Pathophysiology

Complement-1 Esterase Inhibitor (C1-INH) is a member of the serpin family of proteases. These proteins inactivate their target proteases by forming stable, one-to-one complexes with the protein to be inhibited. C1-INH is the only inhibitor of C1r and C1s, the classical complement pathway proteases. It also regulates kinin generation via inactivation of factors XIIa plasma and plasma kallikrein.

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 (Eun, Davis 2002).

Hepatocytes are the primary source of C1-INH, though 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 (Prada 1998).

The regulation of the 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.

All C1-INH deficient patients are heterozygous, which in most cases is insufficient to prevent attacks. In many attacks, no triggering effects are known (Frank 2006).

The actual factor or factors responsible for triggering attacks and the subsequent angioedema remains somewhat controversial. Studies have demonstrated 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 (Davis 2005, Cugno, et al. 2003, Frank 2005).

C1-INH is by far the most efficient inhibitor of factor XIIa (Schousboe 2003). Further, since C1-INH binds with C1, kallikrein, plasmin and XIIa, these proteins may play a role in the triggering/maintenance of angioedema.

Plasmin is the chemical responsible for dissolving blood clots. A lack of binding in plasmin means that the formation of initial blood clots is difficult, a problem that is exacerbated by high levels of unbound kallikrein, which allows higher than normal blood flow.

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 one site.

For more information about HAE see: