell count and platelet count.
      (× 109/L)
      143-332 (150-450)169-358 (150-450)115–290125–342
      WBCs
      • Bain BJ
      Ethnic and sex differences in the total and differential white cell count and platelet count.
      (× 109/L)
      3.6-9.2 (3.5-10.5)3.5-10.8 (3.5-10.5)2.8–7.23.2–7.8
      Neutrophils
      • Bain BJ
      Ethnic and sex differences in the total and differential white cell count and platelet count.
      (× 109/L)
      1.7-6.1 (1.7-7.0)1.7-7.5 (1.7-7.0)0.9–4.21.3–4.2
      Lymphocytes
      • Bain BJ
      Ethnic and sex differences in the total and differential white cell count and platelet count.
      (× 109/L)
      1.0-2.9 (0.9-2.9)0.95-3.3 (0.9-2.9)1.0–3.21.1–3.6
      Monocytes
      • Bain BJ
      Ethnic and sex differences in the total and differential white cell count and platelet count.
      (× 109/L)
      0.18-0.62 (0.3-0.9)0.14-0.61 (0.3-0.9)0.15–0.580.15–0.39
      Eosinophils
      • Bain BJ
      Ethnic and sex differences in the total and differential white cell count and platelet count.
      (× 109/L)
      0.03-0.48 (0.05-0.50)0.04-0.44 (0.05-0.50)0.02–0.790.02–0.41
      Basophils (× 109/L)(0-0.3)(0-0.3)
      * Abstracted from population-based studies from Bain
      • Bain BJ
      Ethnic and sex differences in the total and differential white cell count and platelet count.
      and NHANES-II.
      Hematological and nutritional biochemistry reference data for persons 6 months-74 years of age: United States, 1976-80.
      Mayo Clinic normal values, based primarily on white subjects, are in parentheses for comparison. RBC = red blood cell; WBC = white blood cell.

      Anemia

      The first step in approaching anemia is to classify the process as microcytic (MCV, <80 fL), normocytic (MCV, 80-100 fL), or macrocytic (MCV, >100 fL).
      • Tefferi A
      Anemia in adults: a contemporary approach to diagnosis.
      • Tefferi A
      Practical algorithms in anemia diagnosis [letter].
      This exercise markedly narrows the differential diagnosis that needs to be considered in each patient. Also, we strongly recommend obtaining a PBS during the initial evaluation of anemia, regardless of subtype. A PBS substantially enhances the initial process of differential diagnosis and provides guidance for further testing.

       Microcytic Anemia

      The 3 major diagnostic possibilities for microcytic anemia are iron deficiency anemia (IDA), thalassemia, and anemia of chronic disease (ACD).
      • Tefferi A
      Anemia in adults: a contemporary approach to diagnosis.
      • Tefferi A
      Practical algorithms in anemia diagnosis [letter].
      A fourth possibility, sideroblastic anemia presenting with microcytosis, is not prevalent enough for routine consideration.
      • Alcindor T
      • Bridges KR
      Sideroblastic anaemias.
      Clues from the CBC and PBS for the differential diagnosis of microcytic anemia are outlined in Table 2. Since the most common of the microcytic anemias is IDA, we recommend determination of the serum ferritin level as the initial step for all patients with microcytic anemia (Figure 1).
      • Ho CH
      The differential diagnostic values of serum transferrin receptor, serum ferritin and related parameters in the patients with various causes of anemia [letter].
      A low serum ferritin level is diagnostic of IDA. Similarly, contrary to current dogma regarding acute phase reaction, a diagnosis of IDA is unlikely in the presence of a persistently normal or elevated serum ferritin level.
      • Barron BA
      • Hoyer JD
      • Tefferi A
      A bone marrow report of absent stainable iron is not diagnostic of iron deficiency.
      In general, we do not recommend either other serum iron studies (serum iron, total iron-binding capacity, transferrin saturation) or bone marrow biopsy for evaluation of IDA.
      • Tefferi A
      Anemia in adults: a contemporary approach to diagnosis.
      • Tefferi A
      Practical algorithms in anemia diagnosis [letter].
      • Alcindor T
      • Bridges KR
      Sideroblastic anaemias.
      • Ho CH
      The differential diagnostic values of serum transferrin receptor, serum ferritin and related parameters in the patients with various causes of anemia [letter].
      • Barron BA
      • Hoyer JD
      • Tefferi A
      A bone marrow report of absent stainable iron is not diagnostic of iron deficiency.
      TABLE 2Clues From CBC and PBS in the Differential Diagnosis of Anemias
      * CBC = complete blood cell count; CD = Casteleman disease; MDS = myelodysplastic syndrome; MMM = myelofibrosis with myeloid metaplasia; PBS = peripheral blood smear; RBC = red blood cell; RDW = RBC distribution width.
      Category of anemiaDifferential diagnosisCBC cluesPBS clues
      MicrocyticIron deficiency anemiaIncreased RDWAnisocytosis
      ThrombocytosisPoikilocytosis
      Elliptocytosis
      ThalassemiaNormal or elevated RBC countPolychromasia
      Normal or elevated RDWTarget cells
      Basophilic stippling
      Anemia of chronic diseaseNormal RDWUnremarkable (typically)
      Rouleaux formation (CD)
      Myelophthisis (MMM)
      Myelophthisis implies the presence of nucleated RBCs, immature myeloid cells, and tear-drop–shaped RBCs.
      NormocyticBleedingUsually unremarkablePolychromasia
      Nutritional anemiaIncreased RDWAnisocytosis
      Dimorphic RBCs
      Anemia of renal insufficiencyNormal RDWUsually unremarkable
      HemolysisNormal or elevated RDWPolychromasia
      ThrombocytosisSpherocytes
      Schistocytes
      Bite cells
      Anemia of chronic diseaseNormal RDWUnremarkable
      A primary bone marrow disorderIncreased RDWDimorphic RBCs (MDS)
      Other cytopeniasPseudo Pelger-Huët anomaly (MDS)
      MonocytosisOval macrocytes (MDS)
      LeukocytosisMyelophthisis (MMM)
      Myelophthisis implies the presence of nucleated RBCs, immature myeloid cells, and tear-drop–shaped RBCs.
      ThrombocytosisRouleaux (myeloma)
      Abnormal differentialBlasts (acute leukemia)
      Presence of abnormal cells
      MacrocyticDrug-inducedIncreased RDWOval macrocytes
      Marked or mild macrocytosis
      NutritionalIncreased RDWOval macrocytes
      Marked or mild macrocytosisHypersegmented neutrophils
      MDS or other bone marrow disorderIncreased RDWDimorphic RBCs
      Pseudo Pelger-Huët anomaly cells
      Oval macrocytes
      Liver disease, alcohol useNormal RDWRound macrocytes
      ThrombocytopeniaTarget cells
      HypothyroidismNormal RDWRound macrocytes
      HemolysisNormal or elevated RDWPolychromasia
      * CBC = complete blood cell count; CD = Casteleman disease; MDS = myelodysplastic syndrome; MMM = myelofibrosis with myeloid metaplasia; PBS = peripheral blood smear; RBC = red blood cell; RDW = RBC distribution width.
      Myelophthisis implies the presence of nucleated RBCs, immature myeloid cells, and tear-drop–shaped RBCs.
      Figure thumbnail gr1
      FIGURE 1Diagnostic algorithm for microcytic anemia.
      If the serum ferritin level is normal, the next step is to determine whether the microcytosis is new (Figure 1). In patients with chronic microcytosis, a diagnosis of thalassemia should be considered, and Hgb electrophoresis should be ordered as the initial test.
      • Old JM
      Screening and genetic diagnosis of haemoglobin disorders.
      However, we underscore that Hgb electrophoresis does not always detect the presence of thalassemia and that a hematology consultation may be necessary for accurate interpretation of test results. In general, Hgb electrophoresis results are normal in the a-thalassemia trait and abnormal in the β-thalassemia trait as well as in other thalassemic syndromes.
      • Old JM
      Screening and genetic diagnosis of haemoglobin disorders.
      Furthermore, during the interpretation of Hgb electrophoresis, one must remember that concomitant IDA may mask the typical abnormality seen in the β-thalassemia trait, which is an increase in Hgb A2 (a2d2) level from the normal value of 2% to a value of 3% to 6%.
      • Old JM
      Screening and genetic diagnosis of haemoglobin disorders.
      Acquired microcytic anemia that is not IDA is indicative of an underlying systemic disease and is labeled operationally as microcytic ACD.
      • Thomas L
      Anemia of chronic disease—pathophysiology and laboratory diagnosis.
      • Weiss G
      • Goodnough LT
      Anemia of chronic disease.
      Both usual and unusual systemic disease may accompany microcytic ACD (Figure 1).
      • Cash JM
      • Sears DA
      The anemia of chronic disease: spectrum of associated diseases in a series of unselected hospitalized patients.
      Further laboratory investigation in this instance as well as the need for a hematology consultation is dictated by patient history and findings from both the physical examination and the PBS.

