12:e0188943. 36. Iyer VN, Apala DR, Pannu BS, et al. Intravenous Bevacizumab for Refractory Hereditary Hemorrhagic Telangiectasia-Related Epistaxis and Gastrointestinal Bleeding. Mayo Clin Proc 2018; 93:155. 37. Al-Samkari H, Kritharis A, Rodriguez-Lopez JM, Kuter DJ. Systemic bevacizumab for the treatment of chronic bleeding in hereditary haemorrhagic telangiectasia. J Intern Med 2019; 285:223. 38. Dupuis-Girod S, Ginon I, Saurin JC, et al. Bevacizumab in patients with hereditary hemorrhagic telangiectasia and severe hepatic vascular malformations and high cardiac output. JAMA 2012; 307:948. 39. V zquez C, Gonzalez ML, Ferraris A, et al. Bevacizumab for treating Hereditary Hemorrhagic Telangiectasia patients with severe hepatic involvement or refractory anemia. PLoS One 2020; 15:e0228486. 40. Thompson AB, Ross DA, Berard P, et al. Very low dose bevacizumab for the treatment of epistaxis in patients with hereditary hemorrhagic telangiectasia. Allergy Rhinol (Providence) 2014; 5:91. 41. Chavan A, Schumann-Binarsch S, Schmuck B, et al. Emerging role of bevacizumab in management of patients with symptomatic hepatic involvement in Hereditary Hemorrhagic Telangiectasia. Am J Hematol 2017; 92:E641. https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 34/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate 42. Epperla N, Kapke JT, Karafin M, et al. Effect of systemic bevacizumab in severe hereditary hemorrhagic telangiectasia associated with bleeding. Am J Hematol 2016; 91:E313. 43. Rosenberg T, Fialla AD, Kjeldsen J, Kjeldsen AD. Does severe bleeding in HHT patients respond to intravenous bevacizumab? Review of the literature and case series. Rhinology 2019; 57:242. 44. Al-Samkari H, Albitar HA, Olitsky SE, et al. An international survey to evaluate systemic bevacizumab for chronic bleeding in hereditary haemorrhagic telangiectasia. Haemophilia 2020; 26:1038. 45. Albitar HA, Almodallal Y, Nishimura R, Iyer VN. Mobile Mitral and Aortic Valvular Masses in Patients With Hereditary Hemorrhagic Telangiectasia Receiving Intravenous Bevacizumab. Mayo Clin Proc Innov Qual Outcomes 2020; 4:460. 46. Al-Samkari H, Kasthuri RS, Parambil JG, et al. An international, multicenter study of intravenous bevacizumab for bleeding in hereditary hemorrhagic telangiectasia: the InHIBIT-Bleed study. Haematologica 2021; 106:2161. 47. Gossage JR. The Current Role of Bevacizumab in the Treatment of Hereditary Hemorrhagic Telangiectasia-Related Bleeding. Mayo Clin Proc 2018; 93:130. 48. Hosman A, Westermann CJ, Snijder R, et al. Follow-up of Thalidomide treatment in patients with Hereditary Haemorrhagic Telangiectasia. Rhinology 2015; 53:340. 49. Bauditz J, Lochs H. Angiogenesis and vascular malformations: antiangiogenic drugs for treatment of gastrointestinal bleeding. World J Gastroenterol 2007; 13:5979. 50. Bowcock SJ, Patrick HE. Lenalidomide to control gastrointestinal bleeding in hereditary haemorrhagic telangiectasia: potential implications for angiodysplasias? Br J Haematol 2009; 146:220. 51. Lebrin F, Srun S, Raymond K, et al. Thalidomide stimulates vessel maturation and reduces epistaxis in individuals with hereditary hemorrhagic telangiectasia. Nat Med 2010; 16:420. 52. Harrison L, Kundra A, Jervis P. The use of thalidomide therapy for refractory epistaxis in hereditary haemorrhagic telangiectasia: systematic review. J Laryngol Otol 2018; 132:866. 53. http://www.ema.europa.eu/docs/en_GB/document_library/Orphan_designation/2017/03/W C500224884.pdf (Accessed on March 08, 2018). 54. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/orphans/2017/03/ human_orphan_001929.jsp&mid=WC0b01ac058001d12b (Accessed on March 14, 2018). 