What is the significance of a mildly elevated hemoglobin and mildly decreased lymphocyte count, and how should it be evaluated?

Evaluation of Mildly Elevated Hemoglobin and Mildly Decreased Lymphocytes

This combination warrants systematic evaluation to exclude polycythemia vera (PV), secondary erythrocytosis, and underlying hematologic malignancies, with serum erythropoietin (EPO) level as the critical first diagnostic test after confirming the abnormality. 1

Initial Confirmation and Assessment

• Repeat complete blood count (CBC) with manual differential within 12-24 hours to confirm the abnormality and assess for additional findings such as band forms, platelet count, and red blood cell morphology 1, 2
• Document the patient's baseline hemoglobin values, as an increase above individual baseline may indicate pathology even if within the reference range 1
• Assess for PV-related features including thrombocytosis, leukocytosis, microcytosis from iron deficiency, splenomegaly, aquagenic pruritus, unusual thrombosis (including Budd-Chiari syndrome), or erythromelalgia 1

Lymphocyte Evaluation

• Calculate absolute lymphocyte count to determine true lymphopenia (generally <1.0 × 10⁹/L in adults) versus relative lymphopenia 1
• An absolute lymphocyte count <0.96 × 10⁹/L combined with other findings may suggest viral infection, chronic inflammatory conditions, or early hematologic disease 1
• Evaluate for leukocytosis with left shift: if total band count ≥1,500 cells/mm³ or percentage of band neutrophils ≥6%, this indicates high probability of bacterial infection regardless of fever presence 1

Hemoglobin Elevation Workup Algorithm

Step 1: Serum Erythropoietin Level

• Low serum EPO (specificity >90%) is highly suggestive of PV but can also occur in essential thrombocythemia or rare congenital polycythemia with EPOR mutations 1
• Normal serum EPO does not exclude PV (sensitivity <70% for low EPO in PV), and further evaluation is required 1
• Elevated serum EPO makes PV unlikely and suggests secondary erythrocytosis from hypoxia, renal disease, or EPO-secreting tumors 1

Step 2: Bone Marrow Examination (if EPO low or normal)

• Perform bone marrow aspirate and biopsy with cytogenetics to evaluate for characteristic PV findings: hypercellularity, increased megakaryocytes with clustering, giant megakaryocytes, pleomorphism, mild reticulin fibrosis (12% of cases), and decreased iron stores 1
• Include immunohistochemistry for CD117, CD25, and tryptase to exclude systemic mastocytosis, which can present with eosinophilia and elevated hemoglobin 1

Step 3: Molecular Testing

• JAK2 V617F mutation testing is essential, as it is positive in approximately 11% of patients referred for elevated hemoglobin 3
• If JAK2 V617F is negative, test for JAK2 exon 12 mutations 3
• Consider next-generation sequencing (NGS) myeloid panel targeting 40 key genes, as additional mutations (TET2, DNMT3A, ASXL1) are found in 34.5% of JAK2-positive PV patients and affect prognosis 3
• Screen for BCR/ABL1 fusion to exclude chronic myeloid leukemia, which can present with elevated hemoglobin 3

Additional Diagnostic Considerations

• Serum tryptase and vitamin B12 levels: Elevated levels suggest myeloproliferative neoplasms, particularly those with PDGFRA fusion genes 1
• Peripheral blood smear review for dysplasia, monocytosis, circulating blasts, or abnormal cell morphology 1, 4
• Hemoglobin electrophoresis or HPLC if hemoglobinopathy is suspected based on ethnicity, family history, or red cell morphology 4, 5

Red Flags Requiring Urgent Hematology Referral

• Cytopenias in multiple cell lines (bicytopenia or pancytopenia) 2
• Presence of circulating blasts on peripheral smear 1
• Constitutional symptoms: fever, night sweats, weight loss, or significant fatigue lasting >1 month 1
• Splenomegaly or hepatomegaly on physical examination 1
• Hemoglobin >16.5 g/dL in males or >16.0 g/dL in females with low EPO and no obvious secondary cause 1
• JAK2-negative patients meeting 2016 WHO criteria for PV with mutations in SRSF2, TET2, IDH2, or ASXL1 3

Common Pitfalls to Avoid

• Do not assume mild lymphopenia is benign without assessing absolute count and clinical context, as it may indicate early chronic lymphocytic leukemia (CLL) or immunodeficiency 1
• Do not rely solely on hematocrit >60% to diagnose PV, as red cell mass measurement is costly and redundant in this setting 1
• Do not dismiss borderline-high hemoglobin if accompanied by thrombocytosis, leukocytosis, or other PV-related features 1
• Recognize that normal or low hemoglobin does not exclude PV if other criteria are met, particularly after phlebotomy treatment 1