Download PDF
CC BY 4.0 · Semin Thromb Hemost
DOI: 10.1055/s-0042-1758820
Review Article

Hereditary Angioedema: The Clinical Picture of Excessive Contact Activation

Remy S. Petersen
1   Department of Vascular Medicine, University of Amsterdam, Amsterdam Cardiovascular Sciences, Amsterdam UMC, Amsterdam, the Netherlands
,
Lauré M. Fijen
1   Department of Vascular Medicine, University of Amsterdam, Amsterdam Cardiovascular Sciences, Amsterdam UMC, Amsterdam, the Netherlands
,
Marcel Levi
1   Department of Vascular Medicine, University of Amsterdam, Amsterdam Cardiovascular Sciences, Amsterdam UMC, Amsterdam, the Netherlands
,
Danny M. Cohn
1   Department of Vascular Medicine, University of Amsterdam, Amsterdam Cardiovascular Sciences, Amsterdam UMC, Amsterdam, the Netherlands
› Author Affiliations
› Further Information
   Permissions and Reprints

Abstract

Hereditary angioedema is a rare, genetic disorder characterized by painful, debilitating and potentially life-threatening angioedema attacks in subcutaneous and submucosal tissue. While usually unpredictable, attacks can be provoked by a variety of triggers including physical injury and certain medication and are often preceded by prodromal symptoms. Hereditary angioedema has a profound influence on the patients' lives. The fundamental cause of hereditary angioedema in almost all patients is a mutation in the SERPING1 gene leading to a deficiency in C1-inhibitor. Subsequently, the contact activation cascade and kallikrein-kinin pathway are insufficiently inhibited, resulting in excessive bradykinin production triggering vascular leakage. While C1-inhibitor is an important regulator of the intrinsic coagulation pathway, fibrinolytic system and complement cascade, patients do not have an increased risk of coagulopathy, autoimmune conditions or immunodeficiency disorders. Hereditary angioedema is diagnosed based on C1-inhibitor level and function. Genetic analysis is only required in rare cases where hereditary angioedema with normal C1-inhibitor is found. In recent years, new, highly specific therapies have greatly improved disease control and angioedema-related quality of life. This article reviews the clinical picture of hereditary angioedema, the underlying pathophysiology, diagnostic process and currently available as well as investigational therapeutic options.

Keywords

hereditary angioedema - bradykinin - C1-inhibitor - contact activation - therapy


Publication History

Article published online:
23 November 2022

© 2022. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 

  • References

  • 1 Aygören-Pürsün E, Magerl M, Maetzel A, Maurer M. Epidemiology of Bradykinin-mediated angioedema: a systematic investigation of epidemiological studies. Orphanet J Rare Dis 2018; 13 (01) 73
    CrossrefPubMedGoogle Scholar
  • 2 Bork K, Meng G, Staubach P, Hardt J. Hereditary angioedema: new findings concerning symptoms, affected organs, and course. Am J Med 2006; 119 (03) 267-274
    CrossrefPubMedGoogle Scholar
  • 3 Christiansen SC, Davis DK, Castaldo AJ, Zuraw BL. Pediatric hereditary angioedema: onset, diagnostic delay, and disease severity. Clin Pediatr (Phila) 2016; 55 (10) 935-942
    CrossrefPubMedGoogle Scholar
  • 4 Hofman ZL, Relan A, Hack CE. Hereditary angioedema attacks: local swelling at multiple sites. Clin Rev Allergy Immunol 2016; 50 (01) 34-40
    CrossrefPubMedGoogle Scholar
