Diagnostic Approach to Erythrocytosis with Leukopenia and Lymphocytosis
This constellation of findings—high hemoglobin, high hematocrit, high RBCs, low WBCs, and high lymphocytes—requires immediate evaluation for polycythemia vera (PV) with JAK2 mutation testing as the first priority, while simultaneously excluding secondary causes of erythrocytosis and investigating the leukopenia with lymphocytosis, which may represent a separate hematologic process or overlap syndrome. 1, 2
Initial Diagnostic Confirmation
Confirm true erythrocytosis by repeating hemoglobin and hematocrit measurements after ensuring adequate hydration, as a single measurement is unreliable and relative polycythemia from dehydration must be excluded. 1, 2
Verify erythrocytosis thresholds: Hemoglobin >18.5 g/dL in men or >16.5 g/dL in women, and hematocrit >55% in men or >49.5% in women indicate true erythrocytosis requiring workup. 3, 1
Document the leukopenia and lymphocytosis with absolute counts, not just percentages, as relative lymphocytosis can occur with neutropenia but absolute lymphocytosis suggests a distinct pathologic process. 3
Comprehensive Laboratory Workup
For Erythrocytosis Evaluation
Order JAK2 mutation testing immediately (both exon 14 V617F and exon 12 mutations), as JAK2 mutations are present in up to 97% of polycythemia vera cases and this is the cornerstone of diagnosis. 3, 1
Measure serum erythropoietin (EPO) level, which is typically low or low-normal in PV but elevated in secondary erythrocytosis, helping differentiate primary from secondary causes. 2, 4, 5
Assess iron status with serum ferritin and transferrin saturation, as iron deficiency can coexist with erythrocytosis and mask the full extent of elevated hemoglobin while increasing stroke risk. 1, 2
Obtain peripheral blood smear to evaluate red cell morphology and assess for microcytosis that might indicate concurrent iron deficiency. 1, 2
Check red cell distribution width (RDW), as high RDW with normal or low MCV suggests possible iron deficiency coexisting with erythrocytosis. 1
For Leukopenia and Lymphocytosis Evaluation
Obtain complete blood count with differential including absolute lymphocyte count, absolute neutrophil count, and reticulocyte count to characterize the cytopenias. 3, 1
Perform immunophenotyping of peripheral blood lymphocytes by flow cytometry to evaluate for chronic lymphocytic leukemia (CLL) or other lymphoproliferative disorders, as this is essential when lymphocytosis is present. 3
Measure serum immunoglobulins and direct antiglobulin test (DAT) as part of the lymphocytosis workup, particularly if CLL is suspected. 3
Diagnostic Criteria for Polycythemia Vera
The WHO criteria for PV diagnosis require:
Major Criterion 1: Hemoglobin ≥18.5 g/dL in men or ≥16.5 g/dL in women (or other evidence of increased red cell volume). 3
Major Criterion 2: Presence of JAK2 V617F or other functionally similar mutation such as JAK2 exon 12 mutation. 3
Minor Criteria: (1) Bone marrow biopsy showing hypercellularity with trilineage growth (panmyelosis); (2) Serum EPO level below normal range; (3) Endogenous erythroid colony formation in vitro. 3
Diagnosis requires both major criteria plus one minor criterion, OR the first major criterion plus two minor criteria. 3
Bone Marrow Evaluation
Perform bone marrow aspirate and biopsy if JAK2 mutation is positive or if diagnosis remains unclear, to assess for trilineage proliferation characteristic of PV and to evaluate the cause of leukopenia. 3
Request cytogenetic analysis (FISH) for del(13q), del(11q), del(17p), trisomy 12, and del(6q) if lymphoproliferative disorder is suspected based on immunophenotyping. 3
Evaluation for Secondary Causes of Erythrocytosis
Obtain detailed smoking history, as "smoker's polycythemia" results from chronic carbon monoxide exposure causing tissue hypoxia and stimulating EPO production. 1
Screen for obstructive sleep apnea with sleep study if nocturnal hypoxemia is suspected, as this produces hypoxemia-driven EPO production. 1, 2
