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