What is the diagnosis and management for a patient with elevated blood cell counts, including leukocytosis, erythrocytosis, and thrombocytosis?

Diagnosis and Management of Elevated Blood Cell Counts

This patient requires immediate evaluation for a myeloproliferative neoplasm (MPN), specifically testing for BCR-ABL1 fusion to exclude chronic myeloid leukemia (CML), followed by JAK2/CALR/MPL mutation testing if CML is excluded. 1, 2

Initial Diagnostic Workup

The priority is distinguishing between a primary myeloproliferative neoplasm versus a reactive process, as this fundamentally determines treatment strategy. 2

Mandatory First-Line Testing

• Peripheral blood FISH for BCR-ABL1 fusion gene using dual probes for BCR and ABL genes to confirm or exclude CML 1, 2
• Complete blood count with differential - already obtained, showing WBC 11.5, RBC 5.26, Hct 47.4%, platelets 405, absolute neutrophils 8,637 1
• Bone marrow biopsy with cytogenetics - essential for definitive diagnosis, as morphologic evaluation distinguishes between ET, PV, and prefibrotic myelofibrosis 1, 3

Second-Line Molecular Testing (if BCR-ABL1 negative)

• JAK2V617F mutation testing - present in ~98% of PV cases and ~60% of ET cases 1, 4
• CALR and MPL mutations if JAK2 negative - found in ~25% and ~3% of ET patients respectively 1, 5
• Serum erythropoietin level - subnormal in PV, helps differentiate from secondary erythrocytosis 1, 4

Additional Baseline Studies

• Serum LDH - elevated in myelofibrosis and some MPNs 1
• Screening for acquired von Willebrand syndrome if platelets >1,000 × 10⁹/L before starting aspirin 6, 5, 7

Diagnostic Algorithm Based on WHO 2016 Criteria

If Polycythemia Vera (PV) Suspected

Major criteria (all 3 required OR first 2 + minor criterion): 1

• Hemoglobin >16.5 g/dL (men) or >16 g/dL (women), OR Hematocrit >49% (men) or >48% (women)
• Bone marrow showing hypercellularity with trilineage myeloproliferation
• Presence of JAK2 mutation

Minor criterion: 1

• Subnormal serum erythropoietin level

If Essential Thrombocythemia (ET) Suspected

All 4 major criteria required: 1

• Platelet count ≥450 × 10⁹/L
• Bone marrow with megakaryocyte proliferation, large and mature morphology
• Not meeting WHO criteria for CML, PV, PMF, or MDS
• Presence of JAK2, CALR, or MPL mutation

If Chronic Myeloid Leukemia (CML) Confirmed

Hallmark findings: 1

• Leukocytosis with basophilia and immature granulocytes (metamyelocytes, myelocytes, promyelocytes)
• BCR-ABL1 fusion gene detected by FISH or RT-PCR
• Philadelphia chromosome t(9;22) on cytogenetics

Risk Stratification

For Essential Thrombocythemia (IPSET Criteria)

Calculate thrombotic risk score: 1

• Age >60 years: 1 point
• Cardiovascular risk factors: 1 point
• Previous thrombosis: 2 points
• JAK2V617F mutation: 2 points

Risk categories: 1

• Low risk: score 0-1
• Intermediate risk: score 2
• High risk: score ≥3

For Polycythemia Vera

High-risk defined by: 6, 5, 7

• Age >60 years OR
• History of thrombosis

Additional risk factors for shortened survival: 6, 5

• Leukocytosis
• History of thrombosis
• Advanced age

Treatment Algorithm

If CML Confirmed (BCR-ABL1 Positive)

Start tyrosine kinase inhibitor immediately once Philadelphia chromosome or BCR-ABL1 fusion detected: 2

• Imatinib is first-line treatment for chronic phase CML 2
• Hydroxyurea 50-60 mg/kg per day for rapid cytoreduction if WBC >10-20 × 10⁹/L with symptoms 2, 8
• Monitor BCR-ABL transcript levels every 3 months during treatment 1, 2
• Bone marrow cytogenetics at 6 and 12 months from therapy initiation 1, 2

