Symposium: Hereditary Angioedema Update

HAE Update: Special considerations in the female patient

with hereditary angioedema
Bob Geng, M.D. and Marc A. Riedl, M.D., M.S.

ABSTRACT
This review on hereditary angioedema (HAE) focuses on special topics regarding HAE in female patients. HAE is a

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bradykinin-mediated disorder, and the role of hormonal regulation of disease expression will be discussed focusing on the effect
of estrogen on disease mechanism. The impact of exogenous estrogen on symptom exacerbation leads to special consideration
regarding choice of contraceptives and safety of hormone replacement therapy. The effects of pregnancy and childbirth will be
examined on the course of disease control. Unique considerations regarding therapeutic management for female HAE patients

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will be addressed, including the role of C1 inhibitor (C1-INH), ecallantide, and icatibant. Finally, this review will provide an
overview of the more recently characterized HAE with normal C1-INH (HAE type III) that predominantly affects women and
is in some cases associated with factor XII gene mutations.
(Allergy Asthma Proc 34:13–18, 2013; doi: 10.2500/aap.2013.34.3635)

H ereditary angioedema (HAE) is a rare genetic dis-

order causing transient swelling of subcutane-

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resulting in clinical manifestation of localized subcuta-
neous edema. In the contact activation system, prekal-

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ous and submucosal tissues of the face, tongue, upper likrein is converted to kallikrein in the presence of
airway, extremities, genitals, and gastrointestinal tract factor XII, and kallikrein then cleaves high–molecular
that generally lasts for several days if left untreated. weight kininogen to form bradykinin. Unlike hista-
The estimated prevalence ranges from 1:10,000 to mine-mediated angioedema, HAE presents without ur-

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1:50,000.1 Unrecognized and untreated edema of the ticaria or pruritus. There are currently three identified
upper airways can lead to asphyxiation and death. types of HAE with the first two related to mutations
Underrecognized angioedema of the gastrointestinal leading to deficiency of complement C1 inhibitor (C1-
tract can present as severe abdominal pain often lead- INH) activity. C1-INH regulates the contact activation
ing to unnecessary surgical intervention. Although system by inhibiting factor XII and kallikrein, and de-

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HAE clinical symptoms are highly variable, women ficiency in C1-INH thus leads to increased bradykinin
generally suffer a more severe clinical course.2 Recent production. HAE type I represents ⬃85% of HAE due
epidemiological studies indicate that women account to C1-INH deficiency and is defined as a quantitative
for 56.5% of angioedema-related emergency depart- deficiency of C1-INH. HAE type II represents 15% of

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ment visits and two-thirds of HAE-related hospitaliza- C1-INH– deficient HAE and is defined as a functional
tions.3,4 deficiency of C1-INH (normal level but abnormal func-
HAE symptoms are mediated by the vasoactive pep- tion).1 Both types are inherited in an autosomal dom-
tide bradykinin, a product of the contact activation inant pattern with high penetrance but variable expres-
system, which leads to increased vascular permeability sivity.1 The third type of HAE is identified as HAE
with normal C1-INH (HAE type III). The pathophysi-
ology of this familial condition is poorly understood,
From the Section of Clinical Immunology and Allergy, Department of Medicine, although it appears bradykinin-mediated and a sub-
University of California, Los Angeles–David Geffen School of Medicine, Los Angeles, group of affected individuals carry mutations in coag-
California ulation factor XII possibly leading to dysregulation of
From the Eastern Allergy Conference, June 1, 2012, Palm Beach, Florida
MA Riedl is a grant recipient, consultant and speaker for CSL Behring, Dyax, Shire, the contact activation system.5
Pharming, ViroPharma and Biocryst. B Geng has no conflicts of interest to declare
pertaining to this article
Address correspondence and reprint requests to Marc A. Riedl, M.D., M.S., Univer-
sity of California, Los Angeles–David Geffen School of Medicine, 10833 Le Conte
HORMONAL INFLUENCES ON HAE
Avenue, 37-131 CHS, Los Angeles, CA, 90095 SECONDARY TO C1-INH DEFICIENCY
E-mail address: mriedl@mednet.UCLA.edu
Copyright © 2013, OceanSide Publications, Inc., U.S.A.
Female sex hormones appear to play a significant
role in the regulation of disease course in HAE. Al-