55. Fang J, Chen X, Zhu B, et al. Thalidomide for Epistaxis in Patients with Hereditary Hemorrhagic Telangiectasia: A Preliminary Study. Otolaryngol Head Neck Surg 2017; 157:217. https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 35/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate 56. Parambil JG, Woodard TD, Koc ON. Pazopanib effective for bevacizumab-unresponsive epistaxis in hereditary hemorrhagic telangiectasia. Laryngoscope 2018; 128:2234. 57. Faughnan ME, Gossage JR, Chakinala MM, et al. Pazopanib may reduce bleeding in hereditary hemorrhagic telangiectasia. Angiogenesis 2019; 22:145. 58. Skaro AI, Marotta PJ, McAlister VC. Regression of cutaneous and gastrointestinal telangiectasia with sirolimus and aspirin in a patient with hereditary hemorrhagic telangiectasia. Ann Intern Med 2006; 144:226. 59. Wheatley-Price P, Shovlin C, Chao D. Interferon for metastatic renal cell cancer causing regression of hereditary hemorrhagic telangiectasia. J Clin Gastroenterol 2005; 39:344. 60. Spiekerkoetter E, Tian X, Cai J, et al. FK506 activates BMPR2, rescues endothelial dysfunction, and reverses pulmonary hypertension. J Clin Invest 2013; 123:3600. 61. Shovlin CL. Hereditary haemorrhagic telangiectasia: pathophysiology, diagnosis and treatment. Blood Rev 2010; 24:203. 62. Geisthoff UW, Nguyen HL, R th A, Seyfert U. How to manage patients with hereditary haemorrhagic telangiectasia. Br J Haematol 2015; 171:443. 63. Hitchings AE, Lennox PA, Lund VJ, Howard DJ. The effect of treatment for epistaxis secondary to hereditary hemorrhagic telangiectasia. Am J Rhinol 2005; 19:75. 64. K hnel TS, Wagner BH, Schurr CP, Strutz J. Clinical strategy in hereditary hemorrhagic telangiectasia. Am J Rhinol 2005; 19:508. 65. Bergler W, Sadick H, Gotte K, et al. Topical estrogens combined with argon plasma coagulation in the management of epistaxis in hereditary hemorrhagic telangiectasia. Ann Otol Rhinol Laryngol 2002; 111:222. 66. Folz BJ, Tennie J, Lippert BM, Werner JA. Natural history and control of epistaxis in a group of German patients with Rendu-Osler-Weber disease. Rhinology 2005; 43:40. 67. Steineger J, Osnes T, Heimdal K, Dheyauldeen S. Long-term experience with intranasal bevacizumab therapy. Laryngoscope 2018; 128:2237. 68. Lund VJ, Darby Y, Rimmer J, et al. Nasal closure for severe hereditary haemorrhagic telangiectasia in 100 patients. The Lund modification of the Young's procedure: a 22-year experience. Rhinology 2017; 55:135. 69. Simonds J, Miller F, Mandel J, Davidson TM. The effect of bevacizumab (Avastin) treatment on epistaxis in hereditary hemorrhagic telangiectasia. Laryngoscope 2009; 119:988. 70. Karnezis TT, Davidson TM. Efficacy of intranasal Bevacizumab (Avastin) treatment in patients with hereditary hemorrhagic telangiectasia-associated epistaxis. Laryngoscope 2011; 121:636. https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 36/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate 71. Elphick A, Shovlin CL. Relationships between epistaxis, migraines, and triggers in hereditary hemorrhagic telangiectasia. Laryngoscope 2014; 124:1521. 72. Chamali B, Finnamore H, Manning R, et al. Dietary supplement use and nosebleeds in hereditary haemorrhagic telangiectasia - an observational study. Intractable Rare Dis Res 2016; 5:109. 73. Shovlin CL, Jackson JE, Bamford KB, et al. Primary determinants of ischaemic stroke/brain abscess risks are independent of severity of pulmonary arteriovenous malformations in hereditary haemorrhagic telangiectasia. Thorax 2008; 63:259. 74. http://www.ema.europa.eu/docs/en_GB/document_library/Orphan_designation/2010/06/W C500093985.pdf (Accessed on March 08, 2018). 75. Albi ana V, Bernabeu-Herrero ME, Zarrabeitia R, et al. Estrogen therapy for hereditary haemorrhagic telangiectasia (HHT): Effects of raloxifene, on Endoglin and ALK1 expression in endothelial cells. Thromb Haemost 2010; 103:525. 