{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T21:39:43Z","timestamp":1790631583644,"version":"4.1.0"},"reference-count":127,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2024,10,14]],"date-time":"2024-10-14T00:00:00Z","timestamp":1728864000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University of Medicine and Pharmacy of Craiova, Romania"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Hereditary angioedema (HAE) is a rare and potentially life-threatening genetic disorder, constituting approximately 2% of all clinical cases of angioedema, with a global prevalence estimated between 1 in 50,000 and 1 in 150,000 individuals. The condition affects individuals of all genders and ethnic backgrounds without significant variation. HAE is classified into three types. Type I HAE, which accounts for 85% of cases, is characterized by a deficiency of the C1 esterase inhibitor (C1-INH) gene. Type II HAE, making up 15% of cases, involves a dysfunctional C1-INH. Type III HAE, which represents about 5% to 10% of cases, is often estrogen-dependent and although several mutations have been identified, it typically involves normal C1-INH activity. Despite the differences in C1-INH functionality, all three types of HAE manifest with similar clinical symptoms. HAE leads to recurrent episodes of non-pruritic angioedema, which occurs in the absence of urticaria. Breakthroughs in understanding HAE pathophysiology have revolutionized treatment, leading to the development of highly targeted therapies for both acute management and long-term prevention. Meanwhile, cutting-edge advancements in omics technologies are unlocking new possibilities for biomarker discovery, paving the way for more precise diagnoses and personalized treatment strategies that could significantly enhance patient outcomes. This review will delve into the intricate pathophysiology, diverse clinical presentations, and diagnostic challenges of HAE while exploring emerging biomarkers and innovative approaches to therapeutic management and prevention strategies. Additionally, it will underscore the vital importance of screening family members of affected individuals, even when symptoms are not present.<\/jats:p>","DOI":"10.3390\/biom14101298","type":"journal-article","created":{"date-parts":[[2024,10,14]],"date-time":"2024-10-14T04:02:58Z","timestamp":1728878578000},"page":"1298","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Unveiling the Complexities of Hereditary Angioedema"],"prefix":"10.3390","volume":"14","author":[{"given":"Cristina Violeta","family":"Tutunaru","sequence":"first","affiliation":[{"name":"Department of Dermatology, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oana Maria","family":"Ic\u0103","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George G.","family":"Mitroi","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen Daniela","family":"Neagoe","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George F.","family":"Mitroi","sequence":"additional","affiliation":[{"name":"Department of Urology, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7813-5736","authenticated-orcid":false,"given":"Olgu\u021ba Anca","family":"Orzan","sequence":"additional","affiliation":[{"name":"Department of Oncologic Dermatology, \u201cElias\u201d Emergency University Hospital, \u201cCarol Davila\u201d University of Medicine and Pharmacy, 020021 Bucharest, Romania"},{"name":"Clinic of Dermatology, \u201cElias\u201d Emergency University Hospital, 011461 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-6652-4125","authenticated-orcid":false,"given":"Beatrice","family":"B\u0103l\u0103ceanu-Gur\u0103u","sequence":"additional","affiliation":[{"name":"Department of Oncologic Dermatology, \u201cElias\u201d Emergency University Hospital, \u201cCarol Davila\u201d University of Medicine and Pharmacy, 020021 Bucharest, Romania"},{"name":"Clinic of Dermatology, \u201cElias\u201d Emergency University Hospital, 011461 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simona Laura","family":"Iano\u0219i","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,10,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"814","DOI":"10.1007\/s12325-022-02401-0","article-title":"Hereditary Angioedema: Diagnosis, Clinical Implications, and Pathophysiology","volume":"40","author":"Sinnathamby","year":"2023","journal-title":"Adv Ther."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.emc.2021.09.002","article-title":"Hereditary Angioedema","volume":"40","author":"Wilkerson","year":"2022","journal-title":"Emerg. Med. Clin."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Andrejevi\u0107, S., Koro\u0161ec, P., \u0160ilar, M., Ko\u0161nik, M., Mijanovi\u0107, R., Bona\u010di-Nikoli\u0107, B., and Rijavec, M. (2015). Hereditary angioedema due to C1 inhibitor deficiency in Serbia: Two novel mutations and evidence of genotype\u2013phenotype association. