What is the management and treatment approach for a patient with polycythemia, considering the risk of thrombotic events and cardiovascular complications?

Management of Polycythemia Vera

Risk Stratification

All patients with polycythemia vera must be stratified into low-risk (age <60 years and no history of thrombosis) or high-risk (age ≥60 years and/or history of thrombosis) categories, as this determines the intensity of cytoreductive therapy. 1, 2

• Advanced age (>60 years) and prior thrombosis are the two most consistent and important prognostic factors for cardiovascular events and thrombotic complications 1
• Low-risk patients can typically be managed with phlebotomy and aspirin alone 2, 3
• High-risk patients require the addition of cytoreductive therapy to phlebotomy and aspirin 1, 2

Universal First-Line Treatment for All Patients

Phlebotomy

Maintain hematocrit strictly below 45% through therapeutic phlebotomy, as the CYTO-PV trial definitively demonstrated that hematocrit levels of 45-50% result in a 3.91-fold increased risk of cardiovascular death or major thrombotic events. 1, 2

• Target hematocrit of approximately 42% for women and African Americans due to physiological differences in baseline values 2
• Perform phlebotomy with careful fluid replacement to prevent hypotension, particularly in elderly patients with cardiovascular disease 2
• Aggressive phlebotomy has improved median survival to >10 years compared to <4 years historically with inadequate phlebotomy 2

Aspirin Therapy

Administer low-dose aspirin (81-100 mg daily) to all patients without contraindications, as the ECLAP trial showed significant reduction in cardiovascular death, non-fatal myocardial infarction, stroke, and major venous thromboembolism. 1, 2

• Low-dose aspirin (40-100 mg) does not increase bleeding risk 2
• Continue aspirin during the perioperative period to reduce thrombotic risk 4

Cardiovascular Risk Factor Management

Aggressively manage all modifiable cardiovascular risk factors including hypertension, hyperlipidemia, diabetes, and mandate smoking cessation counseling. 1, 2

Cytoreductive Therapy for High-Risk Patients

First-Line Cytoreductive Options

Hydroxyurea is the first-line cytoreductive agent (Level II, A evidence) for patients >40 years old, starting at 500 mg twice daily. 1, 2, 5

• Use hydroxyurea with caution in patients <40 years due to potential leukemogenic risk with prolonged exposure 2, 5
• Hydroxyurea resistance or intolerance is defined as: need for phlebotomy after 3 months of ≥2 g/day, uncontrolled myeloproliferation, failure to reduce massive splenomegaly, or cytopenia/unacceptable side effects at any dose 2, 5

Interferon-α (starting dose 3 million units subcutaneously 3 times weekly) is the preferred first-line cytoreductive agent (Level III, B evidence) for younger patients (<40 years), women of childbearing age, and pregnant patients. 1, 2, 5

• Interferon-α achieves up to 80% hematologic response rate and is non-leukemogenic 2, 5
• Particularly effective for refractory pruritus 2
• Can reduce JAK2V617F allelic burden 2
• Mandatory choice for pregnant patients requiring cytoreductive therapy 1, 2

Additional Indications for Cytoreductive Therapy

Initiate cytoreductive therapy in low-risk patients who develop: 1, 2

• Frequent or persistent need for phlebotomy with poor tolerance
• Symptomatic or progressive splenomegaly
• Severe disease-related symptoms (pruritus, night sweats, fatigue)
• Platelet count >1,500 × 10⁹/L
• Progressive leukocytosis

Second-Line Cytoreductive Therapy

Ruxolitinib is indicated for patients with inadequate response to or intolerance of hydroxyurea, as demonstrated by the RESPONSE trial showing improved hematocrit control, splenomegaly reduction, and symptom burden improvement (Level II, B evidence). 1, 2

• Consider ruxolitinib for severe and protracted pruritus or marked splenomegaly not responding to first-line agents 3

Busulfan may be considered only in elderly patients >70 years due to significantly increased leukemia risk in younger patients. 2

Management of Thrombotic Events

For patients with active thrombosis, initiate clinically appropriate anticoagulant therapy (low-molecular-weight heparin, direct oral anticoagulant, or warfarin) following American College of Chest Physicians Guidelines. 1

• Assess need for cytoreductive therapy and initiate if not already done to maintain hematocrit <45% 1
• Duration of anticoagulation depends on severity of thrombotic event, degree of disease control, and likelihood of recurrence 1
• Meticulous control of anticoagulation intensity is critical, as recurrent events are associated with INR <2.0 when using warfarin 6

Management of Bleeding Complications

Rule out other potential causes and withhold aspirin until bleeding is controlled. 1

• Consider cytoreductive therapy to normalize platelet counts 1
• Perform coagulation tests to evaluate for acquired von Willebrand disease in patients with elevated platelet count, splenomegaly, or unexplained bleeding 1
• For gastrointestinal bleeding with splenomegaly and portal hypertension, obtain hepatology or gastroenterology consultation for endoscopic evaluation 1

Perioperative Management

For elective surgery, achieve normalization or near-normalization of complete blood count without causing prohibitive cytopenias prior to the procedure. 1

• Multi-disciplinary management with surgical and perioperative teams is essential 1
• For high venous thromboembolism risk procedures (cancer surgery, splenectomy, orthopedic, cardiovascular surgery), consider extended prophylaxis with low-molecular-weight heparin 1
• Emergency surgery should proceed as necessary with close postoperative surveillance for thrombosis and bleeding 1

Symptom Management

For pruritus, consider selective serotonin receptor antagonists, interferon-α, JAK2 inhibitors, or antihistamines. 2

For erythromelalgia (occurring in ~3% of patients), low-dose aspirin is typically effective for platelet-mediated microvascular symptoms. 2

Monitoring and Follow-Up

Monitor patients every 3-6 months for new thrombosis or bleeding, signs/symptoms of disease progression, and assess symptom burden regularly. 2

• Maintain hematocrit levels at target values through regular monitoring 2
• Perform bone marrow aspirate and biopsy to rule out disease progression to myelofibrosis prior to initiating cytoreductive therapy 2
• No routine indication to monitor JAK2V617F allele burden except when using interferon-α therapy 2

Critical Pitfalls to Avoid

• Never accept hematocrit targets of 45-50%, as this definitively increases thrombotic risk 2
• Avoid chlorambucil and ³²P in younger patients due to significantly increased leukemia risk 2
• Do not perform phlebotomy without adequate fluid replacement, particularly in elderly patients with cardiovascular disease 2
• Never administer routine blood transfusions in polycythemia vera patients, as this counteracts the therapeutic goal of maintaining hematocrit <45% 4

Disease Transformation Risk

• 10% risk of transformation to myelofibrosis in the first decade 2
• 5% risk of acute leukemia with progressive increase beyond the first decade 2