Medications to Reduce Hematocrit
Phlebotomy is the primary intervention to reduce hematocrit in all patients, with a strict target of <45%, while hydroxyurea is the first-line cytoreductive medication for high-risk patients (age ≥60 years or prior thrombosis) who require pharmacologic reduction of hematocrit. 1
Universal First-Line Approach for All Patients
Therapeutic phlebotomy is the cornerstone treatment to maintain hematocrit strictly below 45%, as demonstrated by the CYTO-PV trial which showed a 3.91-fold increased risk of cardiovascular death and major thrombosis when hematocrit was maintained at 45-50% versus <45% (2.7% vs 9.8% event rate, P=0.007) 1, 2
Consider lower hematocrit targets of approximately 42% for women and African Americans due to physiological differences in baseline hematocrit values 1
Perform phlebotomy with careful fluid replacement to prevent hypotension or fluid overload, particularly in elderly patients with cardiovascular disease 1
Low-dose aspirin (81-100 mg daily) should be added for all patients without contraindications to reduce thrombotic risk 1, 3
Cytoreductive Medications (For High-Risk Patients)
Hydroxyurea - First-Line Cytoreductive Agent
Hydroxyurea is the preferred first-line cytoreductive medication for high-risk patients (age ≥60 years and/or history of thrombosis), with Level II, A evidence for efficacy and tolerability 1
Starting dose is 500 mg twice daily (or 15-20 mg/kg/day), with a typical maintenance dose of 2 g/day (2.5 g/day if body weight >80 kg) 1, 4
Achieves initial control of elevated hematocrit and platelet count within 12 weeks in over 80% of patients 4
Use with caution in young patients (<40 years) due to potential leukemogenic risk with prolonged exposure 1
Interferon-α - Alternative First-Line Option
Interferon-α is the preferred cytoreductive agent for younger patients (<40 years), women of childbearing age, and pregnant patients due to its non-leukemogenic profile 1
Starting dose is 3 million units subcutaneously 3 times weekly 5
Achieves up to 80% hematologic response rate and can reduce the JAK2V617F allelic burden 1
Particularly effective for patients with refractory pruritus 1
Ruxolitinib - Second-Line Option
Indicated for patients with inadequate response or intolerance to hydroxyurea, as demonstrated by the RESPONSE phase III study 1
Particularly effective for reducing splenomegaly and symptom burden 1, 3
Can alleviate pruritus in patients intolerant of or resistant to hydroxyurea 3
Defining Treatment Failure and When to Switch
Hydroxyurea resistance/intolerance is defined as: need for phlebotomy to keep hematocrit <45% after 3 months of at least 2 g/day, uncontrolled myeloproliferation (platelet count >400 × 10⁹/L and WBC count >10 × 10⁹/L after 3 months), failure to reduce massive splenomegaly, or cytopenia/unacceptable side effects at any dose 1
When hydroxyurea fails, switch to interferon-α as the preferred second-line agent due to its non-leukemogenic profile 1
Common Pitfalls to Avoid
Never accept hematocrit targets of 45-50%, as the CYTO-PV trial definitively showed increased thrombotic risk at these levels 1, 2
Avoid inadequate fluid replacement during phlebotomy, which can precipitate hypotension, particularly in elderly patients with cardiovascular disease 1
Avoid chlorambucil and ³²P in younger patients, as these agents carry significantly increased leukemia risk 1
Do not perform repeated routine phlebotomies without monitoring for iron deficiency, as iron-deficient red blood cells have reduced oxygen-carrying capacity and deformability, increasing stroke risk 6, 7
Special Populations
For pregnant patients requiring cytoreductive therapy, interferon-α is the agent of choice over hydroxyurea due to its safer profile 1
Consider cytoreductive therapy for extreme thrombocytosis (>1,500 × 10⁹/L) even in otherwise low-risk patients 1
Busulfan may be considered only in elderly patients (>70 years) due to increased leukemia risk in younger patients 1