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0142174"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1586\/1744666X.2016.1100963","article-title":"Optimizing hereditary angioedema management through tailored treatment approaches","volume":"12","author":"Nasr","year":"2016","journal-title":"Expert. Rev. Clin. Immunol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"391","DOI":"10.12968\/hmed.2019.80.7.391","article-title":"Hereditary angioedema: An update on causes, manifestations and treatment","volume":"80","author":"Longhurst","year":"2019","journal-title":"Br. J. Hosp. Med. (Lond.)"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1159\/000486312","article-title":"Hereditary and Acquired Angioedema: Heterogeneity of Pathogenesis and Clinical Phenotypes","volume":"175","author":"Bova","year":"2018","journal-title":"Int. Arch. Allergy Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Santacroce, R., D\u2019Andrea, G., Maffione, A.B., Margaglione, M., and d\u2019Apolito, M. (2021). The Genetics of Hereditary Angioedema: A Review. J. Clin. Med., 10.","DOI":"10.3390\/jcm10092023"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/B978-0-12-800100-4.00002-7","article-title":"Pathogenic mechanisms of bradykinin mediated diseases: Dysregulation of an innate inflammatory pathway","volume":"121","author":"Kaplan","year":"2014","journal-title":"Adv. Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1397","DOI":"10.1111\/j.1398-9995.2011.02686.x","article-title":"New topics in bradykinin research","volume":"66","author":"Maurer","year":"2011","journal-title":"Allergy"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1007\/s12016-021-08845-6","article-title":"Biomarkers in Hereditary Angioedema","volume":"60","author":"Porebski","year":"2021","journal-title":"Clin. Rev. Allergy Immunol."},{"key":"ref_11","unstructured":"Memon, R.J., and Tiwari, V. (2022, August 08). Angioedema, StatPearls, Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK538489."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1111\/acem.12341","article-title":"A consensus parameter for the evaluation and management of angioedema in the emergency department","volume":"21","author":"Moellman","year":"2014","journal-title":"Acad. Emerg. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1056\/NEJMcp0803977","article-title":"Hereditary angioedema","volume":"359","author":"Zuraw","year":"2008","journal-title":"N. Engl. J. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2119","DOI":"10.1016\/S0140-6736(17)32206-7","article-title":"Recurrent ascites: A need to evaluate for hereditary angio-oedema","volume":"390","author":"Dobru","year":"2017","journal-title":"Lancet"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2017221027","DOI":"10.1136\/bcr-2017-221027","article-title":"Anchoring bias in a case of recurrent abdominal pain","volume":"2017","author":"Keeney","year":"2017","journal-title":"BMJ Case Rep."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"AB32","DOI":"10.1016\/j.jaci.2013.12.143","article-title":"Clinical features of pediatric hereditary angioedema","volume":"133","author":"Elenburg","year":"2014","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1016\/j.pop.2022.11.005","article-title":"Hereditary Angioedema: A Disease Often Misdiagnosed and Mistreated","volume":"50","author":"Sarkar","year":"2023","journal-title":"Primary Care"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1961","DOI":"10.1111\/all.15214","article-title":"The international WAO\/EAACI guideline for the management of hereditary angioedema-The 2021 revision and update","volume":"77","author":"Maurer","year":"2022","journal-title":"Allergy"},{"key":"ref_19","first-page":"103","article-title":"Hereditary angioedema: Epidemiology, management, and role of icatibant","volume":"7","author":"Ghazi","year":"2013","journal-title":"Biologics"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1666","DOI":"10.1056\/NEJM199606203342510","article-title":"Hereditary angioedema","volume":"334","author":"Cicardi","year":"1996","journal-title":"N. Engl. J. Med."},{"key":"ref_21","first-page":"129","article-title":"Concerning the acute localized edema of the skin","volume":"1","author":"Quincke","year":"1882","journal-title":"Monatsh Prakt Derm"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1097\/00000441-188804000-00004","article-title":"Hereditary angioneurotic edema","volume":"95","author":"Osler","year":"1888","journal-title":"Am. J. Med. Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/0002-9343(63)90162-1","article-title":"A biochemical abnormality in hereditary angioneurotic edema: Absence of serum inhibitor of C\u2019 1-esterase","volume":"35","author":"Donaldson","year":"1963","journal-title":"Am. J. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2417","DOI":"10.1001\/archinte.161.20.2417","article-title":"Hereditary angioedema: A broad review for clinicians","volume":"161","author":"Nzeako","year":"2001","journal-title":"Arch. Intern. Med."},{"key":"ref_25","unstructured":"Goldman, L., and Schafer, A.I. (2011). Urticaria and angioedema. Cecil Medicine, Saunders Elsevier. [24th ed.]. Chap 260."},{"key":"ref_26","first-page":"471","article-title":"Hereditary angioedema: An infrequent cause of abdominal pain with ascites","volume":"90","author":"Talavera","year":"1995","journal-title":"Am. J. Gastroenterol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"S51","DOI":"10.1016\/j.jaci.2004.06.047","article-title":"Hereditary and acquired angioedema: Problems and progress: Proceedings of the third C1 esterase inhibitor deficiency workshop and beyond","volume":"114","author":"Agostoni","year":"2004","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"580","DOI":"10.7326\/0003-4819-84-5-580","article-title":"Hereditary angioedema: The clinical syndrome and its management","volume":"84","author":"Frank","year":"1976","journal-title":"Ann. Intern. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1016\/j.anai.2022.08.003","article-title":"Isolated angioedema: A review of classification and update on management","volume":"129","author":"Kesh","year":"2022","journal-title":"Ann. Allergy Asthma Immunol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1111\/cei.12910","article-title":"Comparing acquired angioedema with hereditary angioedema (types I\/II): Findings from the Icatibant Outcome Survey","volume":"188","author":"Longhurst","year":"2017","journal-title":"Clin. Exp. Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/j.tmrv.2019.08.002","article-title":"The Role of Complement in Hereditary Angioedema","volume":"33","author":"Levi","year":"2019","journal-title":"Transfus. Med. Rev."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1089\/ped.2014.0425","article-title":"Pathophysiology of hereditary angioedema","volume":"27","author":"Caccia","year":"2014","journal-title":"Pediatr. Allergy Immunol. Pulmonol."},{"key":"ref_33","first-page":"2315","article-title":"Hereditary Angioedema: A Review of the Current and Evolving Treatment Landscape. The journal of allergy and clinical immunology","volume":"11","author":"Betschel","year":"2023","journal-title":"In Practice"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1111\/all.13270","article-title":"Hereditary angioedema with a mutation in the plasminogen gene","volume":"73","author":"Bork","year":"2018","journal-title":"Allergy"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1007\/s12016-021-08832-x","article-title":"Current and Prospective Targets of Pharmacologic Treatment of Hereditary Angioedema Types 1 and 2","volume":"61","author":"Fijen","year":"2021","journal-title":"Clinic. Rev. Allerg. Immunol."},{"key":"ref_36","first-page":"S292","article-title":"Severity of hereditary angioedema, prevalence, and diagnostic considerations","volume":"24","author":"Bernstein","year":"2018","journal-title":"Am. J. Manag. Care"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"701","DOI":"10.2147\/TCRM.S86293","article-title":"Diagnosis and screening of patients with hereditary angioedema in primary care","volume":"12","author":"Henao","year":"2016","journal-title":"Ther. Clin. Risk. Manag."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"213","DOI":"10.2169\/internalmedicine.1559-18","article-title":"Recurrent acute abdomen as the main manifestation of hereditary angioedema","volume":"58","author":"Iwanami","year":"2019","journal-title":"Intern. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1016\/j.jaci.2012.05.055","article-title":"Fatal laryngeal attacks and mortality in hereditary angioedema due to C1-INH deficiency","volume":"130","author":"Bork","year":"2012","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"796","DOI":"10.4103\/idoj.idoj_398_21","article-title":"Hereditary angioedema: Diagnostic algorithm and current treatment concepts","volume":"12","author":"Jindal","year":"2021","journal-title":"Indian Dermatol Online J."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1080\/00325481.2021.1905364","article-title":"The importance of recognizing and managing a rare form of angioedema: Hereditary angioedema due to C1-inhibitor deficiency","volume":"133","author":"Jacobs","year":"2021","journal-title":"Postgrad. Med."