What is the next step for a patient with persisting polycythemia and low reticulocyte count, without anemia?

Next Step: Bone Marrow Biopsy and Aspirate Analysis

For a patient with persisting polycythemia and low reticulocyte count without anemia, the next step is bone marrow biopsy and aspirate analysis to evaluate for polycythemia vera (PV) and exclude primary bone marrow disease. 1

Diagnostic Rationale

The combination of polycythemia with low reticulocytes is highly concerning and requires immediate investigation:

• Low reticulocyte count in the setting of polycythemia is paradoxical and suggests either inappropriate erythropoiesis or primary bone marrow disease rather than appropriate compensatory erythropoiesis 1
• This pattern excludes hemolysis (which would show elevated reticulocytes) and points toward a production disorder 1
• The persistence of polycythemia despite low reticulocytes strongly suggests a clonal myeloproliferative process like PV rather than secondary polycythemia 1, 2

Essential Workup Before or Concurrent with Bone Marrow Biopsy

Immediate Laboratory Testing

• JAK2 V617F mutation testing - present in >95% of PV cases and helps distinguish primary from secondary polycythemia 1, 2
• Serum erythropoietin (EPO) level - typically low or low-normal in PV (specificity >90%), whereas secondary polycythemia shows elevated EPO 1, 3
• Complete blood count with differential - assess for thrombocytosis (53% of PV) and leukocytosis (49% of PV) which support myeloproliferative disease 2
• Peripheral blood smear - evaluate red cell morphology, look for microcytosis suggesting iron deficiency from increased erythropoiesis 1

Additional Assessments

• Abdominal examination and/or ultrasound for splenomegaly (present in 36% of PV patients) 1, 2
• History focused on aquagenic pruritus (33%), erythromelalgia (5.3%), transient visual changes (14%), and thrombotic events 1, 2

Bone Marrow Examination Specifics

The bone marrow biopsy should include 1:

• Histology assessment for hypercellularity, trilinear hyperplasia, megakaryocyte morphology and clustering, and reticulin fibrosis grading 1
• Cytogenetic studies to detect abnormalities (present in 13-18% at diagnosis) and exclude myelodysplastic syndrome 1
• Iron stores evaluation - typically decreased in PV due to chronic phlebotomy effect or iron-deficient erythropoiesis 1

Critical Pitfalls to Avoid

• Do not assume secondary polycythemia without excluding PV first - the low reticulocyte count makes secondary causes less likely since they typically show appropriate erythropoietin-driven reticulocytosis 1, 3
• Do not delay workup based on hematocrit level alone - PV can present with borderline-high hematocrit if accompanied by other features like low reticulocytes, thrombocytosis, or splenomegaly 1
• Do not skip JAK2 testing - while bone marrow is important, JAK2 mutation status is essential for diagnosis and present in >95% of cases 2
• Consider thrombosis risk immediately - 16% of patients have arterial thrombosis and 7% have venous thrombosis at or before diagnosis, including unusual sites like splanchnic veins 2

If PV is Confirmed

Once diagnosed, all PV patients require 1, 2:

• Therapeutic phlebotomy to maintain hematocrit <45% (reduces thrombosis risk significantly) 1, 2
• Low-dose aspirin (if no contraindications) to prevent microvascular complications 1, 2
• Risk stratification based on age ≥60 years or prior thrombosis to determine need for cytoreductive therapy with hydroxyurea or interferon 1