Pathophysiology of Acute HAE Attacks

HAE is caused by a genetic disorder that results in insufficient levels of a properly functioning blood protein C1-INH in the body. Without adequate amount of fully functioning C1-INH, a series of chemical reactions occur in our bodies that, when unregulated, ultimately produce an excessive amount of a chemical called bradykinin.  Among other effects, bradykinin causes blood vessels to expand (dilate) and leak serum and other fluids. This results in increased blood flow to a certain area of the body as well as fluid build up in tissues under the skin. Accumulation of fluid under the skin is called edema and is the cause of swelling and pain associated with an acute HAE attack.

Specifically, limited levels of properly functioning C1-INH affect a chemical reaction called the kallikrein-kinin, or "Contact", cascade. This cascade activates another important protein, called plasma kallikrein, which is a protein in our blood that usually occurs in an inactive form.  When plasma kallikrein is activated, it causes the release of bradykinin.  

If the kallikrein-kinin cascade is unregulated, so is the activity of plasma kallikrein and this results in release of large quantities of bradykinin.  In order to prevent this overproduction of bradykinin, plasma kallikrein activity must be blocked. Normally this is the role of the protein C1-INH, which binds to plasma kallikrein and inhibits (blocks) it.

During an acute attack, C1-INH activity in HAE patients is below a critical level.  As a result, plasma kallikrein activity is no longer controlled and excessive levels of bradykinin are produced leading to the swelling, inflammation and pain, characteristic of an acute HAE attack.