76. de Gussem EM, Snijder RJ, Disch FJ, et al. The effect of N-acetylcysteine on epistaxis and quality of life in patients with HHT: a pilot study. Rhinology 2009; 47:85. 77. Parambil JG, Gossage JR, McCrae KR, et al. Pazopanib for severe bleeding and transfusion- dependent anemia in hereditary hemorrhagic telangiectasia. Angiogenesis 2022; 25:87. 78. Kroon S, Snijder RJ, Hosman AE, et al. Oral itraconazole for epistaxis in hereditary hemorrhagic telangiectasia: a proof of concept study. Angiogenesis 2021; 24:379. 79. Sargeant IR, Loizou LA, Rampton D, et al. Laser ablation of upper gastrointestinal vascular ectasias: long term results. Gut 1993; 34:470. 80. Finnamore H, Le Couteur J, Hickson M, et al. Hemorrhage-adjusted iron requirements, hematinics and hepcidin define hereditary hemorrhagic telangiectasia as a model of hemorrhagic iron deficiency. PLoS One 2013; 8:e76516. 81. Rizvi A, Macedo P, Babawale L, et al. Hemoglobin Is a Vital Determinant of Arterial Oxygen Content in Hypoxemic Patients with Pulmonary Arteriovenous Malformations. Ann Am Thorac Soc 2017; 14:903. 82. Shovlin CL, Patel T, Jackson JE. Embolisation of PAVMs reported to improve nosebleeds by a subgroup of patients with hereditary haemorrhagic telangiectasia. ERJ Open Res 2016; 2. 83. Shovlin CL, Gilson C, Busbridge M, et al. Can Iron Treatments Aggravate Epistaxis in Some Patients With Hereditary Hemorrhagic Telangiectasia? Laryngoscope 2016; 126:2468. 84. Mollet IG, Patel D, Govani FS, et al. Low Dose Iron Treatments Induce a DNA Damage Response in Human Endothelial Cells within Minutes. PLoS One 2016; 11:e0147990. https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 37/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate 85. Thielemans L, Layton DM, Shovlin CL. Low serum haptoglobin and blood films suggest intravascular hemolysis contributes to severe anemia in hereditary hemorrhagic telangiectasia. Haematologica 2019; 104:e127. 86. Boother EJ, Brownlow S, Tighe HC, et al. Cerebral Abscess Associated With Odontogenic Bacteremias, Hypoxemia, and Iron Loading in Immunocompetent Patients With Right-to- Left Shunting Through Pulmonary Arteriovenous Malformations. Clin Infect Dis 2017; 65:595. 87. Santhirapala V, Williams LC, Tighe HC, et al. Arterial oxygen content is precisely maintained by graded erythrocytotic responses in settings of high/normal serum iron levels, and predicts exercise capacity: an observational study of hypoxaemic patients with pulmonary arteriovenous malformations. PLoS One 2014; 9:e90777. 88. Ahmedzai S, Balfour-Lynn IM, Bewick T, et al. Managing passengers with stable respiratory disease planning air travel: British Thoracic Society recommendations. Thorax 2011; 66 Suppl 1:i1. 89. Gawecki F, Strangeways T, Amin A, et al. Exercise capacity reflects airflow limitation rather than hypoxaemia in patients with pulmonary arteriovenous malformations. QJM 2019; 112:335. 90. Gawecki F, Myers J, Shovlin CL. Veterans Specific Activity Questionnaire (VSAQ): a new and efficient method of assessing exercise capacity in patients with pulmonary arteriovenous malformations. BMJ Open Respir Res 2019; 6:e000351. 91. Mason CG, Shovlin CL. Flight-related complications are infrequent in patients with hereditary haemorrhagic telangiectasia/pulmonary arteriovenous malformations, despite low oxygen saturations and anaemia. Thorax 2012; 67:80. 92. Fatania G, Gilson C, Glover A, et al. Uptake and radiological findings of screening cerebral magnetic resonance scans in patients with hereditary haemorrhagic telangiectasia. Intractable Rare Dis Res 2018; 7:236. 93. Brinjikji W, Nasr DM, Wood CP, Iyer VN. Pulmonary Arteriovenous Malformations Are Associated with Silent Brain Infarcts in Hereditary Hemorrhagic Telangiectasia Patients. Cerebrovasc Dis 2017; 44:179. 