Allergy and Asthma Proceedings 13

though symptoms vary widely between individuals, are well tolerated in HAE, and evidence shows they
overall female patients present with more severe may improve disease course in some patients.6 Intra-
symptoms.1 A significant number of female patients uterine devices (IUDs) have been tolerated well by 83%
describe disease worsening during puberty, and some of women in the PREHAEAT study.6 Either progester-
describe more frequent attacks just before or during one-eluting or copper-T IUDs can be used, but estro-
menses. Use of exogenous estrogen in the form of oral gen-eluting IUDs should be avoided.
contraception (OC) and hormone replacement therapy

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(HRT) has been shown to worsen disease.6 Studies
show that 60 – 80% of HAE patients on OC with estro- PREGNANCY, LABOR, AND DELIVERY IN HAE
gen reported increased frequency and/or severity of PATIENTS

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disease exacerbations.6,7 Pregnancy is associated with various effects on the
Hormonal regulation of disease severity in HAE was disease course of HAE. The first trimester appears to be
examined in the European PREHAEAT (novel meth- associated with greater severity of HAE symptoms.1,11
ods for predicting preventing and treating attacks in The second trimester is associated with the lowest

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patients with hereditary angioedema) study that col- symptom profile during pregnancy. It is hypothesized
lected data from 150 postpubertal women with HAE that this effect may be secondary to consistent and
secondary to C1-INH deficiency. The study examined proportional hormone levels between estrogen and
the influence of puberty, menstruation, and meno- progesterone.1 The severity of disease rises again dur-

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pause on the course of disease. Puberty appeared to ing the third trimester likely secondary to continued
have worsened disease in 62% of patients with 38% rise of estrogen and placental prolactogenic hor-
reporting no change.6 Menstruation triggered HAE at- mone.1,11 Aside from increased abdominal exacerba-
tacks in 35% of patients and ovulation triggered attacks tions, the anatomic region of angioedema episodes was

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in 14% of patients.6 Use of combined OC was associ- found to be the same in patients before and during
ated with exacerbations in 80% of patients, and for use pregnancy.11 Pregnancy was associated with increased
of progesterone only OC was associated with improve- exacerbations in 38% of patients and decreased exac-
ment in 64% of patients.6 This provides some evidence erbations in 30% of patients.6 Thirty-two percent of

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that estrogen is an important factor influencing disease patients showed no change of symptoms during preg-
severity. However, menopause was reported to have nancy.6
worsened disease in 32%, resulted in no change for HAE secondary to C1-INH deficiency rarely presents
55%, and was only associated with improvement of for the first time during pregnancy.1 However, the

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symptoms in 13% of patients.6 diagnosis of C1-INH deficiency during pregnancy is
Estrogen has been shown to affect the kallikrein- potentially complicated given that serum C1-INH con-
kinin and coagulation systems, both of which are key centration falls during pregnancy because of increased
elements of the pathogenesis of bradykinin-mediated total body plasma volume.1 Pregnant patients without
angioedema. In animal models, female rats had three- HAE can develop a temporary decrease in the C1-INH

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to fourfold higher levels of kininogen mRNA in the concentration that returns to a normal baseline after
liver than male rats.8 In the same study, estradiol sup- delivery.12 Therefore, if HAE secondary to C1-INH
plementation of ovariectomized female rats showed deficiency is suspected during pregnancy, it is impor-
up-regulation of both kininogen and kallikrein gene tant to conduct postpartum C1-INH concentration test-

