Current Allergy and Asthma Reports

, Volume 7, Issue 4, pp 264–269 | Cite as

C1-inhibitor deficiencies (hereditary angioedema): Where are we with therapies?

  • R. J. Lock
  • M. M. GompelsEmail author


Hereditary angioedema, an autosomal dominant disorder, presents clinically as recurrent episodes of swelling. It results from either deficient production or function of C1 inhibitor. Acquired angioedema is associated with lymphoproliferative or autoimmune disease. Conventionally attenuated androgens and antifibrinolytics have been used for prophylaxis, both for the long term and presurgically. Fresh frozen plasma and plasma-derived C1 inhibitor concentrate have been used primarily for treatment of acute attacks. All have drawbacks in side effects or potential for infection transmission. New treatments (recombinant C1 inhibitor, icatibant, DX-88, and for acquired angioedema, rituximab) so far show good safety profiles. Early data suggest these may be effective treatment alternatives. The efficacy of current treatment and the potential held by newer agents that target specific elements in complement or kinin pathways are examined. Some agents are likely to have a wider role in treatment of other, more common, forms of angioedema.


Angioedema Allergy Clin Immunol Tranexamic Acid Fresh Freeze Plasma Hereditary Angioedema 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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References and Recommended Reading

  1. 1.
    Osler W: Hereditary angioneurotic oedema. Am J Med Sci 1888, 95:362–367.CrossRefGoogle Scholar
  2. 2.
    Donaldson VH, Evans RR: A biochemical abnormality in hereditary angioneurotic edema: absence of serum inhibitor of C’1-esterase. Am J Med 1963, 35:37–44.PubMedCrossRefGoogle Scholar
  3. 3.
    Cicardi M, Bergamaschini L, Marasini B, et al.: Hereditary angioedema: an appraisal of 104 cases. Am J Med Sci 1982, 284:2–9.PubMedCrossRefGoogle Scholar
  4. 4.
    Fay A, Abinun M: Current management of hereditary angiooedema (C’1 esterase inhibitor deficiency). J Clin Pathol 2002, 55:266–270.PubMedGoogle Scholar
  5. 5.
    Tosi M: Molecular genetics of C’1-inhibitor. Immunobiology 1998, 199:358–365.PubMedGoogle Scholar
  6. 6.
    Cicardi M, Bergamaschini L, Cugno M, et al.: Pathogenetic and clinical aspects of C1 inhibitor deficiency. Immunobiology 1998, 199:366–376.PubMedGoogle Scholar
  7. 7.
    Freiberger T, Grombirikova H, Kuklinek P, Litzman J: Search for factors affecting clinical manifestation of hereditary angioedema. Presented at the 12th Meeting of the European Society for Immunodeficiencies (ESID). Budapest, Hungary; April 7, 2006.Google Scholar
  8. 8.
    Prada AE, Zahedi K, Davis AE: Regulation of C’1-inhibitor synthesis. Immunobiology 1998, 199:377–388.PubMedGoogle Scholar
  9. 9.
    Bork K, Barnstedt S, Koch P, Traupe H: Hereditary angioedema with normal C1-inhibitor activity in women. Lancet 2000, 356:213–217.PubMedCrossRefGoogle Scholar
  10. 10.
    Levy JH, O’Donnell PS: The therapeutic potential of a kallikrein inhibitor for treating hereditary angioedema. Expert Opin Investig Drugs 2006, 19:1077–1090.CrossRefGoogle Scholar
  11. 11.
    Cugno M, Nussberger J, Cicardi M, Agostoni A: Bradykinin and the pathophysiology of angioedema. Int Immunopharmacol 2003, 3:311–317.PubMedCrossRefGoogle Scholar
  12. 12.
    Zahedi R, Bissler JJ, Davis AE, et al.: Unique C1 inhibitor dysfunction in a kindred without angioedema. II. Identification of an Ala443 —>Val substitution and functional analysis of the recombinant mutant protein. J Clin Invest 1995, 95:1299–1305.PubMedCrossRefGoogle Scholar
  13. 13.
