Workup of Polycythemia (Erythrocytosis)
Polycythemia workup should first determine whether an absolute erythrocytosis is present and then classify it as polycythaemia vera (PV) versus secondary (hypoxia-, drug-, or EPO-producing) causes. [1] An erythrocytosis investigation algorithm recommends clinical assessment and first-line laboratory testing with serum erythropoietin (EPO) and JAK2 V617F mutation analysis. [1]
Initial Confirmation of Persistent Erythrocytosis
Persistent elevation of hemoglobin and hematocrit should be confirmed, including repeat complete blood count (CBC) testing when appropriate. [1] An absolute erythrocytosis can be assumed when hematocrit (Hct) is above 0.60 in males or above 0.56 in females. [1] When Hct is not clearly in the absolute range, evaluation for absolute red cell mass using red cell mass studies can be considered in selected settings. [1]
Directed History and Physical Examination
History should include smoking, chronic lung disease, cyanotic heart disease, sleep apnoea or obesity, renal disease, and medication exposures that can increase hemoglobin or hematocrit. [1] Medication exposures that should be reviewed include testosterone, growth hormone, erythropoietin, and diuretics. [1] Physical examination and clinical context should assess for potential secondary causes and PV-associated findings such as splenomegaly. [1]
First-Line Molecular and Hormonal Testing
JAK2 V617F mutational analysis in peripheral blood is recommended as a stage-1 investigation for suspected PV. [1] Serum EPO measurement is included in the investigation of erythrocytosis to support PV versus secondary etiologies. [1] When secondary causes are not immediately apparent and JAK2 V617F testing is negative, further investigation is recommended. [1]
Secondary Cause Evaluation (Acquired Erythrocytosis)
Clinical evaluation should actively assess for hypoxia-related etiologies such as chronic lung disease, cyanotic heart disease, and sleep apnoea. [1] Renal causes should be evaluated clinically and with renal-directed testing when suggested by history. [1] Abdominal ultrasound is recommended as a simple imaging approach that can exclude renal and hepatic pathology, including hepatocellular carcinoma, and can support the diagnostic evaluation for JAK2 V617F–negative PV through detection of splenomegaly. [1] If JAK2 is negative, EPO results should guide the next diagnostic step: low EPO supports PV-spectrum disease, while normal or elevated EPO supports secondary or hereditary erythrocytosis evaluation. [2]
Congenital or Hereditary Erythrocytosis Evaluation
Further gene testing for congenital erythrocytosis is recommended when young onset or a positive family history is present. [1] Congenital erythrocytosis gene testing can include a panel approach targeting loci such as HBAA, HBB, BPGM, VHL, EGLN1, and EPAS1. [1]
PV Diagnostic Workup After Negative or Inconclusive JAK2 V617F Testing
In JAK2 V617F–negative patients with persistent significant erythrocytosis and no clear secondary cause, additional evaluation is recommended rather than attributing the finding to idiopathic erythrocytosis without further testing. [1] In cases where a secondary cause is not identified and PV remains suspected, additional testing can include further molecular assessment and PV-consistent diagnostic evaluation. [1]
Common Pitfalls to Avoid
PV is rare in the absence of a JAK2 V617F mutation, which increases the risk of missed secondary causes if the evaluation stops after an isolated CBC result. [1] Over-reliance on red cell mass testing without clinical and laboratory correlation can miss the practical diagnostic differentiation between absolute erythrocytosis and apparent erythrocytosis. [1] Incomplete medication and hypoxia history can lead to failure to identify reversible secondary erythrocytosis drivers such as testosterone or sleep apnoea. [1]
Practical Diagnostic Output of the Workup
The investigation algorithm assigns diagnostic pathways based on the combination of confirmed absolute erythrocytosis status, EPO level, JAK2 V617F result, and identification or exclusion of secondary causes. [1] PV is favored when persistent significant erythrocytosis is present with supportive molecular and clinical findings, while clear secondary causes redirect the diagnosis toward secondary erythrocytosis. [1]