94. Shovlin CL, Condliffe R, Donaldson JW, et al. British Thoracic Society Clinical Statement on Pulmonary Arteriovenous Malformations. Thorax 2017; 72:1154. 95. Shovlin C, Bamford K, Sabb C, et al. Prevention of serious infections in hereditary hemorrhagic telangiectasia: roles for prophylactic antibiotics, the pulmonary capillaries-but not vaccination. Haematologica 2019; 104:e85. https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 38/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate 96. Lacombe P, Lacout A, Marcy PY, et al. Diagnosis and treatment of pulmonary arteriovenous malformations in hereditary hemorrhagic telangiectasia: An overview. Diagn Interv Imaging 2013; 94:835. 97. Gill SS, Roddie ME, Shovlin CL, Jackson JE. Pulmonary arteriovenous malformations and their mimics. Clin Radiol 2015; 70:96. 98. Woodward CS, Pyeritz RE, Chittams JL, Trerotola SO. Treated pulmonary arteriovenous malformations: patterns of persistence and associated retreatment success. Radiology 2013; 269:919. 99. Hsu CC, Kwan GN, Evans-Barns H, van Driel ML. Embolisation for pulmonary arteriovenous malformation. Cochrane Database Syst Rev 2018; 1:CD008017. 100. Shovlin CL, Gibbs JS, Jackson JE. Management of pulmonary arteriovenous malformations in pulmonary hypertensive patients: a pressure to embolise? Eur Respir Rev 2009; 18:4. 101. Shovlin CL, Tighe HC, Davies RJ, et al. Embolisation of pulmonary arteriovenous malformations: no consistent effect on pulmonary artery pressure. Eur Respir J 2008; 32:162. 102. Alsafi A, Jackson JE, Fatania G, et al. Patients with in-situ metallic coils and Amplatzer vascular plugs used to treat pulmonary arteriovenous malformations since 1984 can safely undergo magnetic resonance imaging. Br J Radiol 2019; 92:20180752. 103. Shovlin CL, Buscarini E, Hughes JMB, et al. Long-term outcomes of patients with pulmonary arteriovenous malformations considered for lung transplantation, compared with similarly hypoxaemic cohorts. BMJ Open Respir Res 2017; 4:e000198. 104. https://www.gov.uk/government/publications/the-never-events-list-for-2012-13. 105. Shovlin C, Bamford K, Wray D. Post-NICE 2008: Antibiotic prophylaxis prior to dental procedures for patients with pulmonary arteriovenous malformations (PAVMs) and hereditary haemorrhagic telangiectasia. Br Dent J 2008; 205:531. 106. Revuz S, Decullier E, Ginon I, et al. Pulmonary hypertension subtypes associated with hereditary haemorrhagic telangiectasia: Haemodynamic profiles and survival probability. PLoS One 2017; 12:e0184227. 107. Vorselaars V, Velthuis S, van Gent M, et al. Pulmonary Hypertension in a Large Cohort with Hereditary Hemorrhagic Telangiectasia. Respiration 2017; 94:242. 108. Letteboer TG, Mager JJ, Snijder RJ, et al. Genotype-phenotype relationship in hereditary haemorrhagic telangiectasia. J Med Genet 2006; 43:371. 109. Lesca G, Olivieri C, Burnichon N, et al. Genotype-phenotype correlations in hereditary hemorrhagic telangiectasia: data from the French-Italian HHT network. Genet Med 2007; https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 39/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate 9:14. 110. Buscarini E, Leandro G, Conte D, et al. Natural history and outcome of hepatic vascular malformations in a large cohort of patients with hereditary hemorrhagic teleangiectasia. Dig Dis Sci 2011; 56:2166. 111. European Association for the Study of the Liver. Electronic address: easloffice@easloffice.eu. EASL Clinical Practice Guidelines: Vascular diseases of the liver. J Hepatol 2016; 64:179. 112. https://vascern.eu/wp-content/uploads/2018/03/Hepatic-AVM-Workshop-2017.pdf (Accesse d on August 30, 2019). 