Medical and Interventional Management of Hereditary Hemorrhagic Telangiectasia

Abstract

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder of the blood vessels that leads to the formation of telangiectasias and arteriovenous malformations (AVMs). HHT affects ∼1/5,000 people, but this varies significantly by geography and ancestry. The Curaçao criteria for HHT consist of four diagnostic criteria: spontaneous epistaxis, first-degree relative with HHT, AVMs in characteristic location (liver, lung, brain), and telangiectasias. Sequelae and major symptomology include recurrent epistaxis, dyspnea, heart failure, and stroke from paradoxical emboli among others. HHT patients are best cared for by a multidisciplinary team, ideally all with HHT-specific experience, but in this review, we will discuss the major aspects of the disease including etiology, diagnosis, and treatment recommendations.

Keywords

hereditary hemorrhagic telangiectasia - vascular malformations - interventional radiology

Publikationsverlauf

Artikel online veröffentlicht:
07. November 2024

• References

• 1 Shovlin CL, Simeoni I, Downes K. et al. Mutational and phenotypic characterization of hereditary hemorrhagic telangiectasia. Blood 2020; 136 (17) 1907-1918
• 2 Cartin-Ceba R, Swanson KL, Krowka MJ. Pulmonary arteriovenous malformations. Chest 2013; 144 (03) 1033-1044
• 3 McDonald J, Wooderchak-Donahue W, VanSant Webb C, Whitehead K, Stevenson DA, Bayrak-Toydemir P. Hereditary hemorrhagic telangiectasia: genetics and molecular diagnostics in a new era. Front Genet 2015; 6: 1
• 4 Snodgrass RO, Chico TJA, Arthur HM. Hereditary haemorrhagic telangiectasia, an inherited vascular disorder in need of improved evidence-based pharmaceutical interventions. Genes (Basel) 2021; 12 (02) 174
• 5 Kritharis A, Al-Samkari H, Kuter DJ. Hereditary hemorrhagic telangiectasia: diagnosis and management from the hematologist's perspective. Haematologica 2018; 103 (09) 1433-1443
• 6 El Hajjam M, Mekki A, Palmyre A. et al. RASA1 phenotype overlaps with hereditary haemorrhagic telangiectasia: two case reports. J Med Genet 2021; 58 (09) 645-647
• 7 Hammill AM, Wusik K, Kasthuri RS. Hereditary hemorrhagic telangiectasia (HHT): a practical guide to management. Hematology (Am Soc Hematol Educ Program) 2021; 2021 (01) 469-477
• 8 Xu B, Wu YQ, Huey M. et al. Vascular endothelial growth factor induces abnormal microvasculature in the endoglin heterozygous mouse brain. J Cereb Blood Flow Metab 2004; 24 (02) 237-244
• 9 Hao Q, Zhu Y, Su H. et al. VEGF induces more severe cerebrovascular dysplasia in Endoglin than in Alk1 mice. Transl Stroke Res 2010; 1 (03) 197-201
• 10 Tual-Chalot S, Garcia-Collado M, Redgrave RE. et al. Loss of endothelial Endoglin promotes high-output heart failure through peripheral arteriovenous shunting driven by VEGF signaling. Circ Res 2020; 126 (02) 243-257
• 11 Han C, Choe SW, Kim YH. et al. VEGF neutralization can prevent and normalize arteriovenous malformations in an animal model for hereditary hemorrhagic telangiectasia 2. Angiogenesis 2014; 17 (04) 823-830
• 12 Al Tabosh T, Al Tarrass M, Tourvieilhe L, Guilhem A, Dupuis-Girod S, Bailly S. Hereditary hemorrhagic telangiectasia: from signaling insights to therapeutic advances. J Clin Invest 2024; 134 (04) e176379
• 13 Adams DM, Trenor III CC, Hammill AM. et al. Efficacy and safety of sirolimus in the treatment of complicated vascular anomalies. Pediatrics 2016; 137 (02) e20153257
• 14 Parambil JG, Gossage JR, McCrae KR. et al. Pazopanib for severe bleeding and transfusion-dependent anemia in hereditary hemorrhagic telangiectasia. Angiogenesis 2022; 25 (01) 87-97
• 15 Invernizzi R, Quaglia F, Klersy C. 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
