What is the treatment approach for Hereditary Hemorrhagic Telangiectasia (HHT)?

Hereditary Hemorrhagic Telangiectasia: Comprehensive Management Approach

Overview and Pathophysiology

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant bleeding disorder affecting 1 in 5,000 persons worldwide, characterized by vascular malformations driven by excess VEGF that cause recurrent bleeding, with management now centered on systemic antiangiogenic and antifibrinolytic therapies alongside traditional procedural interventions. 1

• HHT results from mutations in ENG (type 1), ACVRL1/ALK1 (type 2), or SMAD4 (juvenile polyposis-HHT overlap), identified in 97% of clinically definite cases 2, 3
• The underlying pathophysiology involves VEGF excess that supports telangiectasia growth and bleeding 1
• Each child of an affected parent has a 50% chance of inheriting the disease 2

Diagnosis

Apply the Curaçao criteria for clinical diagnosis, requiring 3 of 4 features for definite HHT: spontaneous/recurrent epistaxis, multiple telangiectasias at characteristic sites (lips, oral cavity, fingers, nose), visceral lesions (pulmonary/hepatic/cerebral AVMs or GI telangiectasias), and first-degree relative with HHT. 2

• Definite diagnosis requires 3 criteria; possible/suspected with 2 criteria; unlikely with fewer than 2 2
• Genetic testing should be performed, particularly for asymptomatic family members, to enable early screening and preventive treatment 2, 3
• Diagnosis is often delayed by an average of 26 years from symptom onset 4

Mandatory Screening for Visceral Involvement

All patients with confirmed or suspected HHT require comprehensive organ screening to detect life-threatening arteriovenous malformations that can be treated presymptomatically. 2

Pulmonary Screening

• Perform contrast echocardiography or chest CT to detect pulmonary AVMs in all HHT patients 2
• Pulmonary AVMs occur in approximately 60% of patients and can cause life-threatening complications 4

Hepatic Screening

• Doppler ultrasonography is first-line imaging for liver involvement in all HHT patients 2
• Never perform liver biopsy in HHT patients due to severe hemorrhage risk 2
• Grade liver involvement (0-4) based on hepatic artery diameter, peak flow velocity, resistivity index, and peripheral hypervascularization 2

Cerebral Screening

• Obtain brain MRI to detect cerebral vascular malformations 2

Gastrointestinal Evaluation

• Perform upper endoscopy for patients with unexplained anemia disproportionate to epistaxis severity 2
• GI telangiectasias typically manifest in late middle age (mean age 55 years) 4

Stepwise Treatment Algorithm for Epistaxis

Epistaxis occurs in >90% of adults with HHT and represents the primary cause of morbidity, requiring a stepwise escalation from topical therapies to systemic antiangiogenic agents. 1, 3

Step 1: First-Line Therapies

• Nasal moisturization through air humidification and topical saline solution or gels to prevent cracking of fragile telangiectasias 1
• Oral tranexamic acid for epistaxis unresponsive to moisturization alone, demonstrating 17.3% reduction in epistaxis duration and 54% reduction in composite epistaxis endpoints without increasing thrombotic risk 1
• Local ablative therapies: laser treatment, sclerotherapy, radiofrequency ablation, or electrosurgery 1
• Use resorbable packing materials to reduce rebleeding risk during removal 2

Step 2: Systemic Antiangiogenic Therapy

For patients failing first-line therapies with moderate-to-severe bleeding requiring IV iron or blood transfusions, initiate systemic bevacizumab as the antiangiogenic agent with the strongest evidence base. 1, 5

Bevacizumab Protocol

• Induction: 5 mg/kg IV every 2 weeks for 4-6 doses 5
• Maintenance: 5 mg/kg IV every 1-3 months (either scheduled continuous or as-needed intermittent strategies) 5
• The InHIBIT-Bleed study (238 patients) demonstrated 82% reduction in red cell transfusion requirements, 70% reduction in iron infusions, and 50% improvement in epistaxis severity scores 5
• Venous thromboembolism rate was only 2% despite theoretical thrombotic concerns 5
• Critical caveat: Discontinuation leads to eventual rebleeding in most patients, requiring long-term maintenance 5

Alternative Antiangiogenic Agents

• Thalidomide downregulates VEGF and improves vascular wall integrity, with documented effectiveness in small studies (67 patients), but persistent neuropathy limits long-term use 1
• Thalidomide showed notable improvement in epistaxis, melena, and anemia in case reports 4
• Other agents under investigation include pomalidomide, pazopanib, nintedanib, and doxycycline 1

Important distinction: Topical and intranasal bevacizumab injections did not show significant benefit, unlike systemic administration 1, 5

Management of Anemia and Iron Deficiency

Iron replacement therapy and anemia monitoring are mandatory for all HHT patients with recurrent bleeding, as bleeding and anemia represent the most common complications. 2, 4

• Chronic bleeding leads to iron deficiency anemia requiring oral iron supplementation 3, 6
• Severe cases may require IV iron infusions or blood transfusions 5
• Antifibrinolytic therapy (tranexamic acid) serves dual purpose of reducing bleeding and supporting hemoglobin maintenance 1, 3

Anticoagulation Considerations

The Second International HHT Guidelines address anticoagulation management as a priority topic, though specific recommendations require individualized assessment of thrombotic versus bleeding risk. 1

• Bevacizumab has demonstrated reassuring safety profile with only 2% VTE rate in large studies 5
• A study of 69 HHT patients treated with bevacizumab for mean 11 months reported no VTE events and only one arterial thrombotic event 5

Multidisciplinary Care Model

Refer all diagnosed HHT patients to a multidisciplinary team with HHT expertise, as optimal management requires coordination across multiple specialties. 2, 6, 7

• The Second International HHT Guidelines were developed using AGREE-II framework and GRADE methodology, published in Annals of Internal Medicine 1
• Multidisciplinary approach is essential given variable clinical manifestations affecting otolaryngology, gastroenterology, hepatology, pulmonology, neurology, and hematology 6, 4, 7
• Early diagnosis through family screening enables presymptomatic treatment of life-threatening AVMs 2

Key Clinical Pitfalls to Avoid

• Never perform liver biopsy in proven or suspected HHT due to catastrophic hemorrhage risk 2
• Do not rely on topical or intranasal bevacizumab for epistaxis control—only systemic administration is effective 1, 5
• Avoid delaying systemic bevacizumab in patients with severe anemia requiring transfusions or IV iron 5
• Do not use non-resorbable nasal packing materials due to rebleeding risk during removal 2
• Recognize that local ablative therapies provide only limited and short-lived efficacy 4
• Understand that bevacizumab is not curative and requires long-term maintenance to prevent rebleeding 5, 6

Genetic Counseling

Offer genetic testing to all affected individuals and asymptomatic family members, as early identification enables presymptomatic screening and treatment of life-threatening complications. 2, 3

• Simultaneous sequencing and deletion/duplication analysis of ENG and ACVRL1 identifies approximately 96% of mutations 2
• Include SMAD4 testing when juvenile polyposis features coexist 2
• Genetic counseling is critical given 50% transmission risk to offspring 2