113. Andrejecsk JW, Hosman AE, Botella LM, et al. Executive summary of the 12th HHT international scientific conference. Angiogenesis 2018; 21:169. 114. Dickstein K, Cohen-Solal A, Filippatos G, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association of the ESC (HFA) and endorsed by the European Society of Intensive Care Medicine (ESICM). Eur Heart J 2008; 29:2388. 115. Lerut J, Orlando G, Adam R, et al. Liver transplantation for hereditary hemorrhagic telangiectasia: Report of the European liver transplant registry. Ann Surg 2006; 244:854. 116. Flieger D, Hainke S, Fischbach W. Dramatic improvement in hereditary hemorrhagic telangiectasia after treatment with the vascular endothelial growth factor (VEGF) antagonist bevacizumab. Ann Hematol 2006; 85:631. 117. Mitchell A, Adams LA, MacQuillan G, et al. Bevacizumab reverses need for liver transplantation in hereditary hemorrhagic telangiectasia. Liver Transpl 2008; 14:210. 118. Oosting S, Nagengast W, de Vries E. More on bevacizumab in hereditary hemorrhagic telangiectasia. N Engl J Med 2009; 361:931; author reply 931. 119. Olsen LB, Kjeldsen AD, Poulsen MK, et al. High output cardiac failure in 3 patients with hereditary hemorrhagic telangiectasia and hepatic vascular malformations, evaluation of treatment. Orphanet J Rare Dis 2020; 15:334. 120. Maestraggi Q, Bouattour M, Toquet S, et al. Bevacizumab to Treat Cholangiopathy in Hereditary Hemorrhagic Telangiectasia: Be Cautious: A Case Report. Medicine (Baltimore) 2015; 94:e1966. 121. DeLeve LD, Valla DC, Garcia-Tsao G, American Association for the Study Liver Diseases. Vascular disorders of the liver. Hepatology 2009; 49:1729. 122. Boillot O, Bianco F, Viale JP, et al. Liver transplantation resolves the hyperdynamic circulation in hereditary hemorrhagic telangiectasia with hepatic involvement. Gastroenterology 1999; https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 40/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate 116:187. 123. Dupuis-Girod S, Chesnais AL, Ginon I, et al. Long-term outcome of patients with hereditary hemorrhagic telangiectasia and severe hepatic involvement after orthotopic liver transplantation: a single-center study. Liver Transpl 2010; 16:340. 124. Krowka MJ, Wiesner RH, Heimbach JK. Pulmonary contraindications, indications and MELD exceptions for liver transplantation: a contemporary view and look forward. J Hepatol 2013; 59:367. 125. http://www.arubastudy.org/ (Accessed on August 30, 2012). 126. Mohr JP, Parides MK, Stapf C, et al. Medical management with or without interventional therapy for unruptured brain arteriovenous malformations (ARUBA): a multicentre, non- blinded, randomised trial. Lancet 2014; 383:614. 127. https://www.orpha.net/consor/www/cgi-bin/OC_Exp.php?lng=EN&Expert=774 (Accessed on August 28, 2019). 128. Mohr JP, Overbey JR, Hartmann A, et al. Medical management with interventional therapy versus medical management alone for unruptured brain arteriovenous malformations (ARUBA): final follow-up of a multicentre, non-blinded, randomised controlled trial. Lancet Neurol 2020; 19:573. 129. Yang W, Liu A, Hung AL, et al. Lower risk of intracranial arteriovenous malformation hemorrhage in patients with hereditary hemorrhagic telangiectasia. Neurosurgery 2016; 78:684. 130. Ganesan V, Robertson F, Berg J. Neurovascular screening in hereditary haemorrhagic telangiectasia: dilemmas for the paediatric neuroscience community. Dev Med Child Neurol 2013; 55:405. 131. Shovlin CL, Sodhi V, McCarthy A, 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; 115:1108. 132. Shovlin CL, Winstock AR, Peters AM, et al. Medical complications of pregnancy in hereditary haemorrhagic telangiectasia. QJM 1995; 88:879. 