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expression in vivo.8 Animal models also showed up- ing.1
regulation of bradykinin 2-receptor gene expression and Several factors may influence the highly variable
function by estrogen.9 In women taking exogenous estro- course of HAE during pregnancy. First, early onset of
gen (OC or HRT), estrogen has been associated with symptoms in life is associated with greater severity and
elevations in factor XII, prekallikrein, kallikrein, and frequency of exacerbations during pregnancy.11 Sec-
high–molecular weight kininogen.10 These changes may ond, having a fetus with HAE secondary to C1-INH is
lead to increases in bradykinin production and C1-INH associated with increased frequency of attacks dur-
consumption that could result in exacerbations of HAE.6 ing pregnancy.1 The postulated mechanism explain-
ing this phenomenon is that C1-INH protein is trans-
ferred through the placental circulation into the fetus
CONTRACEPTION AND HAE and consumed in the fetal circulation.11 Third, the
Given the deleterious effects of estrogen on disease PREHAEAT study correlated symptom triggering during
control, contraception in female HAE patients presents menses with exacerbations during pregnancy. Of 37 women
special challenges. Estrogen-containing contraceptives who reported triggering of attacks by menses, 59% re-
should not be used. This is not limited to oral supple- ported exacerbations during pregnancy.6 Of 70 women
mentation, but includes estrogen-containing patches who did not report any change with menses, only 24%
and vaginal rings. Progesterone-only contraceptives reported exacerbations during pregnancy.6 Therefore,

14 January–February 2013, Vol. 34, No. 1

disease exacerbation during menses may be a prognostic system such as icatibant (bradykinin B2-receptor an-
factor for worsening of HAE during pregnancy. Finally, tagonist) or ecallantide (inhibitor of plasma kallikrein
although some studies show that the course of disease preventing the generation of bradykinin). If none of the
during previous pregnancies does not provide useful previously mentioned proven options are available,
prediction for the course of disease in subsequent preg- fresh frozen plasma (FFP) may be used. To date, no
nancies,1 the PREHAEAT study showed that the effects female-specific adverse effects have been identified for
on HAE symptoms were consistent for subsequent preg- the aforementioned agents, although, currently, a pau-

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nancies.6 city of safety date exists during pregnancy and lacta-
Management of HAE patients during labor and de- tion.1
livery requires special consideration. The process of For preprocedural prophylaxis in nonpregnant fe-

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labor and delivery rarely causes HAE exacerbation. male patients, the treatment options are similar to that
According to the PREHAEAT study, only 6% of of the general HAE population.15 Plasma-derived C1-
women experienced an attack immediately or within 2 INH is useful for this indication or androgen therapy
days of delivery, and 89% of those women received no (danazol) may be administered for several days before

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prophylactic treatment during delivery.6 However, af- surgical, dental, or other invasive procedures.16 Short-
ter childbirth the incidence of vulvar edema is shown term use of androgens for preprocedural prophylaxis
to be higher than the incidence of genital edema before has not been observed to cause virilization in female
pregnancy.1 Additionally, there have been reports of patients.1 If the aforementioned agents are not avail-

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occasional worsening of symptoms during the postpar- able, FFP use may be considered. Although no data
tum period.13 HAE is not associated with an increased exist on the efficacy of antifibrinolytics as preproce-
number of cesarean sections,1 but vaginal delivery is dural or short-term prophylaxis, some consensus state-
preferred over surgical delivery because of the like- ments and expert opinions have suggested their use-

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lihood of surgical stress/trauma provoking an at- fulness.16
tack. If cesarean section is required, epidural anes- Agents for long-term prophylaxis in nonpregnant
thesia is preferred over general anesthesia because of female patients include plasma-derived human C1-
concern that endotracheal intubation may provoke INH, androgen therapy, and antifibrinolytics.1,16 –18

