Hereditary Hemorrhagic Telangiectasia

Overview and Epidemiology

Hereditary Hemorrhagic Telangiectasia (HHT), also known as Osler-Weber-Rendu syndrome or disease, is an autosomal dominant disorder of blood-vessel formation. The Second International HHT Guidelines (Faughnan 2020) give an estimated prevalence of 1 in 5,000; a 2009 review (Govani and Shovlin) gives 1 in 5,000–8,000. The vascular malformations it produces cause chronic bleeding, acute hemorrhage, and complications from blood shunting through the malformations (Faughnan 2020). A 2024 review describes HHT as the second most common inherited bleeding disorder worldwide (Al-Samkari 2024).

Each child of a person with HHT has a 50% chance of inheriting the family's pathogenic variant, and the disease shows considerable variability within families and age-related penetrance of individual features (GeneReviews, McDonald et al.). The 2011 international guidelines describe HHT as under-diagnosed, with families often unaware of the available screening and treatment, which the guideline authors link to avoidable stroke and life-threatening hemorrhage in children and adults (Faughnan 2011). The 2020 guidelines added 36 recommendations across six areas: epistaxis, gastrointestinal bleeding, anemia and iron deficiency, liver vascular malformations, pediatric care, and pregnancy and delivery (Faughnan 2020).

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Molecular Pathogenesis and TGF-β/BMP Signaling

The genes most commonly mutated in HHT, ENG (endoglin) and ACVRL1 (ALK1), encode proteins that modulate transforming growth factor (TGF)-β superfamily signaling in vascular endothelial cells; the mutations lead to fragile telangiectatic vessels and arteriovenous malformations (Govani and Shovlin 2009). ENG mutations cause HHT type 1 and ACVRL1 mutations cause HHT type 2 (Letteboer 2006). SMAD4 mutations cause a combined syndrome of juvenile polyposis and HHT (Gallione 2004), and GeneReviews describes colonoscopy surveillance beginning at age 15 in SMAD4-related HHT. Mutations in GDF2 (BMP9) were found in three unrelated people with a vascular-anomaly syndrome that overlaps with HHT (Wooderchak-Donahue 2013).

ALK1 is a receptor for circulating BMP9, which induces vascular quiescence (the resting state of mature blood vessels). In newborn mice, blocking BMP9 increased retinal vascular density, and BMP10 could substitute for BMP9 in postnatal vascular remodeling (Ricard 2012, an animal study). In HHT the resulting lesions lack intervening capillaries and connect arteries directly to veins: small ones, the telangiectases, appear on the lips, tongue, buccal and gastrointestinal mucosa, fingers and nose, while large arteriovenous malformations (AVMs) occur most often in the lungs, liver and brain (GeneReviews). Shunts through these malformations bypass specific capillary beds, which underlies many complications (Shovlin 2010). Anti-VEGF (vascular endothelial growth factor) treatments such as bevacizumab were tested in HHT on the hypothesis that they might be effective (Dupuis-Girod 2012).

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Curaçao Diagnostic Criteria

The consensus clinical diagnostic criteria, known as the Curaçao criteria, were published in 2000 on behalf of the Scientific Advisory Board of the HHT Foundation International (Shovlin 2000). The four criteria are: (1) epistaxis (recurrent nosebleeds); (2) telangiectases, multiple and at characteristic sites; (3) visceral lesions (arteriovenous malformations in organs such as the lungs, liver or brain); and (4) an appropriate family history, which GeneReviews defines as a first-degree relative diagnosed with HHT on the same criteria.

The diagnosis is definite when three criteria are present. With only two criteria, HHT cannot be established but is recorded as possible or suspected, to keep clinical suspicion high. With fewer than two, HHT is unlikely, although the criteria's authors note that children of affected individuals remain at risk because features appear with age (Shovlin 2000). At one HHT center, among 152 family probands who met strictly applied Curaçao criteria, a variant known or suspected to be causal was found in ENG in 44.1%, ACVRL1 in 52.0% and SMAD4 in 1.3%; only 4 of 152 (2.6%) had no variant in these genes. The authors contrast this with the lower detection rates (about 75–85%) reported by laboratories receiving samples from a wide range of clinicians (McDonald 2020). Once the family's variant is known, predictive testing of at-risk relatives is possible (GeneReviews).

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Epistaxis: The Cardinal Symptom

Recurrent nosebleeds (epistaxis) are the most common clinical manifestation of HHT, beginning on average at age 12; telangiectases generally appear later (GeneReviews). Repeated bleeding from telangiectases in the nose and gut causes substantial illness, including severe iron-deficiency anemia (Shovlin 2010), and the 2016 North American trial described epistaxis as a major factor reducing quality of life in HHT (Whitehead 2016).