133. Gershon AS, Faughnan ME, Chon KS, et al. Transcatheter embolotherapy of maternal pulmonary arteriovenous malformations during pregnancy. Chest 2001; 119:470. 134. Cottin V, Plauchu H, Bayle JY, et al. Pulmonary arteriovenous malformations in patients with hereditary hemorrhagic telangiectasia. Am J Respir Crit Care Med 2004; 169:994. 135. Kjeldsen A, Aagaard KS, T rring PM, et al. 20-year follow-up study of Danish HHT patients- survival and causes of death. Orphanet J Rare Dis 2016; 11:157. https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 41/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate 136. Donaldson JW, McKeever TM, Hall IP, et al. Complications and mortality in hereditary hemorrhagic telangiectasia: A population-based study. Neurology 2015; 84:1886. 137. Krings T, Ozanne A, Chng SM, et al. Neurovascular phenotypes in hereditary haemorrhagic telangiectasia patients according to age. Review of 50 consecutive patients aged 1 day-60 years. Neuroradiology 2005; 47:711. 138. Kim H, Nelson J, Krings T, et al. Hemorrhage rates from brain arteriovenous malformation in patients with hereditary hemorrhagic telangiectasia. Stroke 2015; 46:1362. 139. Kjeldsen AD, T rring PM, Nissen H, Andersen PE. Cerebral abscesses among Danish patients with hereditary haemorrhagic telangiectasia. Acta Neurol Scand 2014; 129:192. 140. Droege F, Thangavelu K, Stuck BA, et al. Life expectancy and comorbidities in patients with hereditary hemorrhagic telangiectasia. Vasc Med 2018; 23:377. 141. Sabb C, Pasculli G, Suppressa P, et al. Life expectancy in patients with hereditary haemorrhagic telangiectasia. QJM 2006; 99:327. 142. Shovlin CL, Awan I, Cahilog Z, et al. Reported cardiac phenotypes in hereditary hemorrhagic telangiectasia emphasize burdens from arrhythmias, anemia and its treatments, but suggest reduced rates of myocardial infarction. Int J Cardiol 2016; 215:179. 143. Hosman AE, Devlin HL, Silva BM, Shovlin CL. Specific cancer rates may differ in patients with hereditary haemorrhagic telangiectasia compared to controls. Orphanet J Rare Dis 2013; 8:195. 144. Duarte CW, Black AW, Lucas FL, Vary CP. Cancer incidence in patients with hereditary hemorrhagic telangiectasia. J Cancer Res Clin Oncol 2017; 143:209. 145. Hosman AE, Shovlin CL. Cancer and hereditary haemorrhagic telangiectasia. J Cancer Res Clin Oncol 2017; 143:369. Topic 109902 Version 31.0 https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 42/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate GRAPHICS Overview of the incidence, presenting findings, evaluation, and management of the major clinical features of hereditary hemorrhagic telangiectasia (HHT) Presentation patterns Site Incidence Evaluation Treatment Nasal telangiectasia >90% Nose bleeds are usually the first History, inspection Routine therapy includes nasal lubrication and manifestation of treatment of iron deficiency when needed. HHT, frequently commencing in Laser treatment is generally preferred over childhood. cauterization. Surgery in expert hands offers good results for selected patients. Medical (systemic) treatments are an alternative and may be highly beneficial, but carry risks of prothrombotic side effects. Emergency treatments such as packing may be required. Mucocutaneous telangiectasia 50 to 80% Increase in size and number Inspection (oral, mucosa, Generally not indicated, but laser therapy can be with age. Main concerns are conjunctivae, face, trunk, used. cosmetic. May extremities, nail hemorrhage. beds) Gastrointestinal 11 to 40% Onset generally Flexible Iron supplementation telangiectasia over 30 years: Iron deficiency endoscopy, endoscopy and transfusion are the mainstays of treatment. anemia, angiogram, Medical (systemic) treatments are available occasionally acute capsule endoscopy and may be highly