What is the best treatment for a 62‑year‑old patient with Janus kinase 2 (JAK2)‑positive polycythemia vera, thrombocytosis, and markedly elevated hematocrit?

Treatment for JAK2-Positive Polycythemia Vera with Severe Thrombocytosis and Erythrocytosis

This 62-year-old patient with JAK2-positive PV, hematocrit 66%, and platelets 1.2 million requires immediate triple therapy: urgent phlebotomy to reduce hematocrit below 45%, cytoreductive therapy with hydroxyurea, and careful consideration of aspirin given the extreme thrombocytosis. 1, 2, 3

Immediate Risk Stratification

This patient is definitively high-risk based on age >60 years, which mandates cytoreductive therapy regardless of thrombosis history. 4, 1, 2 The combination of markedly elevated hematocrit (66%) and extreme thrombocytosis (1.2 million) creates dual competing risks: thrombosis from erythrocytosis and bleeding from acquired von Willebrand syndrome (AvWS). 5, 6

First Priority: Urgent Phlebotomy

• Initiate aggressive phlebotomy immediately to reduce hematocrit from 66% to strictly below 45% (target ~42% given individual variation). 1, 2, 3
• Perform phlebotomy with careful fluid replacement to prevent hypotension, particularly critical in this 62-year-old who may have cardiovascular comorbidities. 1
• The CYTO-PV trial definitively showed that hematocrit levels >44% are associated with progressive increases in thrombotic events, making this the most urgent intervention. 1, 2
• Phlebotomy may need to be performed as frequently as every 2-3 days initially until target hematocrit is achieved. 1

Second Priority: Cytoreductive Therapy with Hydroxyurea

Start hydroxyurea immediately at 500 mg twice daily (or 2 g/day if body weight <80 kg, 2.5 g/day if >80 kg). 1, 3, 7

Rationale for hydroxyurea as first-line:

• This patient meets multiple indications for cytoreductive therapy: high-risk age category, extreme thrombocytosis (>1,500 × 10⁹/L), and markedly elevated hematocrit requiring frequent phlebotomy. 4, 1, 3
• Hydroxyurea carries Level II, Grade A evidence as first-line cytoreductive therapy for patients >40 years. 1, 3
• The treatment goals are: hematocrit <45% without phlebotomy requirement, platelet count ≤400 × 10⁹/L, and WBC ≤10 × 10⁹/L. 3

Alternative consideration—Interferon-α:

• While hydroxyurea is preferred for this age group, interferon-α (pegylated formulation, 45 mcg subcutaneously weekly) should be considered if the patient is female of childbearing potential or if rapid control of extreme thrombocytosis is needed. 4, 1, 3
• Interferon-α is non-leukemogenic and achieves up to 80% hematologic response rate. 1, 3

Critical Decision: Aspirin Management

Do NOT start aspirin until platelet count decreases below 1,000 × 10⁹/L. 4, 1, 6

The extreme thrombocytosis creates a bleeding paradox:

• Platelet counts >1,000 × 10⁹/L are associated with acquired von Willebrand syndrome (AvWS), which significantly increases bleeding risk. 4, 5, 6
• Before considering aspirin, screen for AvWS with ristocetin cofactor activity and von Willebrand factor multimer analysis. 4, 6
• If AvWS is present, aspirin must be avoided until platelet count normalizes with cytoreductive therapy. 6
• Once platelets decrease to <1,000 × 10⁹/L and AvWS is excluded, initiate low-dose aspirin 81-100 mg daily. 1, 2, 7

Monitoring Strategy

• Hematocrit monitoring: Check every 2-3 days during initial phlebotomy phase, then weekly until stable below 45%. 1
• Complete blood count: Monitor weekly during hydroxyurea initiation to assess platelet and WBC response. 1, 3
• Assess hydroxyurea response at 3 months: If still requiring phlebotomy to maintain hematocrit <45% after 3 months on at least 2 g/day hydroxyurea, this defines treatment resistance. 1, 3
• Screen for AvWS before initiating aspirin, particularly given the extreme thrombocytosis. 6

Defining Treatment Failure and Second-Line Options

Hydroxyurea resistance is defined by: 1, 3

• Need for phlebotomy to keep hematocrit <45% after 3 months of ≥2 g/day hydroxyurea
• Uncontrolled myeloproliferation (platelet >400 × 10⁹/L and WBC >10 × 10⁹/L) after 3 months of ≥2 g/day
• Cytopenia or unacceptable side effects at any dose

If hydroxyurea fails, switch to:

• Ruxolitinib (JAK1/JAK2 inhibitor): FDA-approved for hydroxyurea-resistant PV, with superior hematocrit control and symptom reduction demonstrated in the RESPONSE trial. 4, 1, 3
• Interferon-α (pegylated): Preferred alternative with non-leukemogenic profile. 1, 3, 7

Cardiovascular Risk Factor Management

Aggressively manage all modifiable thrombotic risk factors concurrently: 1, 2

• Mandatory smoking cessation if applicable
• Target blood pressure <130/80 mmHg
• Achieve LDL-cholesterol <70 mg/dL if any vascular disease history
• Optimize diabetes control if present
• These interventions are as essential as pharmacologic therapy for reducing thrombotic risk. 1

Critical Pitfalls to Avoid

• Do not accept hematocrit 45-50%: The CYTO-PV trial definitively showed increased thrombotic risk at these levels. 1
• Do not give aspirin with platelet count >1,000 × 10⁹/L without first excluding AvWS—this creates major bleeding risk. 4, 6
• Do not use chlorambucil or ³²P in any patient, but especially avoid in younger patients due to significantly increased leukemia risk. 1, 3
• Do not delay cytoreductive therapy in this high-risk patient—age >60 years mandates treatment regardless of symptom burden. 4, 1, 2
• Do not perform phlebotomy without adequate fluid replacement—this can precipitate hypotension and paradoxically increase thrombotic risk through hemoconcentration. 1

Expected Timeline and Outcomes

• Hematocrit should normalize within 2-4 weeks with aggressive phlebotomy. 1
• Platelet count typically begins declining within 4-6 weeks of hydroxyurea initiation. 3
• Once platelet count falls below 1,000 × 10⁹/L and AvWS is excluded, aspirin can be safely added. 6
• Full hematologic response (hematocrit <45% without phlebotomy, platelets ≤400 × 10⁹/L, WBC ≤10 × 10⁹/L) should be achieved by 3 months if hydroxyurea is effective. 3