How to Interpret a CBC with differential

Normal ranges varies slightly by labs.

WBC

Elevated WBC (>11k)

• Common causes of significant leukocytosis (>15k):

  • Sepsis/ bacterial infection

  • C.difficile

    • C. diff detected in ~25% of patients with WBC >30k without hematologic malignancy

    • Leukocytosis can even precede diarrheal symptoms

    • If no obvious source, test for C. diff even without diarrhea

  • Malignancy (hematologic malignancy, neoplastic syndrome from solid malignancies)

  • Medication (steroid, G-CSF)

  • Physiologic stress (surgery, trauma, critical illness)

• Autoimmune diseases typically produce only mild-to-moderate elevations

  • Vasculitis causes neutrophil-driven inflammation (high neutrophil-to-lymphocyte ratio)

Low WBC (<4k)

• Look at the differential: which cell line is low?

  • Neutropenia: Absolute Neutrophil Count (ANC) <1500

    • Degree of neutropenia:

      • 1000< ANC <1500: Mild neutropenia:

      • 500< ANC <1000: Moderate neutropenia

      • ANC <500: Severe neutropenia

    • Febrile neutropenia (fever + ANC <500) is a medical emergency and requires emergent blood cultures and IV broad-spectrum antibiotics before any workup.

    • Common causes:

      • Medication:

        • Antipsychotic, anticonvulsants, antithyroid agents, chemotherapy, etc

        • The medication list is the single most important thing to review.

      • Autoimmune diseases

      • Infections:

        • Viral infections (EBV, parvo B19, CMV, hepatitis B/C, HIV)

        • Bacterial sepsis through BM reserve exhaustion

      • Hematologic malignancies:

        • MDS, Acute leukemia

      • Benign ethnic neutropenia:

        • Mild neutropenia

        • Common in individuals of African and Middle Eastern

        • Does not increase risk of infection

      • Hypersplenism

      • Aplastic anemia:

        • Pancytopenia with hypocellular bone marrow

  • Lymphopenia: Absolute Lymphocyte Count (ALC) <1000

    • Common causes: HIV, steroids, lymphoma

  • Neutropenia + Lymphopenia:

    • Common causes: Bone marrow failure, MDS, Severe systemic illness

RBC

Elevated RBC:

• Erythrocytosis (elevated RBC/hemoglobin/hematocrit)

• Is this real or relative?

  • True erythrocytosis: Increased red cell mass

  • Relative erythrocytosis: Normal red cell mass but reduced plasma volume (eg. dehydration, diuretic use)

• If it is real erythrocytosis:

  • Is it medication induced?

    • Testosterone/anabolic steroids

    • Erythropoietin-stimulating agents (ESAs)

    • SGLT2 inhibitors

      • Typically raise hemoglobin by 0.5–1.0 g/dL

  • Is erythrocytosis primary or secondary?

    • Primary (high RBC → low EPO):

      • Intrinsic bone marrow defect such as Polycythemia Vera

      • independent of EPO

    • Secondary (high/inappropriately normal EPO → high RBC):

      • Hypoxia-driven:

        • OSA, smoking, chronic lung disease

      • EPO secreting tumor

      • Renal causes:

        • Renal artery stenosis, polycystic kidney disease

  • None? Consider:

    • Congenital/hereditary:

      • EPO receptor (EPOR) mutations

Low RBC:

• It is a marker of anemia, but it should always be interpreted alongside hemoglobin, hematocrit, and RBC indices (MCV, MCHC)

• Etiology:

  • Impaired RBC production:

    • Nutritional deficiencies (Iron, folate, B12)

    • Chronic inflammation (Anemia of chronic disease)

    • Clonal disorders in bone marrow (Myelodysplastic syndrome, Aplastic anemia)

  • RBC loss:

    • Acute bleeding

  • Accelerated RBC destruction:

    • Sickle cell anemia, hemolytic anemia

Hb (Hemoglobin)

Normal Hb ranges are approximately:

• 14-18.5 g/dL for males

• 12-16.5 g/dL for females

Elevated Hb

• See the "Erythrocytosis" section above.

• First rule out Hemoconcentration (relative erythrocytosis)

Low Hb

• Anemia Evaluation

  • Clinical symptoms:

    • Mild or chronic anemia causes weakness, low concentration and pallor

    • Severe or acute anemia causes tachycardia, hypotension and syncope

  • Check MCV to differentiate different causes of anemia

    • See the "MCV" section below.

  • Check retic count to evaluate bone marrow (BM) response

    • Calculate Reticulocyte Index (RI) = %Retic × (Patient Hct/ Normal Hct​)

      • RI <2% → Inadequate BM response

        • Iron deficiency

        • Vitamin B12 or folate deficiency

        • Anemia of chronic disease

        • Bone marrow disorders

      • RI ≥2% → Appropriate BM response

        • Hemolysis

        • Acute blood loss (after several days)

        • Recovery from nutritional deficiency

HCT (Hematocrit)

Definition:

• Percentage of whole blood volume occupied by RBC:

  • HCT = (Volume of RBCs / Total blood volume​) ×100%

Normal HCT ranges are approximately:

• 38- 48% for males

• 35- 45% for females

Elevated Hct

• See the "Erythrocytosis" section above.

Low Hct

• See the "Low RBC" and "Low Hb" sections above.

MCV

Definition:

• The average size (volume) of an individual RBC.

Normal MCV range is 80-100 fL.

Elevated MCV

• Macrocytosis (>100 fL)

• Common causes:

  • Vitamin B12 and folate deficiency, Alcohol use, liver disease, Hypothyroidism

Low MCV

• Microcytosis (<80 fL)

• Common causes:

  • Iron deficiency, Thalassemia, Lead poisoning

• Mentzer index:

  • Calculated as MCV divided by RBC count.

  • Differentiate iron deficiency anemia from beta-thalassemia trait in microcytic anemia.

    • Mentzer index >13 suggests iron deficiency anemia

    • Mentzer index < 13 suggests beta-thalassemia trait

  • Should be used as a screening tool rather than a definitive diagnostic test.

RDW

• Measures variation in red blood cell size

Elevated RDW:

• Anistocytosis:

• Common causes:

  • Nutritional deficiency anemias:

    • Iron deficiency anemia:

      • Newly produced microcytes coexist with older normocytic cells → dimorphic RBC population → high RDW

      • RDW may be the earliest CBC abnormality in iron deficiency, appearing before MCV drops.

      • Elevated RDW is sensitive for iron deficiency, but not specific.

    • B12 and folate deficiency:

      • Macrocytes coexist with normal-sized cells → dimorphic RBC population → high RDW

      • Elevated RDW is less sensitive for B12/folate deficiency than it is for iron deficiency.

  • Sickle cell disease:

    • Anisocytosis from sickling, reticulocytosis, and fragmentation of RBCs.

  • Post-transfusion:

    • Donor RBCs of different size mix with the recipient's cells.

Low/Normal RDW:

• A low/normal RDW indicates a homogeneous RBC population and has limited established clinical significance.

Differential:

• Common causes (beside malignancies):

  • Elevated monocytes:

    • Chronic infections

    • Rheumatologic conditions

  • Elevated eosinophils:

    • Parasitic infections

    • Allergic reactions

    • Connective tissue disorders

  • Elevated neutrophils:

    • Infection

    • Inflammation

    • Stress response

    • Splenic sequestration

    • Asplenia

  • Elevated lymphocytes:

    • Viral infection (EBV, CMV, etc)

    • Pertussis

    • Tuberculosis

    • Splenic sequestration

    • Asplenia

  • Elevated basophils:

    • Viral infections

    • Inflammatory conditions

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