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Hereditary angioedema: General care and long-term prophylaxis

Marco Cicardi, MD
Bruce Zuraw, MD
Section Editor
Sarbjit Saini, MD
Deputy Editor
Anna M Feldweg, MD


Hereditary angioedema (HAE or inherited C1 inhibitor [C1INH] deficiency) is a rare genetic disorder resulting from deficiency (type I) or dysfunction (type II) of C1INH. It is characterized by recurrent episodes of angioedema without pruritus or urticaria, which most often affect the skin or mucosal tissues of the upper respiratory and gastrointestinal tracts. Although swelling resolves spontaneously in two to five days in the absence of treatment, angioedema is often temporarily debilitating, and laryngeal angioedema may cause fatal asphyxiation.

In patients with sufficiently frequent or severe episodes of angioedema, regularly administered prophylaxis is required to maintain an acceptable quality of life. This is referred to as long-term prophylaxis, in contrast to short-term prophylaxis, which is premedication given briefly before a specific medical or dental procedure. Short-term prophylaxis is discussed separately. (See "Hereditary angioedema: Temporary prophylaxis before procedures or stress to prevent angioedema episodes".)

The general management of adults and children with HAE and the various long-term prophylactic therapies that are used to prevent attacks will be reviewed here. The management of acute attacks as well as the clinical manifestations, pathogenesis, and diagnosis of this condition are discussed elsewhere:

(See "Hereditary angioedema: Treatment of acute attacks".)

(See "Hereditary angioedema: Epidemiology, clinical manifestations, exacerbating factors, and prognosis".)

