Can a patient have both Hereditary Hemorrhagic Telangiectasia (HHT) and Polycythemia Vera (PV) simultaneously?

Can a Patient Have Both HHT and Polycythemia Vera Simultaneously?

Yes, a patient can have both Hereditary Hemorrhagic Telangiectasia (HHT) and Polycythemia Vera (PV) simultaneously, though this represents a rare co-occurrence of two distinct genetic disorders rather than a causally linked syndrome.

Evidence for Co-Occurrence

The medical literature documents that these two conditions can coexist in the same patient, though the relationship remains incompletely understood:

• A 1982 case series reported two patients with coexistent HHT and primary thrombocythemia (a related myeloproliferative neoplasm), suggesting that such combinations may occur more frequently than previously recognized, though the authors could not definitively establish whether this represented coincidence or a true syndrome 1
• Chronic myeloproliferative disorders including polycythemia vera are listed as "possible" risk factors for pulmonary arterial hypertension in patients with HHT, indicating recognized clinical overlap between these conditions 2

Distinct Pathophysiologic Mechanisms

These are fundamentally separate disease processes with different genetic origins:

• HHT is an autosomal dominant vascular disorder caused by loss-of-function mutations in genes encoding proteins of the BMP signaling pathway (primarily ENG, ACVRL1, SMAD4, or GDF2), affecting vascular endothelium and causing abnormal blood vessel formation 2, 3, 4, 5
• Polycythemia Vera is a clonal myeloproliferative neoplasm caused by acquired somatic mutations (≥95% have JAK2V617F mutation, 2-4% have JAK2 exon 12 mutations), affecting hematopoietic stem cells and causing erythrocytosis 2

Critical Clinical Implications of Co-Occurrence

When both conditions coexist, management becomes exceptionally complex due to competing bleeding and thrombotic risks:

Bleeding Risk Considerations

• HHT causes widespread telangiectases and arteriovenous malformations that are prone to rupture and bleeding, with recurrent epistaxis occurring in >90% of adults and gastrointestinal bleeding being common 2, 3, 4
• Iron deficiency anemia from chronic bleeding affects approximately 50% of HHT patients, which can paradoxically mask the elevated red cell mass of PV by lowering the pathologic baseline to within normal reference range 6, 7
• Liver biopsy must be strictly avoided in any patient with proven or suspected HHT due to catastrophic hemorrhage risk from hepatic vascular malformations 2, 6

Thrombotic Risk Considerations

• PV significantly increases thrombotic risk, with high-risk patients (age >60 years and/or prior thrombosis) requiring cytoreductive therapy in addition to phlebotomy 2, 8
• All PV patients require phlebotomy to maintain hematocrit strictly <45% to reduce thrombotic events 8
• Low-dose aspirin (81-100 mg daily) is standard for PV patients to reduce cardiovascular events, but this must be carefully weighed against HHT bleeding risk 8

Management Algorithm for Co-Occurrence

Step 1: Confirm Both Diagnoses

• Establish HHT diagnosis using Curaçao criteria (requiring 3 of 4: epistaxis, telangiectasias, visceral AVMs, affected first-degree relative) with genetic testing for ENG, ACVRL1, SMAD4, or GDF2 mutations 6, 3, 4
• Confirm PV diagnosis with JAK2 mutation testing (V617F or exon 12) and bone marrow evaluation per WHO criteria 2

Step 2: Comprehensive HHT Screening (Critical to Avoid Catastrophic Complications)

• Perform Doppler ultrasonography for hepatic vascular malformations (never liver biopsy) 2, 6
• Screen for pulmonary AVMs with contrast echocardiography or chest CT, as these can be treated presymptomatically to prevent stroke and cerebral abscess 2, 6
• Perform brain MRI to detect cerebral vascular malformations 6
• Assess for gastrointestinal telangiectasias with upper endoscopy if anemia is disproportionate to epistaxis 6

Step 3: Risk-Stratify PV and Initiate Baseline Therapy

• Classify as high-risk (age >60 or prior thrombosis) versus low-risk (age ≤60 with no thrombosis history) 8
• Initiate phlebotomy targeting hematocrit <45% in all patients (this is non-negotiable regardless of bleeding risk) 8
• Critical decision point for aspirin: In standard PV, low-dose aspirin is recommended for all patients without contraindications 8. However, in patients with active HHT bleeding manifestations, aspirin should be withheld or used with extreme caution given the competing hemorrhagic risk 9

Step 4: Address HHT Bleeding Manifestations

• Begin with nasal moisturization (air humidification, topical saline/gels) for epistaxis 6
• Escalate to oral tranexamic acid if moisturization inadequate (reduces epistaxis duration by 17.3% and composite endpoints by 54%) 6
• Consider local ablative therapies for refractory epistaxis 6
• Reserve systemic bevacizumab for severe refractory bleeding (produces 50% reduction in epistaxis severity score) 6
• Implement aggressive iron replacement therapy (oral or IV) to maintain iron stores, as iron deficiency will mask PV erythrocytosis and complicate diagnosis 6, 7

Step 5: Cytoreductive Therapy Decision (PV High-Risk Patients)

• High-risk PV patients require cytoreductive therapy regardless of HHT status 8
• First-line agent selection: Hydroxyurea (starting 500 mg twice daily, titrated to ≥2 g/day) is standard first-line for patients >40 years 8
• Alternative for younger patients: Interferon-α (including pegylated formulations) is preferred for patients <40 years and women of childbearing potential 8
• Monitor for treatment resistance/intolerance (defined as need for phlebotomy after 3 months of ≥2 g/day hydroxyurea, uncontrolled myeloproliferation, cytopenia, or unacceptable toxicity) 8

Step 6: Anticoagulation Decisions (If Thrombosis Occurs)

• Recent evidence suggests HHT patients can be safely anticoagulated when necessary, with worsened epistaxis being the most frequent complication 9
• If anticoagulation is required for thrombosis, factor IIa and Xa inhibitors have less intracranial bleeding than warfarin and may be preferred 9
• Anticoagulation decisions must account for individual bleeding risk based on severity and location of HHT vascular malformations 9

Critical Pitfalls to Avoid

• Do not assume anemia excludes PV: Iron deficiency from HHT bleeding can mask the elevated red cell mass of PV, causing measured values to fall within normal range 7. Assess complete iron studies (hemoglobin, ferritin, transferrin saturation) and consider JAK2 mutation testing even with normal hematocrit if clinical suspicion exists 2, 7
• Do not perform liver biopsy: This is absolutely contraindicated in HHT patients due to catastrophic hemorrhage risk from hepatic vascular malformations 2, 6
• Do not withhold phlebotomy due to bleeding concerns: Maintaining hematocrit <45% is essential to prevent thrombosis and takes priority, as thrombotic events in PV are life-threatening 8
• Do not use platelet count alone to guide cytoreductive therapy: Extreme thrombocytosis (>1,000-1,500 × 10⁹/L) paradoxically increases bleeding risk due to acquired von Willebrand disease, which occurs in more than one-third of PV patients with extreme platelet elevation 8
• Do not ignore quality of life: Treatment decisions should prioritize quality of life, not just laboratory values, as both HHT epistaxis and PV symptoms cause significant psychosocial morbidity and impact daily functioning 6

Coordination of Care

• Manage these patients through a multidisciplinary team including hematology/oncology for PV management and an HHT specialist center for comprehensive vascular malformation screening and treatment 6, 3
• Serial monitoring of blood counts is more valuable than isolated readings, as both conditions cause fluctuations over time 7
• Genetic counseling should address the 50% inheritance risk for HHT in offspring (PV is acquired and not inherited) 6