Pathophysiology

In hereditary angioedema (HAE), the low levels of functional C1-INH in plasma lead to unregulated activation of the complement, contact, fibrinolytic, and coagulation cascades and the development of angioedema with its associated complications. Complement system activation results in decreased levels of C4 and C2, while contact system activation results in cleavage of high-molecular-weight kininogen.10

Hepatocytes are the primary source of C1-INH, although a number of other cell types, including peripheral blood monocytes, microglial cells, fibroblasts, endothelial cells, the placenta, and megakaryocytes, also synthesize and secrete the protein both in vivo and in vitro.10

The regulation of protein production is not completely understood, but since patients respond clinically to androgen therapy with increased levels of C1-INH, androgens apparently stimulate C1-INH synthesis in the liver.10

Which factor or factors are responsible for triggering attacks and the subsequent angioedema remains a subject of controversy. Studies have demonstrated that activation of the kinin system and increased bradykinin concentrations may be responsible for the vasodilation and capillary leakage associated with clinical flares. However, other components of the alternative pathways that C1-INH regulates may play a role in the initiation and continuation of the expression of bradykinin.10

C1-INH is by far the most efficient inhibitor of factor XIIa. Furthermore, since C1-INH binds with C1, kallikrein, plasmin, and XIIa, these proteins may play a role in the triggering/maintenance of angioedema.11

With the absence or dysfunction of the C1-INH protein, the functions of blood flow, blood clotting, and immune response are impaired in individuals affected by hereditary angioedema and thus not normalized by treatments that act at only 1 site.2

Registration

Register for updated information on HAE disease management.

MOA of an acute treatment

Learn how an acute treatment for HAE works. Find out more.

Diagnosing HAE

HAE is often misdiagnosed because its symptoms mimic those of other conditions, such as allergic reaction, acute appendicitis, and gallbladder attack. Learn more about diagnosing HAE.