Interpreting an Abnormal CBC Nicholas A. Forward MD, MSc, FRCPC Assistant Professor Division of Hematology Dalhousie University [email protected] Interpreting an Abnormal CBC – April 11, 2018 1 Disclosures • No conflicts of interest particularly relevant to this talk • Advisory Boards • Celgene • Co-/sub-investigator on a number therapeutic trials for various hematologic malignancies including leukemia, lymphoma, myeloma • Not discussing “off-label” medication use Interpreting an Abnormal CBC – April 11, 2018 2 Lecture Objectives • 1. Understand normal blood cell production at a very broad level • 2. Develop an initial approach to working up CBC abnormalities • Cytopenias • “-Cytosis” • 3. Recognize concerning complete blood count abnormalities • Recognize hematologic emergencies/red flags • When to refer and our local triage criteria Interpreting an Abnormal CBC – April 11, 2018 3 Refresher- Normal Hematopoiesis Bone marrow Normal bone marrow Interpreting an Abnormal CBC – April 11, 2018 4 Refresher- Normal Hematopoiesis Courtesy of Dr. Clinton Campbell, Hematopathology Interpreting an Abnormal CBC – April 11, 2018 5 Refresher- Normal Hematopoiesis Courtesy of Dr. Clinton Campbell, Hematopathology Interpreting an Abnormal CBC – April 11, 2018 6 Refresher- The Peripheral Blood Smear Courtesy of Dr. Clinton Campbell, Hematopathology Interpreting an Abnormal CBC – April 11, 2018 7 Refresher – The bone marrow Normal bone marrow Interpreting an Abnormal CBC – April 11, 2018 8 Refresher- CBC Parameters Parameter Normal Range* Units WBC (White blood cells) 4.50-11.00 X 109 cells/L RBC (Red blood cells) 4.50-6.50 X 1012 cells/L Hgb (Hemoglobin) 140-180 g/L Hct (Hematocrit) 0.420-0.540 MCV (Mean corpuscular volume) 80.0-97.0 fL MCH (Mean corpuscular hemoglobin) 28.0-32.0 pg MCHC (Mean corpuscular hgb concentration) 315-350 g/L RDW (Red cell distribution width) 11.5-14.5 % Plt (Platelet) 150-350 X 109 cells/L MPV (Mean plateler volume) 9.0-12.5 fL Reticulocyte count 28.80-94.0 X 109 cells/L Reticulocyte percent 0.56-1.52 % Interpreting an Abnormal CBC – April 11, 2018 *QEII lab, male patient 9 Refresher – CBC Parameters Parameter Normal Range* Units Neutrophils (i.e. ANC, absolute neutrophil count) 2.00-7.50 X 109 cells/L Myelocytes* - Metamyelocytes* - Promyelocytes* - Blasts* - Lymphocytes 1.50-4.00 X 109 cells/L Monocytes 0.10-0.90 X 109 cells/L Eosinophils 0.00-0.50 X 109 cells/L Basophils 0.00-0.10 X 109 cells/L Immature granulocyte fraction (“IG”) 0.00-0.09 X 109 cells/L *Neutrophil precursors, will only be reported on manual differential (generally abnormal) KEY MESSAGE: The absolute counts are more important/helpful than the percentage counts Interpreting an Abnormal CBC – April 11, 2018 10 KEY MESSAGE: For WBC differential, focus on absolute counts, not percentages Interpreting an Abnormal CBC – April 11, 2018 11 Cytopenias – Conceptual Overview Courtesy of Dr. Clinton Campbell, Hematopathology Interpreting an Abnormal CBC – April 11, 2018 12 Cytopenias • Conceptual definition: • Decreased quantity (absolute) of a given cell lineage due to the inability of body to support effective hematopoiesis • Imbalance of supply and demand • Technical definition: • Cell concentration below reference range for age and gender • Generally measured in cells/L Interpreting an Abnormal CBC – April 11, 2018 13 Pancytopenia • Pancytopenia = decrease below reference range (for age) of neutrophils, platelets, and erythrocytes • Does not generally refer to lymphocytes, monocytes, other WBC lineages Interpreting an Abnormal CBC – April 11, 2018 14 A conceptual approach to pancytopenia Courtesy of Dr. Clinton Campbell, Hematopathology Interpreting an Abnormal CBC – April 11, 2018 15 A conceptual approach to workup of pancytopenia Courtesy of Dr. Clinton Campbell, Hematopathology Interpreting an Abnormal CBC – April 11, 2018 16 Anemia • Reticulocyte count • Elevated (destruction, blood loss) • Decreased, “abnormally normal” for degree of anemia • (decreased production) • Reticulocyte index • Absolute reticulocyte count/maturation factor • Hct ≥ 0.35: 1.0 • 0.35> Hct ≥ 0.25: 1.5 • 0.25 > Hct ≥ 0.20: 2.0 • 0.20 > Hct: 2.5 • RI >0.02 = adequate marrow response; RI <0.02 = inadequate response Interpreting an Abnormal CBC – April 11, 2018 17 Anemia – Kinetic approach Increased reticsre Decreased reticsre Easy! Bleeding or Hemolysis More difficult… Broader differential • Source of bleeding? • Morphologic approach • Hemolysis workup • Size of cells (MCV) • LDH (increased) • Unconjugated Bilirubin (increased) • Haptoglobin (decreased) • DAT (autoimmune) Microcytic Normocytic Macrocytic • Peripheral smear • Specialized testing • Membrane defects • Hemoglobin electrophoresis • PNH screen (flow cytometry) Interpreting an Abnormal CBC – April 11, 2018 18 Anemia - Microcytosis Iron status • Ferritin* Normal, Low iron • %sat • (Reticulated hemoglobin)1 elevated iron (Soluable transferrin receptor)2 Iron deficiency anemia Acquired Chronic • Other clues: • Increased RDW • Reactive thrombocytosis Anemia of chronic Thalassemias • Decreased MCV disease/inflammation • Normal or high RBC proportionate to (Hepcidin-mediated) count degree of anemia • Low MCV out of • Infection, inflammation • Identify source proportion to anemia Heavy metal toxicity *Consider IDA if ferritin <100-200 particularly if Sideroblastic anemia concomitant inflammation (Lead, others – rare) • (congenital; very rare) 1. Mast et al. Am J Hematol. 