       Normocytic Anemia

      The first step in approaching normocytic anemia is to exclude potentially treatable causes from the standpoint of anemia, including bleeding, nutritional anemia, anemia of renal insufficiency,
      • Pendse S
      • Singh AK
      Complications of chronic kidney disease: anemia, mineral metabolism, and cardiovascular disease.
      and hemolysis (Figure 2). Clues from the CBC and PBS for each of these categories are listed in Table 2. Patient history is key in implicating bleeding as a cause of anemia, and a fecal occult blood test can be ordered if indicated. Regarding nutritional anemia, it should be noted that both iron and vitamin B12/folate deficiencies are possible causes of “normocytic” anemia, despite their usual association with microcytic and macrocytic anemia, respectively.
      • Ho CH
      The differential diagnostic values of serum transferrin receptor, serum ferritin and related parameters in the patients with various causes of anemia [letter].
      • Pruthi RK
      • Tefferi A
      Pernicious anemia revisited.
      Anemia of renal insufficiency is addressed easily by checking the serum creatinine level. Hemolytic anemia is usually normocytic but can be macrocytic if accompanied by marked reticulocytosis.
      Figure thumbnail gr2
      FIGURE 2Diagnostic algorithm for normocytic anemia. AIHA = autoimmune hemolytic anemia; DIC = disseminated intravascular coagulation; HS = hereditary spherocytosis; PBS = peripheral blood smear; TTP/HUS = thrombotic thrombocytopenic purpura/ hemolytic uremic syndrome.
      Initial laboratory tests that should be ordered when hemolysis is suspected and/or to exclude the possibility of active hemolysis include serum levels of haptoglobin, lactate dehydrogenase (LDH), and indirect bilirubin as well as reticulocyte count and the PBS (Figure 2).
      • Beutler E
      • Luzzatto L
      Hemolytic anemia.
      • Gehrs BC
      • Friedberg RC
      Autoimmune hemolytic anemia.
      In general, active hemolysis is suspected if a low haptoglobin level is associated with increased LDH, indirect bilirubin, or reticulocyte count. The differential diagnosis of a normocytic anemia that is not linked to bleeding, nutrition, renal insufficiency, or hemolysis is either normocytic ACD or a primary bone marrow disorder.
      • Weiss G
      • Goodnough LT
      Anemia of chronic disease.
      Patient history and PBS results provide the most helpful information in distinguishing the two (Table 2; Figure 2).
      In general, in patients with normocytic anemia, a hematology consultation may be unnecessary if the patient history, the initial laboratory test results described previously, and the PBS results are consistent with nutritional anemia, anemia of renal insufficiency, or normocytic ACD. Furthermore, some PBS results may dictate the ordering of additional laboratory tests without waiting for approval from a hematologist: (1) a Coombs test and if results are negative, an osmotic fragility test for patients with spherocytosis and (2) coagulation, haptoglobin, and LDH tests for patients with schistocytosis (Figure 2). Similarly, a urinary hemosiderin test is extremely helpful if valvular hemolysis is suspected. All other scenarios require a hematology consultation. Finally, the possibility of drug-induced hemolysis always must be considered.
      • Beutler E
      • Luzzatto L
      Hemolytic anemia.

       Macrocytic Anemia

      Use of certain drugs (eg, hydroxyurea, zidovudine) and alcohol consumption are notoriously associated with macrocytosis and should be first considerations during evaluation of macrocytic anemia (Figure 3).
      • Spier S
      • Solomon LM
      • Esterly NB
      • Fried W
      Hydroxyurea and macrocytosis.
      • Richman DD
      • Fischl MA
      • Grieco MH
      • et al.
      The toxicity of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex: a double-blind, placebo-controlled trial.
      The next step is to rule out nutritional causes (B12 or folate deficiency); we prefer to use serum homocysteine for initial screening because of its higher test sensitivity.
      • Pruthi RK
      • Tefferi A
      Pernicious anemia revisited.
      • Tefferi A
      • Pruthi RK
      The biochemical basis of cobalamin deficiency.
      However, we advocate concomitant determination of the serum B12 level to safeguard against laboratory error in view of the dire clinical consequences associated with vitamin B12 deficiency (Figure 3). If 1 of the 2 tests has abnormal results, the serum methylmalonic acid level should be checked; an increased level strongly suggests B12 deficiency.
      Figure thumbnail gr3
      FIGURE 3Diagnostic algorithm for macrocytic anemia. MCV = mean corpuscular volume; MDS = myelodysplastic syndrome; MMA = methylmalonic acid.
      In patients with vitamin B12 deficiency, the next step is to screen for the presence of intrinsic factor antibodies
      • Coffey RL
      • Zile MR
      • Luskin AT
      Immunologic tests of value in diagnosis, 1: acute phase reactants and autoantibodies.
      • Snow CF
      Laboratory diagnosis of vitamin B12 and folate deficiency: a guide for the primary care physician.
      ; if present, a working diagnosis of pernicious anemia (PA) is made. Otherwise, the Schilling test is performed to differentiate PA from primary intestinal malabsorptive disorders.
      • Snow CF
      Laboratory diagnosis of vitamin B12 and folate deficiency: a guide for the primary care physician.
      • Strauchen JA
      An augmented Schilling test in the diagnosis of pernicious anaemia.
      Further investigation of macrocytic anemia that is neither drug-induced nor nutritional is simplified by subcategorizing the process into either a marked (MCV, >110 fL) or mild (MCV, 100-110 fL) subtype. In this instance, markedly macrocytic anemia is almost always associated with primary bone marrow disease, whereas mildly macrocytic anemia also can be associated with more benign conditions (Figure 3).
      • Colon-Otero G
      • Menke D
      • Hook CC
      A practical approach to the differential diagnosis and evaluation of the adult patient with macrocytic anemia.
      • Zittoun J
      Macrocytic anemia in adults: physiopathology, etiology, diagnosis and treatment [in French].