GeneReviews lists the supportive measures used for epistaxis as humidification, topical moisturizing therapy, hemostatic products, ablation therapy, septodermoplasty, and Young's nasal closure as needed, with oral tranexamic acid or intravenous bevacizumab as targeted therapies and pomalidomide or pazopanib for refractory bleeding. The trial evidence for each:

A 2024 review notes that no therapy has regulatory-agency approval for HHT, while multiple large studies, including randomized trials, support antifibrinolytics for mild-to-moderate bleeding and systemic antiangiogenic drugs such as pomalidomide and bevacizumab for moderate-to-severe bleeding (Al-Samkari 2024, Blood). GeneReviews lists iron replacement, and blood transfusion if needed, for gastrointestinal bleeding and anemia.

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Pulmonary Arteriovenous Malformations (PAVMs)

In a population-based Danish study of HHT families in the County of Fyn, pulmonary angiography found PAVMs in 18 of 59 screened HHT patients (24%) (Kjeldsen 2000). PAVMs are more frequent in HHT type 1 (ENG) than in type 2 (ACVRL1) (Letteboer 2006; Kjeldsen 2005), and in HHT type 1 they are more prevalent in women than in men (Letteboer 2006).

A PAVM is a direct artery-to-vein connection in the lung, so blood bypasses the pulmonary capillary bed (Shovlin 2010). In a cohort of 323 consecutive people with PAVMs and/or HHT, 57 of those with both PAVMs and HHT had had a brain abscess or ischemic stroke, usually before the PAVMs or HHT were diagnosed. Most of the 201 people with both conditions had no respiratory symptoms and were unaware they had HHT. The risks did not track PAVM severity; men had higher brain-abscess rates, and treatment histories and bacterial isolates pointed to dental sources (Shovlin 2008, Thorax). In a single-institution series of 321 HHT patients, a history of cerebral infarction or transient ischemic attack was found in 29.6% of HHT patients with a pulmonary arteriovenous fistula (Maher 2001).

PAVM embolization (blocking the feeding artery through a catheter) significantly reduced the ischemic stroke rate in that cohort, and no strokes or abscesses occurred after all angiographically visible PAVMs had been obliterated (Shovlin 2008, Thorax). GeneReviews summarizes current practice as follows: pulmonary AVMs with a feeding vessel 2–3 mm or greater in diameter typically require occlusion for stroke prevention; screening for PAVMs is repeated every five years with transthoracic contrast (bubble) echocardiography in adults, and with contrast echocardiography or chest radiograph with pulse oximetry in children; and when pulmonary shunting is present, antibiotic prophylaxis is used for dental and non-sterile invasive procedures, with care to keep air bubbles out of intravenous lines (including an air filter where available).

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Hepatic AVMs and Cerebral Vascular Malformations

Hepatic vascular malformations are more frequent in HHT type 2 (ACVRL1), and in both main types more frequent in women (Letteboer 2006). A 2024 review describes them as common but less often symptomatic; when they cause problems these include high-output cardiac failure, portal hypertension and biliary ischemia (Kelly 2024). In an Italian referral-center cohort of 154 patients with hepatic vascular malformations followed for a median of 44 months, 39 (25.3%) had complications and 8 (5.2%) died of complications related to the malformations; the complete response rate to therapy was 63% (Buscarini 2011). GeneReviews states that symptomatic hepatic AVMs are managed medically, with liver transplantation for people who do not respond and develop refractory high-output heart failure, and lists liver biopsy among the circumstances to avoid in HHT.

In a single-center phase 2 trial of 25 patients with severe hepatic involvement and a high cardiac index, intravenous bevacizumab (5 mg/kg every 14 days, 6 infusions) reduced the median cardiac index from 5.05 to 4.2 L/min/m² at 3 months. Of 24 patients with echocardiograms available for re-reading, 3 had normalization of cardiac index, 17 a partial response and 4 no response; epistaxis duration and quality of life also improved (Dupuis-Girod 2012). The 2024 liver review describes bevacizumab as effective in reducing cardiac output in heart failure from hepatic malformations, and liver transplantation as the only curative option (Kelly 2024).