},{"key":"ref_42","first-page":"333","article-title":"Consensus statement on the diagnosis, management, and treatment of angioedema mediated by bradykinin. Part I. Classification, epidemiology, pathophysiology, genetics, clinical symptoms, and diagnosis","volume":"21","author":"Caballero","year":"2011","journal-title":"J. Investig. Allergol. Clin. Immunol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1016\/j.iac.2013.07.001","article-title":"Diagnosing angioedema","volume":"33","author":"Cicardi","year":"2013","journal-title":"Immunol. Allergy Clin. N. Am."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"445","DOI":"10.5114\/ada.2020.98226","article-title":"Angioedema. Interdisciplinary diagnostic and therapeutic recommendations of the Polish Dermatological Society (PTD) and Polish Society of Allergology (PTA)","volume":"37","author":"Nowicki","year":"2020","journal-title":"Postepy Dermatol. Alergol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1136\/jcp.2003.12021","article-title":"Normal complement C4 values do not exclude hereditary angioedema","volume":"57","author":"Karim","year":"2004","journal-title":"J. Clin. Pathol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1111\/j.1365-2249.2007.03438.x","article-title":"An evaluation of tests used for the diagnosis and monitoring of C1 inhibitor deficiency: Normal serum C4 does not exclude hereditary angio-oedema","volume":"149","author":"Tarzi","year":"2007","journal-title":"Clin. Exp. Immunol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.jim.2008.06.004","article-title":"Functional C1-inhibitor diagnostics in hereditary angioedema: Assay evaluation and recommendations","volume":"338","author":"Drouet","year":"2008","journal-title":"J. Immunol. Methods"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1016\/j.clinbiochem.2017.04.007","article-title":"Complement factor C4 activation in patients with hereditary angioedema","volume":"50","author":"Aabom","year":"2017","journal-title":"Clin. Biochem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1007\/s12016-021-08854-5","article-title":"Mitigating disparity in health-care resources between countries for management of hereditary angioedema","volume":"61","author":"Jindal","year":"2021","journal-title":"Clin. Rev. Allergy Immunol."},{"key":"ref_50","first-page":"28","article-title":"Diagnosis and management of hereditary angioedema","volume":"111","author":"Johnston","year":"2011","journal-title":"J. Osteopath. Med."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1016\/j.jaip.2019.10.004","article-title":"International consensus on the use of genetics in the management of hereditary angioedema","volume":"8","author":"Germenis","year":"2020","journal-title":"J. Allergy Clin. Immunol. Pract."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"6","DOI":"10.3389\/fmed.2019.00028","article-title":"Genetic Variation of Kallikrein-Kinin System and Related Genes in Patients with Hereditary Angioedema","volume":"6","author":"Veronez","year":"2019","journal-title":"Front. Med."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.clim.2011.01.003","article-title":"Parameters of the classical complement pathway predict disease severity in hereditary angioedema","volume":"139","author":"Csuka","year":"2011","journal-title":"Clin. Immunol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"102312","DOI":"10.1016\/j.jaut.2019.102312","article-title":"Driving towards precision medicine for angioedema without wheals","volume":"104","author":"Germenis","year":"2019","journal-title":"J. Autoimmun."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.1172\/JCI114555","article-title":"Plasma levels of C1\u2212 inhibitor complexes and cleaved C1\u2212 inhibitor in patients with hereditary angioneurotic edema","volume":"85","author":"Cugno","year":"1990","journal-title":"J. Clin. Investig."},{"key":"ref_56","first-page":"38","article-title":"Generation of plasmin during acute attacks of hereditary angioedema","volume":"121","author":"Cugno","year":"1993","journal-title":"J. Lab. Clin. Med."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"768","DOI":"10.1016\/0091-6749(91)90120-D","article-title":"Long-term treatment of hereditary angioedema with attenuated androgens: A survey of a 13-year experience","volume":"87","author":"Cicardi","year":"1991","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/j.jaip.2014.08.002","article-title":"Comparison of chromogenic and ELISA functional C1 inhibitor tests in diagnosing hereditary angioedema","volume":"3","author":"Li","year":"2015","journal-title":"J. Allergy Clin. Immunol. Pract."