      Thrombocytopenia

      The first step in treating thrombocytopenia is to exclude the possibility of spurious thrombocytopenia caused by EDTA-induced platelet clumping (Figure 4).
      • Bizzaro N
      EDTA-dependent pseudothrombocytopenia: a clinical and epidemiological study of 112 cases, with 10-year follow-up.
      The situation is clarified by either examining the PBS or repeating the CBC using sodium citrate as an anticoagulant. Another important point to consider before starting a costly search for disease is the fact that healthy women may experience mild to moderate thrombocytopenia (platelets, 75-150 × 10
      Hematological and nutritional biochemistry reference data for persons 6 months-74 years of age: United States, 1976-80.
      /L) during pregnancy, and such incidental thrombocytopenia of pregnancy requires no further investigation.
      • Crowther MA
      • Burrows RF
      • Ginsberg J
      • Kelton JG
      Thrombocytopenia in pregnancy: diagnosis, pathogenesis and management.
      Figure thumbnail gr4
      FIGURE 4Diagnostic approach to thrombocytopenia. ANA = antinuclear antibody; DIC = disseminated intravascular coagulation; HIT = heparin-induced thrombocytopenia; HIV = human immunodeficiency virus; ITP = idiopathic thrombocytopenic purpura; LDH = lactate dehydrogenase; PBS = peripheral blood smear; SPEP = serum protein electrophoresis; TTP/HUS = thrombotic thrombocytopenic purpura/hemolytic uremic syndrome.
      The second step in treating patients with thrombocytopenia is to always consider the possibility of thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS) because of the urgency for specific therapy for these diagnoses (ie, plasma apheresis).
      • Sadler JE
      • Moake JL
      • Miyata T
      • George JN
      Recent advances in thrombotic thrombocytopenic purpura.
      • Elliott MA
      • Nichols Jr, WL
      • Plumhoff EA
      • et al.
      Posttransplantation thrombotic thrombocytopenic purpura: a single-center experience and a contemporary review.
      This is why we recommend PBS (to look for schistocytes); serum levels of haptoglobin and LDH (to assess for concomitant hemolysis) and creatinine; and coagulation tests including plasma levels of D-dimer, in most instances of thrombocytopenia. Both TTP/HUS and disseminated intravascular coagulation are characterized by microangiopathic hemolytic anemia and thus display schistocytes on PBS, an increased LDH level, and a decreased haptoglobin level.
      • Tefferi A
      • Elliott MA
      Schistocytes on the peripheral blood smear.
      However, coagulation studies are usually normal in TTP/HUS, whereas clotting times are prolonged in disseminated intravascular coagulation. Regardless, suspected TTP/HUS requires a hematology consultation.
      The third step is consideration of both drug-related thrombocytopenia and hypersplenism in all instances.
      • George JN
      • Raskob GE
      • Shah SR
      • et al.
      Drug-induced thrombocytopenia: a systematic review of published case reports.
      • van den Bemt PM
      • Meyboom RH
      • Egberts AC
      Drug-induced immune thrombocytopenia.
      • Peck-Radosavljevic M
      Hypersplenism.
      Thrombocytopenia is more likely to occur in the presence of hypersplenism associated with cirrhosis.
      • Bashour FN
      • Teran JC
      • Mullen KD
      Prevalence of peripheral blood cytopenias (hypersplenism) in patients with nonalcoholic chronic liver disease.
      The most frequently implicated drugs in thrombocytopenia are antibiotics including trimethoprim-sulfamethoxazole, cardiac medications (eg, quinidine, procainamide), thiazide diuretics, antirheumatics including gold salts, and heparin.
      • George JN
      • Raskob GE
      • Shah SR
      • et al.
      Drug-induced thrombocytopenia: a systematic review of published case reports.
      Heparin-induced thrombocytopenia is potentially catastrophic and requires immediate cessation of drug use, including heparin flushes.
      • Warkentin TE
      Heparin-induced thrombocytopenia: diagnosis and management.
      A diagnosis of heparin-induced thrombocytopenia may be confirmed by in vitro testing to detect heparin-dependent platelet antibodies.
      After microangiopathic hemolytic anemia, drug-induced thrombocytopenia, and hypersplenism have been ruled out, idiopathic thrombocytopenic purpura (ITP) becomes the major contender in the differential diagnosis of isolated thrombocytopenia.
      • Huber MR
      • Kumar S
      • Tefferi A
      Treatment advances in adult immune thrombocytopenic purpura.
      • Stasi R
      • Provan D
      Management of immune thrombocytopenic purpura in adults.
      • George JN
      • Vesely SK
      How can we provide the best care for our patients with immune thrombocytopenic pupura? [editorial].
      However, ITP is currently a diagnosis of exclusion that requires consideration of other causes of immune-mediated thrombocytopenia including connective tissue disease, lymphoproliferative disorders, and human immunodeficiency virus (HIV) infection.
      • Evatt BL
      HIV infection and thrombocytopenia.
      Therefore, we recommend laboratory tests for HIV, antinuclear antibodies, and monoclonal protein for further investigation. In contrast, neither platelet antibody test nor bone marrow biopsy is indicated in the work-up of most patients with isolated thrombocytopenia that is consistent with ITP.
      • George JN
      Idiopathic thrombocytopenic purpura in adults: current issues for pathogenesis, diagnosis and management.
      Rare causes of isolated thrombocytopenia include hereditary thrombocytopenias that may be associated with giant platelets on PBS (eg, May-Hegglin anomaly, gray platelet syndrome, Bernard-Soulier syndrome, and X-linked Wiskott-Aldrich syndrome),
      • Cines DB
      • Bussel JB
      • McMillan RB
      • Zehnder JL
      Congenital and acquired thrombocytopenia.
      myelodysplastic syndrome (MDS) (rarely presents with isolated thrombocytopenia),
      • Kuroda J
      • Kimura S
      • Kobayashi Y
      • Wada K
      • Uoshima N
      • Yoshikawa T
      Unusual myelodysplastic syndrome with the initial presentation mimicking idiopathic thrombocytopenic purpura.
      amegakaryocytic thrombocytopenia (a bone marrow biopsy is required for diagnosis),
      • Boggs DR
      Amegakaryocytic thrombocytopenia.
      and posttransfusion purpura (a rare complication of blood transfusion).
      • Gonzalez CE
      • Pengetze YM
      Post-transfusion purpura.
      A history of blood component transfusion at 1 to 2 weeks before onset of thrombocytopenia should suggest posttransfusion purpura. In all the aforementioned situations, a hematology consultation is advised.

