Hereditary Angioedema (HAE)

Hereditary angioedema (HAE), a rare genetic disease with autosomal-dominant inheritance, is characterized by a deficiency of C1-esterase inhibitor (C1-INH) protein.1 Patients experience recurrent and usually unpredictable episodes of swelling of the abdomen, face, extremities, and upper airway.1 The absence or dysfunction of C1-INH interferes with the enzymatic pathway and results in the excessive formation of bradykinin, which is the primary mediator of swelling in types 1 and 2 HAE.2,3 The binding of bradykinin to receptors located on the endothelial cells of blood vessels causes vasodilation, an increase in vascular permeability, and episodes of swelling.3

HAE is managed primarily with avoidance of the triggers that initiate attacks and with pharmacotherapy, used either on demand or as prophylaxis.1,4 Several drugs have been approved for the management of HAE; these were developed with the aim of optimizing care and improving patients’ quality of life. The pharmacologic agents currently available for the treatment of HAE target the contact/kallikrein-kinin system. Mechanisms of action include the replacement of C1-INH, inhibition of the kallikrein enzyme, and blockage of bradykinin B2 receptors.2,3

Plasma-Derived and Recombinant C1-INH Formulations

C1-INH is a serine protease inhibitor whose main role is to inhibit proteases such as kallikrein.5 C1-INH formulations have been designed to replenish deficient or dysfunctional C1-INH and the subsequent accumulation of bradykinin in patients with HAE.3

C1-INH products include human-plasma derived formulations (Cinryze®, approved by the US Food and Drug Administration [FDA] in 2008); Berinert, approved in 2009; and Haegarda®, approved in 2017) and recombinant and purified protein formulations developed from rabbit milk (Ruconest®, approved in 2014); these can be used as prophylaxis and in the management of acute episodes of HAE.3 Despite similar mechanisms of action, the 2 types of formulation differ in plasma half-life, which is longer for human-derived products.3 Fresh frozen plasma (FFP) can also be used as a source of C1-INH; however, because of the risk for the transmission of blood-borne agents, its use as a first-line therapy is limited.6

Typically, intravenous access is required for the administration of C1-INH concentrates; however, patients can be trained to self-administer their medications. Since the approval of Haegarda®, an alternate route of administration has been available.4

Read more about HAE treatments

Kallikrein Inhibition

Bradykinin is generated through the kallikrein-kinin system, and kallikrein is formed following the activation of prekallikrein by factor XIIa.3 Kallikrein inhibitors are therefore used in HAE to bind plasma kallikrein and prevent the cleavage of high-molecular-weight kininogen (HMWK) to form bradykinin. Ecallantide (Kalbitor®, approved in 2009) is a subcutaneously administered reversible kallikrein inhibitor.7

Other kallikrein inhibitors are lanadelumab (Takhzyro®, approved in 2018), a fully human immunoglobulin G1 monoclonal antibody that is administered subcutaneously, and berotralstat (Orladeyo®, approved in 2020), the first kallikrein inhibitor that can be taken orally.4

Bradykinin B2-Receptor Antagonists

Bradykinin binding to its receptors causes vascular leakage and attacks of angioedema. Icatibant (Firazyr®, approved in 2011) is a bradykinin B2-receptor antagonist that selectively and specifically prevents bradykinin receptor binding. Icatibant is administered subcutaneously.3 

Attenuated Androgens

Attenuated androgens are thought to stimulate the synthesis of C1-INH within hepatocytes.1,4 They also increase C1-INH mRNA expression in mononuclear cells in peripheral blood and interfere with the catabolism of bradykinin.4 This group of drugs includes danazol (Danocrine), oxandrolone (Oxandrin), and stanozolol (Winstrol), which are administered orally.4 

Although their efficacy has been demonstrated in many patients with HAE, attenuated androgens may cause severe side effects, so that their long-term use is limited.8 Attenuated androgens are also contraindicated in pregnant women, children, patients with certain cancers, and patients with liver disease.3


The drugs in this group, which includes tranexamic acid and epsilon aminocaproic acid, are not approved by the FDA and are not recommended as first-line therapy, either on demand or as prophylaxis, in HAE because benefits are limited and evidence of efficacy is lacking.3,4,6 Antifibrinolytics may be used for patients for whom no first-line therapy is available or for whom androgens are contraindicated.6

Gene Therapy

Gene therapy, in which C1-INH deficiency is corrected by using adeno-associated virus vectors to deliver extrachromosomal copies of the SERPING1 gene, has been explored as potential treatment for HAE.9 Other approaches include the use of antisense oligonucleotides to regulate the production of prekallikrein and of RNA interference to regulate FXII expression.5,10


1. Barmettler S, Li Y, Banerji A. New and evolving therapies for hereditary angioedema. Allergy Asthma Proc. 2019;40(1):7-13. doi:10.2500/aap.2019.40.4195

2. Kaplan AP, Joseph K. Pathogenesis of hereditary angioedema: the role of the bradykinin-forming cascade. Immunol Allergy Clin North Am. 2017;37(3):513-525. doi:10.1016/j.iac.2017.04.001

3. Lumry WR. Current and emerging therapies to prevent hereditary angioedema attacks. Am J Manag Care. 2018;24(14 Suppl):S299-S307.

4. Fijen LM, Bork K, Cohn DM. Current and prospective targets of pharmacologic treatment of hereditary angioedema types 1 and 2. Clin Rev Allergy Immunol. 2021;61(1):66-76. doi:10.1007/s12016-021-08832-x

5. Nicola S, Rolla G, Brussino L. Breakthroughs in hereditary angioedema management: a systematic review of approved drugs and those under research. Drugs Context. 2019;8:212605. doi:10.7573/dic.212605. Erratum in: Drugs Context. 2019;8

6. 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. Epub ahead of print. doi:10.1111/all.15214.x

7. Busse P, Kaplan A. Specific targeting of plasma kallikrein for treatment of hereditary angioedema: a revolutionary decade. J Allergy Clin Immunol Pract. 2022;10(3):716-722. doi:10.1016/j.jaip.2021.11.011. Erratum in: J Allergy Clin Immunol Pract. 2022;10(6):1673

8. 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(2):153-161. doi:10.1016/S1081-1206(10)60424-3

9. Qiu T, Chiuchiolo MJ, Whaley AS, et al. Gene therapy for C1 esterase inhibitor deficiency in a murine model of hereditary angioedema. Allergy. 2019;74(6):1081-1089. doi:10.1111/all.13582

10. Ferrone JD, Bhattacharjee G, Revenko AS, et al. IONIS-PKKRx a novel antisense inhibitor of prekallikrein and bradykinin production. Nucleic Acid Ther. 2019;29(2):82-91. doi:10.1089/nat.2018.0754 

Reviewed by Hasan Avcu, MD, on 6/30/2022.