Hematology: Diagnostic and Management Essentials
Diagnostic Tests for Anemia Evaluation
Begin with a complete blood count (CBC) including hemoglobin, white blood cells, and platelets to assess bone marrow function, as hemoglobin is more reproducible than hematocrit and unaffected by storage time or serum glucose levels 1.
Essential Initial Laboratory Tests
- Hemoglobin measurement defines anemia as <12 g/dL in non-pregnant women, <11 g/dL in pregnant women, and <13 g/dL in men 2
- Red cell indices including mean corpuscular volume (MCV) and red cell distribution width (RDW) are critical for classification 2, 3
- Reticulocyte count (absolute or reticulocyte index) evaluates bone marrow response appropriateness to anemia 1, 2
- Serum ferritin serves as surrogate marker for tissue iron stores 1
- Transferrin saturation represents iron available for erythropoiesis 1
- C-reactive protein helps assess inflammation status when interpreting iron studies 1, 2
Additional Tests Based on MCV Classification
- For microcytic anemia (MCV <80 fL): Iron studies (ferritin, transferrin saturation, total iron-binding capacity), and consider hemoglobin electrophoresis if thalassemia suspected 1, 2, 3
- For normocytic anemia (MCV 80-100 fL): Evaluate for hemorrhage, hemolysis (haptoglobin, LDH, bilirubin), or chronic inflammation 2, 3
- For macrocytic anemia (MCV >100 fL): Measure vitamin B12, folate levels, methylmalonic acid, and homocysteine 1, 2, 4
Specialized Testing
- Peripheral blood smear provides morphological assessment and characteristic findings 1, 5
- Coombs testing for patients with chronic lymphocytic leukemia, non-Hodgkin's lymphoma, or autoimmune disease history 1
- Bone marrow examination when abnormalities exist in two or more cell lines or diagnosis remains unclear 1
Common Causes of Anemia
Microcytic Anemia (MCV <80 fL)
- Iron deficiency anemia - most common cause worldwide, characterized by low ferritin (<30 μg/L without inflammation) and low transferrin saturation 2, 3, 5
- Thalassemia - inherited hemoglobin synthesis disorder with normal or elevated ferritin 1, 3
- Anemia of chronic disease - elevated ferritin (>100 μg/L), low transferrin saturation (<20%) 2, 3
Normocytic Anemia (MCV 80-100 fL)
- Acute blood loss - hemorrhage with elevated reticulocyte response 2, 3
- Hemolysis - increased red cell destruction with elevated reticulocytes 2, 6
- Anemia of chronic inflammation - inadequate erythropoietin production or inflammation 1, 2
- Chronic kidney disease - insufficient erythropoietin production 1
Macrocytic Anemia (MCV >100 fL)
- Vitamin B12 deficiency - including pernicious anemia 1, 2, 4
- Folate deficiency - nutritional or malabsorption-related 1, 2
- Myelodysplastic syndromes - bone marrow failure 6, 7
- Alcohol use, thyroid disease, certain medications (hydroxyurea, antiretrovirals) 7
Bone Marrow Failure Causes
- Aplastic anemia - deficient erythropoiesis 6
- Myelodysplastic syndromes - clonal bone marrow disorders 6, 7
- Hematological malignancies - leukemia, lymphoma, myeloma 6, 7
- Bone marrow infiltration - metastatic disease 1
Reticulocyte Count Calculations and Interpretation
Absolute Reticulocyte Count Formula
Absolute Reticulocyte Count = (Reticulocyte % × RBC count) / 100
Reticulocyte Index (Corrected Reticulocyte Count) Formula
Reticulocyte Index = (Reticulocyte % × Patient Hematocrit) / (Normal Hematocrit × Maturation Factor)
- Normal hematocrit: 45% for men, 40% for women
- Maturation factor: 1.0 (Hct ≥35%), 1.5 (Hct 25-35%), 2.0 (Hct 15-25%), 2.5 (Hct <15%)
Interpretation
- Low or normal reticulocyte count (<2%) indicates impaired erythropoiesis from iron deficiency, vitamin deficiencies, bone marrow failure, or insufficient erythropoietin 1, 2
- Elevated reticulocyte count (>2-3%) suggests appropriate bone marrow response to hemolysis or acute blood loss 2, 3, 5
- Reticulocyte index <2 indicates inadequate bone marrow response for degree of anemia 1, 3
- Reticulocyte index >2-3 indicates appropriate compensatory response 3, 8
Genetic Translocations in Leukemia
Acute Myeloid Leukemia (AML)
- t(15;17) PML-RARA - acute promyelocytic leukemia (APL/M3)
- t(8;21) RUNX1-RUNX1T1 - AML with maturation (M2)
- inv(16) or t(16;16) CBFB-MYH11 - acute myelomonocytic leukemia (M4Eo)
- t(9;11) MLL-MLLT3 - monocytic leukemia
Acute Lymphoblastic Leukemia (ALL)
- t(9;22) BCR-ABL1 - Philadelphia chromosome positive ALL
- t(12;21) ETV6-RUNX1 - common in pediatric B-ALL
- t(1;19) TCF3-PBX1 - pre-B ALL
- t(4;11) MLL-AF4 - infant ALL
Chronic Myeloid Leukemia (CML)
- t(9;22) BCR-ABL1 - Philadelphia chromosome, present in >95% of CML cases
Drug of Choice for Chronic Myeloid Leukemia
Imatinib mesylate is the drug of choice for Philadelphia chromosome positive chronic myeloid leukemia 9.
