13
2.0 Understanding How C1-INH
Deficiency Causes HAE Symptoms
By preventing the initial fall of various “dominoes” early in
these cascades, C1-INH inhibits the production of brady-
kinin, a potent mediator of vascular permeability that occurs
downstream in the KKS. Without this regulation, individuals
with HAE develop spontaneous episodes of localized
cutaneous or mucous membrane edemas.
5,6,8
Cutaneous attacks can result in temporary dysfunction
and disfigurement of the affected site during the epi-
sode.
5,6,7,9,10
Attacks in the gastrointestinal (GI) mucosa can
cause symptoms of hypotension, severe cramping, vomiting,
diarrhea, and debilitating pain.
5,6,8-11
However, the most
dangerous swelling episodes are those that develop in the
upper airway and can result in asphyxiation.
5-7,9,10
In Europe, the registered indication of Berinert
®
, pnfC1-INH,
is:
•
Hereditary angioedema type I and II (HAE)
•
Treatment and pre-procedure prevention of acute
episodes
in adult and pediatric patients.
HAE is an inherited disease due to a quantitative and/or
qualitative deficiency in C1-INH, the primary regulator of
mediators of inflammation and vascular permeability. HAE
was described clinically by Quincke in 1882 and mapped
through 5 generations by Osler in 1888.
2,3
However,
it wasn’t until 1963 that Donaldson and Evans defined
C1-INH deficiency as the biochemical defect underlying
the condition.
4
C1-INH exerts its effect by acting as a brake on target
proteases in multiple systems, including the complement
system, kallikrein-kinin system (KKS, or contact system),
fibrinolytic system, and coagulation cascade.
5-7
Chapter 2 Highlights
•
The fundamental cause of HAE is
quantitative and/or qualitative deficiency
in C1-INH, which can result from more
than 230 distinct mutations of the
SERPING1
gene.
•
C1-INH is the primary control protein
that downregulates 4 interconnected
pathways that, among other effects,
mediate inflammation and vascular
permeability and the formation of
bradykinin.
2.1 Brief Synopsis of C1-INH Deficiency in HAE
HAE