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laryngeal edema.1 The effect of lactation on HAE Long-term androgen use may be difficult to tolerate for
symptoms is unclear. Limited data from one study female patients because of adverse effects including
suggests that disease exacerbation may occur during virilization, hirsutism, voice changes, menstrual distur-
the period of lactation, especially in patients who bances, and weight gain.1,19 Long-term androgen ther-

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had primarily abdominal symptoms.11 apy must be used with caution in all patients because
of possible medication-induced hepatotoxicity and hy-
HAE AND OTHER GYNECOLOGICAL percholesterolemia. Side effects are generally believed
DISORDERS to be dose dependent and may be reduced by admin-
istering the lowest effective dose. Spironolactone,
The prevalence of various gynecologic and obstetric

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which has antiandrogen effects, has occasionally been
diseases in the HAE population has been evaluated,
used to control the side effects of androgen therapy.1,20
and it does not appear that HAE leads to increased
Antifibrinolytics can be used for long-term prophylaxis
development of such disorders. In European HAE pa-
although supportive efficacy data are less robust for

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tients, spontaneous abortions occurred in 12.7% of pa-
this approach.17,18 Tranexamic acid can lead to mild
tients, benign mammary diseases in 4% of patients, and
dysmenorrhea in female patients.1 Although there ex-
sterility in 4% of patients.6 These values are all within
ists the theoretical risk of thrombosis by using an an-
the prevalence range observed in the general popula-
tifibrinolytic agent, evidence from controlled studies
tion. The prevalence of polycystic ovarian disease
has not shown increased risk for patients without ad-
(4.7%) and fibroids (5.3%) in the HAE population are
ditional risk factors for thromboembolic disease.21
lower than observed in the general population.6
Plasma-derived C1-INH is an effective agent for long-
term prophylaxis in HAE.16 No specific issues have
TREATMENT OF HAE IN WOMEN been identified related to efficacy or safety for women.
Acute treatment options for angioedema attacks in During pregnancy, the drug of choice for HAE from
nonpregnant female HAE C1-INH deficiency patients C1-INH deficiency is plasma-derived human C1-INH
are the same as for the general HAE population.14 One for acute treatment, preprocedural, and long-term pro-
option is replacement of C1-INH using either plasma- phylaxis.11,16 Although no rigorous prospective studies
derived human C1-INH or recombinant human C1- have been performed using C1-INH therapy in preg-
INH, although the latter remains investigational in the nant or lactating women, substantial retrospective data
United States. Other treatment options include tar- support the safety and efficacy of this approach.11 If
geted drugs blocking elements of the contact activation plasma-derived human C1-INH is not available, FFP

Allergy and Asthma Proceedings 15

can be used. Because of lack of data regarding effect on onset of disease within the first decade of life.2 HAE
pregnancy, more recently developed medications such normal C1-INH patients may experience more disease-
as icatibant, ecallantide, and recombinant C1-INH free intervals and the proportion of patients presenting
should be avoided during pregnancy and stopped 1 with recurrent attacks of only one anatomic location is
week before attempting conception.1 Androgen therapy higher compared with types I and II.5 Furthermore,
is contraindicated during pregnancy. Androgens can erythema marginatum has not been reported in HAE
cross the placenta and lead to virilization of female fe- normal C1-INH although patients may experience

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tuses.22 Androgens should be stopped 2 months before hemorrhaging into areas of skin swelling, a finding
attempting conception, and it is recommended that a that appears unique to this HAE subtype.5
pregnancy test should be obtained before considering the Similar to C1-INH deficiency, specific triggers have

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initiation of androgen therapy.1 Tranexamic acid crosses been associated with angioedema episodes in patients
the placenta but may be considered if necessary for long- with HAE normal C1-INH. In a series of 35 patients, 18
term prophylaxis during pregnancy. No harmful effects described attacks after acute trauma to the affected
on fetal development have been reported21 with animal area, 12 reported onset of symptoms after physical