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Literature review current through: Nov 2017. | This topic last updated: Oct 25, 2017.
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  1. Bowen T, Cicardi M, Farkas H, et al. 2010 International consensus algorithm for the diagnosis, therapy and management of hereditary angioedema. Allergy Asthma Clin Immunol 2010; 6:24.
  2. Cicardi M, Bork K, Caballero T, et al. Evidence-based recommendations for the therapeutic management of angioedema owing to hereditary C1 inhibitor deficiency: consensus report of an International Working Group. Allergy 2012; 67:147.
  3. Zuraw BL, Banerji A, Bernstein JA, et al. US Hereditary Angioedema Association Medical Advisory Board 2013 recommendations for the management of hereditary angioedema due to C1 inhibitor deficiency. J Allergy Clin Immunol Pract 2013; 1:458.
  4. Bork K, Hardt J, Witzke G. Fatal laryngeal attacks and mortality in hereditary angioedema due to C1-INH deficiency. J Allergy Clin Immunol 2012; 130:692.
  5. Caballero T, Farkas H, Bouillet L, et al. 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; 129:308.
  6. Bouillet L, Longhurst H, Boccon-Gibod I, et al. Disease expression in women with hereditary angioedema. Am J Obstet Gynecol 2008; 199:484.e1.
  7. Martinez-Saguer I, Rusicke E, Aygören-Pürsün E, et al. Characterization of acute hereditary angioedema attacks during pregnancy and breast-feeding and their treatment with C1 inhibitor concentrate. Am J Obstet Gynecol 2010; 203:131.e1.
  8. Craig T, Aygören-Pürsün E, Bork K, et al. WAO Guideline for the Management of Hereditary Angioedema. World Allergy Organ J 2012; 5:182.
  9. Yoo SM, Khan DA. Implantable venous access device associated complications in patients with hereditary angioedema. J Allergy Clin Immunol Pract 2013; 1:524.
  10. Berntorp E, Shapiro AD. Modern haemophilia care. Lancet 2012; 379:1447.
  11. Farkas H, Csuka D, Zotter Z, et al. Prophylactic therapy in children with hereditary angioedema. J Allergy Clin Immunol 2013; 131:579.
  12. Frank MM. 8. Hereditary angioedema. J Allergy Clin Immunol 2008; 121:S398.
  13. Gompels MM, Lock RJ, Abinun M, et al. C1 inhibitor deficiency: consensus document. Clin Exp Immunol 2005; 139:379.
  14. Waytes AT, Rosen FS, Frank MM. Treatment of hereditary angioedema with a vapor-heated C1 inhibitor concentrate. N Engl J Med 1996; 334:1630.
  15. Zuraw BL, Busse PJ, White M, et al. Nanofiltered C1 inhibitor concentrate for treatment of hereditary angioedema. N Engl J Med 2010; 363:513.
  16. 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; 117:904.
  17. Kreuz W, Rusicke E, Martinez-Saguer I, et al. Home therapy with intravenous human C1-inhibitor in children and adolescents with hereditary angioedema. Transfusion 2012; 52:100.
  18. Zuraw BL, Kalfus I. Safety and efficacy of prophylactic nanofiltered C1-inhibitor in hereditary angioedema. Am J Med 2012; 125:938.e1.
  19. Cicardi M, Zingale L. How do we treat patients with hereditary angioedema. Transfus Apher Sci 2003; 29:221.
  20. Gandhi PK, Gentry WM, Bottorff MB. 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. Pharmacotherapy 2012; 32:902.
  21. Busse P, Bygum A, Edelman J, et al. Safety of C1-esterase inhibitor in acute and prophylactic therapy of hereditary angioedema: findings from the ongoing international Berinert patient registry. J Allergy Clin Immunol Pract 2015; 3:213.
  22. Schürmann D, Herzog E, Raquet E, et al. C1-esterase inhibitor treatment: preclinical safety aspects on the potential prothrombotic risk. Thromb Haemost 2014; 112:960.
  23. Cicardi M, Mannucci PM, Castelli R, et al. Reduction in transmission of hepatitis C after the introduction of a heat-treatment step in the production of C1-inhibitor concentrate. Transfusion 1995; 35:209.
  24. De Filippi F, Castelli R, Cicardi M, et al. Transmission of hepatitis G virus in patients with angioedema treated with steam-heated plasma concentrates of C1 inhibitor. Transfusion 1998; 38:307.
  25. Gröner A, Nowak T, Schäfer W. Pathogen safety of human C1 esterase inhibitor concentrate. Transfusion 2012; 52:2104.
  26. Riedl MA, Grivcheva-Panovska V, Moldovan D, et al. Recombinant human C1 esterase inhibitor for prophylaxis of hereditary angio-oedema: a phase 2, multicentre, randomised, double-blind, placebo-controlled crossover trial. Lancet 2017; 390:1595.
  27. Zuraw BL, Cicardi M, Longhurst HJ, et al. Phase II study results of a replacement therapy for hereditary angioedema with subcutaneous C1-inhibitor concentrate. Allergy 2015; 70:1319.
  28. Longhurst H, Cicardi M, Craig T, et al. Prevention of Hereditary Angioedema Attacks with a Subcutaneous C1 Inhibitor. N Engl J Med 2017; 376:1131.
  29. US FDA approval letter: https://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/FractionatedPlasmaProducts/UCM564383.pdf (Accessed on June 27, 2017).
  30. Ott HW, Mattle V, Hadziomerovic D, et al. Treatment of hereditary angioneurotic oedema (HANE) with tibolone. Clin Endocrinol (Oxf) 2007; 66:180.
  31. FOX M, MINOT AS, LIDDLE GW. Oxandrolone: a potent anabolic steroid of novel chemical configuration. J Clin Endocrinol Metab 1962; 22:921.
  32. Church JA. Oxandrolone treatment of childhood hereditary angioedema. Ann Allergy Asthma Immunol 2004; 92:377.