  • 5 Hahn J, Hoess A, Friedrich DT. et al. Unnecessary abdominal interventions in patients with hereditary angioedema. J Dtsch Dermatol Ges 2018; 16 (12) 1443-1449
    CrossrefPubMedGoogle Scholar
  • 6 Landerman NS. Hereditary angioneurotic edema. I. Case reports and review of the literature. J Allergy 1962; 33: 316-329
    CrossrefPubMedGoogle Scholar
  • 7 Minafra FG, Gonçalves TR, Alves TM, Pinto JA. The mortality from hereditary angioedema worldwide: a review of the real-world data literature. Clin Rev Allergy Immunol 2022; 62 (01) 232-239
    CrossrefPubMedGoogle Scholar
  • 8 Maurer M, Magerl M, Betschel S. et al. The international WAO/EAACI guideline for the management of hereditary angioedema-The 2021 revision and update. Allergy 2022; 77 (07) 1961-1990
    CrossrefPubMedGoogle Scholar
  • 9 Caballero T, Farkas H, Bouillet L. et al; C-1-INH Deficiency Working Group. International consensus and practical guidelines on the gynecologic and obstetric management of female patients with hereditary angioedema caused by C1 inhibitor deficiency. J Allergy Clin Immunol 2012; 129 (02) 308-320
    CrossrefPubMedGoogle Scholar
  • 10 Zotter Z, Csuka D, Szabó E. et al. The influence of trigger factors on hereditary angioedema due to C1-inhibitor deficiency. Orphanet J Rare Dis 2014; 9: 44
    CrossrefPubMedGoogle Scholar
  • 11 Caballero T, Maurer M, Longhurst HJ, Aberer W, Bouillet L, Fabien V. IOS Study Group. Triggers and prodromal symptoms of angioedema attacks in patients with hereditary angioedema. J Investig Allergol Clin Immunol 2016; 26 (06) 383-386
    CrossrefPubMedGoogle Scholar
  • 12 Magerl M, Doumoulakis G, Kalkounou I. et al. Characterization of prodromal symptoms in a large population of patients with hereditary angio-oedema. Clin Exp Dermatol 2014; 39 (03) 298-303
    CrossrefPubMedGoogle Scholar
  • 13 Reshef A, Prematta MJ, Craig TJ. Signs and symptoms preceding acute attacks of hereditary angioedema: results of three recent surveys. Allergy Asthma Proc 2013; 34 (03) 261-266
    CrossrefPubMedGoogle Scholar
  • 14 Leibovich-Nassi I, Reshef A, Somech R, Golander H. Prodromes as predictors of hereditary angioedema attacks. Allergy 2022; 77 (04) 1309-1312
    CrossrefPubMedGoogle Scholar
  • 15 Fouche AS, Saunders EF, Craig T. Depression and anxiety in patients with hereditary angioedema. Ann Allergy Asthma Immunol 2014; 112 (04) 371-375
    CrossrefPubMedGoogle Scholar
  • 16 Caballero T, Aygören-Pürsün E, Bygum A. et al. The humanistic burden of hereditary angioedema: results from the Burden of Illness Study in Europe. Allergy Asthma Proc 2014; 35 (01) 47-53
    CrossrefPubMedGoogle Scholar
  • 17 Banerji A, Davis KH, Brown TM. et al. Patient-reported burden of hereditary angioedema: findings from a patient survey in the United States. Ann Allergy Asthma Immunol 2020; 124 (06) 600-607
    CrossrefPubMedGoogle Scholar
  • 18 Savarese L, Mormile I, Bova M. et al. Psychology and hereditary angioedema: a systematic review. Allergy Asthma Proc 2021; 42 (01) e1-e7
    CrossrefPubMedGoogle Scholar
  • 19 Fijen LM, Petersen RS, Levi M, Lakeman P, Henneman L, Cohn DM. Patient perspectives on reproductive options for hereditary angioedema: a cross-sectional survey study. J Allergy Clin Immunol Pract 2022; 10 (09) 2483-2486.e1
    CrossrefPubMedGoogle Scholar
  • 20 Levi M, Cohn DM. The role of complement in hereditary angioedema. Transfus Med Rev 2019; 33 (04) 243-247
    CrossrefPubMedGoogle Scholar