A 2017 meta-analysis of 30 prevalence studies found brain AVMs in 10.4% of people with HHT: 13.4% in HHT type 1 and 2.4% in HHT type 2. 55.2% of these AVMs were symptomatic, and 86.9% were Spetzler-Martin grade 2 or less (Brinjikji 2017). In the single-institution series of 321 patients, 12 (3.7%) had a cerebral vascular malformation, and 7 (2.1%) presented with intracranial hemorrhage at an average age of 25.4 years. The authors judged the risk of intracranial hemorrhage in HHT to be low and did not find a compelling indication for routine screening for silent cerebral malformations, noting that PAVMs were a much more frequent cause of neurological symptoms (Maher 2001). GeneReviews, by contrast, describes brain MRI in infancy and again by age 18–20 years as current surveillance, with cerebral AVMs treated, as indicated by size, location or symptoms, by surgery, embolotherapy and/or stereotactic radiosurgery.

Gastrointestinal bleeding occurs in some people with HHT and is rarely seen before age 50 (GeneReviews). HHT type 1 patients in the Danish cohort had experienced more severe gastrointestinal bleeding than HHT type 2 patients (Kjeldsen 2005).

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Diagnosis, Genetic Testing, and Surveillance Protocol

The clinical diagnosis rests on three or more Curaçao criteria, and the molecular diagnosis on finding a heterozygous pathogenic variant in ACVRL1, ENG or SMAD4 (GeneReviews). The authors of a 2013 exome study state that about 15% of people with clinical features of HHT have no mutation in these three genes; among 191 such people, they found GDF2 (BMP9) mutations in three (Wooderchak-Donahue 2013).

The surveillance described in GeneReviews is: an annual evaluation by a clinician familiar with HHT, with annual hematocrit, hemoglobin and ferritin; PAVM evaluation every five years (contrast echocardiography in adults); brain MRI in infancy and again by age 18–20 years; clinical evaluation for heart or liver failure and hepatic imaging in adults; and, in SMAD4-related HHT, colonoscopy from age 15. The 2011 international guidelines produced 33 recommendations for diagnosis and management, 30 of them with at least 80% expert agreement (Faughnan 2011). Europe's reference network for rare vascular diseases (VASCERN HHT) has published position statements on care in general and specialty settings, including screening for cerebral vascular malformations, anti-angiogenic therapies and anticoagulation (Shovlin 2022).

Pregnancy: in a tertiary-referral-center series of 262 pregnancies in 111 women with HHT and PAVMs, 1.0% of pregnancies involved a major PAVM bleed, 1.2% a stroke (not all HHT-related) and 1.0% a maternal death; 74% of the women had not been diagnosed at the time of pregnancy, and all the deaths occurred in women previously considered well. The authors conclude that most HHT pregnancies proceed normally but that pregnancy in a woman with HHT is high risk, and prior awareness of the diagnosis was associated with better survival after a life-threatening event (Shovlin 2008, BJOG). GeneReviews describes screening and treatment for pulmonary and cerebral AVMs in women considering pregnancy, with sizable PAVMs found during pregnancy treated in the second trimester.

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Systemic Therapies: Bevacizumab, Pomalidomide, Thalidomide, Pazopanib

Bevacizumab is an anti-VEGF monoclonal antibody given intravenously in HHT for bleeding and for high-output cardiac failure from hepatic malformations, as described above (Al-Samkari 2021; Dupuis-Girod 2012; Kelly 2024). In InHIBIT-Bleed, outcomes were similar regardless of the underlying mutation; scheduled maintenance after the initial induction infusions gave higher hemoglobin and lower epistaxis scores than as-needed maintenance, at the cost of more drug exposure. Hypertension, fatigue and proteinuria were the most common adverse events, and venous thromboembolism occurred in 2% of patients (Al-Samkari 2021). In a European survey of 69 HHT patients treated with bevacizumab, the most common reported adverse events were joint pain (10%), headache (4.4%) and proteinuria (3%) (Buscarini 2019). Nasal-spray and submucosal forms are covered in the epistaxis section; the sprays did not beat placebo.

Pomalidomide was tested in the PATH-HHT trial: 144 patients with moderate-to-severe epistaxis were randomized 2:1 to pomalidomide 4 mg daily or placebo for 24 weeks. The trial was closed to enrollment after a planned interim analysis met its efficacy threshold. The epistaxis severity score fell by 0.94 points more with pomalidomide than with placebo (a reduction of 0.71 points or more is considered clinically significant), and the HHT-specific quality-of-life score also improved. Neutropenia, constipation and rash were more common on pomalidomide (Al-Samkari 2024, NEJM).

