What is the recommended treatment plan for a patient with hereditary hemorrhagic telangiectasia (HHT)?

Hereditary Hemorrhagic Telangiectasia: Comprehensive Management Approach

Overview and Diagnosis

HHT is an autosomal dominant vascular disorder affecting 1 in 5,000 persons, making it the second most common inherited bleeding disorder worldwide, characterized by telangiectases and arteriovenous malformations that cause recurrent bleeding and life-threatening complications. 1, 2

Clinical Diagnosis Using Curaçao Criteria

• Diagnosis requires 3 of 4 clinical features: spontaneous/recurrent epistaxis, multiple telangiectasias at characteristic sites (lips, oral cavity, fingers, nose), visceral arteriovenous malformations (pulmonary, hepatic, cerebral, spinal, or GI), and first-degree relative with HHT 3, 4
• Diagnosis is definite with 3 criteria, possible with 2 criteria, and unlikely with fewer than 2 criteria 3
• Genetic testing identifies causative mutations in 97% of clinically definite cases, targeting ENG (HHT type 1, ~54% of families), ACVRL1 (HHT type 2, ~43% of families), and SMAD4 (juvenile polyposis-HHT overlap, 1-2% of cases) 3, 4

Mandatory Screening for Arteriovenous Malformations

All patients with confirmed or suspected HHT must undergo comprehensive screening for asymptomatic but potentially life-threatening AVMs, as these can be treated presymptomatically to prevent stroke, cerebral abscess, and hemorrhage. 3, 5

Pulmonary AVM Screening

• Perform contrast echocardiography or chest CT in all HHT patients to detect pulmonary AVMs, which create right-to-left shunts causing hypoxemia and paradoxical emboli leading to stroke or brain abscess 3, 5
• Pulmonary AVMs are more frequent and larger in HHT type 1 (ENG mutations) 3
• Treat all identified pulmonary AVMs with percutaneous transcatheter embolization regardless of feeding artery size due to paradoxical embolism risk 3, 5

Cerebral AVM Screening

• Perform 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 3

Hepatic AVM Screening

• Perform Doppler ultrasonography as first-line imaging for liver involvement in all HHT patients 1, 3
• Hepatic involvement occurs in 44-74% of HHT patients but only 5-8% are symptomatic 3
• NEVER perform liver biopsy in any patient with proven or suspected HHT due to catastrophic hemorrhage risk from vascular malformations 1, 3, 6

SMAD4-Specific Screening

• SMAD4 mutation carriers require upper GI tract surveillance every 1-3 years starting at age 18 years due to 73% prevalence of gastric polyposis and significantly higher risk of gastric cancer 3
• All gastric cancers in one cohort occurred exclusively in SMAD4 carriers 3

Management of Epistaxis: Stepwise Escalation Algorithm

Begin with nasal moisturization, 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, 3

Step 1: Nasal Moisturization (First-Line)

• Implement air humidification and topical application of saline solution or gels to prevent cracking and bleeding of fragile nasal telangiectasias 3
• This reduces mucosal trauma but often proves inadequate as monotherapy for most patients with significant epistaxis 3

Step 2: Oral Tranexamic Acid (Second-Line)

• Start at 500 mg twice daily, gradually increasing up to 1000 mg 4 times daily or 1500 mg 3 times daily 1
• Reduces epistaxis duration by 17.3% and composite epistaxis endpoints by 54% 3, 7
• Absolute contraindication: recent thrombosis; relative contraindications: atrial fibrillation or known thrombophilia 1, 6
• Can be coadministered with systemic antiangiogenic therapy 1, 6

Step 3: Local Ablative Therapies (Third-Line)

• Consider laser therapy or other ablative treatments for patients failing moisturization and tranexamic acid 1
• These provide temporary relief but do not address underlying disease progression 1

Step 4: Systemic Bevacizumab (Fourth-Line for Refractory Cases)

• Induction: 5 mg/kg IV every 2 weeks for 4-6 doses 1, 6
• Maintenance: 5 mg/kg IV every 1-3 months (variable dosing) 1, 6
• Produces 50% reduction in Epistaxis Severity Score (mean ESS improved from 6.81 to 3.44) 1, 7
• Monitor for hypertension, proteinuria, infection, delayed wound healing, and venous thromboembolism (VTE rate 2%, no fatal adverse events in InHIBIT-Bleed study) 1, 6, 7

Alternative Surgical Options

• Consider septodermoplasty or nasal closure for patients who fail medical therapies or cannot tolerate systemic antiangiogenic medications 1
• Shared decision-making with patients is crucial when considering these irreversible procedures 1

Management of Gastrointestinal Bleeding

GI bleeding develops in approximately 30% of HHT patients, with incidence increasing with age, and systemic therapies are now recommended as the primary modality rather than repetitive procedural interventions. 1

Severity Grading System

• Mild GI bleeding: patient meets hemoglobin goals with oral iron replacement 1
• Moderate GI bleeding: patient meets hemoglobin goals with IV iron treatment 1
• Severe GI bleeding: patient does not meet hemoglobin goals despite adequate iron replacement 1

Treatment Algorithm by Severity

Mild GI Bleeding:

• Start with oral tranexamic acid (500 mg twice daily, titrating up to 1000 mg 4 times daily) 1, 6
• Limited evidence of effectiveness but low potential for harm 1

Moderate to Severe GI Bleeding:

• Systemic bevacizumab is recommended for patients requiring intravenous iron or red cell transfusion 1
• Expected outcomes: mean hemoglobin improvement of 3-4 g/dL, 82% reduction in red cell transfusions, 70% reduction in iron infusions 1, 6
• Same dosing protocol as for epistaxis: induction 5 mg/kg IV every 2 weeks for 4-6 doses, then maintenance every 1-3 months 1, 6

Procedural Hemostatic Treatments:

• Argon Plasma Coagulation is recommended ONLY to treat emergent, brisk bleeding or acutely bleeding GI vascular lesions visualized at diagnostic endoscopy 1
• Insufficient data to support systematic and repeated use to minimize telangiectasia burden 1

Management of Iron Deficiency Anemia

All adults with HHT should be screened for iron deficiency and anemia regardless of symptoms, as chronic bleeding causes iron deficiency in approximately 50% of patients, resulting in fatigue, reduced exercise tolerance, and significantly impaired quality of life. 1, 6

Screening Recommendations

• Screen all adults with HHT regardless of symptoms (high quality evidence, strong recommendation) 1, 6
• Screen all children with recurrent bleeding and/or symptoms of anemia 1, 6
• Assess complete iron studies including hemoglobin, ferritin, and transferrin saturation—not just hemoglobin alone 6
• Screening interval should be individualized given heterogeneity of bleeding symptoms 1

Iron Replacement Protocol

Oral Iron (First-Line):

• Start with 35-65 mg of elemental iron daily 1, 6
• If inadequate response, increase to twice daily dosing or higher daily dose 1, 6
• If not tolerated, attempt alternate oral iron preparation 1, 6
• Reassess at 1 month for adequate response (hemoglobin rise ≥1.0 g/dL, normalization of ferritin and transferrin saturation) 1, 6

Intravenous Iron (First-Line in Specific Circumstances):

• Use IV iron as first-line therapy in patients with: severe anemia at presentation, oral iron not effective/absorbed/tolerated, or expected inadequacy of oral replacement 1, 6
• IV iron dose can be guided by total iron deficit (Ganzoni formula) or empiric dose of 1 gram with interval reassessment 1
• Regularly-scheduled iron infusions may be needed and should be expected unless chronic bleeding is halted through systemic therapies 1

Red Blood Cell Transfusion Indications

• Transfuse RBCs in: hemodynamic instability/shock, comorbidities requiring higher hemoglobin target, need to increase hemoglobin acutely (prior to surgery or during pregnancy), or inability to maintain adequate hemoglobin despite frequent iron infusions 1, 6

Critical Pitfall

• Evaluate for additional causes of anemia if response to iron replacement is inadequate, as concomitant hemolysis may contribute in a subset of patients 1, 6
• Consider hematology consultation in patients with anemia but without reduced ferritin 1
• Recognize that fatigue may persist despite hemoglobin normalization if iron stores (ferritin, transferrin saturation) remain depleted 6

Anticoagulation and Antiplatelet Therapy Considerations

Bleeding in HHT is NOT an absolute contraindication for anticoagulation or antiplatelet therapy when there is a clear indication, but careful risk-benefit assessment is required. 1, 7

Key Recommendations

• Patients with HHT should receive anticoagulation (prophylactic or therapeutic) or antiplatelet therapy when there is an indication, with consideration of their individualized bleeding risks 1
• Prefer heparin agents and vitamin K antagonists over direct oral anticoagulants due to better tolerability and lower bleeding risk in HHT 7
• Avoid dual antiplatelet therapy and/or combination of antiplatelet therapy with anticoagulation where possible 1, 6
• Combination therapy, or at least minimization of duration, is recommended wherever possible 1

Alternative Strategies

• Patients with HHT and atrial fibrillation who do not tolerate anticoagulation or are too high-risk can consider left atrial appendage closure 1
• In patients poorly tolerating indicated anticoagulation, consider hemostatic treatments (systemic or local) or anticoagulation modification 1

Quality of Life Considerations

Treatment decisions should prioritize quality of life, not just hemoglobin levels, as epistaxis causes significant psychosocial morbidity, social isolation, and difficulties with employment, travel, and routine daily activities. 1, 3

• Epistaxis significantly impacts quality of life beyond anemia, causing psychosocial morbidity that affects daily functioning 1, 3
• Patients described underrecognition and undertreatment of anemia that negatively impacted quality of life in preguidelines surveys 1
• With proper use of antiangiogenic therapies, patients with even the most severe bleeding manifestations can achieve durable hemostasis with minimal side effects, dramatically improving health-related quality of life 8

Multidisciplinary Care Coordination

All patients diagnosed with HHT should be referred to a multidisciplinary team with expertise in HHT management, particularly those with SMAD4 mutations who require coordination between HHT specialists and gastroenterologists for juvenile polyposis surveillance. 3

• SMAD4 mutation carriers must be managed in conjunction with a specialist HHT center with experience in evaluating and managing both HHT and juvenile polyposis complications 3
• Comprehensive care requires coordination between hematology, otolaryngology, gastroenterology, interventional radiology, and genetics 3, 5