What are the management and treatment options for Hereditary Hemorrhagic Telangiectasia (HHT)?

Management and Treatment of Hereditary Hemorrhagic Telangiectasia (HHT)

All adults with HHT should be screened for iron deficiency regardless of bleeding or anemia symptoms, and systemic therapies with tranexamic acid and bevacizumab have become the primary treatment modalities for bleeding manifestations, representing a paradigm shift away from repetitive procedural interventions. 1

Anemia and Iron Deficiency Management

Screening Approach

• Screen all adults with HHT for iron deficiency irrespective of bleeding or anemia symptoms 1
• Screen children with recurrent bleeding and/or symptoms of anemia 1
• Screening intervals should be individualized based on bleeding severity, though specific timing is not defined in guidelines 1

Iron Replacement Strategy

• Start with oral iron as initial therapy for mild anemia 1
• Use intravenous iron as first-line treatment for severe anemia or when oral replacement is expected to be inadequate or ineffective 1
• Consider hematology consultation for patients with anemia but normal ferritin to evaluate alternative or complicating etiologies 1

Epistaxis Management

Stepwise Treatment Algorithm

Step 1: Moisturizing topical therapies (first-line for all patients) 1

Step 2: Oral tranexamic acid for epistaxis not responding to topical therapies 1

• Start at 500 mg twice daily 1
• Gradually increase up to 1000 mg four times daily or 1500 mg three times daily 1
• Contraindications: recent thrombosis 1
• Relative contraindications: atrial fibrillation or known thrombophilia 1

Step 3: Systemic antiangiogenic agents for epistaxis failing topical therapies, ablative therapies, and/or tranexamic acid 1

• IV bevacizumab dosing: 5 mg/kg every 2 weeks for 4-6 doses (induction), followed by maintenance at 5 mg/kg every 1-3 months 1
• In 146 patients treated for 3 months, mean Epistaxis Severity Score improved from 6.81 to 3.44 (50% relative reduction) 1
• Monitor for hypertension, proteinuria, infection, delayed wound healing, and venous thromboembolism 1
• Oral thalidomide can be considered, though side effects often limit long-term use 1

Gastrointestinal Bleeding Management

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 Based on Severity

• Mild GI bleeding: tranexamic acid (limited evidence of effectiveness but low potential for harm) 1
• Moderate or severe GI bleeding: systemic bevacizumab (primary recommendation) 1
• Bevacizumab produces substantial improvements with mean hemoglobin increases of 3-4 g/dL 1
• Procedural hemostatic treatments (Argon Plasma Coagulation) should only be used for emergent, brisk bleeding or acutely bleeding lesions visualized at endoscopy 1
• Insufficient data support systematic and repeated use of endoscopic procedures to minimize telangiectasia burden 1

Anticoagulation and Antiplatelet Therapy Considerations

Key Principles

• HHT is not an absolute contraindication for anticoagulation or antiplatelet therapy 1
• Avoid dual antiplatelet therapy and/or combination of antiplatelet therapy with anticoagulation where possible (weak recommendation) 1
• Prefer heparin agents and vitamin K antagonists over direct oral anticoagulants due to increased bleeding risk with DOACs 1
• For patients with atrial fibrillation who cannot tolerate anticoagulation, consider left atrial appendage closure 1
• Minimize duration of combination therapy wherever possible 1

Organ-Specific Screening Requirements

Pulmonary Screening

• All HHT patients should undergo screening for pulmonary arteriovenous malformations as these can be treated presymptomatically to prevent life-threatening complications 2
• Use contrast echocardiography or chest CT for detection 2

Liver Screening

• Doppler ultrasonography is first-line imaging for liver involvement in all HHT patients 2
• Strictly avoid liver biopsy in any patient with proven or suspected HHT due to hemorrhage risk 2
• Grade liver involvement (0-4) based on hepatic artery diameter, peak flow velocity, resistivity index, and peripheral hepatic hypervascularization 2

Cerebral Screening

• MRI of the brain to detect cerebral vascular malformations 2
• Cerebral AVMs are rare in non-symptomatic HHT patients, but screening commonly detects silent cerebral infarction due to pulmonary AVMs 3

Gastrointestinal Evaluation

• Upper endoscopy to evaluate for gastrointestinal telangiectasias, especially in patients with unexplained anemia disproportionate to epistaxis severity 2

Critical Pitfalls to Avoid

• Never perform liver biopsy in HHT patients due to catastrophic hemorrhage risk 2
• Do not rely solely on procedural treatments for GI bleeding as they are ineffective for long-term management 1
• Avoid direct oral anticoagulants when possible in favor of heparin agents or vitamin K antagonists 1
• Do not undertreat anemia as this significantly impacts quality of life 1
• Recognize that discontinuation of bevacizumab leads to eventual rebleeding in most patients, though the bleeding-free interval shows high interpatient variability 1

Multidisciplinary Care

• Refer all diagnosed HHT patients to a multidisciplinary team with HHT expertise 2
• Care should involve hematology, otolaryngology, gastroenterology, interventional radiology, and genetics 1, 4

Emerging Therapies and Uncertainties

• Limited data exist for hormonal therapies (estrogens, progestins, tamoxifen, raloxifene, bazedoxifene) with inconsistent benefits and significant thromboembolic risks 1
• Optimal bevacizumab maintenance strategy remains uncertain, with both continuous scheduled maintenance and intermittent as-needed strategies being used 1
• Long-term treatment-emergent adverse events from chronic antiangiogenic therapy require further study 1
• Tranexamic acid showed no increased thrombotic risk in studies limited to 3 months, but concerns remain about indefinite daily use 1