Thalidomide was studied in a single-center, non-randomized phase 2 study of 31 patients with severe epistaxis refractory to minimally invasive procedures: all 31 responded (3 complete, 28 partial), most at 50 mg/day, with grade 1 adverse effects, mainly constipation, drowsiness and peripheral edema (Invernizzi 2015). In the European survey of 67 thalidomide-treated patients, the most common adverse events were peripheral neuropathy (18%), drowsiness (12%) and dizziness (9%), and three fatal adverse events were considered possibly related to thalidomide (Buscarini 2019).

Pazopanib, an oral tyrosine kinase inhibitor that blocks VEGF receptors, improved hemoglobin and/or epistaxis in all seven patients treated at 50 mg daily in an open-label proof-of-concept study (Faughnan 2019). In 13 transfusion-dependent patients treated on an institutional pathway (median dose 150 mg daily for a median of 22 months), all became transfusion-independent; the authors state that a randomized trial is needed to confirm the findings (Parambil 2022). Both studies used doses lower than those used for cancer.

Decisions about these medicines belong with a clinician experienced in HHT.

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Key Research Papers

  1. Faughnan ME, et al. International guidelines for the diagnosis and management of hereditary haemorrhagic telangiectasia. J Med Genet. 2011;48(2):73-87. — PubMed PMID: 19553198
  2. McDonald J, Gossage JR, Stevenson DA. Hereditary Hemorrhagic Telangiectasia. GeneReviews [Internet]. 2000 [updated 2026]. — PubMed PMID: 20301525
  3. Dupuis-Girod S, et al. Bevacizumab in patients with hereditary hemorrhagic telangiectasia and severe hepatic vascular malformations and high cardiac output. JAMA. 2012;307(9):948-955. — PubMed PMID: 22396517
  4. Shovlin CL. Hereditary haemorrhagic telangiectasia: pathophysiology, diagnosis and treatment. Blood Rev. 2010;24(6):203-219. — PubMed PMID: 20870325
  5. Govani FS, Shovlin CL. Hereditary haemorrhagic telangiectasia: a clinical and scientific review. Eur J Hum Genet. 2009;17(7):860-871. — PubMed PMID: 19337313
  6. Kjeldsen AD, et al. Prevalence of pulmonary arteriovenous malformations (PAVMs) and occurrence of neurological symptoms in patients with hereditary haemorrhagic telangiectasia (HHT). J Intern Med. 2000;248(3):255-262. — PubMed PMID: 10971793
  7. Shovlin CL, et al. Primary determinants of ischaemic stroke/brain abscess risks are independent of severity of pulmonary arteriovenous malformations in hereditary haemorrhagic telangiectasia. Thorax. 2008;63(3):259-266. — PubMed PMID: 17981912
  8. Letteboer TG, et al. Genotype-phenotype relationship in hereditary haemorrhagic telangiectasia. J Med Genet. 2006;43(4):371-377. — PubMed PMID: 16155196
  9. Maher CO, et al. Cerebrovascular manifestations in 321 cases of hereditary hemorrhagic telangiectasia. Stroke. 2001;32(4):877-882. — PubMed PMID: 11283386
  10. Invernizzi R, et al. Efficacy and safety of thalidomide for the treatment of severe recurrent epistaxis in hereditary haemorrhagic telangiectasia: results of a non-randomised, single-centre, phase 2 study. Lancet Haematol. 2015;2(11):e465-e473. — PubMed PMID: 26686256
  11. Ricard N, et al. BMP9 and BMP10 are critical for postnatal retinal vascular remodeling. Blood. 2012;119(25):6162-6171. — PubMed PMID: 22566602
  12. Shovlin CL, et al. The European Rare Disease Network for HHT Frameworks for management of hereditary haemorrhagic telangiectasia in general and speciality care. Eur J Med Genet. 2022;65(1):104370. — PubMed PMID: 34737116
  13. Shovlin CL, et al. Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome). Am J Med Genet. 2000;91(1):66-67. — PubMed PMID: 10751092
  14. Faughnan ME, et al. Second International Guidelines for the Diagnosis and Management of Hereditary Hemorrhagic Telangiectasia. Ann Intern Med. 2020;173(12):989-1001. — PubMed PMID: 32894695