      Leukopenia

       Neutropenia

      The absolute neutrophil count (ANC) is either derived by multiplying the total leukocyte count by the percentage of band neutrophils and segmented neutrophils or obtained directly from an electronic cell counter. Neutropenia is clinically most relevant when it is severe (ANC, <0.5 × 10
      Hematological and nutritional biochemistry reference data for persons 6 months-74 years of age: United States, 1976-80.
      / L) because of the associated risk of infection.
      • Bodey GP
      • Buckley M
      • Sathe YS
      • Freireich EJ
      Quantitative relationships between circulating leukocytes and infection in patients with acute leukemia.
      Severe neutropenia is classified into congenital and acquired categories. The congenital category includes Kostmann syndrome (congenital agranulocytosis), cyclic neutropenia, and other lesser known entities.
      • Berliner N
      • Horwitz M
      • Loughran Jr, TP
      Congenital and acquired neutropenia.
      Both hematology and medical genetics consultations are advised for patients with congenital severe neutropenia but not for those with benign chronic neutropenia that occurs usually in persons of African or Yemenite Jewish ancestry without sparing other ethnic groups.
      • Shaper AG
      • Lewis P
      Genetic neutropenia in people of African origin.
      • Djaldetti M
      • Joshua H
      • Kalderon M
      Familial leukopenia-neutropenia in Yemenite Jews: observations on eleven families.
      • Shoenfeld Y
      • Modan M
      • Berliner S
      • et al.
      The mechanism of benign hereditary neutropenia.
      • Berliner S
      • Shapira I
      • Toker S
      • Melamed S
      • Shirom A
      • Rogowski O
      Benign hereditary leukopenia-neutropenia does not result from lack of low grade inflammation: a new look in the era of microinflammation.
      • Shoenfeld Y
      • Alkan ML
      • Asaly A
      • Carmeli Y
      • Katz M
      Benign familial leukopenia and neutropenia in different ethnic groups.
      The ANC in benign chronic neutropenia ranges usually between 0.5 × 10
      Hematological and nutritional biochemistry reference data for persons 6 months-74 years of age: United States, 1976-80.
      /L and 1.5 × 10
      Hematological and nutritional biochemistry reference data for persons 6 months-74 years of age: United States, 1976-80.
      /L, and the clinical course is asymptomatic.
      The most frequent cause of acquired neutropenia is drug therapy; the most commonly implicated agents are listed in Table 3.
      • Berliner N
      • Horwitz M
      • Loughran Jr, TP
      Congenital and acquired neutropenia.
      • Boxer L
      • Dale DC
      Neutropenia: causes and consequences.
      • van Staa TP
      • Boulton F
      • Cooper C
      • Hagenbeek A
      • Inskip H
      • Leufkens HG
      Neutropenia and agranulocytosis in England and Wales: incidence and risk factors.
      However, any drug should be assumed to be a potential offender until proved otherwise. Infection is another common cause of neutropenia, and the major culprits are viruses and sepsis. In the clinical setting, where either drug- or infection-associated neutropenia is suspected, appropriate immediate measures include discontinuation of the presumed offending agent, close monitoring of daily CBC, and consideration of treatment with a myeloid growth factor in patients with uncontrolled bacterial or fungal infection.
      TABLE 3Drugs Frequently Implicated in Neutropenia
      Drug categoryDrugs
      AnticonvulsantsCarbamazepine, valproic acid, diphenylhydantoin
      Thyroid inhibitorsCarbimazole, methimazole, propylthiouracil
      AntibioticsPenicillins, cephalosporins, sulfonamides, chloramphenicol, vancomycin, trimethoprim-sulfamethoxazole
      AntipsychoticsClozapine
      AntiarrhythmicsProcainamide
      AntirheumaticsGold salts, hydroxychloroquine, penicillamine
      Aminosalicylates
      Nonsteroidal anti-inflammatory drugs
      Other causes of acquired neutropenia include immune neutropenia, large granular lymphocyte (LGL) leukemia, and other hematologic malignancies that present only rarely with isolated neutropenia (eg, MDS).
      • Berliner N
      • Horwitz M
      • Loughran Jr, TP
      Congenital and acquired neutropenia.
      • Dhodapkar MV
      • Li CY
      • Lust JA
      • Tefferi A
      • Phyliky RL
      Clinical spectrum of clonal proliferations of T-large granular lymphocytes: a T-cell clonopathy of undetermined significance?.
      • Tefferi A
      • Li CY
      • Witzig TE
      • Dhodapkar MV
      • Okuno SH
      • Phyliky RL
      Chronic natural killer cell lymphocytosis: a descriptive clinical study.
      • Las Heras G
      • Marti JM
      • Villamor N
      • Ribera JM
      • Feliu E
      • Rozman C
      Intense neutropenia of 14 years duration as the only manifestation of a myelodysplastic syndrome [in Spanish].
      In all such patients, we recommend PBS, lymphocyte immunophenotyping by flow cytometry, T-cell receptor (TCR) gene rearrangement studies, and antineutrophil antibody testing as initial screening. The inability to appreciate LGLs on PBS does not rule out the possibility of LGL leukemia, and definitive diagnosis requires review of both the TCR gene rearrangement and flow cytometry results. Immune neutropenia may or may not be associated with an autoimmune disease (eg, lupus, Felty syndrome), and detection of an antineutrophil antibody supports the diagnosis.
      • Berliner N
      • Horwitz M
      • Loughran Jr, TP
      Congenital and acquired neutropenia.