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1136\/jcp.55.2.145","article-title":"A multicentre evaluation of the diagnostic efficiency of serological investigations for C1 inhibitor deficiency","volume":"55","author":"Gompels","year":"2002","journal-title":"J. Clin. Pathol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1016\/j.clim.2009.11.002","article-title":"Baseline level of functional C1-inhibitor correlates with disease severity scores in hereditary angioedema","volume":"134","author":"Kelemen","year":"2010","journal-title":"Clin. Immunol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1131","DOI":"10.1056\/NEJMoa1613627","article-title":"Prevention of hereditary angioedema attacks with a subcutaneous C1 inhibitor","volume":"376","author":"Longhurst","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1111\/j.1398-9995.2011.02716.x","article-title":"Target levels of functional C1-inhibitor in hereditary angioedema","volume":"67","author":"Hack","year":"2012","journal-title":"Allergy"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"892","DOI":"10.1016\/j.jaip.2019.10.003","article-title":"C1 inhibitor activity and angioedema attacks in patients with hereditary angioedema","volume":"8","author":"Kaplan","year":"2020","journal-title":"J. Allergy Clin. Immunol. Pract."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1186\/s13223-019-0376-8","article-title":"The International\/Canadian Hereditary Angioedema Guideline","volume":"15","author":"Betschel","year":"2019","journal-title":"Allergy Asthma Clin. Immunol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1454","DOI":"10.1016\/j.molimm.2006.04.020","article-title":"C1-inhibitor (C1-INH) autoantibodies in hereditary angioedema. Strong correlation with the severity of disease in C1-INH concentrate na\u00efve patients","volume":"44","author":"Varga","year":"2007","journal-title":"Mol. Immunol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"3596","DOI":"10.4049\/jimmunol.1402838","article-title":"The levels of the lectin pathway serine protease MASP-1 and its complex formation with C1 inhibitor are linked to the severity of hereditary angioedema","volume":"195","author":"Hansen","year":"2015","journal-title":"J. Immunol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1388","DOI":"10.1016\/j.jaci.2014.05.030","article-title":"Activation of the ficolin-lectin pathway during attacks of hereditary angioedema","volume":"134","author":"Csuka","year":"2014","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1693","DOI":"10.1016\/S0140-6736(97)09137-X","article-title":"Plasma bradykinin in angio-oedema","volume":"351","author":"Nussberger","year":"1998","journal-title":"Lancet"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1321","DOI":"10.1016\/S0091-6749(99)70030-8","article-title":"Local bradykinin generation in hereditary angioedema","volume":"104","author":"Nussberger","year":"1999","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1503","DOI":"10.1111\/cea.12293","article-title":"High-molecular-weight kininogen cleavage correlates with disease states in the bradykinin-mediated angioedema due to hereditary C1-inhibitor deficiency","volume":"44","author":"Suffritti","year":"2014","journal-title":"Clin. Exp. Allergy"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1016\/0162-3109(96)00086-0","article-title":"Activation of the factor XII and cleavage of high molecular weight kininogen during acute attacks in hereditary and acquired C1-inhibitor deficiencies","volume":"33","author":"Cugno","year":"1996","journal-title":"Immunopharmacology"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1016\/S1081-1206(10)60493-0","article-title":"Studies of the mechanisms of bradykinin generation in hereditary angioedema plasma","volume":"101","author":"Joseph","year":"2008","journal-title":"Ann. Allergy Asthma Immunol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1186\/s13023-015-0351-5","article-title":"Comprehensive study into the activation of the plasma enzyme systems during attacks of hereditary angioedema due to C1-inhibitor deficiency","volume":"10","author":"Csuka","year":"2015","journal-title":"Orphanet. J. Rare Dis."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1159\/000371814","article-title":"Distinct conditions support a novel classification for bradykinin-mediated angio-oedema","volume":"230","author":"Dessart","year":"2015","journal-title":"Dermatology"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1659","DOI":"10.1111\/all.12515","article-title":"Hereditary angioedema with F12 mutation: Factors modifying the clinical phenotype","volume":"69","author":"Charignon","year":"2014","journal-title":"Allergy"},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Defendi, F., Charignon, D., Ghannam, A., Baroso, R., Csopaki, F., Allegret-Cadet, M., Ponard, D., Favier, B., Cichon, S., and Nicolie, B. (2013). Enzymatic assays for the diagnosis of bradykinin-dependent angioedema. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0070140"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1111\/j.1398-9995.2008.01859.x","article-title":"Plasma biomarkers of acute attacks in patients with angioedema due to C1-inhibitor deficiency","volume":"64","author":"Cugno","year":"2009","journal-title":"Allergy"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1111\/all.12587","article-title":"Elevated D-dimers in attacks of hereditary angioedema are not associated with increased thrombotic risk","volume":"70","author":"Reshef","year":"2015","journal-title":"Allergy"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1016\/j.jaci.2011.02.017","article-title":"Hereditary angioedema: Key role for kallikrein and bradykinin in vascular endothelial-cadherin cleavage and edema formation","volume":"128","author":"Bouillet","year":"2011","journal-title":"J. Allergy Clin Immunol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1686","DOI":"10.1016\/j.jaci.2013.12.1072","article-title":"Endothelial cell activation during edematous attacks of hereditary angioedema types I and II","volume":"133","author":"Jani","year":"2014","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1007\/s10875-011-9606-7","article-title":"Endothelial cell function in patients with hereditary angioedema: Elevated soluble E-selectin level during inter-attack periods","volume":"32","author":"Schaffer","year":"2012","journal-title":"J. Clin. Immunol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1007\/s10875-016-0239-8","article-title":"Novel vasoregulatory aspects of hereditary angioedema: The role of arginine vasopressin, adrenomedullin and endothelin-1","volume":"36","author":"Jani","year":"2016","journal-title":"J. Clin. Immunol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.clim.2016.03.007","article-title":"Atrial natriuretic peptide as a novel biomarker of hereditary angioedema","volume":"165","author":"Varga","year":"2016","journal-title":"Clin. Immunol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1159\/000481256","article-title":"Endocan: A novel marker of endothelial dysfunction in C1-inhibitor-deficient hereditary angioedema","volume":"174","author":"Demirturk","year":"2017","journal-title":"Int. Arch. Allergy Immunol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"989","DOI":"10.1111\/all.12862","article-title":"Elevated plasma levels of vascular permeability factors in C1 inhibitor-deficient hereditary angioedema","volume":"71","author":"Loffredo","year":"2016","journal-title":"Allergy"},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Loffredo, S., Ferrara, A.L., Bova, M., Borriello, F., Suffritti, C., Veszeli, N., Petraroli, A., Galdiero, M.R., Varricchi, G., and Granata, F. (2018). Secreted phospholipases A2 in hereditary angioedema with C1-inhibitor deficiency. Front. Immunol., 9.","DOI":"10.3389\/fimmu.2018.01721"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1394","DOI":"10.1111\/all.14160","article-title":"Impaired control of the contact system in hereditary angioedema with normal C1-inhibitor","volume":"75","author":"Bova","year":"2020","journal-title":"Allergy"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"106079","DOI":"10.1016\/j.intimp.2019.106079","article-title":"Hereditary angioedema attack: What happens to vasoactive mediators?","volume":"78","author":"Ferrara","year":"2020","journal-title":"Int. Immunopharmacol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1186\/s13023-019-0995-7","article-title":"Serum fetuin-A, tumor necrosis factor alpha and C-reactive protein concentrations in patients with hereditary angioedema with C1-inhibitor deficiency","volume":"14","author":"Veszeli","year":"2019","journal-title":"Orphanet. J. Rare Dis."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1186\/s13023-015-0374-y","article-title":"Neutrophil activation during attacks in patients with hereditary angioedema due to C1-inhibitor deficiency","volume":"10","author":"Veszeli","year":"2015","journal-title":"Orphanet. J. Rare Dis."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"e91","DOI":"10.1515\/cclm-2013-1008","article-title":"Upregulation of cytokines and IL-17 in patients with hereditary angioedema","volume":"52","author":"Arcoleo","year":"2014","journal-title":"Clin. Chem. Lab Med."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1007\/s10238-015-0340-y","article-title":"Growth factors and IL-17 in hereditary angioedema","volume":"16","author":"Salemi","year":"2016","journal-title":"Clin. Exp. Med."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1111\/cei.12314","article-title":"C-reactive protein levels in hereditary angioedema","volume":"177","author":"Hofman","year":"2014","journal-title":"Clin. Exp. Immunol."