beneficial, but they carry gastrointestinal hemorrhage. https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 43/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate risks of prothrombotic side effects. Pulmonary AVMs >50% Usually silent. Cyanosis, Chest radiography, Therapeutic embolization. clubbing, bruit, dyspnea, blood gas measurement, Antibiotic prophylaxis for dental and surgical paradoxical helical CT, procedures. embolism, cerebral angiography, chest Surgical resection may be indicated in highly abscess. echocardiography selected cases. Cerebral AVMs 10 to 15% Usually silent. Headache, CT, MRI, Doppler sonography, Most do not require treatment. epilepsy, angiography Therapeutic embolization, ischemia, intracerebral neurovascular surgery, or stereotactic radiosurgery hemorrhage. in highly selected cases. Hepatic AVMs 30 to 70% Usually silent. Hepatic artery- Doppler sonography, CT, Most do not require treatment. hepatic vein AVMs: MRI For the small proportion of patients who develop Hyperdynamic symptoms, standard hepatic medical care is circulation. Portasystemic often sufficient to resolve symptoms. shunts: Ascites and Liver transplantation in selected cases. encephalopathy. Embolization is a higher- risk procedure; some centers do not perform embolization unless the patient is accepted into a liver transplantation program. Less-common clinical manifestations include AVMs in other sites, high cardiac output states, and pulmonary hypertension. Refer to UpToDate for additional details of our approach. AVM: arteriovenous malformation; CT: computed tomography; MRI: magnetic resonance imaging. Adapted and updated from the original table in: Shovlin CL, Letarte M. Hereditary hemorrhagic telangiectasia and pulmonary arteriovenous malformations: issues in clinical management and review of pathogenic mechanisms. Thorax 1999; https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 44/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate 54:714. Graphic 74593 Version 3.0 https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 45/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate Arteriovenous malformation in the gastrointestinal tract Endoscopic views of arteriovenous malformations being treated with the argon plasma coagulator (APC). The top panels illustrate the appearance before and after APC coagulation. The bottom panels demonstrate the ability of APC to treat lesions tangentially. It is important to see the black portion of the APC cathether prior to initiating coagulation to prevent damage to the endoscope. Courtesy of Jonathan Cohen, MD. Graphic 79901 Version 2.0 https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 46/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate Contributor Disclosures Claire L Shovlin, PhD, FRCP Patent Holder: Imperial College London [The use of trametinib for treatment of HHT bleeding is the subject of a patent application by my employer]. Grant/Research/Clinical Trial Support: National Institute for Health Research [Imaging angiogenesis by PET CT - A pilot study in patients with arteriovenous malformations and hereditary haemorrhagic telangiectasia]. Consultant/Advisory Boards: European Reference Network for Rare Multisystemic Vascular Diseases [HHT]; Genomics England Respiratory GeCIP [Genomic medicine]; International Guidelines Committee [Cure HHT]; NHS Genomic Medicine Service Alliance [Genomic medicine]; NIH ClinGen Expert Panel for hereditary haemorrhagic telangiectasia GRAMB [HHT]. All of the relevant financial relationships listed have been mitigated. Lawrence LK Leung, MD No relevant financial relationship(s) with ineligible companies to disclose. Jennifer S Tirnauer, MD No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 47/47