  • 21 Zeerleder S, Levi M. Hereditary and acquired C1-inhibitor-dependent angioedema: from pathophysiology to treatment. Ann Med 2016; 48 (04) 256-267
    CrossrefPubMedGoogle Scholar
  • 22 Busse PJ, Christiansen SC. Hereditary angioedema. N Engl J Med 2020; 382 (12) 1136-1148
    CrossrefPubMedGoogle Scholar
  • 23 Bossi F, Fischetti F, Regoli D. et al. Novel pathogenic mechanism and therapeutic approaches to angioedema associated with C1 inhibitor deficiency. J Allergy Clin Immunol 2009; 124 (06) 1303-10.e4
    CrossrefPubMedGoogle Scholar
  • 24 Kaplan AP, Joseph K. Pathogenic mechanisms of bradykinin mediated diseases: dysregulation of an innate inflammatory pathway. Adv Immunol 2014; 121: 41-89
    CrossrefPubMedGoogle Scholar
  • 25 Wuillemin WA, Minnema M, Meijers JC. et al. Inactivation of factor XIa in human plasma assessed by measuring factor XIa-protease inhibitor complexes: major role for C1-inhibitor. Blood 1995; 85 (06) 1517-1526
    CrossrefPubMedGoogle Scholar
  • 26 Levi M, Roem D, Kamp AM, de Boer JP, Hack CE, ten Cate JW. Assessment of the relative contribution of different protease inhibitors to the inhibition of plasmin in vivo. Thromb Haemost 1993; 69 (02) 141-146
    Article in Thieme ConnectPubMedGoogle Scholar
  • 27 van Geffen M, Cugno M, Lap P, Loof A, Cicardi M, van Heerde W. Alterations of coagulation and fibrinolysis in patients with angioedema due to C1-inhibitor deficiency. Clin Exp Immunol 2012; 167 (03) 472-478
    CrossrefPubMedGoogle Scholar
  • 28 Joseph K, Tholanikunnel TE, Kaplan AP. Treatment of episodes of hereditary angioedema with C1 inhibitor: serial assessment of observed abnormalities of the plasma bradykinin-forming pathway and fibrinolysis. Ann Allergy Asthma Immunol 2010; 104 (01) 50-54
    CrossrefPubMedGoogle Scholar
  • 29 Relan A, Bakhtiari K, van Amersfoort ES, Meijers JC, Hack CE. Recombinant C1-inhibitor: effects on coagulation and fibrinolysis in patients with hereditary angioedema. BioDrugs 2012; 26 (01) 43-52
    CrossrefPubMedGoogle Scholar
  • 30 Reshef A, Zanichelli A, Longhurst H, Relan A, Hack CE. Elevated D-dimers in attacks of hereditary angioedema are not associated with increased thrombotic risk. Allergy 2015; 70 (05) 506-513
    CrossrefPubMedGoogle Scholar
  • 31 de Maat S, Joseph K, Maas C, Kaplan AP. Blood clotting and the pathogenesis of types I and II hereditary angioedema. Clin Rev Allergy Immunol 2021; 60 (03) 348-356
    CrossrefPubMedGoogle Scholar
  • 32 Matsushita M, Thiel S, Jensenius JC, Terai I, Fujita T. Proteolytic activities of two types of mannose-binding lectin-associated serine protease. J Immunol 2000; 165 (05) 2637-2642
    CrossrefPubMedGoogle Scholar
  • 33 Davis III AE, Mejia P, Lu F. Biological activities of C1 inhibitor. Mol Immunol 2008; 45 (16) 4057-4063
    CrossrefPubMedGoogle Scholar
  • 34 Triggianese P, Chimenti MS, Toubi E. et al. The autoimmune side of hereditary angioedema: insights on the pathogenesis. Autoimmun Rev 2015; 14 (08) 665-669
    CrossrefPubMedGoogle Scholar
  • 35 Gösswein T, Kocot A, Emmert G. et al. Mutational spectrum of the C1INH (SERPING1) gene in patients with hereditary angioedema. Cytogenet Genome Res 2008; 121 (3-4): 181-188
    CrossrefPubMedGoogle Scholar
  • 36 Ponard D, Gaboriaud C, Charignon D. et al. SERPING1 mutation update: mutation spectrum and C1 Inhibitor phenotypes. Hum Mutat 2020; 41 (01) 38-57 DOI: 10.1002/humu.23917.