},{"key":"ref_94","unstructured":"Food and Drug Administration, HHS (2008). International Conference on Harmonisation; Guidance on E15 Pharmacogenomics Definitions and Sample Coding; Availability. Notice. Fed. Regist., 73, 19074\u201319076."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1016\/j.intimp.2014.03.007","article-title":"Increased eNOS levels in hereditary angioedema","volume":"20","author":"Gelincik","year":"2014","journal-title":"Int. Immunopharmacol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1007\/s12016-016-8543-x","article-title":"Genetics of hereditary angioedema revisited","volume":"51","author":"Germenis","year":"2016","journal-title":"Clin. Rev. Allergy Immunol."},{"key":"ref_97","first-page":"CD013403","article-title":"Interventions for the long-term prevention of hereditary angioedema attacks","volume":"11","author":"Beard","year":"2022","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1159\/000467830","article-title":"Quantification of C1-inhibitor functional activities by immunodiffusion assay in plasma of patients with hereditary angioedema\u2014evidence of a functionally critical level of C1- inhibitor concentration","volume":"1","author":"Spath","year":"1984","journal-title":"Complement"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1098","DOI":"10.1086\/509899","article-title":"Increased activity of coagulation factor XII (Hageman Factor) causes hereditary angioedema type III","volume":"79","author":"Cichon","year":"2006","journal-title":"Am. J. Hum. Genet."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1097\/MBC.0b013e32832811f8","article-title":"Kallikrein-kinin system and fibrinolysis in hereditary angioedema due to factor XII gene mutation Thr309Lys","volume":"20","author":"Bork","year":"2009","journal-title":"Blood Coagul. Fibrinolysis"},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Konings, J., Cugno, M., Suffritti, C., Ten Cate, H., Cicardi, M., and Govers-Riemslag, J.W. (2013). Ongoing contact activation in patients with hereditary angioedema. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0074043"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1719","DOI":"10.1016\/j.jaci.2016.12.982","article-title":"Normal PAI-2 level in French FXII-HAE patients","volume":"139","author":"Marlu","year":"2017","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1159\/000455803","article-title":"Potential biomarkers for the diagnosis of angiotensin-converting enzyme inhibitor-induced angioedema","volume":"79","author":"Bas","year":"2017","journal-title":"ORL J. Otorhinolaryngol. Relat. Spec."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"1","DOI":"10.18176\/jiaci.0653","article-title":"Treatment of Hereditary Angioedema","volume":"31","author":"Caballero","year":"2021","journal-title":"J. Investig. Allergol. Clin. Immunol."},{"key":"ref_105","first-page":"143","article-title":"The Effectiveness and Value of Lanadelumab and C1 Esterase Inhibitors for Prophylaxis of Hereditary Angioedema Attacks","volume":"25","author":"Agboola","year":"2019","journal-title":"J. Manag. Care Spec. Pharm."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1186\/s13023-018-0922-3","article-title":"Treatment patterns and healthcare resource utilization among patients with hereditary angioedema in the United States","volume":"13","author":"Riedl","year":"2018","journal-title":"Orphanet. J. Rare Dis."},{"key":"ref_107","first-page":"S308","article-title":"Economic burden limiting proper healthcare delivery, management, and improvement of patient outcomes","volume":"24","author":"Cardarelli","year":"2018","journal-title":"Am. J. Manag. Care"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1002\/nop2.194","article-title":"Training patients for self-administration of a new subcutaneous C1-inhibitor concentrate for hereditary angioedema","volume":"6","author":"Murphy","year":"2019","journal-title":"Nurs. Open"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/j.jaip.2020.08.046","article-title":"US HAEA medical advisory board 2020 guidelines for the management of hereditary angioedema","volume":"9","author":"Busse","year":"2021","journal-title":"J. Allergy Clin. Immunol. Pract."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"100049","DOI":"10.1016\/j.waojou.2019.100049","article-title":"Fresh frozen plasma for on-demand hereditary angioedema treatment in South Africa and Iran","volume":"12","author":"Wentzel","year":"2019","journal-title":"World Allergy Organ. J."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1111\/j.1365-2249.2005.02726.x","article-title":"C1 inhibitor deficiency: Consensus document","volume":"139","author":"Gompels","year":"2005","journal-title":"Clin. Exp. Immunol."