Science behind the swell: Factor XII and hereditary angioedema

Last updated May 20, 2024, by Lindsey Shapiro, PhD
Fact-checked by Patrícia Silva, PhD

Coagulation factor XII, or FXII, is a blood protein that plays a role in the body’s inflammatory signaling cascade called the kallikrein-kinin pathway. This pathway is ultimately responsible for the swelling attacks that characterize hereditary angioedema (HAE).

Overactivity of FXII is the underlying cause of a subset of HAE cases (HAE type 3). In other forms of the disease (HAE types 1 and 2), a protein that normally keeps FXII activation in check is deficient or dysfunctional.

What is FXII?

FXII is a protein found in the blood that is involved in a series of mechanisms that drive blood clotting and inflammation. It is usually inactive in the bloodstream, becoming active after being in contact with certain surfaces such as damaged blood vessel walls.

The activated form of FXII, called FXIIa, then triggers what is known as the intrinsic coagulation cascade. This involves a series of chemical reactions, ending with the production of thrombin, which enables blood to clot.

FXIIa also is involved in a couple of processes that drive inflammation. First, it can directly activate components of the complement cascade, a series of reactions that help boost the immune system’s response to potentially harmful invaders.

It also initiates a pro-inflammatory chain of events called the kallikrein-kinin cascade that is associated with the swelling that accompanies inflammation in the body. This starts with FXIIa’s activation of a molecule called prekallikrein. Kallikrein-kinin activity further promotes the activation of FXII.

FXII role in HAE

FXII plays a role in HAE by initiating the kallikrein-kinin cascade. The kallikrein-kinin cascade is ultimately responsible for producing bradykinin, a small protein that drives HAE swelling.

Bradykinin binds to receptor proteins on blood vessel walls and makes them more permeable, leading to fluid leakage. Fluid buildup in tissues under the skin are the cause of the swelling, or edema, that accompanies inflammation.

When there is too much bradykinin, it causes HAE swelling attacks. Some cases of HAE type 3 are caused by mutations in the gene that encodes FXII, called F12, that lead to FXII being too active. This, in turn, drives more bradykinin production than is needed.

In HAE types 1 and 2, genetic mutations affect the production of C1-INH, a protein that normally inhibits FXII and the kallikrein-kinin cascade. When that process is not controlled by the body, bradykinin is again overproduced.

Therapeutic approach based on FXII

The management of HAE may involve lifestyle changes to prevent or manage swelling as well as medications targeting the underlying cause of the swelling attacks.

Because FXII is involved in the activation of the kallikrein-kinin cascade, targeting it is being considered as a possible way of treating all types of HAE. Still, there are currently no approved treatments targeting FXII.

The idea behind such a treatment is that by blocking FXII production or inhibiting its activated form, the chain of events that ultimately leads to swelling via the kallikrein-kinin cascade would be stopped at its source, easing HAE symptoms and preventing swelling attacks.

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