    CrossrefPubMedGoogle Scholar
  • 37 Yasuno S, Ansai O, Hayashi R, Nakamura S, Shimomura Y. Evidence for a dominant-negative effect of a missense mutation in the SERPING1 gene responsible for hereditary angioedema type I. J Dermatol 2021; 48 (08) 1243-1249
    CrossrefPubMedGoogle Scholar
  • 38 Haslund D, Ryø LB, Seidelin Majidi S. et al. Dominant-negative SERPING1 variants cause intracellular retention of C1 inhibitor in hereditary angioedema. J Clin Invest 2019; 129 (01) 388-405
    CrossrefPubMedGoogle Scholar
  • 39 Mete Gökmen N, Rodríguez-Alcalde C, Gülbahar O, Lopez-Trascasa M, Onay H, López-Lera A. Novel homozygous variants in the SERPING1 gene in two Turkish families with hereditary angioedema of recessive inheritance. Immunol Cell Biol 2020; 98 (08) 693-699
    CrossrefPubMedGoogle Scholar
  • 40 Blanch A, Roche O, Urrutia I, Gamboa P, Fontán G, López-Trascasa M. First case of homozygous C1 inhibitor deficiency. J Allergy Clin Immunol 2006; 118 (06) 1330-1335
    CrossrefPubMedGoogle Scholar
  • 41 López-Lera A, Favier B, de la Cruz RM, Garrido S, Drouet C, López-Trascasa M. A new case of homozygous C1-inhibitor deficiency suggests a role for Arg378 in the control of kinin pathway activation. J Allergy Clin Immunol 2010; 126 (06) 1307-10.e3
    CrossrefPubMedGoogle Scholar
  • 42 Bafunno V, Divella C, Sessa F. et al. De novo homozygous mutation of the C1 inhibitor gene in a patient with hereditary angioedema. J Allergy Clin Immunol 2013; 132 (03) 748-750.e3
    CrossrefPubMedGoogle Scholar
  • 43 Bork K, Machnig T, Wulff K, Witzke G, Prusty S, Hardt J. Clinical features of genetically characterized types of hereditary angioedema with normal C1 inhibitor: a systematic review of qualitative evidence. Orphanet J Rare Dis 2020; 15 (01) 289
    CrossrefPubMedGoogle Scholar
  • 44 Kulkarni M, Travers JB, Rohan C. High estrogen states in hereditary angioedema: a spectrum. Clin Rev Allergy Immunol 2021; 60 (03) 396-403
    CrossrefPubMedGoogle Scholar
  • 45 Gompel A, Fain O, Boccon-Gibod I, Gobert D, Bouillet L. Exogenous hormones and hereditary angioedema. Int Immunopharmacol 2020; 78: 106080
    CrossrefPubMedGoogle Scholar
  • 46 Bork K, Wulff K, Hardt J, Witzke G, Staubach P. Hereditary angioedema caused by missense mutations in the factor XII gene: clinical features, trigger factors, and therapy. J Allergy Clin Immunol 2009; 124 (01) 129-134
    CrossrefPubMedGoogle Scholar
  • 47 Tarzi MD, Hickey A, Förster T, Mohammadi M, Longhurst HJ. An evaluation of tests used for the diagnosis and monitoring of C1 inhibitor deficiency: normal serum C4 does not exclude hereditary angio-oedema. Clin Exp Immunol 2007; 149 (03) 513-516
    CrossrefPubMedGoogle Scholar
  • 48 Bindke G, Gehring M, Wieczorek D, Kapp A, Buhl T, Wedi B. Identification of novel biomarkers to distinguish bradykinin-mediated angioedema from mast cell-/histamine-mediated angioedema. Allergy 2022; 77 (03) 946-955
    CrossrefPubMedGoogle Scholar
  • 49 Porebski G, Kwitniewski M, Reshef A. Biomarkers in hereditary angioedema. Clin Rev Allergy Immunol 2021; 60 (03) 404-415
    CrossrefPubMedGoogle Scholar