       Lymphopenia

      The possibility of recent therapy with immunosuppressive drugs, including corticosteroids and antilymphocyte monoclonal antibodies, must be considered first in treating the patient with lymphopenia.
      • Gergely P
      Drug-induced lymphopenia: focus on CD4+ and CD8+ cells.
      • Plosker GL
      • Figgitt DP
      Rituximab: a review of its use in non-Hodgkin's lymphoma and chronic lymphocytic leukaemia.
      Other causes of acquired lymphopenia, which should be familiar to the primary care physician, include viral infections such as acquired immunodeficiency syndrome and severe acute respiratory syndrome,
      • Micali S
      Mechanism for the T4 lymphopenia of AIDS.
      • Panesar NS
      Lymphopenia in SARS [letter].
      critical illness including sepsis,
      • Hotchkiss RS
      • Tinsley KW
      • Swanson PE
      • et al.
      Sepsis-induced apoptosis causes progressive profound depletion of B and CD4+ T lymphocytes in humans.
      autoimmune and connective tissue diseases including lupus and rheumatoid arthritis,
      • Noguchi M
      • Iwamori M
      • Hirano T
      • et al.
      Autoantibodies to T and B cell lines detected in serum samples from patients with systemic lupus erythematosus with lymphopenia and hypocomplementaemia.
      • Symmons DP
      • Farr M
      • Salmon M
      • Bacon PA
      Lymphopenia in rheumatoid arthritis.
      • Izzedine H
      • Cacoub P
      • Launay-Vacher V
      • Bagnis C
      • Deray G
      Lymphopenia in Wegener's granulomatosis: a new clinical activity index?.
      sarcoidosis,
      • Selroos O
      • Koivunen E
      Prognostic significance of lymphopenia in sarcoidosis.
      chronic renal failure,
      • Fernandez-Fresnedo G
      • Ramos MA
      • Gonzalez-Pardo MC
      • de Francisco AL
      • Lopez-Hoyos M
      • Arias M
      B lymphopenia in uremia is related to an accelerated in vitro apoptosis and dysregulation of Bcl-2.
      • Bhaskaran M
      • Ranjan R
      • Shah H
      • et al.
      Lymphopenia in dialysis patients: a preliminary study indicating a possible role of apoptosis.
      excess alcohol use,
      • Tonnesen H
      • Andersen JR
      • Pedersen AE
      • Kaiser AH
      Lymphopenia in heavy drinkers—reversibility and relation to the duration of drinking episodes.
      older age,
      • Rea IM
      • Alexander HD
      • Crockard AD
      • Morris TC
      CD4 lymphopenia in very elderly people [letter] [published correction appears in Lancet. 1996;347:914].
      thymoma,
      • Montella L
      • Masci AM
      • Merkabaoui G
      • et al.
      B-cell lymphopenia and hypogammaglobulinemia in thymoma patients.
      and tuberculosis and other bacterial infections.
      • Onwubalili JK
      • Edwards AJ
      • Palmer L
      T4 lymphopenia in human tuberculosis.
      An immunology consultation is advised if congenital lymphopenia is suspected including Bruton X-linked agammaglobulinemia (B-cell deficiency), severe combined immunodeficiency (B-cell and T-cell deficiency), and DiGeorge syndrome (T-cell deficiency).
      • Ochs HD
      • Smith CI
      X-linked agammaglobulinemia: a clinical and molecular analysis.
      • Buckley RH
      Primary cellular immunodeficiencies.
      Regarding common variable immunodeficiency, the most common primary immunodeficiency syndrome that is symptomatic, it is important to know that the lymphocyte count may or may not be normal.
      • Spickett GP
      Current perspectives on common variable immunodeficiency (CVID).

      Polycythemia

      An “increased” Hgb always raises the possibility of polycythemia vera (PV).
      • Tefferi A
      Polycythemia vera: a comprehensive review and clinical recommendations.
      However, many other conditions are associated with increased Hgb that indicate either a real increase in RBC mass (RCM) (true polycythemia) or a spurious perception of an increase in RCM (apparent polycythemia). True polycythemia is caused by either PV, which is a clonal myeloproliferative disorder, or a nonclonal increase in RCM that is often, but not always, driven by erythropoietin (secondary polycythemia). Therefore, PV must be distinguished from both apparent and secondary polycythemia. Figure 5 shows a way to accomplish this distinction without measuring RCM.
      • Tefferi A
      Polycythemia vera: a comprehensive review and clinical recommendations.
      In general, we believe that a well-informed hematologist in partner with an experienced clinical pathologist should be able to make a working diagnosis of PV, based on patient history, physical examination, serum erythropoietin level, and bone marrow examination, without resorting to specialized tests.
      • Tefferi A
      Polycythemia vera: a comprehensive review and clinical recommendations.
      • Knutsen H
      • Tefferi A
      Polycythemia vera evaluation algorithm revisited [letter and reply].
      • Marinella MA
      The red scalp sign [letter].
      However, a new molecular marker (a Janus kinase 2 [JAK2] tyrosine kinase activating mutation, JAK2V617F) that is closely associated with PV has just been described, and current diagnostic algorithms may need to be modified accordingly (see accompanying article by Tefferi and Gilliland
      • Tefferi A
      • Gilliland DG
      The JAK2V617F tyrosine kinase mutation in myeloproliferative disorders: status report and immediate implications for disease classification and diagnosis.
      in the current issue of the Mayo Clinic Proceedings).
      Figure thumbnail gr5
      FIGURE 5Diagnostic algorithm for polycythemia vera (PV).
      *Clinical clues for PV include splenomegaly, thrombosis, aquagenic pruritus, and erythromelalgia. Laboratory clues for PV include thrombocytosis, leukocytosis, and increased leukocyte alkaline phosphatase score. Janus kinase 2 (JAK2) screening is to detect the V617F mutation that occurs in most patients with PV. BM = bone marrow; CBC = complete blood cell count; MPD = myeloproliferative disorders.
      †Alternatively, one can consider mutation screening for JAK2V617F to help decide necessity of BM examination.

