What is the treatment approach for hereditary hemorrhagic telangiectasia (HHT)?

Treatment Approach for Hereditary Hemorrhagic Telangiectasia

Begin with nasal moisturization for epistaxis, escalate to oral tranexamic acid if inadequate, then proceed to local ablative therapies, and reserve systemic bevacizumab for refractory cases that fail all other interventions. 1, 2

Stepwise Management Algorithm for Bleeding Manifestations

First-Line: Nasal Moisturization

• Implement air humidification and topical application of saline solution or gels to prevent cracking and bleeding of fragile nasal telangiectasias 1
• This approach reduces mucosal trauma but is inadequate as monotherapy for most patients with significant epistaxis 1

Second-Line: Oral Tranexamic Acid

• Prescribe oral tranexamic acid when moisturization alone fails to control epistaxis, as it reduces epistaxis duration by 17.3% and composite epistaxis endpoints by 54% 1, 2
• This antifibrinolytic agent demonstrated efficacy in two randomized controlled trials in 2014 and is now recommended as standard treatment in the Second International HHT Guidelines 1
• Apply the same tranexamic acid approach for gastrointestinal bleeding before escalating to more invasive therapies 2

Third-Line: Local Ablative Therapies

• Proceed to surgical interventions including laser ablation, sclerotherapy, or cauterization of telangiectasias when medical management with moisturization and tranexamic acid proves insufficient 1, 3
• Use resorbable packing materials for epistaxis management to reduce rebleeding risk during packing removal 2

Fourth-Line: Systemic Bevacizumab

• Administer systemic bevacizumab (anti-VEGF therapy) for severe epistaxis or GI bleeding failing all prior interventions, which produces a 50% reduction in epistaxis severity score 1, 2
• This antiangiogenic therapy eliminates bleeding telangiectasias by addressing the underlying VEGF excess that supports their growth 1, 4
• Bevacizumab is not curative but represents the most effective systemic option for refractory bleeding 5

Mandatory Organ Screening Protocol

Pulmonary Screening

• Screen all HHT patients for pulmonary arteriovenous malformations using contrast echocardiography or chest CT, as these can be treated presymptomatically to prevent stroke and cerebral abscess 2, 6
• Perform percutaneous transcatheter embolization for pulmonary AVMs regardless of feeding artery size due to paradoxical embolism risk 2, 6
• Pulmonary AVMs create right-to-left shunts causing hypoxemia and risk of paradoxical emboli leading to stroke or brain abscess 2

Cerebral Screening

• Obtain brain MRI to detect cerebral vascular malformations, as cerebral AVMs occur more commonly in HHT1 and nearly one in five HHT patients develop stroke or cerebral abscess 2, 6
• Begin screening in childhood, as epistaxis typically starts at mean age 11 years 2

Hepatic Screening

• Perform Doppler ultrasonography as first-line imaging for liver involvement in all HHT patients 1, 2, 6
• Never perform liver biopsy in any patient with proven or suspected HHT due to catastrophic hemorrhage risk 2, 6
• Hepatic involvement is generally asymptomatic but when symptomatic can cause substantial morbidity and mortality 2
• Reserve invasive therapies including liver transplantation only after failure of intensive medical therapy 2

Gastrointestinal Screening

• Perform upper endoscopy to evaluate for gastrointestinal telangiectasias, especially in patients with unexplained anemia disproportionate to epistaxis severity 2
• GI telangiectasias typically manifest in late middle age (mean age 55.4 years) compared to childhood-onset epistaxis 7

Anemia Management

• Implement iron replacement therapy and monitoring for all patients with recurrent bleeding, as approximately 50% of HHT patients experience iron deficiency anemia from chronic bleeding 2, 6
• Establish baseline iron studies, ferritin, and transferrin saturation even in rare cases of erythrocytosis, as patients may transition to iron deficiency if bleeding worsens 6

Special Genetic Considerations

SMAD4 Mutation Carriers

• Initiate upper GI tract surveillance every 1-3 years starting at age 18 years for SMAD4 carriers due to 73% prevalence of gastric polyposis and high gastric cancer risk 2
• All gastric cancers in one cohort occurred exclusively in SMAD4 pathogenic variant carriers 2
• Manage all SMAD4 mutation patients in conjunction with a specialist HHT center, as these patients develop combined HHT and juvenile polyposis syndrome 2

HHT1 vs HHT2 Differences

• Pulmonary and cerebral AVMs are more frequent and larger in HHT1 (ENG mutations), requiring more aggressive screening 2
• Hepatic involvement is substantially more common and symptomatic in HHT2 (ACVRL1 mutations) with marked female predominance 2

Anticoagulation in HHT Patients

• Anticoagulation is not an absolute contraindication despite bleeding risks 6
• Prefer heparin agents and vitamin K antagonists over direct oral anticoagulants due to better tolerability and lower bleeding risk 6
• Avoid dual antiplatelet therapy and combination antiplatelet/anticoagulation therapy wherever possible 6
• Consider left atrial appendage closure for atrial fibrillation in patients who cannot tolerate anticoagulation 6

Critical Pitfalls to Avoid

• Do not delay diagnosis based on absence of all Curaçao criteria - diagnosis is definite with 3 of 4 criteria (spontaneous recurrent epistaxis, multiple telangiectasias, visceral lesions, affected first-degree relative) 2, 4
• Do not perform liver biopsy - this carries catastrophic hemorrhage risk in HHT patients 2, 6
• Do not focus solely on hemoglobin levels - treatment decisions should prioritize quality of life, as epistaxis causes significant psychosocial morbidity, social isolation, and difficulties with employment, travel, and routine daily activities 1, 2
• Do not fail to screen asymptomatic family members - genetic testing is particularly important for asymptomatic persons from families with known HHT, as 97% of patients with definite clinical diagnosis have identifiable mutations in ENG, ACVRL1, or SMAD4 2, 4

Multidisciplinary Coordination

• Refer all diagnosed HHT patients to a multidisciplinary team with expertise in HHT management, preferably at an HHT Center of Excellence 2, 8
• Coordinate care across otolaryngology, hematology, interventional radiology, gastroenterology, and genetics 5, 3
• The average diagnostic delay is 26 years from onset of symptoms, emphasizing the need for early recognition and specialist referral 7