  • 50 Malbran A, Hammer CH, Frank MM, Fries LF. Acquired angioedema: observations on the mechanism of action of autoantibodies directed against C1 esterase inhibitor. J Allergy Clin Immunol 1988; 81 (06) 1199-1204
    CrossrefPubMedGoogle Scholar
  • 51 Melamed J, Alper CA, Cicardi M, Rosen FS. The metabolism of C1 inhibitor and C1q in patients with acquired C1-inhibitor deficiency. J Allergy Clin Immunol 1986; 77 (02) 322-326
    CrossrefPubMedGoogle Scholar
  • 52 Gobert D, Paule R, Ponard D. et al. A nationwide study of acquired C1-inhibitor deficiency in France: Characteristics and treatment responses in 92 patients. Medicine (Baltimore) 2016; 95 (33) e4363
    CrossrefPubMedGoogle Scholar
  • 53 Pólai Z, Balla Z, Andrási N. et al. A follow-up survey of patients with acquired angioedema due to C1-inhibitor deficiency. J Intern Med 2021; 289 (04) 547-558
    CrossrefPubMedGoogle Scholar
  • 54 Levi M, Cohn D, Zeerleder S, Dziadzio M, Longhurst H. Long-term effects upon rituximab treatment of acquired angioedema due to C1-inhibitor deficiency. Allergy 2019; 74 (04) 834-840
    CrossrefPubMedGoogle Scholar
  • 55 Pappalardo E, Cicardi M, Duponchel C. et al. Frequent de novo mutations and exon deletions in the C1inhibitor gene of patients with angioedema. J Allergy Clin Immunol 2000; 106 (06) 1147-1154
    CrossrefPubMedGoogle Scholar
  • 56 Farkas H, Martinez-Saguer I, Bork K. et al; HAWK. International consensus on the diagnosis and management of pediatric patients with hereditary angioedema with C1 inhibitor deficiency. Allergy 2017; 72 (02) 300-313
    CrossrefPubMedGoogle Scholar
  • 57 Nielsen EW, Johansen HT, Holt J, Mollnes TE. C1 inhibitor and diagnosis of hereditary angioedema in newborns. Pediatr Res 1994; 35 (02) 184-187
    CrossrefPubMedGoogle Scholar
  • 58 Agostoni A, Aygören-Pürsün E, Binkley KE. et al. Hereditary and acquired angioedema: problems and progress: proceedings of the third C1 esterase inhibitor deficiency workshop and beyond. J Allergy Clin Immunol 2004; 114 (suppl 3): S51-S131
    CrossrefPubMedGoogle Scholar
  • 59 Maurer M, Aygören-Pürsün E, Banerji A. et al. Consensus on treatment goals in hereditary angioedema: a global Delphi initiative. J Allergy Clin Immunol 2021; 148 (06) 1526-1532
    CrossrefPubMedGoogle Scholar
  • 60 Maurer M, Aberer W, Bouillet L. et al; IOS Investigators. Hereditary angioedema attacks resolve faster and are shorter after early icatibant treatment. PLoS One 2013; 8 (02) e53773
    CrossrefPubMedGoogle Scholar
  • 61 Banta E, Horn P, Craig TJ. Response to ecallantide treatment of acute attacks of hereditary angioedema based on time to intervention: results from the EDEMA clinical trials. Allergy Asthma Proc 2011; 32 (04) 319-324
    CrossrefPubMedGoogle Scholar
  • 62 Craig TJ, Rojavin MA, Machnig T, Keinecke HO, Bernstein JA. Effect of time to treatment on response to C1 esterase inhibitor concentrate for hereditary angioedema attacks. Ann Allergy Asthma Immunol 2013; 111 (03) 211-215
    CrossrefPubMedGoogle Scholar
  • 63 Gadek JE, Hosea SW, Gelfand JA. et al. Replacement therapy in hereditary angioedema: successful treatment of acute episodes of angioedema with partly purified C1 inhibitor. N Engl J Med 1980; 302 (10) 542-546
    CrossrefPubMedGoogle Scholar