      Thrombocytosis

      Thrombocytosis may represent either a myeloid malignancy (primary thrombocytosis [PT]) or a secondary process related to various clinical conditions including IDA, surgical asplenia, infection, chronic inflammation, hemolysis, tissue damage, and nonmyeloid malignancy (reactive thrombocytosis [RT]).
      • Tefferi A
      Thrombocytosis and essential thrombocythemia.
      The distinction between PT and RT is clinically relevant because the former but not the latter is associated with increased risk of thrombohemorrhagic complications.
      • Tefferi A
      • Murphy S
      Current opinion in essential thrombocythemia: pathogenesis, diagnosis, and management.
      Patient history and physical findings are most helpful in making this distinction and are complemented by other findings on CBC: increased Hgb level, MCV, or WBC count favors a diagnosis of PT, whereas microcytic anemia suggests RT associated with IDA. In general, the degree of thrombocytosis is a poor discriminator of PT and RT, and the latter may be a possibility even when the platelet count is greater than 1000 × 10
      Hematological and nutritional biochemistry reference data for persons 6 months-74 years of age: United States, 1976-80.
      /L.
      • Tefferi A
      Thrombocytosis and essential thrombocythemia.
      • Chuncharunee S
      • Archararit N
      • Ungkanont A
      • et al.
      Etiology and incidence of thrombotic and hemorrhagic disorders in Thai patients with extreme thrombocytosis.
      The first step in treating a patient with thrombocytosis should be a review of old medical records to determine the duration of disease. Chronic thrombocytosis, in the absence of surgical asplenia, is highly suggestive of PT. Initial laboratory tests in this instance, as well as in the absence of clinical evidence for RT, should include PBS, serum ferritin, and C-reactive protein
      • Tefferi A
      • Ho TC
      • Ahmann GJ
      • Katzmann JA
      • Greipp PR
      Plasma interleukin-6 and C-reactive protein levels in reactive versus clonal thrombocytosis.
      (Figure 6). Platelet morphology is normal in RT, but the PBS may reveal the presence of Howell-Jolly bodies in patients with asplenia, anisocytosis and poikilocytosis in patients with IDA, and polychromasia in patients with hemolysis. A normal serum ferritin level excludes the possibility of IDA-associated RT. However, a low serum ferritin level does not exclude the possibility of PT. A measurement of C-reactive protein is helpful in examining the possibility of an occult inflammatory or malignant process as a cause of RT.
      • Tefferi A
      • Ho TC
      • Ahmann GJ
      • Katzmann JA
      • Greipp PR
      Plasma interleukin-6 and C-reactive protein levels in reactive versus clonal thrombocytosis.
      Figure thumbnail gr6
      FIGURE 6Diagnostic approach to thrombocytosis.
      *Clinical evidence of reactive thrombocytosis (RT) includes the presence of infection, inflammatory condition, trauma or surgery, malignancy, hemolytic anemia, iron deficiency anemia, recent bleeding, and history of splenectomy. BM = bone marrow; CBC = complete blood cell count; CRP = C-reactive protein; FISH = fluorescence in situ hybridization; JAK2 = Janus kinase 2; PBS = peripheral blood smear. See text for interpretation of results of testing for serum ferritin and CRP levels and PBS.
      If the previously discussed work-up does not support a diagnosis of RT, then a bone marrow examination with cytogenetic studies as well as fluorescence in situ hybridization (FISH) for bcr/abl is indicated, and a hematology consultation is required to accurately interpret the test results.
      • Thiele J
      • Kvasnicka HM
      • Diehl V
      • Fischer R
      • Michiels J
      Clinicopathological diagnosis and differential criteria of thrombocythemias in various myeloproliferative disorders by histopathology, histochemistry and immunostaining from bone marrow biopsies.
      One must remember that essential thrombocythemia (ET) is not the only cause of PT; other causes include chronic myeloid leukemia (CML), MDS, and the cellular phase of myelofibrosis with myeloid metaplasia.
      Therefore, before a working diagnosis of ET is made, at a minimum the absence of the bcr/abl mutation must be determined by FISH.
      • Tefferi A
      • Dewald GW
      • Litzow ML
      • et al.
      Chronic myeloid leukemia: current application of cytogenetics and molecular testing for diagnosis and treatment.
      As mentioned previously for PV, the presence of the newly described JAK2 mutation (JAK2V617F) favors ET as opposed to RT but cannot distinguish ET from PV (see accompanying article by Tefferi and Gilliland
      • Tefferi A
      • Gilliland DG
      The JAK2V617F tyrosine kinase mutation in myeloproliferative disorders: status report and immediate implications for disease classification and diagnosis.
      in the current issue of the Mayo Clinic Proceedings).

      LEUKOCYTOSIS

      The first step in evaluating an increased WBC count (leukocytosis) is to examine the WBC differential to determine which WBC type is in excess. The differential usually is reported along with the WBC count at no extra charge. The increase in WBCs may be secondary to either immature precursors or blasts (acute leukemia) or expansion of the aforementioned mature leukocyte types (granulocytes, lymphocytes, monocytes). Therefore, a PBS is recommended to exclude the possibility of acute leukemia and to classify the process as granulocytosis, monocytosis, or lymphocytosis. Each of these can be reactive or neoplastic (clonal).

       Granulocytosis

       Neutrophilia

      Neutrophilia represents either a reactive phenomenon (leukemoid reaction) or a myeloid malignancy.
      • Ramos FJ
      • Zamora F
      • Perez-Sicilia M
      • Sang MA
      • del Villar R
      Chronic granulocytic leukemia versus neutrophilic leukemoid reaction.
      A leukemoid reaction often is associated with infection, inflammation, malignancy, or use of drugs including glucocorticoids, psychiatric medications, and myeloid growth factors.
      • Darko DF
      • Rose J
      • Gillin JC
      • Golshan S
      • Baird SM
      Neutrophilia and lymphopenia in major mood disorders.
      • Kayashima T
      • Yamaguchi K
      • Akiyoshi T
      • Nanimatsu H
      • Aragaki S
      • Hosokawa T
      Leukemoid reaction associated with diabetic ketoacidosis—with measurement of plasma levels of granulocyte colony-stimulating factor.
      • Cvitkovic E
      • Bachouchi M
      • Boussen H
      • et al.
      Leukemoid reaction, bone marrow invasion, fever of unknown origin, and metastatic pattern in the natural history of advanced undifferentiated carcinoma of nasopharyngeal type: a review of 255 consecutive cases.
      • Marinella MA
      Extreme leukemoid reaction associated with retroperitoneal hemorrhage [letter].
      • Juturi JV
      • Hopkins T
      • Farhangi M
      Severe leukocytosis with neutrophilia (leukemoid reaction) in alcoholic steatohepatitis [letter].
      • Ferrer A
      • Cervantes F
      • Hernandez-Boluda JC
      • Alvarez A
      • Montserrat E
      Leukemoid reaction preceding the diagnosis of colorectal carcinoma by four years.
      • Au WY
      • Ma SK
      • Kwong YL
      Disseminated hepatosplenic mycobacterial infection masking myeloproliferative diseases as leukemoid reaction: a diagnostic pitfall.
      • Mukhopadhyay S
      • Mukhopadhyay S
      • Banki K
      • Mahajan S
      Leukemoid reaction: a diagnostic clue in metastatic carcinoma mimicking classic Hodgkin lymphoma.
      • Gillan ER
      • Christensen RD
      • Suen Y
      • Ellis R
      • van de Ven C
      • Cairo MS
      A randomized, placebo-controlled trial of recombinant human granulocyte colony-stimulating factor administration in newborn infants with presumed sepsis: significant induction of peripheral and bone marrow neutrophilia.
      Therefore, patient history and findings on physical examination dictate whether further laboratory investigation is necessary to determine the cause of the increased WBC count. Further evaluation, if indicated, starts with a PBS that may show circulating blasts (suggesting acute leukemia), leukoerythroblastic results (suggesting myelofibrosis with myeloid metaplasia or other marrow-infiltrating process), or simply left-shifted neutrophilia. Left-shifted neutrophilia suggests either CML or another myeloproliferative disorder
      • Tefferi A
      Chronic myeloid disorders: classification and treatment overview.
      ; a leukemoid reaction must be distinguished from both of these conditions, and neither the degree of left-shifted granulocytosis nor the leukocyte alkaline phosphatase score is considered diagnostically adequate.
      • Okun DB
      • Tanaka KR
      Leukocyte alkaline phosphatase.
      Therefore, if the patient's history does not suggest a leukemoid reaction, we recommend peripheral blood FISH for bcr/abl to rule out the possibility of CML in mild cases of mature neutrophilia (WBC, <20 × 10
      Hematological and nutritional biochemistry reference data for persons 6 months-74 years of age: United States, 1976-80.
      /L).
      • Tefferi A
      • Dewald GW
      • Litzow ML
      • et al.
      Chronic myeloid leukemia: current application of cytogenetics and molecular testing for diagnosis and treatment.
      A hematology consultation is required in the presence of either a higher degree of leukocytosis or left-shift. Also of note, a rare form of myeloid malignancy, chronic neutrophilic leukemia, presents with mature neutrophilia and minimal left-shift.
      • Elliott MA
      • Hanson CA
      • Dewald GW
      • Smoley SA
      • Lasho TL
      • Tefferi A
      WHO-defined chronic neutrophilic leukemia: a long-term analysis of 12 cases and a critical review of the literature [letter].