Evaluate for chronic lung disease (COPD, pulmonary fibrosis) with pulmonary function tests and chest imaging if clinically indicated. 1
Assess for cyanotic congenital heart disease with echocardiography if right-to-left shunting is suspected, as this causes compensatory erythrocytosis. 1, 2
Review medication history for testosterone use (prescribed or unprescribed) or erythropoietin therapy, both of which can cause erythrocytosis. 1
Consider imaging (CT abdomen/pelvis) to evaluate for EPO-secreting tumors (renal cell carcinoma, hepatocellular carcinoma, pheochromocytoma) if EPO is elevated without clear hypoxic cause. 1
Management Based on Diagnosis
If Polycythemia Vera is Confirmed
Maintain hematocrit strictly below 45% through therapeutic phlebotomy to reduce thrombotic risk, as demonstrated by the CYTO-PV study showing significant reduction in thrombotic events with this target. 1
Initiate low-dose aspirin (81-100 mg daily) as the second cornerstone of therapy for thrombosis prevention in PV. 1
Refer immediately to hematology for ongoing management, risk stratification, and consideration of cytoreductive therapy if indicated. 1, 2
If Secondary Erythrocytosis is Identified
Treat the underlying condition: smoking cessation for smoker's polycythemia, CPAP therapy for obstructive sleep apnea, management of chronic lung disease. 1, 2
Therapeutic phlebotomy is indicated ONLY if hemoglobin >20 g/dL and hematocrit >65% with symptoms of hyperviscosity (headache, visual disturbances, poor concentration) after excluding dehydration. 1, 2
Avoid routine repeated phlebotomies, as they lead to iron depletion, decreased oxygen-carrying capacity, and paradoxically increased stroke risk. 1, 2
Management of Concurrent Iron Deficiency
If iron deficiency is confirmed (low ferritin, low transferrin saturation), provide cautious oral iron supplementation with close hemoglobin monitoring, as rapid increases in red cell mass can occur. 1, 2
Recognize that iron-deficient red blood cells have reduced oxygen-carrying capacity and deformability, increasing stroke risk even in the presence of erythrocytosis. 1
Management of Leukopenia and Lymphocytosis
If CLL is diagnosed by immunophenotyping, follow International Workshop on CLL (iwCLL) guidelines for staging and determining need for treatment based on disease activity and symptoms. 3
Monitor for infectious complications given the combined immunosuppression from both potential PV and lymphoproliferative disorder, with particular attention to bacterial, viral, and fungal infections. 3
Critical Pitfalls to Avoid
Do not assume the erythrocytosis is secondary without JAK2 testing, as up to 97% of PV cases carry this mutation and missing PV diagnosis leads to inadequate thrombosis prevention. 3, 1
Do not perform aggressive phlebotomy to "normal" hematocrit levels without confirming PV diagnosis, as this can cause iron depletion and increased thrombotic risk in secondary erythrocytosis. 1, 2, 6
Do not overlook the lymphocytosis as merely reactive; absolute lymphocytosis requires immunophenotyping to exclude CLL or other lymphoproliferative disorders. 3
Do not use hematocrit alone for monitoring; hemoglobin is more reliable as hematocrit can falsely increase by 2-4% with sample storage and is affected by hyperglycemia. 1
Do not ignore concurrent iron deficiency, as mean corpuscular volume (MCV) is unreliable for screening iron deficiency in erythrocytosis, and serum ferritin/transferrin saturation are required. 1
Monitoring and Follow-up
Ensure adequate hydration as first-line therapy for all patients with erythrocytosis before considering phlebotomy. 2
Monitor hemoglobin and hematocrit periodically in patients with secondary erythrocytosis to assess response to treatment of underlying condition. 2
Assess for symptoms of hyperviscosity (headache, visual disturbances, fatigue, poor concentration) at each visit. 2
Monitor renal function, as chronic erythrocytosis can affect renal glomeruli and lead to reduced glomerular filtration rate. 2