What conditions can cause anemia (low hemoglobin), thrombocytopenia (low platelets), and leukocytosis (elevated white blood cell count) in a non-pregnant female?

Differential Diagnosis: Low Hemoglobin, Low Platelets, and Elevated WBC in Non-Pregnant Females

The combination of anemia, thrombocytopenia, and leukocytosis in a non-pregnant female most commonly suggests bone marrow pathology (particularly myeloproliferative neoplasms or acute leukemia), autoimmune processes, severe infection/sepsis, or disseminated malignancy—with the specific pattern and severity guiding immediate diagnostic workup.

Primary Diagnostic Considerations

Hematologic Malignancies (Highest Priority)

• Acute leukemia presents with pancytopenia or bicytopenia with leukocytosis (often with circulating blasts), requiring urgent peripheral smear and bone marrow evaluation 1
• Myeloproliferative neoplasms can paradoxically present with thrombocytopenia despite being proliferative disorders, particularly when associated with leukocytosis and JAK2V617F mutations 2
• Myelodysplastic syndromes may show dysplastic changes with variable cell line involvement 1

Autoimmune Disorders

• Autoimmune hemolytic anemia with Evans syndrome (combined autoimmune hemolytic anemia and immune thrombocytopenia) can present with leukocytosis as a reactive phenomenon 3
• Specific antibodies against erythrocytes (90.6% of cases), platelets (90.6%), and leukocytes (81.3%) may coexist, though these processes often follow dissociated clinical courses 3
• Systemic lupus erythematosus and other connective tissue diseases can cause multi-lineage cytopenias with reactive leukocytosis 1

Severe Infection/Sepsis

• Bacterial sepsis commonly causes anemia of inflammation, consumptive thrombocytopenia, and marked leukocytosis 1
• Disseminated intravascular coagulation (DIC) secondary to infection produces thrombocytopenia with variable WBC response 4

Hypersplenism with Concurrent Infection

• Splenic sequestration causes thrombocytopenia and anemia, while concurrent infection or inflammation drives leukocytosis 4, 1
• Liver disease with portal hypertension and splenomegaly fits this pattern 4

Bone Marrow Infiltration

• Metastatic solid tumors (breast, lung, gastric) infiltrating marrow cause leukoerythroblastic picture with variable WBC elevation 1
• Lymphoma with marrow involvement may present similarly 1

Critical Diagnostic Workup

Immediate Laboratory Evaluation

• Complete blood count with differential: Examine for blast cells, immature forms, dysplastic changes 1
• Peripheral blood smear review: Essential to identify circulating blasts, schistocytes (suggesting microangiopathy), or morphologic abnormalities 1
• Reticulocyte count: Distinguishes hypoproliferative (low reticulocyte count) from hemolytic/hemorrhagic anemia (elevated reticulocyte count) 5
• Mean corpuscular volume (MCV): Helps categorize anemia type—microcytic suggests iron deficiency or thalassemia, macrocytic suggests B12/folate deficiency or myelodysplasia 5

Hemolysis and Coagulation Assessment

• Direct antiglobulin test (Coombs): Positive in autoimmune hemolytic anemia 3
• Lactate dehydrogenase, indirect bilirubin, haptoglobin: Elevated LDH and bilirubin with low haptoglobin indicate hemolysis 3
• Coagulation studies (PT, aPTT, fibrinogen, D-dimer): Essential to exclude DIC 2
• Platelet antibodies and leukocyte antibodies: Consider when autoimmune process suspected 3

Definitive Diagnostic Studies

• Bone marrow aspiration and biopsy: Required when peripheral smear suggests primary marrow disorder or when diagnosis remains unclear after initial workup 1
• Flow cytometry: Identifies clonal populations in leukemia or lymphoma 1
• Cytogenetics and molecular studies: JAK2V617F mutation testing for myeloproliferative neoplasms 2

Severity-Based Thresholds

Platelet Count Risk Stratification

• >50 × 10³/μL: Generally asymptomatic, low bleeding risk 1
• 20-50 × 10³/μL: Mild cutaneous bleeding (petechiae, purpura, ecchymosis) 1
• <10 × 10³/μL: High risk of serious spontaneous bleeding, may require platelet transfusion 1
• <100 × 10³/μL: Clinically relevant threshold defining thrombocytopenia 2

Hemoglobin Severity

• Mild anemia: Hemoglobin 10.0 g/dL or higher—often iron deficiency, trial of oral iron appropriate 5
• Moderate anemia: Hemoglobin 7.0-9.9 g/dL—requires further investigation beyond simple iron deficiency 5
• Severe anemia: Hemoglobin 4.0-6.9 g/dL—urgent evaluation and potential transfusion 5

Common Pitfalls to Avoid

• Pseudothrombocytopenia: Always exclude by repeating platelet count in heparin or sodium citrate tube before extensive workup 1
• Assuming single etiology: Thrombocytopenia often results from combined mechanisms (decreased production + increased destruction + sequestration) rather than a single process 6
• Delaying bone marrow evaluation: When peripheral smear shows blasts or leukoerythroblastic picture, bone marrow biopsy should not be delayed 1
• Missing drug-induced causes: Comprehensive medication review essential, as drug-induced thrombocytopenia and anemia are common and reversible 1
• Overlooking infection: Leukocytosis with cytopenias may indicate overwhelming sepsis requiring urgent antimicrobial therapy 1

Clinical Algorithm

1. Confirm true cytopenias: Exclude pseudothrombocytopenia and review prior counts to determine acute vs. chronic 1
2. Assess clinical stability: Hemodynamic instability, active bleeding, or signs of sepsis require immediate hospitalization 1
3. Review peripheral smear: Presence of blasts mandates urgent hematology consultation 1
4. Categorize by mechanism: Use reticulocyte count, MCV, and hemolysis markers to determine if anemia is hypoproliferative, hemolytic, or hemorrhagic 5
5. Pursue definitive diagnosis: Bone marrow evaluation when malignancy suspected or diagnosis unclear after initial workup 1