What is the differential diagnosis and recommended work‑up for a patient with simultaneous thrombocytosis, erythrocytosis (elevated hematocrit) and increased red blood cell count?

Differential Diagnosis and Work-Up for Simultaneous Thrombocytosis, Erythrocytosis, and Elevated RBC Count

The combination of elevated platelets, hematocrit, and red blood cells strongly suggests polycythemia vera (PV) and mandates immediate JAK2 mutation testing as the first-line diagnostic test, since this mutation is present in >95% of PV cases and distinguishes primary from secondary causes. 1, 2, 3

Primary Diagnostic Algorithm

Step 1: Confirm True Polycythemia and Assess Concurrent Cytopenias

• Repeat complete blood count with red cell indices, reticulocyte count, and manual differential to confirm sustained elevation of all three cell lines (hemoglobin, hematocrit, RBC, and platelets). 1, 2
• The presence of thrombocytosis (53% of PV patients) and leukocytosis (49% of PV patients) alongside erythrocytosis creates a high pre-test probability for polycythemia vera rather than secondary causes. 3
• Exclude relative polycythemia by assessing for plasma volume depletion: review recent fluid losses (vomiting, diarrhea, burns), diuretic use, and hydration status. 1, 2

Step 2: Order JAK2 Mutation Testing and Serum Erythropoietin Level Immediately

• JAK2 V617F mutation testing should be performed first because it is present in >95% of PV cases, with JAK2 exon 12 mutations accounting for another 2-4%, achieving 97-99% overall sensitivity for PV. 1, 2, 3
• Serum erythropoietin (EPO) level helps distinguish primary from secondary polycythemia:
  • Low or inappropriately normal EPO (specificity >90%) strongly suggests PV. 1
  • Elevated EPO suggests secondary polycythemia from hypoxia-driven or tumor-related causes. 1
  • Critical pitfall: Normal EPO does not exclude PV—sensitivity is only 64-70%—so JAK2 testing remains mandatory. 1

Step 3: Assess Iron Status

• Serum ferritin, iron, and transferrin saturation are essential because iron deficiency can coexist with erythrocytosis and mask the true red cell mass elevation. 1, 2
• Low mean corpuscular volume (MCV) <80 fL in the setting of erythrocytosis suggests iron deficiency from increased utilization or prior phlebotomy, which paradoxically increases stroke risk. 1

Step 4: Peripheral Blood Smear Review

• Manual review by a qualified hematologist is essential to identify abnormal morphology, left shift, or dysplastic features that may indicate myeloproliferative neoplasm. 2

WHO Diagnostic Criteria for Polycythemia Vera

PV is diagnosed when EITHER:

• (a) Both major criteria PLUS one minor criterion are met, OR
• (b) The first major criterion PLUS two minor criteria are met. 1, 2

Major Criteria

1. Elevated hemoglobin or hematocrit:
   • Women: Hb >16.5 g/dL or Hct >49%
   • Men: Hb >18.5 g/dL or Hct >52% 1, 2
2. Presence of JAK2 mutation (V617F or exon 12). 1, 2

Minor Criteria

1. Bone marrow biopsy showing hypercellularity with trilineage growth (erythroid, megakaryocytic, granulocytic proliferation). 1, 2
2. Subnormal serum erythropoietin level (below reference range). 1, 2
3. Endogenous erythroid colony formation in vitro (growth without exogenous EPO). 1, 2

Systematic Evaluation for Secondary Causes (If JAK2 Negative)

If JAK2 mutation is absent, systematically evaluate for secondary polycythemia:

Hypoxia-Driven Causes

• Smoking history and carboxyhemoglobin measurement: Smoker's polycythemia from chronic carbon monoxide exposure is the most common secondary cause and resolves with cessation. 1, 2
• Sleep study for obstructive sleep apnea: Nocturnal hypoxemia drives compensatory erythropoietin production. 1, 2
• Arterial oxygen saturation and chest imaging: Rule out chronic lung disease (COPD), right-to-left cardiopulmonary shunts, or cyanotic congenital heart disease. 1, 2
• Pulse oximetry or arterial blood gas: Arterial oxygen saturation <92% indicates hypoxia-driven secondary polycythemia. 1