Dosing by Disease Phase
- Chronic phase CML: 400 mg orally once daily with a meal and large glass of water 9
- Accelerated phase or blast crisis CML: 600 mg orally once daily 9
- Pediatric chronic phase CML: 340 mg/m²/day 9
Key Monitoring Requirements
- Complete blood counts weekly for first month, biweekly for second month, then every 2-3 months 9
- Liver function tests monthly or as clinically indicated 9
- Regular weight monitoring for fluid retention and edema 9
Dose Adjustments for Hematologic Toxicity
- For chronic phase CML: If ANC <1 × 10⁹/L or platelets <50 × 10⁹/L, stop imatinib until ANC ≥1.5 × 10⁹/L and platelets ≥75 × 10⁹/L, then resume at 400 mg; if recurs, reduce to 300 mg 9
- For accelerated/blast crisis: If ANC <0.5 × 10⁹/L or platelets <10 × 10⁹/L, check marrow to determine if cytopenia is leukemia-related; if unrelated, reduce to 400 mg, then 300 mg if persists 9
Drug of Choice for Acute Promyelocytic Leukemia
All-trans retinoic acid (ATRA) combined with arsenic trioxide is the current standard of care for acute promyelocytic leukemia with t(15;17) translocation.
- ATRA induces differentiation of promyelocytes
- Arsenic trioxide induces apoptosis and differentiation
- This combination has largely replaced anthracycline-based chemotherapy for low-to-intermediate risk APL
- High-risk APL may require addition of chemotherapy
Hodgkin's vs Non-Hodgkin's Lymphoma: Histologic Differentiation
The presence of Reed-Sternberg cells or their variants (Hodgkin cells) definitively distinguishes Hodgkin lymphoma from non-Hodgkin's lymphoma on histology.
Hodgkin Lymphoma Features
- Reed-Sternberg cells: Large binucleated or multinucleated cells with prominent eosinophilic nucleoli ("owl's eye" appearance)
- Hodgkin cells: Mononuclear variants of Reed-Sternberg cells
- Background: Mixed inflammatory infiltrate including lymphocytes, eosinophils, neutrophils, histiocytes, and plasma cells
- Architecture: Typically maintains some nodal architecture with fibrosis
Non-Hodgkin's Lymphoma Features
- Absence of Reed-Sternberg cells
- Monomorphic population: Predominantly malignant lymphocytes (B-cells or T-cells)
- Architecture: Often complete effacement of nodal architecture
- Pattern: Follicular, diffuse, or other specific patterns depending on subtype
Burkitt Lymphoma: Characteristic Histologic Feature
The "starry sky" pattern is the pathognomonic histologic feature of Burkitt lymphoma.
Microscopic Appearance
- Starry sky pattern: Numerous pale-staining tingible body macrophages (the "stars") scattered among sheets of darkly staining monomorphic medium-sized lymphoma cells (the "sky")
- Tingible body macrophages: Contain phagocytosed apoptotic debris from rapidly proliferating and dying tumor cells
- High mitotic rate: Reflects extremely rapid cell turnover (Ki-67 proliferation index approaching 100%)
- Monomorphic cells: Medium-sized lymphocytes with round nuclei, multiple nucleoli, and basophilic cytoplasm
- Cytoplasmic vacuoles: Often visible, representing lipid droplets
Expected Hemoglobin Rise Per Unit of PRBCs
Each unit of packed red blood cells (PRBCs) transfused should raise hemoglobin by approximately 1 g/dL (or hematocrit by 3%) in an average-sized adult without ongoing bleeding or hemolysis.
Important Considerations
- This estimate assumes a standard PRBC unit contains approximately 200-250 mL with hematocrit of 55-60%
- Actual rise depends on patient size: Smaller patients may have greater increases, larger patients smaller increases
- Pediatric dosing: 10-15 mL/kg of PRBCs raises hemoglobin by approximately 2-3 g/dL
- Ongoing blood loss or hemolysis will reduce the expected hemoglobin increment
- Post-transfusion hemoglobin should be checked 15 minutes to 1 hour after transfusion completion for acute assessment, or 24 hours later for equilibrated value
- Volume overload risk: Monitor closely in patients with cardiac disease or renal failure, as each unit contains significant volume
Clinical Pitfall
Do not rely solely on calculated expected rise—always verify with post-transfusion hemoglobin measurement, as failure to achieve expected increment suggests ongoing blood loss, hemolysis, or other complications requiring investigation.