Hereditary Angioedema (HAE)

Hereditary angioedema (HAE) is a rare disease characterized by episodes of swelling of the submucosa and subcutaneous tissues.¹ The angioedema characteristic of this disease is a consequence of an increase in vascular permeability.²

Most often, the development of HAE is due to alterations in SERPING1, the gene that codes for complement component 1 esterase inhibitor (C1-INH).^2,3 C1-INH is a serine protease inhibitor of the serpin superfamily.³ Defects in the SERPING1 gene result in conformational changes in the C1-INH protein, with dimerization and loss of function.¹ C1-INH protein is deficient or absent in type 1 HAE and is dysfunctional in type 2 HAE.² However, some patients with HAE have normal C1-INH levels; in these cases, the disease is caused by alterations in genes other than SERPING1.^2,3 

HAE With C1-INH Deficiency

The pathophysiology underlying HAE with C1-INH deficiency or dysfunction (ie, type 1 and type 2 HAE) is excessive production of the vasoactive peptide bradykinin, which is the major cause of the clinical manifestations of HAE.² 

C1-INH is a key component in the regulation of 3 different cascades: the kallikrein-kinin pathway (also known as the contact system), the complement cascade, and the fibrinolytic system.³ The kallikrein-kinin pathway consists of factor XII (FXII), plasma prekallikrein, and high-molecular-weight kininogen (HK).^2,3 In this pathway, FXII is activated by tissue damage and binds to the cell surface, and FXIIa in turn cleaves the plasma prekallikrein-HK complex. After cleavage of the complex, activated plasma kallikrein releases bradykinin from bound HK.³ Bradykinin then binds to bradykinin B2 receptors, located on the vascular endothelium.⁴ Following receptor binding, downstream events (contraction of the cytoskeleton of cells, which creates spaces between endothelial cells, and release of nitrous oxide) further promote vasodilation. Transfer of fluid into the tissues and subsequent angioedema follow.^2,5 

In addition to the process culminating in the formation of bradykinin, plasma kallikrein may cleave plasminogen to form plasmin. Cleavage of FXI to the activated form, FXIa, may also occur, resulting in thrombin production and fibrin deposition that contribute to the increase in vascular permeability. Within the complement system, C1-INH regulates C1r/C1s convertase, which is responsible for cleaving complement components C4 and C2 and activating further events in the classic complement system.^3,6,7

In HAE, dysregulation of the kallikrein-kinin system due to insufficient or not fully functional C1-INH, the protein that regulates both FXIIa and pre-kallikrein, results in the excessive formation of bradykinin. In a positive feedback loop, plasma kallikrein and plasmin continue to promote the formation of FXIIa through FXII activation, so that bradykinin continues to accumulate and cause recurrent attacks of HAE.^1,3 

However, it is still unclear why swelling usually affects a specific body area in some patients and why swelling is not continuous but rather episodic, occurring with variable frequency in different patients and even in the same patient. As per pathogenesis of HAE, extravascular fluid accumulates in various tissues via non-allergic and non-inflammatory mechanisms causing clinical manifestations like abrupt onset swelling around eyes, face, and extremities.^{1, 3}

HAE With Normal C1-INH Levels

The pathogenesis of HAE in patients with normal C1-INH blood levels is caused by defects in the genes that code for FXII, plasminogen, and angiopoietin.^3,8 Additional studies are needed for a full understanding of the mechanisms involved in the development of HAE in patients carrying these mutated genes. 

When FXII is abnormal, plasmin may activate the defective FXII without any stimuli.⁹ The presence of the most commonly identified mutation in the F12 gene, p.Thr309Lys, has been shown to reduce the threshold for activation of the contact system. HAEIII appears due to hyperactive Thr309Lys mutants that has enhanced susceptibility for contact activation over WT FXII. It is initiated by natural or synthetic contact activators that can increase in both plasma and purified system containing physiological levels of C1INH.¹⁰ Other F12 mutations can be associated with additional plasmin cleavage sites, so that the contact system may be activated in different ways.²

In patients with mutations in the PLG gene, the activation of plasmin within the contact system may be compromised.² However, the formation of excessive amounts of bradykinin in patients who have HAE caused by F12 and PLG mutations still appears to be the basis of their symptoms.³

Mutations in the gene that codes for angiopoietin 1 may interfere with sensitivity of the endothelium, increasing vascular permeability by inhibiting protein aggregation and disturbing cytoskeletal assembly.^1,2,3 In patients with mutant ANGPT1, bradykinin may not be the primary cause of the symptoms of HAE.³

References

1. Banday AZ, Kaur A, Jindal AK, Rawat A, Singh S. An update on the genetics and pathogenesis of hereditary angioedema. Genes Dis. 2019;7(1):75-83. doi:10.1016/j.gendis.2019.07.002

2. Busse PJ, Christiansen SC. Hereditary angioedema. N Engl J Med. 2020;382(12):1136-1148. doi:10.1056/NEJMra1808012

3. Wedner HJ. Hereditary angioedema: pathophysiology (HAE type I, HAE type II, and HAE nC1-INH). Allergy Asthma Proc. 2020;41(Suppl 1):S14-S17. doi:10.2500/aap.2020.41.200081

4. Prado GN, Taylor L, Zhou X, Ricupero D, Mierke DF, Polgar P. Mechanisms regulating the expression, self-maintenance, and signaling-function of the bradykinin B2 and B1 receptors. J Cell Physiol. 2002;193(3):275-286. doi:10.1002/jcp.10175

5. Demirtürk M, Gelincik A, Cınar S, et al. Increased eNOS levels in hereditary angioedema. Int Immunopharmacol. 2014;20(1):264-268. doi:10.1016/j.intimp.2014.03.007

6. Rosi-Schumacher M, Shah SJ, Craig T, Goyal N. Clinical manifestations of hereditary angioedema and a systematic review of treatment options. Laryngoscope Investig Otolaryngol. 2021;6(3):394-403. doi:10.1002/lio2.555

7. Qadri F, Bader M. Kinin B1 receptors as a therapeutic target for inflammation. Expert Opin Ther Targets. 2018;22(1):31-44. doi:10.1080/14728222.2018.1409724

8. Sharma J, Jindal AK, Banday AZ, et al. Pathophysiology of hereditary angioedema (HAE) beyond the SERPING1 gene. Clin Rev Allergy Immunol. 2021;60(3):305-315. doi:10.1007/s12016-021-08835-8.

9. 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(3):1009-1017. doi:10.1016/j.jaci.2017.05.020

10. Björkqvist J, de Maat S, Lewandrowski U, et al. Defective glycosylation of coagulation factor XII underlies hereditary angioedema type III. J Clin Invest. 2015;125(8):3132-46. doi:10.1172/JCI77139

Reviewed by Debjyoti Talukdar, MD, on 6/29/2022.

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Diana Diez Gaspar, PharmD, PhD

Diana earned her PhD and PharmD with distinction in the field of Medicinal and Pharmaceutical Chemistry at the Universidade do Porto. She is an accomplished oncology scientist with 10+ years of experience in developing and managing R&D projects and research staff directed to the development of small proteins fit for medical use.