If Polycythemia Vera Confirmed

All patients (low and high risk): 4, 6, 5

• Goal-directed phlebotomy to maintain hematocrit <45% - reduces thrombotic events and improves survival 4, 6, 5
• Low-dose aspirin (unless contraindicated by extreme thrombocytosis with AvWS) 4, 6, 5

High-risk patients (age >60 or thrombosis history) add: 4, 6, 5

• Hydroxyurea as first-line cytoreductive therapy 4, 6, 5
• Second-line options if hydroxyurea fails: pegylated interferon-alfa, busulfan, or ruxolitinib 4, 6, 5

If Essential Thrombocythemia Confirmed

Low-risk patients (age ≤60, no thrombosis history, no high-risk mutations): 6, 5, 7

• Low-dose aspirin alone 6, 5, 7
• Observation if asymptomatic

High-risk patients (age >60 OR thrombosis history): 6, 5, 7

• Low-dose aspirin 6, 5, 7
• Hydroxyurea 2-4 g per day to restore platelet counts to <400 × 10⁹/L 2, 8

Symptomatic thrombocytosis management: 2

• Evaluate for microvascular symptoms
• Consider age, cardiovascular risk factors, and degree of thrombocytosis

Hydroxyurea Dosing and Monitoring

Dosing per FDA label: 8

• Initial dose: 15 mg/kg once daily (if creatinine clearance ≥60 mL/min) 8
• Reduce dose by 50% if creatinine clearance <60 mL/min 8
• For symptomatic leukocytosis: 50-60 mg/kg per day until WBC <10-20 × 10⁹/L 2, 8
• For symptomatic thrombocytosis: 2-4 g per day to restore platelets <400 × 10⁹/L 2, 8

Monitoring requirements: 2, 8

• Blood counts at least weekly until stable, then every 2-4 weeks 2, 8
• Prophylactic folic acid administration recommended 8
• Monitor for myelosuppression (leukopenia is first manifestation) 8

Critical Warnings and Contraindications

Hydroxyurea Precautions

FDA black box warnings: 8

• Severe myelosuppression - do not initiate if bone marrow function markedly depressed 8
• Human carcinogen - secondary leukemia and skin cancer reported with long-term use 8
• Embryo-fetal toxicity - effective contraception required for 6 months (females) or 1 year (males) after therapy 8

Monitor for and discontinue if: 8

• Hemolytic anemia (acute jaundice, hematuria with worsening anemia) 8
• Cutaneous vasculitic ulcerations or gangrene 8

Aspirin Contraindications

Avoid aspirin in: 1

• Young patients with extreme thrombocytosis (>1,000 × 10⁹/L) due to risk of acquired von Willebrand syndrome and bleeding 1, 6, 5
• Screen for AvWS before administering aspirin if extreme thrombocytosis present 6, 5, 7

Common Pitfalls to Avoid

• Do not rely solely on peripheral blood findings - bone marrow biopsy is mandatory for distinguishing ET from prefibrotic myelofibrosis 1, 3
• Do not miss secondary causes of erythrocytosis - check EPO level, consider smoking, sleep apnea, testosterone use 4
• Do not start cytoreductive therapy in asymptomatic low-risk patients - aspirin and observation may be sufficient 6, 5
• Do not overlook thrombosis risk from hyperviscosity - myeloproliferative neoplasms are a common cause of splanchnic vein thrombosis (30-40% of Budd-Chiari and portal vein thrombosis cases) 1
• Do not forget cardiovascular risk modification - smoking cessation and cardiometabolic disease management reduce thrombotic risk 4

Prognosis and Long-Term Monitoring

Survival expectations: 6, 5

• ET: median survival ~20 years (33 years in younger patients)
• PV: median survival ~14 years (24 years in younger patients)

Transformation risks at 20 years: 6, 5

• Leukemic transformation: <5% (ET), <10% (PV)
• Fibrotic transformation: slightly higher than leukemic rates

Thrombosis risk exceeds 20% - making prevention the primary therapeutic goal 6, 5, 7