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Hereditary Angioedema Mechanism of Disease

Mother and son hugging and smiling.

Most cases of hereditary angioedema (HAE) are caused by a deficiency or dysfunction of C1 esterase inhibitor (C1-INH), resulting in the inability to regulate the contact system. C1-INH inhibits plasma kallikrein and coagulation factor XIIa. In the absence of functional C1-INH, activated factor XII (factor XIIa) activates prekallikrein to form kallikrein, which can then rapidly activate factor XII, resulting in a positive feedback loop.1-3

Increased bradykinin levels trigger an HAE attack2,4

Kallikrein-kinin system

Kallikrein-kinin system showing how HAE attacks are initiated.

Adapted from Zuraw 2008 and Kaplan 2010.1,3

HAE attacks are initiated when the kallikrein-kinin cascade is activated.3,5

In response to this activation, plasma kallikrein activity increases the cleavage of high-molecular-weight kininogen (HMWK) to produce bradykinin.3,4

Excessive bradykinin, after binding to bradykinin B2 receptors, causes an increase in blood vessel permeability. This allows fluid to pass through the blood vessel walls causing subcutaneous or submucosal swelling.2-4

In the classical complement pathway, insufficient or defective C1-INH also results in diminished levels of proteins such as C4, a useful biomarker in the diagnosis of HAE.1,2

  • Factor XIIa icon.

    Factor XIIa

  • Pre-kallikrein icon.

    Pre-kallikrein

  • High-molecular-weight kininogen icon.

    High-Molecular-Weight Kininogen

  • Bradykinin icon.

    Bradykinin

  • Vascular cells icon.

    Vascular cells

  • Kallikrein icon.

    Kallikrein

  • Missing or dysfunctional C1-INH icon.

    Missing/dysfunctional C1-INH

  • Bradykinin B2 receptor icon.

    Bradykinin B2 Receptor

Types of HAE

The two most common types of HAE are Type I and Type II. They are similar in clinical presentation but result from different C1-INH mutations.1

Circle graph showing about 85% of patients have HAE Type 1.
~85%
TYPE I

~85% of patients have Type I, which is characterized by a deficiency in C1-INH1

Circle graph showing about 15% of patients have HAE Type 2.
~15%
TYPE II

~15% of patients have Type II, which is characterized by dysfunctional C1-INH1

HAE Types I and II are caused by a genetic mutation in the SERPING1 gene, which codes for C1-INH.6

There is another type of HAE—HAE with normal C1-INH (formerly known as Type III)—that has the same presentation as Types I and II, but with normal levels and function of C1-INH.6

Genetic aspect

HAE is an autosomal dominant genetic disorder, so a person with HAE has a 50% chance of passing it down to offspring.4,5,7

Most cases of HAE are inherited5:

Circle graph showing about 75% of patients have inherited HAE.
75%
inherited

75% of patients inherit HAE

Circle graph showing about 25% of patients have genetic mutation.
25%
GENETIC
MUTATION

25% of patients have a spontaneous genetic mutation

HAE can affect both adults and children, with symptoms generally worsening after puberty.4

Regardless of the frequency and severity of their own attacks, many patients worry or experience anxiety about possibly passing HAE down to their children.8,a

aBased on a 2017 quality-of-life survey of 445 HAE patients.8

References:

  1. Zuraw BL. Clinical practice. Hereditary angioedema. N Engl J Med. 2008;359(10):1027-1036
  2. Zuraw BL, Christiansen SC. HAE pathophysiology and underlying mechanisms. Clinic Rev Allergy Immunol. 2016;51(2):216-229.
  3. Kaplan AP, Joseph K. The bradykinin-forming cascade and its role in hereditary angioedema. Ann Allergy Asthma Immunol. 2010;104(3):193-204.
  4. Busse PJ, Christiansen SC, Riedl MA, et al. US HAEA Medical Advisory Board 2020 guidelines for the management of hereditary angioedema. J Allergy Clin Immunol Pract. 2021;9(1):132-150. doi:10.1016/j.jaip.2020.08.046
  5. Gompels MM, Lock RJ, Abinun M, et al. C1 inhibitor deficiency: consensus document. Clin Exp Immunol. 2005;139(3):379-394.
  6. Banerji A, Busse P, Christiansen SC, et al. Current state of hereditary angioedema management: a patient survey. Allergy Asthma Proc. 2015;36(3):213-217. doi:10.2500/aap.2015.36.3824
  7. Manning ME. Hereditary angioedema: differential diagnosis, diagnostic tests, and family screening. Allergy Asthma Proc. 2020;41(Suppl 1):S22-S25. doi:10.2500/aap.2020.41.200062
  8. 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(6):600-607.