  • 64 Levi M, Choi G, Picavet C, Hack CE. Self-administration of C1-inhibitor concentrate in patients with hereditary or acquired angioedema caused by C1-inhibitor deficiency. J Allergy Clin Immunol 2006; 117 (04) 904-908
    CrossrefPubMedGoogle Scholar
  • 65 Riedl MA, Bygum A, Lumry W. et al; Berinert Registry investigators. Safety and usage of C1-inhibitor in hereditary angioedema: Berinert Registry Data. J Allergy Clin Immunol Pract 2016; 4 (05) 963-971
    CrossrefPubMedGoogle Scholar
  • 66 Burnham K, Reinert JP. Thromboembolic risk of C1 esterase inhibitors: a systematic review on current evidence. Expert Rev Clin Pharmacol 2020; 13 (07) 779-786
    CrossrefPubMedGoogle Scholar
  • 67 Craig TJ, Bewtra AK, Bahna SL. et al. C1 esterase inhibitor concentrate in 1085 hereditary angioedema attacks–final results of the I.M.P.A.C.T.2 study. Allergy 2011; 66 (12) 1604-1611
    PubMedGoogle Scholar
  • 68 Lumry WR, Li HH, Levy RJ. et al. Randomized placebo-controlled trial of the bradykinin B2 receptor antagonist icatibant for the treatment of acute attacks of hereditary angioedema: the FAST-3 trial. Ann Allergy Asthma Immunol 2011; 107 (06) 529-537
    CrossrefPubMedGoogle Scholar
  • 69 Levy RJ, Lumry WR, McNeil DL. et al. EDEMA4: a phase 3, double-blind study of subcutaneous ecallantide treatment for acute attacks of hereditary angioedema. Ann Allergy Asthma Immunol 2010; 104 (06) 523-529
    CrossrefPubMedGoogle Scholar
  • 70 Craig TJ, Li HH, Riedl M. et al. Characterization of anaphylaxis after ecallantide treatment of hereditary angioedema attacks. J Allergy Clin Immunol Pract 2015; 3 (02) 206-212.e4
    CrossrefPubMedGoogle Scholar
  • 71 Jaffe CJ, Atkinson JP, Gelfand JA, Frank MM. Hereditary angioedema: the use of fresh frozen plasma for prophylaxis in patients undergoing oral surgery. J Allergy Clin Immunol 1975; 55 (06) 386-393
    CrossrefPubMedGoogle Scholar
  • 72 Pickering RJ, Good RA, Kelly JR, Gewurz H. Replacement therapy in hereditary angioedema. Successful treatment of two patients with fresh frozen plasma. Lancet 1969; 1 (7590): 326-330
    PubMedGoogle Scholar
  • 73 Wentzel N, Panieri A, Ayazi M. et al. Fresh frozen plasma for on-demand hereditary angioedema treatment in South Africa and Iran. World Allergy Organ J 2019; 12 (09) 100049
    CrossrefPubMedGoogle Scholar
  • 74 Craig T, Zuraw B, Longhurst H. et al; COMPACT Investigators. Long-term outcomes with subcutaneous c1-inhibitor replacement therapy for prevention of hereditary angioedema attacks. J Allergy Clin Immunol Pract 2019; 7 (06) 1793-1802.e2
    CrossrefPubMedGoogle Scholar
  • 75 Lumry WR, Craig T, Zuraw B. et al. Health-related quality of life with subcutaneous C1-inhibitor for prevention of attacks of hereditary angioedema. J Allergy Clin Immunol Pract 2018; 6 (05) 1733-1741.e3
    CrossrefPubMedGoogle Scholar
  • 76 Banerji A, Riedl MA, Bernstein JA. et al; HELP Investigators. Effect of Lanadelumab compared with placebo on prevention of hereditary angioedema attacks: a randomized clinical trial. JAMA 2018; 320 (20) 2108-2121
    CrossrefPubMedGoogle Scholar
  • 77 Zuraw B, Lumry WR, Johnston DT. et al. Oral once-daily berotralstat for the prevention of hereditary angioedema attacks: a randomized, double-blind, placebo-controlled phase 3 trial. J Allergy Clin Immunol 2021; 148 (01) 164-172.e9
