Is hormone replacement therapy (HRT) contraindicated in patients with polycythemia vera (PV)?

Hormone Replacement Therapy in Polycythemia Vera

Hormone replacement therapy is generally contraindicated in patients with polycythemia vera due to the significantly elevated thrombotic risk from both conditions, though the decision requires careful assessment of individual thrombotic risk factors and consideration of transdermal formulations in highly selected cases.

Understanding the Thrombotic Risk

Polycythemia vera creates a baseline hypercoagulable state through multiple mechanisms that directly conflict with HRT safety:

• PV is characterized by hyperviscosity and prothrombotic mechanisms including abnormal activation of leukocytes, endothelial cells, and platelets, with widespread activation of coagulation proteins and reduced physiologic anticoagulants 1
• Arterial and venous thrombosis are major complications of PV, with 16% of patients experiencing arterial thrombosis and 7% experiencing venous thrombotic events prior to or at diagnosis, often involving unusual sites like splanchnic veins 2
• HRT increases VTE risk 2-3 fold in the general population, with oral estrogen-progestin preparations showing a 2-fold increase over placebo in the Women's Health Initiative study 3
• Hyperviscosity from polycythemia is explicitly listed as a secondary risk factor for venous thromboembolism in European Society of Cardiology guidelines 3

General Contraindications Apply

Previous venous thromboembolic event or stroke represents an absolute contraindication to HRT according to American College of Rheumatology guidelines 3. Given that PV patients have baseline thrombotic events in 23% of cases at or before diagnosis 2, many would already meet this exclusion criterion.

Risk Stratification Approach

If HRT is being considered despite PV diagnosis, apply this algorithmic assessment:

Absolute Contraindications (Do Not Use HRT):

• History of any thrombotic event (arterial or venous) 3
• Active or recent thrombosis within one year 3
• Uncontrolled hematocrit >45% 1, 2
• Extreme thrombocytosis >1000 × 10⁹/L (paradoxically increases bleeding risk from acquired von Willebrand disease present in >33% of PV patients) 1, 4

Relative Contraindications Requiring Extreme Caution:

• Age >60 years (high-risk PV category for thrombosis) 4, 5
• Inadequately controlled cardiovascular risk factors 4
• Suboptimal PV control requiring ongoing phlebotomy 4

If HRT Must Be Considered

In the rare scenario where benefits might outweigh risks (severe vasomotor symptoms significantly impacting quality of life in a young, low-risk PV patient with excellent disease control):

Formulation Selection:

• Transdermal estrogen is mandatory - it avoids hepatic first-pass metabolism and minimizes impact on hemostatic factor synthesis 3
• Transdermal estrogen does not increase VTE risk in healthy women, even those with prothrombotic mutations like Factor V Leiden 3
• Use 50-100 micrograms transdermal 17β-estradiol daily rather than oral formulations 3
• Combine with micronized progesterone (if uterus present), which has the best safety profile for thrombotic risk among progestogens 3

Mandatory Concurrent Management:

• Maintain hematocrit strictly <45% through therapeutic phlebotomy 1, 4, 2
• Continue low-dose aspirin 81-100 mg daily (unless contraindicated by extreme thrombocytosis with bleeding) 4, 2, 5
• Ensure cytoreductive therapy is optimized if patient meets high-risk criteria 4, 5

Critical Pitfalls to Avoid

• Do not use oral estrogen formulations - the hepatic first-pass effect significantly increases prothrombotic effects 3
• Do not prescribe HRT without ensuring PV is optimally controlled with hematocrit <45% 1, 2
• Do not use combined oral contraceptives as HRT substitutes - these contain higher estrogen doses (EE) with greater thrombotic risk than physiologic HRT 3
• Do not ignore the compounding effect - oral HRT in patients with Factor V Leiden increases VTE risk 25-fold compared to mutation-free women not receiving HRT 3, and PV creates similar or greater prothrombotic risk

Clinical Reality

In real-world practice, the prudent approach is to avoid HRT entirely in PV patients and instead manage menopausal symptoms through non-hormonal alternatives (SSRIs, SNRIs, gabapentin, clonidine for vasomotor symptoms) given the unacceptable compounding of thrombotic risks 3. The baseline thrombotic risk in PV (23% at diagnosis) 2 combined with HRT's 2-3 fold VTE increase 3 creates an unjustifiable hazard for most patients, prioritizing mortality and morbidity prevention over symptom management.