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studies showing no evidence of teratogenicity, although pressure on the affected area, 7 reported facial and/or
no human studies have been conducted.1 Tranexamic tongue swelling after dental procedures, one reported
acid is labeled a Food and Drug Administration cate- symptoms after cold exposure.2 Some patients re-
gory B medication for pregnancy, indicating no current ported emotional stress as a possible trigger, and oth-

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evidence of risk. ers reported ingestion of various spices/herbs as trig-
Routine prophylaxis is generally not necessary for gers for abdominal attacks.2
uncomplicated vaginal deliveries.1 However, for pa- The pattern of inheritance seen in the families of
tients who have severe disease or frequent exacerba- patients identified with HAE normal C1-INH appears

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tions during pregnancy or attacks in the genital area, to be autosomal dominant2; however, the manifesta-
predelivery prophylaxis is recommended.1 Predelivery tion of disease is predominantly in women. There is
prophylaxis is also recommended for forceps-assisted evidence to suggest that the phenotypic expression is
vaginal delivery and cesarean sections.1,16 In general, it hormonally mediated or associated.2 To examine the

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is prudent to have plasma-derived C1-INH available role of estrogen on occurrence of angioedema, 35
during the peripartum period in case of exacerbations. women with HAE normal C1-INH were interviewed
Tranexamic acid and androgens are excreted into regarding the influence of OCs, pregnancies, and HRTs
breast milk such that tranexamic acid is not recom- on their symptom presentation.2 Of the 27 women who

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mended and androgen therapy is contraindicated tried OCs, 17 reported that they developed their first
while breast-feeding.1 clinical symptoms of HAE after the initiation of OCs.
Eight of the 27 women reported worsening symptoms
with use of OCs, 2 women reported no change in
HAE WITH NORMAL C1-INH (HAE TYPE III) symptoms, and none reported improvement. Of the 25

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In recent years a third type of HAE has been de- women who experienced one or more pregnancies, 3
scribed as HAE with normal quantity and function of reported development of first clinical symptoms after
C1-INH. This form of HAE, often referred to as HAE pregnancy, 7 reported worsening of existing symp-
type III, predominantly affects women with few cases toms, 10 reported no change in symptoms, and 5 re-

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of affected men described.5,23 HAE normal C1-INH is a ported improvement.2 Of the 7 women who were on
familial disease, and there are no sporadic cases re- HRTs, 3 reported worsening of existing symptoms, 4
ported in the literature.2,5,24 Currently, HAE normal reported no change, and none reported improvement.2
C1-INH is believed to be extremely rare with ⬍300 In another study with 39 HAE normal C1-INH pa-
published cases. tients, 62% reported symptoms either induced or wors-
Clinical manifestations of HAE normal C1-INH are ened by OCs or HRTs.7
similar to the other HAE subtypes including recurrent Worsening of disease during high exogenous estro-
swellings of the extremities, tongue, upper airways, gen intake and endogenous elevated estrogen state of
and gastrointestinal tract.5 Frequency and severity of pregnancy support the hypothesis that HAE normal
episodes is highly variable. However, HAE normal C1-INH is an “estrogen-sensitive” condition. Observa-
C1-INH typically presents with more frequent facial tion that the vast majority of female HAE normal C1-
and tongue swelling and less frequent abdominal at- INH patients develop their first symptoms after pu-
tacks compared with HAE types I and II.5 The age of berty also supports the role of estrogen in disease
symptom onset is older with 92% of HAE normal pathogenesis.2 However, the initiation of symptoms in
C1-INH patients experiencing first symptoms during a few prepubescent female patients, persistence of dis-
or after the second decade of life.25 In contrast, ⬎50% ease after menopause, and presence of disease identi-
of patients with HAE due to C1-INH deficiency report fied in a few male patients23 all suggest that HAE