  33. Sheffer AL, Fearon DT, Austen KF. Methyltestosterone therapy in hereditary angioedema. Ann Intern Med 1977; 86:306.
  34. 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; 295:1444.
  35. Cicardi M, Castelli R, Zingale LC, Agostoni A. Side effects of long-term prophylaxis with attenuated androgens in hereditary angioedema: comparison of treated and untreated patients. J Allergy Clin Immunol 1997; 99:194.
  36. Cicardi M, Bergamaschini L, Tucci A, et al. Morphologic evaluation of the liver in hereditary angioedema patients on long-term treatment with androgen derivatives. J Allergy Clin Immunol 1983; 72:294.
  37. Sheffer AL, Fearon DT, Austen KF. Hereditary angioedema: a decade of management with stanozolol. J Allergy Clin Immunol 1987; 80:855.
  38. Sheffer AL, Fearon DT, Austen KF. Clinical and biochemical effects of impeded androgen (oxymetholone) therapy of hereditary angioedema. J Allergy Clin Immunol 1979; 64:275.
  39. 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; 100:153.
  40. Füst G, Farkas H, Csuka D, et al. Long-term efficacy of danazol treatment in hereditary angioedema. Eur J Clin Invest 2011; 41:256.
  41. Riedl MA. Critical appraisal of androgen use in hereditary angioedema: a systematic review. Ann Allergy Asthma Immunol 2015; 114:281.
  42. Zuraw BL, Davis DK, Castaldo AJ, Christiansen SC. Tolerability and Effectiveness of 17-α-Alkylated Androgen Therapy for Hereditary Angioedema: A Re-examination. J Allergy Clin Immunol Pract 2016; 4:948.
  43. Széplaki G, Varga L, Valentin S, et al. Adverse effects of danazol prophylaxis on the lipid profiles of patients with hereditary angioedema. J Allergy Clin Immunol 2005; 115:864.
  44. Sloane DE, Lee CW, Sheffer AL. Hereditary angioedema: Safety of long-term stanozolol therapy. J Allergy Clin Immunol 2007; 120:654.
  45. Bork K, Schneiders V. Danazol-induced hepatocellular adenoma in patients with hereditary angio-oedema. J Hepatol 2002; 36:707.
  46. Crampon D, Barnoud R, Durand M, et al. Danazol therapy: an unusual aetiology of hepatocellular carcinoma. J Hepatol 1998; 29:1035.
  47. Sheffer AL, Fearon DT, Austen KF. Clinical and biochemical effects of stanozolol therapy for hereditary angioedema. J Allergy Clin Immunol 1981; 68:181.
  48. Wahn V, Aberer W, Eberl W, et al. Hereditary angioedema (HAE) in children and adolescents--a consensus on therapeutic strategies. Eur J Pediatr 2012; 171:1339.
  49. Zuraw BL. Clinical practice. Hereditary angioedema. N Engl J Med 2008; 359:1027.
  50. Bork K, Pitton M, Harten P, Koch P. Hepatocellular adenomas in patients taking danazol for hereditary angio-oedema. Lancet 1999; 353:1066.
  51. O'Neil KM. Complement deficiency. Clin Rev Allergy Immunol 2000; 19:83.
  52. Longstaff C. Studies on the mechanisms of action of aprotinin and tranexamic acid as plasmin inhibitors and antifibrinolytic agents. Blood Coagul Fibrinolysis 1994; 5:537.
  53. 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:S51.
  54. Ohsawa I, Honda D, Nagamachi S, et al. Clinical manifestations, diagnosis, and treatment of hereditary angioedema: survey data from 94 physicians in Japan. Ann Allergy Asthma Immunol 2015; 114:492.
  55. Wintenberger C, Boccon-Gibod I, Launay D, et al. Tranexamic acid as maintenance treatment for non-histaminergic angioedema: analysis of efficacy and safety in 37 patients. Clin Exp Immunol 2014; 178:112.
  56. Gwynn CM. Therapy in hereditary angioneurotic oedema. Arch Dis Child 1974; 49:636.
  57. Agostoni A, Marasini B, Cicardi M, et al. Hepatic function and fibrinolysis in patients with hereditary angioedema undergoing long-term treatment with tranexamic acid. Allergy 1978; 33:216.
  58. Farkas H, Varga L, Széplaki G, et al. Management of hereditary angioedema in pediatric patients. Pediatrics 2007; 120:e713.
  59. Berntorp E, Follrud C, Lethagen S. No increased risk of venous thrombosis in women taking tranexamic acid. Thromb Haemost 2001; 86:714.
  60. Taparia M, Cordingley FT, Leahy MF. Pulmonary embolism associated with tranexamic acid in severe acquired haemophilia. Eur J Haematol 2002; 68:307.
  61. Snir M, Axer-Siegel R, Buckman G, Yassur Y. Central venous stasis retinopathy following the use of tranexamic acid. Retina 1990; 10:181.
  62. Frank MM, Sergent JS, Kane MA, Alling DW. Epsilon aminocaproic acid therapy of hereditary angioneurotic edema. A double-blind study. N Engl J Med 1972; 286:808.
  63. Cornpropst M, Collis P, Collier J, et al. Safety, pharmacokinetics, and pharmacodynamics of avoralstat, an oral plasma kallikrein inhibitor: phase 1 study. Allergy 2016; 71:1676.
  64. Aygören-Pürsün E, Magerl M, Graff J, et al. Prophylaxis of hereditary angioedema attacks: A randomized trial of oral plasma kallikrein inhibition with avoralstat. J Allergy Clin Immunol 2016; 138:934.
  65. Efficacy and safety of BCX7353 to prevent angioedema attacks in subjects with hereditary angioedema [APeX-1]; NCT02870972. https://clinicaltrials.gov/ct2/show/NCT02870972 (Accessed on April 04, 2017).
  66. Chyung Y, Vince B, Iarrobino R, et al. A phase 1 study investigating DX-2930 in healthy subjects. Ann Allergy Asthma Immunol 2014; 113:460.
  67. Banerji A, Busse P, Shennak M, et al. Inhibiting Plasma Kallikrein for Hereditary Angioedema Prophylaxis. N Engl J Med 2017; 376:717.