2008;83:307 2. Mast et al. Clin Chem. 1998;44:45 Interpreting an Abnormal CBC – April 11, 2018 19 Anemia- Macrocytosis Macrocytic • 6-MP/azathioprine • Hydroxyurea • Carbemazepine Rule out • Metformin medication effect • Isoniazid • Zidovudane • Trimethoprim B12, folate • Many others (MMA, homocysteine if borderline) • reviewed in Hesdorffer NEJM; 2015;373:1649 If normal… Mild increased MCV Marked increased MCV (100-110 fL) Apparent macrocytosis (>110 fL) • “Round macrocytes” • Clumps of cells • MDS • Reticulocytosis • Agglutination • Other marrow disorders • Liver disease • Rouleaux • EtOH effect • Hypothyroidism • Monoclonal protein • “Oval macrocytes” (SPEP) • MDS • Inflammation/Infection Interpreting an Abnormal CBC – April 11, 2018 20 Anemia- Normocytic Normocytic High retics Low/Normal retics Renal insufficiency? (high creatinine, low EPO) Bleeding, hemolysis Early/concomitant B12/folate or iron deficiency? Hypothyroidism? Anemia of inflammation/ Marrow failure Marrow infiltration “chronic disease” • Infection • (congenital) • Acute leukemia • Sepsis, HIV, HepB/C, • MDS parvovirus, EBV, CMV etc. • Myelofibrosis • Inflammatory disorders • Aplastic anemia • Lymphoma • Malignancy • Pure red cell aplasia • Myeloma • Metastatic cancer Medication effect • Granulomatous diseases • Storage diseases • Fungal infection Interpreting an Abnormal CBC – April 11, 2018 21 Example Case #1 • Asymptomatic 50 year old woman presenting with anemia on routine CBC • Hgb 101 g/L => 103 g/L 3 years ago • MCV 60.5 fL => 61.7 g/L 3 years ago • RBC 5.6 x 1012 cells/L • Peripheral smear: “Mild anemia with severe microcytosis, target cells” • Likely diagnosis: • VOTE: • 1. Iron deficiency • 2. Thalassemia trait • 3. Anemia of chronic disease • 4. Lead poisoning Interpreting an Abnormal CBC – April 11, 2018 22 Example Case #1 • Asymptomatic 40 year old woman presenting with anemia on routine CBC • Hgb 101 g/L => 103 g/L 3 years ago • MCV 60.5 fL => 61.7 g/L 3 years ago • RBC 5.6 x 1012 cells/L • Peripheral smear: “Mild anemia with severe microcytosis, target cells” • Likely diagnosis: • VOTE: • 1. Iron deficiency • 2. Thalassemia trait => Hemoglobin electrophoresis confirms beta thalassemia trait • 3. Anemia of chronic disease • 4. Lead poisoning Interpreting an Abnormal CBC – April 11, 2018 23 Example Case # 2 • 40 year old woman presenting with fatigue x several months • Hgb 45 g/L => 105 g/L 1 year ago • MCV 59.0 fL => MCV 80.0 fL 1 year ago • Peripheral smear: “Severe microcytic, hypochromic anemia with pencil cells” • No history of GI bleeding/menorrhagia; normal diet; no other symptoms • Likely diagnosis: • VOTE: 1. Iron deficiency 2. Thalassemia trait 3. Anemia of chronic disease 4. Lead poisoning Interpreting an Abnormal CBC – April 11, 2018 24 Example Case # 2 • 40 year old woman presenting with fatigue x several months • Hgb 45 g/L => 105 g/L 1 year ago • MCV 59.0 fL => MCV 80.0 fL 1 year ago • Peripheral smear: “Severe microcytic, hypochromic anemia with pencil cells” • No history of GI bleeding/menorrhagia; normal diet; no other symptoms • Likely diagnosis: • VOTE: 1. Iron deficiency => Ferritin 3; responded to IV iron; diagnosed with celiac dz. 2. Thalassemia trait 3. Anemia of chronic disease 4. Lead poisoning Interpreting an Abnormal CBC – April 11, 2018 25 Example case #3 • 53 year old male presenting with fatigue, back pain – no prior bloodwork • Hgb 88 g/L • MCV 104 g/L • Serum total protein 130 g/L (ULN 83) • Creatinine 117 umol/L • Peripheral smear: “Rouleaux present” • Likely diagnosis: • VOTE 1. B12 deficiency 2. Liver disease 3. Myeloma 4. MDS Interpreting an Abnormal CBC – April 11, 2018 26 Example case #3 • 53 year old male presenting with fatigue, lower back pain – no prior bloodwork • Hgb 88 g/L • MCV 104 g/L • Serum total protein 130 g/L (ULN 83) • Creatinine 117 umol/L • Peripheral smear: “Rouleaux present” • Likely diagnosis: • VOTE 1. B12 deficiency 2. Liver disease 3. Myeloma => IgG 98 g/L, SPEP- monoclonal IgG kappa, marrow:50% plasma cells, skeletal survery => large lytic lesion left iliac bone 4. MDS Interpreting an Abnormal CBC – April