• 16 Al-Samkari H, Kasthuri RS, Iyer V. et al. PATH-HHT, a double-blind, randomized, placebo-controlled trial in hereditary hemorrhagic telangiectasia demonstrates that pomalidomide reduces epistaxis and improved quality of life. Blood 2023; 142 (02) LBA-3
• 17 James M, Sehgal VS. Pioneering the future: CRISPR-Cas9 gene therapy for hereditary hemorrhagic telangiectasia. Eur J Intern Med 2024; S0953 -6205(24)00252-8
• 18 Gossage JR, Kanj G. Pulmonary arteriovenous malformations. A state of the art review. Am J Respir Crit Care Med 1998; 158 (02) 643-661
• 19 Swanson KL, Prakash UB, Stanson AW. Pulmonary arteriovenous fistulas: Mayo Clinic experience, 1982-1997. Mayo Clin Proc 1999; 74 (07) 671-680
• 20 Ference BA, Shannon TM, White Jr RI, Zawin M, Burdge CM. Life-threatening pulmonary hemorrhage with pulmonary arteriovenous malformations and hereditary hemorrhagic telangiectasia. Chest 1994; 106 (05) 1387-1390
• 21 Bari O, Cohen PR. Hereditary hemorrhagic telangiectasia and pregnancy: potential adverse events and pregnancy outcomes. Int J Womens Health 2017; 9: 373-378
• 22 Shovlin CL, Sodhi V, McCarthy A, Lasjaunias P, Jackson JE, Sheppard MN. Estimates of maternal risks of pregnancy for women with hereditary haemorrhagic telangiectasia (Osler-Weber-Rendu syndrome): suggested approach for obstetric services. BJOG 2008; 115 (09) 1108-1115
• 23 Parra JA, Bueno J, Zarauza J. et al. Graded contrast echocardiography in pulmonary arteriovenous malformations. Eur Respir J 2010; 35 (06) 1279-1285
• 24 Gazzaniga P, Buscarini E, Leandro G. et al. Contrast echocardiography for pulmonary arteriovenous malformations screening: does any bubble matter?. Eur J Echocardiogr 2009; 10 (04) 513-518
• 25 Lee DW, White Jr RI, Egglin TK. et al. Embolotherapy of large pulmonary arteriovenous malformations: long-term results. Ann Thorac Surg 1997; 64 (04) 930-939 , discussion 939–940
• 26 Meek ME, Meek JC, Beheshti MV. Management of pulmonary arteriovenous malformations. Semin Intervent Radiol 2011; 28 (01) 24-31
• 27 Conrad MB, Ishaque BM, Surman AM. et al. Intraprocedural safety and technical success of the MVP Micro Vascular Plug for embolization of pulmonary arteriovenous malformations. J Vasc Interv Radiol 2015; 26 (11) 1735-1739
• 28 Remy-Jardin M, Dumont P, Brillet PY, Dupuis P, Duhamel A, Remy J. Pulmonary arteriovenous malformations treated with embolotherapy: helical CT evaluation of long-term effectiveness after 2-21-year follow-up. Radiology 2006; 239 (02) 576-585
• 29 Hong J, Lee SY, Cha JG. et al. Pulmonary arteriovenous malformation (PAVM) embolization: prediction of angiographically-confirmed recanalization according to PAVM Diameter changes on CT. CVIR Endovasc 2021; 4 (01) 16
• 30 Takao S, Masuda T, Yamada T. et al. Pulmonary arteriovenous malformation exhibiting recanalization >10 years after coil embolization: two case reports. Medicine (Baltimore) 2020; 99 (02) e18694
• 31 Al-Samkari H. Hereditary hemorrhagic telangiectasia: systemic therapies, guidelines, and an evolving standard of care. Blood 2021; 137 (07) 888-895
• 32 Reh DD, Hur K, Merlo CA. Efficacy of a topical sesame/rose geranium oil compound in patients with hereditary hemorrhagic telangiectasia associated epistaxis. Laryngoscope 2013; 123 (04) 820-822
• 33 Hashimoto T, Matsumoto MM, Li JF, Lawton MT, Young WL. University of California, San Francisco, BAVM Study Group. Suppression of MMP-9 by doxycycline in brain arteriovenous malformations. BMC Neurol 2005; 5 (01) 1
• 34 Arthur H, Geisthoff U, Gossage JR. et al. Executive summary of the 11th HHT international scientific conference. Angiogenesis 2015; 18 (04) 511-524
• 35 Thompson KP, Sykes J, Chandakkar P. et al. Randomized, double-blind, placebo-controlled, crossover trial of oral doxycycline for epistaxis in hereditary hemorrhagic telangiectasia. Orphanet J Rare Dis 2022; 17 (01) 405
• 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 (02) 155-166