       Eosinophilia

      The first step in treating a patient with blood eosinophilia is to exclude the possibility of “secondary” eosinophilia caused by parasite infestation, drugs, comorbid conditions such as asthma and other allergic conditions, vasculitides, lymphoma, and metastatic cancer.
      • Tefferi A
      Blood eosinophilia: a new paradigm in disease classification, diagnosis, and treatment.
      Therefore, the initial approach should include obtaining a good patient history and ordering a stool test for ova and parasites. In contrast, in all patients with “primary” eosinophilia, a bone marrow biopsy is recommended to distinguish between clonal eosinophilia and the hypereosinophilic syndrome (HES).
      • Tefferi A
      Blood eosinophilia: a new paradigm in disease classification, diagnosis, and treatment.
      Bone marrow examination in patients with suspected HES should include cytogenetic studies, FISH for FIP1L1-PDGFRA mutation, immunohistochemical stains for tryptase, and mast cell immunophenotyping. These tests are necessary to determine whether a patient will respond to treatment with imatinib mesylate.
      • Pardanani A
      • Brockman SR
      • Paternoster SF
      • et al.
      FIP1L1-PDGFRA fusion: prevalence and clinicopathologic correlates in 89 consecutive patients with moderate to severe eosinophilia.
      • Pardanani A
      • Tefferi A
      Imatinib targets other than bcr/abl and their clinical relevance in myeloid disorders.
      Additional blood studies that are currently considered during the evaluation of primary eosinophilia include serum tryptase (an increased level suggests mastocytosis and warrants molecular studies to detect FIP1L1-PDGFRA), T-cell immunophenotyping as well as TCR gene rearrangement analysis (positive test results suggest an underlying clonal T-cell disorder), serum interleukin 5 (an elevated level requires careful evaluation of the bone marrow for the presence of a clonal T-cell disease), and serum IgE level (patients with increased IgE level may be at a lower risk of developing eosinphilia-associated heart disease).
      • Tefferi A
      Blood eosinophilia: a new paradigm in disease classification, diagnosis, and treatment.
      In addition to looking for the cause of eosinophilia, initial evaluation also should include laboratory tests to assess possible eosinophilic-mediated tissue damage. Noninvasive tests include chest radiography, pulmonary function tests, echocardiography, and measurement of serum troponin levels. An increased level of serum cardiac troponin has been shown to correlate with the presence of cardiomyopathy in HES.
      • Tefferi A
      Blood eosinophilia: a new paradigm in disease classification, diagnosis, and treatment.

       Basophilia

      Peripheral blood basophilia is an extremely rare condition that suggests chronic basophilic leukemia.
      • Pardanani AD
      • Morice WG
      • Hoyer JD
      • Tefferi A
      Chronic basophilic leukemia: a distinct clinico-pathologic entity?.
      Such a finding requires a bone marrow examination and a prompt hematology consultation.

       Monocytosis

      Absolute monocytosis that is persistent should be considered a marker of a myeloproliferative disorder (eg, chronic myelomonocytic leukemia) until proved otherwise by bone marrow examination and cytogenetic studies.
      • Tefferi A
      • Hoagland HC
      • Therneau TM
      • Pierre RV
      Chronic myelomonocytic leukemia: natural history and prognostic determinants.
      Therefore, we recommend a hematology consultation for further evaluation. Relative monocytosis often is seen during recovery from chemotherapy or drug-induced neutropenia and does not require additional work-up. Reactive absolute monocytosis rarely may accompany chronic infectious, inflammatory, or granulomatous processes as well as metastatic cancer, lymphoma, radiation therapy, and depression and may follow acute myocardial infection.
      • Maldonado JE
      • Hanlon DG
      Monocytosis: a current appraisal.
      • Tsukahara T
      • Yaguchi A
      • Horiuchi Y
      Significance of monocytosis in varicella and herpes zoster.
      • Karayalcin G
      • Khanijou A
      • Kim KY
      • Aballi AJ
      • Lanzkowsky P
      Monocytosis in congenital syphilis.
      • Radhakrishna Pillai M
      • Balaram P
      • Bindu S
      • Hareendran NK
      • Padmanabhan TK
      • Nair MK
      Radiation associated eosinophilia and monocytosis in carcinoma of the uterine cervix: a simple reliable clinical and prognostic indicator.
      • Maes M
      • Van der Planken M
      • Stevens WJ
      • et al.
      Leukocytosis, monocytosis and neutrophilia: hallmarks of severe depression.