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"902","DOI":"10.1002\/j.1875-9114.2012.01126","article-title":"Thrombotic events associated with C1 esterase inhibitor products in patients with hereditary angioedema: Investigation from the United States Food and Drug Administration adverse event reporting system database","volume":"32","author":"Gandhi","year":"2012","journal-title":"Pharmacother. J. Hum. Pharmacol. Drug Ther."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"73","DOI":"10.2165\/11204500-000000000-00000","article-title":"Icatibant","volume":"70","author":"Deeks","year":"2010","journal-title":"Drugs"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1016\/j.jaip.2014.09.001","article-title":"Characterization of anaphylaxis after ecallantide treatment of hereditary angioedema attacks","volume":"3","author":"Craig","year":"2015","journal-title":"J. Allergy Clin. Immunol. Pract."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.anai.2016.10.006","article-title":"Short-term prophylactic use of C1-inhibitor concentrate in hereditary angioedema: Findings from an international patient registry","volume":"118","author":"Magerl","year":"2017","journal-title":"Ann. Allergy Asthma Immunol."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1002\/cia2.12029","article-title":"The use of tranexamic acid for on-demand and prophylactic treatment of hereditary angioedema: A systematic review","volume":"1","author":"Horiuchi","year":"2018","journal-title":"J. Cutan Immunol. Allergy"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"292.e5","DOI":"10.1016\/j.ajem.2020.10.029","article-title":"Tranexamic acid for ACE inhibitor induced angioedema","volume":"43","author":"Wang","year":"2021","journal-title":"Am. J. Emerg. Med."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1016\/j.jaip.2014.12.013","article-title":"Recombinant human-C1 inhibitor is effective and safe for repeat hereditary angioedema attacks","volume":"3","author":"Li","year":"2015","journal-title":"J. Allergy Clin. Immunol. Pract."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1159\/000477541","article-title":"Preventing hereditary angioedema attacks in children using Cinryze\u00ae: Interim efficacy and safety phase 3 findings","volume":"173","author":"Soteres","year":"2017","journal-title":"Int. Arch. Allergy Immunol."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"1733","DOI":"10.1016\/j.jaip.2017.12.039","article-title":"Health-related quality of life with subcutaneous C1-inhibitor for prevention of attacks of hereditary angioedema","volume":"6","author":"Lumry","year":"2018","journal-title":"J. Allergy Clin. Immunol. Pract."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1016\/j.jaci.2011.11.025","article-title":"International consensus and practical guidelines on the gynecologic and obstetric management of female patients with hereditary angioedema caused by C1 inhibitor deficiency","volume":"129","author":"Caballero","year":"2012","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"2108","DOI":"10.1001\/jama.2018.16773","article-title":"Effect of lanadelumab compared with placebo on prevention of hereditary angioedema attacks: A randomized clinical trial","volume":"320","author":"Banerji","year":"2018","journal-title":"JAMA"},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"1439","DOI":"10.2217\/imt-2019-0128","article-title":"Oral plasma kallikrein inhibitor BCX7353 for treatment of hereditary angioedema","volume":"11","author":"Hwang","year":"2019","journal-title":"Immunotherapy"},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"948","DOI":"10.1016\/j.jaip.2016.03.024","article-title":"Tolerability and effectiveness of 17-\u03b1-alkylated androgen therapy for hereditary angioedema: A re-examination","volume":"4","author":"Zuraw","year":"2016","journal-title":"J. Allergy Clin. Immunol. Pract."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1111\/cei.12379","article-title":"Tranexamic acid as maintenance treatment for non-histaminergic angioedema: Analysis of efficacy and safety in 37 patients","volume":"178","author":"Wintenberger","year":"2014","journal-title":"Clin. Exp. Immunol."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1007\/s12016-018-8684-1","article-title":"Update on the Use of C1-Esterase Inhibitor Replacement Therapy in the Acute and Prophylactic Treatment of Hereditary Angioedema","volume":"56","author":"Riedl","year":"2019","journal-title":"Clin. Rev. Allergy Immunol."},{"key":"ref_127","first-page":"266","article-title":"Prophylaxis in hereditary angioedema (HAE) with C1 inhibitor deficiency","volume":"14","author":"Greve","year":"2016","journal-title":"J. Dtsch. Dermatol. 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