    CrossrefPubMedGoogle Scholar
  • 78 Gelfand JA, Sherins RJ, Alling DW, Frank MM. Treatment of hereditary angioedema with danazol. Reversal of clinical and biochemical abnormalities. N Engl J Med 1976; 295 (26) 1444-1448
    CrossrefPubMedGoogle Scholar
  • 79 Pappalardo E, Zingale LC, Cicardi M. Increased expression of C1-inhibitor mRNA in patients with hereditary angioedema treated with Danazol. Immunol Lett 2003; 86 (03) 271-276
    CrossrefPubMedGoogle Scholar
  • 80 Drouet C, Désormeaux A, Robillard J. et al. Metallopeptidase activities in hereditary angioedema: effect of androgen prophylaxis on plasma aminopeptidase P. J Allergy Clin Immunol 2008; 121 (02) 429-433
    CrossrefPubMedGoogle Scholar
  • 81 Bork K, Bygum A, Hardt J. Benefits and risks of danazol in hereditary angioedema: a long-term survey of 118 patients. Ann Allergy Asthma Immunol 2008; 100 (02) 153-161
    CrossrefPubMedGoogle Scholar
  • 82 Craig T, Magerl M, Levy DS. et al. Prophylactic use of an anti-activated factor XII monoclonal antibody, garadacimab, for patients with C1-esterase inhibitor-deficient hereditary angioedema: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet 2022; 399 (10328): 945-955
    CrossrefPubMedGoogle Scholar
  • 83 KalVista. Factor XIIa. 2022 . Accessed June 24, 2022, at: https://www.kalvista.com/products-pipeline/factor-xiia
    PubMedGoogle Scholar
  • 84 Clermont A. Identification of novel potent oral Factor XIIa inhibitors that block kallikrein kinin system activation in a preclinical model of angioedema. Conference session presented at: EAACI Hybrid Congress; 1–3 July 2022 2022; Prague
    PubMedGoogle Scholar
  • 85 Fijen LM, Riedl MA, Bordone L. et al. Inhibition of Prekallikrein for hereditary angioedema. N Engl J Med 2022; 386 (11) 1026-1033
    CrossrefPubMedGoogle Scholar
  • 86 OASIS-HAE. A Study to Evaluate the Safety and Efficacy of Donidalorsen (ISIS 721744 or IONIS-PKK-LRx) in Participants with Hereditary Angioedema (HAE),. at: https://ClinicalTrials.gov/show/NCT05139810
    PubMedGoogle Scholar
  • 87 Fijen LM, Petersen RS, Meijers JCM, Bordone L, Levi M, Cohn DM. The influence of plasma prekallikrein oligonucleotide antisense therapy on coagulation and fibrinolysis assays: a post-hoc analysis. Thromb Haemost 17 Aug 2022 (e-pub ahead of print). DOI: 10.1055/a-1926-2367.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 88 Maetzel A, Smith MD, Duckworth EJ. et al. KVD900, an oral on-demand treatment for hereditary angioedema: phase 1 study results. J Allergy Clin Immunol 2022; 149 (06) 2034-2042
    CrossrefPubMedGoogle Scholar
  • 89 A Phase III, Crossover Trial Evaluating the Efficacy and Safety of KVD900 for On-Demand Treatment of Angioedema Attacks in Adolescent and Adult Patients With Hereditary Angioedema (HAE). Accessed 5 July 2022, at: https://ClinicalTrials.gov/show/NCT05259917
    PubMedGoogle Scholar
  • 90 A Trial to Evaluate the Efficacy and Safety of Different Doses of KVD824 for Prophylactic Treatment of HAE Type I or II,. Accessed 5 July 2022, at: https://ClinicalTrials.gov/show/NCT05055258