• 37 Dür C, Anschuetz L, Negoias S, Bulut OC, Angelillo-Scherrer A, Caversaccio M. Long-term efficacy assessment of current treatment options for epistaxis in HHT. Eur Arch Otorhinolaryngol 2021; 278 (11) 4321-4328
• 38 Parambil JG, Woodard TD, Koc ON. Pazopanib effective for bevacizumab-unresponsive epistaxis in hereditary hemorrhagic telangiectasia. Laryngoscope 2018; 128 (10) 2234-2236
• 39 Yaniv E, Preis M, Hadar T, Shvero J, Haddad M. Antiestrogen therapy for hereditary hemorrhagic telangiectasia: a double-blind placebo-controlled clinical trial. Laryngoscope 2009; 119 (02) 284-288
• 40 Riss D, Burian M, Wolf A, Kranebitter V, Kaider A, Arnoldner C. Intranasal submucosal bevacizumab for epistaxis in hereditary hemorrhagic telangiectasia: a double-blind, randomized, placebo-controlled trial. Head Neck 2015; 37 (06) 783-787
• 41 Richer SL, Geisthoff UW, Livada N. et al. The Young's procedure for severe epistaxis from hereditary hemorrhagic telangiectasia. Am J Rhinol Allergy 2012; 26 (05) 401-404
• 42 Manfredi G, Crinò SF, Alicante S. et al. Gastrointestinal bleeding in patients with hereditary hemorrhagic telangiectasia: long-term results of endoscopic treatment. Endosc Int Open 2023; 11 (12) E1145-E1152
• 43 Khalid SK, Garcia-Tsao G. Hepatic vascular malformations in hereditary hemorrhagic telangiectasia. Semin Liver Dis 2008; 28 (03) 247-258
• 44 Amanzada A, Töppler GJ, Cameron S, Schwörer H, Ramadori G. A case report of a patient with hereditary hemorrhagic telangiectasia treated successively with thalidomide and bevacizumab. Case Rep Oncol 2010; 3 (03) 463-470
• 45 Dupuis-Girod S, Buscarini E. Hereditary hemorrhagic telangiectasia: to transplant or not to transplant?. Liver Int 2016; 36 (12) 1741-1744
• 46 Beard JL, Connor JR. Iron status and neural functioning. Annu Rev Nutr 2003; 23: 41-58
• 47 Tolkien Z, Stecher L, Mander AP, Pereira DI, Powell JJ. Ferrous sulfate supplementation causes significant gastrointestinal side-effects in adults: a systematic review and meta-analysis. PLoS One 2015; 10 (02) e0117383
• 48 Stoffel NU, Cercamondi CI, Brittenham G. et al. Iron absorption from oral iron supplements given on consecutive versus alternate days and as single morning doses versus twice-daily split dosing in iron-depleted women: two open-label, randomised controlled trials. Lancet Haematol 2017; 4 (11) e524-e533
• 49 Georgieff MK. Iron deficiency in pregnancy. Am J Obstet Gynecol 2020; 223 (04) 516-524
• 50 Wiegersma AM, Dalman C, Lee BK, Karlsson H, Gardner RM. Association of prenatal maternal anemia with neurodevelopmental disorders. JAMA Psychiatry 2019; 76 (12) 1294-1304
• 51 Brinjikji W, Iyer VN, Wood CP, Lanzino G. Prevalence and characteristics of brain arteriovenous malformations in hereditary hemorrhagic telangiectasia: a systematic review and meta-analysis. J Neurosurg 2017; 127 (02) 302-310
• 52 Brinjikji W, Iyer VN, Yamaki V. et al. Neurovascular manifestations of hereditary hemorrhagic telangiectasia: a consecutive series of 376 patients during 15 years. AJNR Am J Neuroradiol 2016; 37 (08) 1479-1486
• 53 Yang W, Liu A, Hung AL. et al. Lower risk of intracranial arteriovenous malformation hemorrhage in patients with hereditary hemorrhagic telangiectasia. Neurosurgery 2016; 78 (05) 684-693
• 54 Kim HJ, Lee JS, Oh YM. et al. Clinical characteristics of pulmonary arteriovenous malformations in Koreans. Respirology 2015; 20 (01) 155-159
• 55 Meybodi AT, Kim H, Nelson J. et al. Surgical treatment vs. nonsurgical treatment for brain arteriovenous malformations in patients with hereditary hemorrhagic telangiectasia: A retrospective multicenter consortium study [published correction appears in Neurosurgery. 2018; 82 (02) 253 . Doi: 10.1093/neuros/nyx621]. Neurosurgery. 2018;82(1):35-47. Doi:10.1093/neuros/nyx168