       Lymphocytosis

      The first step in the evaluation of lymphocytosis is a PBS to review the morphology of the excess lymphocytes. Reactive lymphocytosis is characterized by LGL morphology and must be distinguished from LGL leukemia.
      • Dhodapkar MV
      • Li CY
      • Lust JA
      • Tefferi A
      • Phyliky RL
      Clinical spectrum of clonal proliferations of T-large granular lymphocytes: a T-cell clonopathy of undetermined significance?.
      • Tefferi A
      • Li CY
      • Witzig TE
      • Dhodapkar MV
      • Okuno SH
      • Phyliky RL
      Chronic natural killer cell lymphocytosis: a descriptive clinical study.
      • Hutchinson RE
      • Kurec AS
      • Davey FR
      Lymphocytic surface markers in lymphoid leukemoid reactions.
      Reactive T-cell lymphocytosis (eg, from viral infection) and LGL leukemia can be distinguished by the nonhematologist by TCR gene rearrangement studies from the peripheral blood. However, a specific test should not be ordered if the clinical scenario is consistent with viral infection; after the patient recovers, the CBC and PBS should be repeated to see whether the abnormality has resolved. Similarly, a mild increase in LGL level with no symptoms or cytopenia may require no further investigation.
      Lymphocytosis with normal-appearing small-lymphocyte morphology suggests B-cell chronic lymphocytic leukemia.
      • Tefferi A
      • Li C-Y
      • Phyliky RL
      Role of immunotyping in chronic lymphocytosis: review of the natural history of the condition in 145 adult patients.
      A spectrum of other morphologic abnormalities characterize other lymphoid neoplasms including acute leukemia (leukemic blasts could be mistaken for lymphocytes) or chronic lymphoid leukemias that are not chronic lymphocytic leukemia (Table 4). Such processes may be derived from B-cell, T-cell, or natural killer cell lineage.
      • Tefferi A
      • Li C-Y
      • Phyliky RL
      Role of immunotyping in chronic lymphocytosis: review of the natural history of the condition in 145 adult patients.
      However, the PBS has limited value in the differential diagnosis of lymphocytosis; we recommend, in addition, immunophenotyping by flow cytometry in all such cases. The immunophenotypic profile that accompanies the myriad of chronic lymphoid leukemia is outlined in Table 4 as a resource for the hematologist. In general, we recommend a hematology consultation for any lymphocytosis that is not reactive.
      TABLE 4Variants of Chronic Lymphoid Leukemia and Their Immunophenotypic Profile
      TypeImmunophenotypic profile
      B-cell chronic lymphocytic leukemia (CLL)CD20+ (dim)sIg(dim)CD5+CD23+
      Hairy cell leukemia (B cell)CD20+ (bright), sIg(bright), CD11c+ (bright)CD5CD25+ (bright)CD103+
      Hairy cell leukemia-variant (B cell)CD20+ (bright), sIg(bright), CD11c+ (bright)CD5CD25CD103
      Mantle cell lymphoma (B cell)CD20+ (bright)sIg(bright), CD5+CD23CD22+FMC7+
      Small cleaved cell leukemia (B cell)CD20+ (bright)sIg(bright)CD5CD10+
      Splenic marginal zone lymphoma (B cell)CD20+ (bright), CD22+, sIg(bright), CD5, CD10, CD25, CD103, CD11c+/–
      Lymphoplasmacytoid lymphoma (Waldenström)CD20+, CD22+, sIg(bright), CD5, CD10, CD25, CD103, CD11c+/–
      B-prolymphocytic leukemiaCD20+ (bright), sIg(bright), CD5CD23FMC7+
      T-prolymphocytic leukemia (T-helper CLL)CD3+CD7+CD4+CD5+CD8+/–CD25
      Hepatosplenic γ/δ T-cell lymphomaCD2+ (bright)CD3+CD7+CD16+CD4CD8−/+CD5CD25, γ/δ receptor+
      T-large granular lymphocyte leukemiaCD3+CD8+ (dim)CD2+ (dim)CD4CD57+CD16+
      Adult T-cell leukemia/lymphoma (ATL)CD3+ (dim)CD7CD4+CD25+
      Sézary syndrome (T cell)CD3+ (dim)CD7CD4+CD8CD25
      Chronic natural killer cell lymphocytosisCD3CD20CD16+CD56+

      Conclusion

      A nonhematologist should be able to address some but not all CBC abnormalities. We hope to have provided some guidance in this regard. In general, it is prudent to perform a PBS in most instances of abnormal CBC, along with basic tests that are dictated by the type of CBC abnormalities. The latter may include, for example, serum ferritin in patients with microcytic anemia or lymphocyte immunophenotyping by flow cytometry in patients with lymphocytosis; whether a hematology consultation is needed can be based on the initial laboratory results, which always are reviewed in the context of the clinical history. However, a prompt hematology consultation is encouraged in patients with severe cytopenia, pancytopenia, or extreme cytosis of any type or when a PBS report suggests TTP or acute leukemia. Finally, we strongly encourage the practice of always reviewing old medical records before initiating a costly work-up of an “abnormal” CBC.

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      Questions About Abnormal CBC in Adults

      • 1
        A 68-year-old woman was found to have an increased WBC count on routine laboratory testing. The PBS revealed lymphocytosis with mature-appearing morphology. Immunophenotyping by flow cytometry revealed a monoclonal (ie, light chain- restricted) B-cell population that expressed CD20 (bright), CD5, but not CD23 or CD10. Which one of the following is the most likely diagnosis?
        • a
          Hairy cell leukemia
        • b
          Mantle cell lymphoma
        • c
          B-cell chronic lymphocytic leukemia
        • d
          Small cleaved cell leukemia
        • e
          Marginal zone lymphoma
      • 2
        During evaluation for microcytic anemia in a patient with rheumatoid arthritis, the patient's serum ferritin level was found to have increased. Which one of the following statements is true regarding this case?
        • a
          IDA is unlikely
        • b
          IDA cannot be ruled out
        • c
          The patient could have both IDA and ACD
        • d
          ACD is unlikely
        • e
          Thalassemia can be ruled out
      • 3
        During evaluation for low normal serum B12 level associated with normocytic anemia, the patient's serum homocysteine level was found to be normal. Which one of the following statements is false regarding this case?
        • a
          PA is unlikely
        • b
          The serum methylmalonic acid level must be determined to rule out B12 deficiency
        • c
          The Schilling test is not necessary
        • d
          The PBS is unlikely to show hypersegmented neutrophils
        • e
          B12 deficiency is not always associated with macrocytic anemia
      • 4
        A 20-year-old African American man presents with a WBC count of 3 × 10
        Hematological and nutritional biochemistry reference data for persons 6 months-74 years of age: United States, 1976-80.
        /L. The WBC differential reveals an ANC of 1.2 × 10
        Hematological and nutritional biochemistry reference data for persons 6 months-74 years of age: United States, 1976-80.
        /L. The patient is completely asymptomatic, and his family history, medical history, and medication history are all unremarkable. Review of old medical records shows that the patient usually has a mildly low WBC count. Which one of the following is the next appropriate step?
        • a
          Bone marrow biopsy
        • b
          Hematology consultation
        • c
          Periodic monitoring of WBC count with no further investigation at this point
        • d
          Long-term use of myeloid growth factors to keep the WBC count normal
        • e
          Long-term use of prophylactic antibiotics
      • 5
        A 33-year-old white man presents with heart failure and blood eosinophilia (absolute eosinophil count, 5 × 10
        Hematological and nutritional biochemistry reference data for persons 6 months-74 years of age: United States, 1976-80.
        /L). Extensive work-up disclosed no cause for reactive eosinophilia. Which one of the following tests provides the most treatment-relevant information?
        • a
          Serum interleukin 5 level
        • b
          PBS or bone marrow FISH for CHIC2 deletion
        • c
          T-cell immunophenotyping and TCR gene rearrangement studies
        • d
          Bone marrow histological examination
        • e
          Bone marrow karyotype analysis

      Correct answers:
      1. b, 2. a, 3. b, 4. c, 5. b