  15. Whitehead KJ, et al. Effect of Topical Intranasal Therapy on Epistaxis Frequency in Patients With Hereditary Hemorrhagic Telangiectasia: A Randomized Clinical Trial. JAMA. 2016;316(9):943-951. — PubMed PMID: 27599329
  16. Dupuis-Girod S, et al. Effect of Bevacizumab Nasal Spray on Epistaxis Duration in Hereditary Hemorrhagic Telangectasia: A Randomized Clinical Trial. JAMA. 2016;316(9):934-942. — PubMed PMID: 27599328
  17. Riss D, et al. Intranasal submucosal bevacizumab for epistaxis in hereditary hemorrhagic telangiectasia: a double-blind, randomized, placebo-controlled trial. Head Neck. 2015;37(6):783-787. — PubMed PMID: 24595923
  18. Khanwalkar AR, et al. Randomized, controlled, double-blinded clinical trial of effect of bevacizumab injection in management of epistaxis in hereditary hemorrhagic telangiectasia patients undergoing surgical cauterization. Int Forum Allergy Rhinol. 2022;12(8):1034-1042. — PubMed PMID: 34989143
  19. Gaillard S, et al. Tranexamic acid for epistaxis in hereditary hemorrhagic telangiectasia patients: a European cross-over controlled trial in a rare disease. J Thromb Haemost. 2014;12(9):1494-1502. — PubMed PMID: 25040799
  20. Geisthoff UW, et al. Treatment of epistaxis in hereditary hemorrhagic telangiectasia with tranexamic acid – a double-blind placebo-controlled cross-over phase IIIB study. Thromb Res. 2014;134(3):565-571. — PubMed PMID: 25005464
  21. Al-Samkari H, et al. An international, multicenter study of intravenous bevacizumab for bleeding in hereditary hemorrhagic telangiectasia: the InHIBIT-Bleed study. Haematologica. 2021;106(8):2161-2169. — PubMed PMID: 32675221
  22. Al-Samkari H, et al. Pomalidomide for Epistaxis in Hereditary Hemorrhagic Telangiectasia. N Engl J Med. 2024;391(11):1015-1027. — PubMed PMID: 39292928
  23. Al-Samkari H. How I treat bleeding in hereditary hemorrhagic telangiectasia. Blood. 2024;144(9):940-954. — PubMed PMID: 38864625
  24. Faughnan ME, et al. Pazopanib may reduce bleeding in hereditary hemorrhagic telangiectasia. Angiogenesis. 2019;22(1):145-155. — PubMed PMID: 30191360
  25. Parambil JG, et al. Pazopanib for severe bleeding and transfusion-dependent anemia in hereditary hemorrhagic telangiectasia. Angiogenesis. 2022;25(1):87-97. — PubMed PMID: 34292451
  26. Buscarini E, et al. Safety of thalidomide and bevacizumab in patients with hereditary hemorrhagic telangiectasia. Orphanet J Rare Dis. 2019;14(1):28. — PubMed PMID: 30717761
  27. Buscarini E, et al. Natural history and outcome of hepatic vascular malformations in a large cohort of patients with hereditary hemorrhagic teleangiectasia. Dig Dis Sci. 2011;56(7):2166-2178. — PubMed PMID: 21290179
  28. Kelly C, et al. Hepatic manifestations of hereditary haemorrhagic telangiectasia. Liver Int. 2024;44(9):2220-2234. — PubMed PMID: 38847503
  29. Brinjikji W, et al. Prevalence and characteristics of brain arteriovenous malformations in hereditary hemorrhagic telangiectasia: a systematic review and meta-analysis. J Neurosurg. 2017;127(2):302-310. — PubMed PMID: 27767404
  30. McDonald J, et al. Curaçao diagnostic criteria for hereditary hemorrhagic telangiectasia is highly predictive of a pathogenic variant in ENG or ACVRL1 (HHT1 and HHT2). Genet Med. 2020;22(7):1201-1205. — PubMed PMID: 32300199
  31. Gallione CJ, et al. A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4). Lancet. 2004;363(9412):852-859. — PubMed PMID: 15031030
  32. Wooderchak-Donahue WL, et al. BMP9 mutations cause a vascular-anomaly syndrome with phenotypic overlap with hereditary hemorrhagic telangiectasia. Am J Hum Genet. 2013;93(3):530-537. — PubMed PMID: 23972370
  33. Kjeldsen AD, et al. Clinical symptoms according to genotype amongst patients with hereditary haemorrhagic telangiectasia. J Intern Med. 2005;258(4):349-355. — PubMed PMID: 16164574
  34. Shovlin CL, et al. Estimates of maternal risks of pregnancy for women with hereditary haemorrhagic telangiectasia (Osler-Weber-Rendu syndrome): suggested approach for obstetric services. BJOG. 2008;115(9):1108-1115. — PubMed PMID: 18518871

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