16 January–February 2013, Vol. 34, No. 1

normal C1-INH may not be solely an estrogen-depen- published cases of danazol report efficacy in preven-
dent condition, but that the hormone is a strong cofac- tion of attacks during treatment.5 Tranexamic acid
tor for phenotype expression. showed lower efficacy than the other prophylactic
The pathological mechanism of HAE normal C1-INH agents with only two of five published cases reporting
patients is unknown. Given the marked similarities to effective prevention.5
C1-INH deficiency, underlying dysregulation of the
contact system is strongly suspected but currently un-

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CONCLUSION
proven. The postulated etiology of a subgroup of HAE
normal C1-INH is related to described mutations of the HAE is a complex condition with unique issues in
gene encoding factor XII (Hageman factor) of the coagu- the affected female population. Hormonal regulation
of disease mechanism is a significant aspect of the

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lation system.2,25,26 Two such mutations are missense
leading to threonine-to-lysine (Thr309Lys) and threonine- unique clinical issues pertaining to the management of
to-arginine (Thr309Arg) substitutions.27 These missense female HAE patients. Estrogen appears to have a del-
mutations are inherited in an autosomal dominant pat- eterious effect on the course of disease in all types of

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tern with incomplete penetrance.2 A third mutation in- HAE, and its exogenous intake is clearly contraindi-
volves a deletion of 72 base pairs in the same gene cated in HAE patients. The effect of pregnancy is vari-
region as the missense threonine substitutions.26 These able and can either improve, worsen, or have no effect
mutations of factor XII discovered in a small subgroup on the course of disease for individual patients. Plas-

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of the described HAE normal C1-INH population have ma-derived human C1-INH is currently considered the
been proposed to be associated with gain-of-function treatment of choice during pregnancy for acute attacks,
of the coagulation factor leading to up-regulation of preprocedural and long-term prophylaxis. Additional
contact activation system and increased bradykinin re- studies are needed to assess the safety of newer ther-
apeutic agents during pregnancy.

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lease.5,26 However, data regarding the effect of these
mutations on factor XII activity are conflicting and thus HAE normal C1-INH (type III) is a more recently
the importance of such mutations in the pathogenesis recognized and rare subtype of HAE predominately
of this condition is currently unclear. affecting women. Estrogen is again found to be an
exacerbating factor, and any exogenous intake is con-

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Although the exact mechanism of HAE normal C1-
INH is uncertain, several factors strongly support a traindicated. Understanding of the pathophysiology of
bradykinin-mediated pathophysiology. First, absence of HAE normal C1-INH is still developing, but current
urticaria and inefficacy of corticosteroids and antihista- data support bradykinin-mediated symptoms and a

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mine therapy support a nonhistaminergic process. Sec- subgroup of patients are found to have mutations in
ond, estrogen with its known effects on the kinin system coagulation factor XII. If or how such mutations result
also leads to worsening of disease in HAE normal C1- in dysregulated bradykinin production is currently un-
INH.6,8,9 Third, angiotensin-converting enzyme inhibi- clear. To date, the treatment recommendations for
tors with known effects on bradykinin can exacerbate HAE normal C1-INH are based on individual reports

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attack frequency and severity. There is limited evidence and case series. For acute treatment, efficacy has been
from case reports that angiotensin II receptor blockers reported for plasma-derived human C1-INH, icatibant,
may be associated with disease exacerbation in some and ecallantide. Progesterone, attenuated androgens,
patients. Although angiotensin II receptor blockers are and tranexamic acid have been shown to have some

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generally believed to be well-tolerated in HAE.26,28 benefit when used for long-term prophylaxis. How-
Currently, there are no controlled trials of medica- ever, more rigorous controlled studies will be helpful
tions for prophylactic or acute treatment of angio- in establishing stronger treatment recommendations
edema episodes due to HAE normal C1-INH. For acute for patients affected by this condition.
attacks, steroids and antihistamines are ineffective.5
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