    Zahedi R, Wisnieski J, Davis AE: Role of the P2 residue of complement 1 inhibitor (Ala443) in determination of target protease specificity: inhibition of complement and contact system proteases. J Immunol 1997, 159:983–988.PubMedGoogle Scholar
  14. 14.
    Gompels MM, Lock RJ, Abinun M, et al.: C1 inhibitor deficiency: consensus document. Clin Exp Immunol 2005, 141:189–190.CrossRefGoogle Scholar
  15. 15.
    Bowen T, Cicardi M, Farkas H, et al.: J Allergy Clin Immunol 2004, 114:629–637.PubMedCrossRefGoogle Scholar
  16. 16.
    Gompels MM, Lock RJ: C1 inhibitor deficiency: management. Clin Exp Dermatol 2005, 30:737–740.PubMedCrossRefGoogle Scholar
  17. 17.
    Frank MM, Gelfand JA, Atkinson JP: Hereditary angioedema: the clinical syndrome and its management. Ann Intern Med 1976, 84:580–593.PubMedGoogle Scholar
  18. 18.
    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, 99:194–196.PubMedCrossRefGoogle Scholar
  19. 19.
    Bork K, Pitton M, Harten P, Koch P: Hepatocelluar adenomas in patients taking danazol for hereditary angiooedema. Lancet 1999, 353:1066–1067.PubMedCrossRefGoogle Scholar
  20. 20.
    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, 115:864–869.PubMedCrossRefGoogle Scholar
  21. 21.
    Cicardi M, Zingale LC, Pappalardo E, et al.: Autoantibodies and lymphoproliferative diseases in acquired C1-inhibitor deficiencies. Medicine (Baltimore) 2003, 82:274–281.CrossRefGoogle Scholar
  22. 22.
    Agostoni A, Cicardi M, Cugno M, Storti E: Clinical problems in the C1-inhibitor deficient patient. Behring Inst Mitt 1993, 93:306–312.PubMedGoogle Scholar
  23. 23.
    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, 286:808–812.PubMedCrossRefGoogle Scholar
  24. 24.
    Cicardi M, Zingale L: How do we treat patients with hereditary angioedema? Transfus Apheresis Sci 2003, 29:221–227.CrossRefGoogle Scholar
  25. 25.
    Lindoff C, Rybo G, Astedt B: Treatment with tranexamic acid during pregnancy, and the risk of thrombo-embolic complications. Thromb Haemost 1993, 70:238–240.PubMedGoogle Scholar
  26. 26.
    Turner MD, Oughbourli A, Haeney K, Selvaggi T: Use of recombinant plasma kallikrein inhibitor in hereditary angioedema: a case report and review of the management of the disorder. J Oral Maxillofac Surg 2004, 62:1553–1556.PubMedCrossRefGoogle Scholar
  27. 27.
    Longhurst HJ: Emergency treatment of acute attacks in hereditary angioedema due to C1 inhibitor deficiency: what is the evidence? Int J Clin Pract 2005, 59:594–599.PubMedCrossRefGoogle Scholar
  28. 28.
    Frank MM: Hereditary angioedema: a half century of progress. J Allergy Clin Immunol 2004, 114:626–628.PubMedCrossRefGoogle Scholar
  29. 29.
    Waytes AT, Rosen FS, Frank MM: Treatment of hereditary angioedema with a vapor-heated C1 inhibitor concentrate. N Engl J Med 1996, 334:1630–1634.PubMedCrossRefGoogle Scholar
  30. 30.
    Kunschak M, Engl W, Maritsch F, et al.: A randomized, controlled trial to study the efficacy and safety of C1 inhibitor concentrate in treating hereditary angioedema. Transfusion 1998, 38:540–549.PubMedCrossRefGoogle Scholar
  31. 31.
    Bork K, Meng G, Staubach P, Hardt J: Treatment with C1 inhibitor concentrate in abdominal pain attacks of patients with hereditary angioedema. Transfusion 2005, 45:1774–1784.PubMedCrossRefGoogle Scholar
  32. 32.
    Levi M, Choi G, Picavet MA, Hack CE: Self-administration of C1-inhibitor concentrate in patients with hereditary and acquired angioedema caused by C1-inhibitor deficiency. J Allergy Clin Immunol 2006, 117:904–908.PubMedCrossRefGoogle Scholar
  33. 33.
    De Serres J, Groner A, Lindner J: Safety and efficacy of pasteurized C1 inhibitor concentrate (Berinert P) in hereditary angioedema: a review. Transfus Apheresis Sci 2003, 29:247–254.CrossRefGoogle Scholar