    PubMedGoogle Scholar
  • 91 Hofman ZLM, Clark CC, Hack CE, de Maat S, Maas C. Detecting oral kallikrein-targeting therapy through triggered contact activation: A phase I study. J Allergy Clin Immunol 2020; 146 (06) 1446-1449.e5
    CrossrefPubMedGoogle Scholar
  • 92 Bista P, Nichols A. STAR-0215 Is a Long-Acting Monoclonal Antibody Plasma Kallikrein Inhibitor in Development for Treatment of HAE. Poster presentation presented at: American Academy of Allergy, Asthma & Immunology Annual Scientific Virtual Meeting. 2022 ; Phoenix, AZ. https://astriatx.com/pdfs/Poster-02-25-22-Astria-AAAAI.pdf
    PubMedGoogle Scholar
  • 93 Crabbé R. PHA-022121: a novel and potent bradykinin 2 receptor antagonist for oral treatment of hereditary angioedema. J Allergy Clin Immunol 2021; 147 (02) AB242
    CrossrefPubMedGoogle Scholar
  • 94 A Gene Therapy Study of BMN 331 in Subjects With Hereditary Angioedema,. at: https://ClinicalTrials.gov/show/NCT05121376
    PubMedGoogle Scholar
  • 95 NTLA-2002 in Adults With Hereditary Angioedema (HAE). , Accessed 5 July 2022, at: https://ClinicalTrials.gov/show/NCT05120830
    PubMed
  • 96 Orchard therapeutics. Our Portfolio and Focus. 2022 . Accessed 5 July 2022, at: https://www.orchard-tx.com/approach/pipeline/
    PubMedGoogle Scholar
  • 97 Dewald G, Bork K. Missense mutations in the coagulation factor XII (Hageman factor) gene in hereditary angioedema with normal C1 inhibitor. Biochem Biophys Res Commun 2006; 343 (04) 1286-1289
    CrossrefPubMedGoogle Scholar
  • 98 Bork K, Wulff K, Meinke P, Wagner N, Hardt J, Witzke G. A novel mutation in the coagulation factor 12 gene in subjects with hereditary angioedema and normal C1-inhibitor. Clin Immunol 2011; 141 (01) 31-35
    CrossrefPubMedGoogle Scholar
  • 99 Kiss N, Barabás E, Várnai K. et al. Novel duplication in the F12 gene in a patient with recurrent angioedema. Clin Immunol 2013; 149 (01) 142-145
    CrossrefPubMedGoogle Scholar
  • 100 Bafunno V, Firinu D, D'Apolito M. et al. Mutation of the angiopoietin-1 gene (ANGPT1) associates with a new type of hereditary angioedema. J Allergy Clin Immunol 2018; 141 (03) 1009-1017
    CrossrefPubMedGoogle Scholar
  • 101 Bork K, Wulff K, Steinmüller-Magin L. et al. Hereditary angioedema with a mutation in the plasminogen gene. Allergy 2018; 73 (02) 442-450
    CrossrefPubMedGoogle Scholar
  • 102 Dickeson SK, Kumar S, Sun MF. et al. A mechanism for hereditary angioedema caused by a lysine 311-to-glutamic acid substitution in plasminogen. Blood 2022; 139 (18) 2816-2829
    CrossrefPubMedGoogle Scholar
  • 103 Bork K, Wulff K, Rossmann H. et al. Hereditary angioedema cosegregating with a novel kininogen 1 gene mutation changing the N-terminal cleavage site of bradykinin. Allergy 2019; 74 (12) 2479-2481
    CrossrefPubMedGoogle Scholar
  • 104 Ariano A, D'Apolito M, Bova M. et al. A myoferlin gain-of-function variant associates with a new type of hereditary angioedema. Allergy 2020; 75 (11) 2989-2992
    CrossrefPubMedGoogle Scholar
  • 105 Bork K, Wulff K, Möhl BS. et al. Novel hereditary angioedema linked with a heparan sulfate 3-O-sulfotransferase 6 gene mutation. J Allergy Clin Immunol 2021; 148 (04) 1041-1048
    CrossrefPubMedGoogle Scholar