Hypoxia-Independent (Tumor-Related) Causes

• Abdominal ultrasound or CT: Screen for EPO-producing tumors including renal cell carcinoma, hepatocellular carcinoma, uterine leiomyomas, pheochromocytoma, meningioma, or parathyroid carcinoma. 1, 2
• Renal function tests: Evaluate for post-renal transplant erythrocytosis. 1

Medication and Exogenous Causes

• Medication review: Exogenous testosterone, anabolic steroids, or administered erythropoietin can cause secondary erythrocytosis. 1, 4, 2

Critical Red Flags Requiring Urgent Action

Immediate Hematology Referral Indications

• Positive JAK2 mutation requires immediate hematology referral for PV management. 2
• Hemoglobin >20 g/dL and hematocrit >65% with hyperviscosity symptoms (headache, visual disturbances, dizziness) requires urgent therapeutic phlebotomy after excluding dehydration. 1, 4, 2
• Unexplained splenomegaly (present in 36% of PV patients) with elevated blood counts mandates hematology evaluation. 2, 3
• Unusual thrombosis sites (splanchnic veins, cerebral veins) suggest PV—16% of patients have arterial thrombosis and 7% have venous thrombosis at or before diagnosis. 3

Additional PV-Related Features That Trigger Workup

• Aquagenic pruritus (itching after warm water exposure, present in 33% of PV patients). 1, 3
• Erythromelalgia (burning pain in extremities, present in 5.3% of PV patients). 1, 3
• Transient visual changes (present in 14% of PV patients). 3

Management Based on Diagnosis

If Polycythemia Vera Is Confirmed

All PV patients require two cornerstone therapies:

1. Therapeutic phlebotomy to maintain hematocrit strictly <45% to reduce thrombotic risk (2.7% vs 9.8% event rate, P=0.007 in CYTO-PV trial). 1, 4, 3
2. Low-dose aspirin (81-100 mg daily) for thrombosis prevention (if no contraindications). 1, 3

High-risk patients (age ≥60 years OR prior thrombosis) require cytoreductive therapy:

• Hydroxyurea or interferon to lower thrombosis risk and decrease symptoms. 1, 3
• Ruxolitinib (JAK inhibitor) for patients intolerant of or resistant to hydroxyurea, particularly for pruritus and splenomegaly. 3

If Secondary Polycythemia Is Confirmed

• Treat the underlying condition: smoking cessation, CPAP for sleep apnea, management of COPD or cardiac disease. 1, 2
• Phlebotomy is contraindicated in most secondary polycythemia cases because the elevated hematocrit serves a compensatory physiological role. 1, 4
• Phlebotomy is indicated ONLY when:
  • Hematocrit >65% AND hemoglobin >20 g/dL
  • Documented hyperviscosity symptoms present
  • Dehydration has been excluded
  • Iron deficiency has been excluded (transferrin saturation >20%) 1, 4

Common Diagnostic Pitfalls to Avoid

• Do not assume normal EPO excludes PV: EPO sensitivity for PV is only 64-70%; normal EPO with elevated hemoglobin still requires JAK2 testing. 1
• Do not overlook coexisting iron deficiency: Iron-deficient RBCs have reduced oxygen-carrying capacity and deformability, paradoxically increasing stroke risk despite elevated hematocrit. 1, 2
• Do not perform aggressive phlebotomy in secondary polycythemia: This causes iron depletion, decreased oxygen-carrying capacity, and increased stroke risk. 1, 4
• Do not miss the diagnosis in patients with borderline hemoglobin and microcytosis: Iron deficiency can mask PV by suppressing hemoglobin elevation; look for accompanying thrombocytosis, leukocytosis, or splenomegaly. 1
• Do not use standard PV thresholds at high altitude: Physiologic adaptation increases hemoglobin by 0.2-4.5 g/dL depending on elevation (1000-4500 meters). 1

Prognosis and Long-Term Monitoring

• Median survival from PV diagnosis is 14.1-27.6 years across seven cohorts. 3
• Transformation risk: 12.7% develop myelofibrosis and 6.8% develop acute myeloid leukemia. 3
• Thrombosis is the major cause of morbidity and mortality in both PV and secondary polycythemia, with unexplained thrombocytosis and secondary erythrocytosis associated with the highest rate of recurrent events. 5