  34. 34.
    Altman AD, McLaughlin J, Schellenberg R, et al.: Hereditary angioedema managed with low-dose danazol and c1 esterase inhibitor concentrate: a case report. J Obstet Gynaecol Can 2006, 28:27–31.PubMedGoogle Scholar
  35. 35.
    Longhurst HJ, O’Grady C: Home therapy for HAE: the Barts experience. J Allergy Clin Immunol 2007, 114:S99–S100.Google Scholar
  36. 36.
    van Doorn MB, Burggraaf J, Van Dam T, et al.: A phase I study of recombinant human C1 inhibitor in asymptomatic patients with hereditary angioedema. J Allergy Clin Immunol 2005, 116:876–883.PubMedCrossRefGoogle Scholar
  37. 37.
    Porebski G, Bilo B, Obtulowicz K, et al.: Recombinant human C1-inhibitor is effective in the treatment of acute attacks of hereditary angioedema—case report [in Polish]. Przegl Lek 2005, 62:317–320.PubMedGoogle Scholar
  38. 38.
    Nuijens JH, Hack CE: Recombinant C1 inhibitor. J Allergy Clin Immunol 2004, 113:S100–S104.Google Scholar
  39. 39.
    Trachsel D, Hammer J: A vote for inhaled adrenaline in the treatment of severe upper airway obstruction caused by piercing of the tongue in hereditary angioedema. Intensive Care Med 1999, 25:1335–1336.PubMedGoogle Scholar
  40. 40.
    Williams A, Baird LG: DX-88 and HAE: a developmental perspective. Transfus Apheresis Sci 2003, 29:255–258.CrossRefGoogle Scholar
  41. 41.
    Cicardi M, González-Quivedo T, Caballero T, et al.: DX-88 a recombinant inhibitor of human plasma kallikrein: efficacy and safety in hereditary and acquired angioedema. Mol Immunol 2003, 40:197–198.Google Scholar
  42. 42.
    Caballero T, López-Serrano C: Anaphylactic reaction and antibodies to DX-88 (kallikrein inhibitor) in a patient with hereditary angioedema. J Allergy Clin Immunol 2006, 117:476–477.PubMedCrossRefGoogle Scholar
  43. 43.
    Nussberger J, Cugno M, Amstutz C, et al.: Plasma bradykinin in angio-oedema. Lancet 1998, 351:1693–1697.PubMedCrossRefGoogle Scholar
  44. 44.
    Bork K: Current treatment of HAE and future treatment options. J Allergy Clin Immunol 2007, 113:S94–S96.Google Scholar
  45. 45.
    Bas M, Bier H, Greve J, et al.: Novel pharmacotherapy of acute hereditary angioedema with bradykinin B2-receptor antagonist icatibant. Allergy 2006, 61:1490–1492.PubMedCrossRefGoogle Scholar
  46. 46.
    Eisenberg R, Albert D: B-cell targeted therapies in rheumatoid arthritis and systemic lupus erythematosus. Nat Clin Pract Rheumatol 2006, 2:20–27.PubMedCrossRefGoogle Scholar
  47. 47.
    Johnston S, Kennedy C: Images in clinical medicine. Pemphigus foliaceus. N Engl J Med 2005, 353:2589.PubMedCrossRefGoogle Scholar
  48. 48.
    Held G, Poschel V, Pfreundschuh M: Rituximab for the treatment of diffuse large B-cell lymphomas. Expert Rev Anticancer Ther 2006, 6:1175–1186.PubMedCrossRefGoogle Scholar
  49. 49.
    Ziakas PD, Giannouli S, Psimenou E, et al.: Acquired angioedema: a new target for rituximab? Haematologica 2004, 89:ELT13.PubMedGoogle Scholar
  50. 50.
    Levi M, Hack CE, van Oers MH: Rituximab-induced elimination of acquired angioedema due to C1-inhibitor deficiency. Am J Med 2006, 119:e3–e5.PubMedCrossRefGoogle Scholar
  51. 51.
    Subasinghe NL, Travins JM, Ali F, et al.: A novel series of arylsulfonylthiophene-2-carboxamidine inhibitors of the complement component C1s. Bioorg Med Chem Lett 2006, 16:2200–2204.PubMedCrossRefGoogle Scholar
  52. 52.
    Zhang J, Krishnan R, Arnold CS, et al.: Discovery of highly potent small molecule kallikrein inhibitors. Med Chem 2006, 2:545–553.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  1. 1.Immunology and Immunogenetics, North Bristol NHS TrustSouthmead HospitalWestbury-on-Trym, BristolUK

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