Hereditary angioedema and bradykinin-mediated angioedema

Hereditary angioedema &
Bradykinin-mediated
angioedema
Suda Sibunruang, M.D.

Zuraw BL. and Christiansen SC. Middleton’s Allergy Principle and Practice. 8th edition, 2014
Angioedema
Asymmetric, non-dependent, non-pruritic, swelling
involving cutaneous or mucosal surfaces

Kulthanan K. et. al. Clinical and Developmental Immunology 2007; article ID 26438:1-6
Records of OPD patients  15 yr with angioedema
between 2005-2006 were retrospectively reviewed
• 105 patients, 82 cases (78.1%) were female
• Mean age 39.4 ± 18.4 yrs (ranged 15-88 yrs)
• 55 (52.4%) had angioedema without urticaria
Bradykinin mediated angioedema 25 (23.8%)

Cicardi M. et. al. Classification, diagnosis, and approach to treatment for angioedema:
consensus report from the Hereditary Angioedema International Working Group. Allergy 2014;69:602–16

Epidemiology

Bork K. et. al. Lancet 2000;356:213–17
Hereditary angioedema with normal C1-inhibitor activity in women
• In 1985, Bork K. assessed a large family, in which five
women had recurrent angioedema with normal C1-inhibitor
function
• We assessed other families with similar cases at
angioedema clinic from 1986 to 1999
• Results:
- 10 women with recurrent angioedema and
normal C1 INH
- Family history disclosed another 26 affected women
- Of those, 14 could be studied and had normal
C1-inhibitor concentration and function
• Occasional:
- Onset after oral contraceptives (OC) started
- Limited to time when OC are given or
when patient is pregnant

Bork K, et. al. Br J Dermatol 2006;154:542-5
Hereditary angio-oedema with normal C1 inhibitor
in a family with affected women and men

Bork K. Immunol Allergy Clin North Am 2006;26:709-24

Bouillet L. et al. Immunol Allergy Clin N Am 2013;33:505–11
Caballero T. et. al. International consensus and practical guidelines on the gynecologic and obstetric management of female patients
with hereditary angioedema caused by C1 inhibitor deficiency. J Allergy Clin Immunol 2012;129:308-20
Estrogens regulate B2 receptor gene expression and function

• Lymphoma
• CLL
• MGUS
• Myeloma
• W. macroglobulinemia
• Cryoglobulinemia
• Echinococcus
granulosus
• Rheumatoid arthritis
• SLE
• AIHA
• Adenocarcinoma of
gastric
• Carcinoma of breast,
pancreas, bladder,
colon, rectum
Literature on acquired C1 INH deficiency
Zingale LC, et. al. Immunol Allergy Clin North Am 2006;26:669-90

Epidemiology
Polymorphisms in
XPNPEP2/APP associated
with higher risk

Abbas AK et al. Cellular and Molecular immunology. Eighth Edition
C1 INH: Regulation of complement activation
Pathogenesis: C1 INH deficiency

• Complement system proteases C1r and C1s
• Mannose-binding lectin pathway proteases
• Contact system proteases
• Plasma kallikrein
• Factor XIIa and factor XIIf
• Intrinsic coagulation pathway protease factor Xia
• Fibrinolytic pathway protease plasmin
C1INH involves in regulating the activity of multiple proteases

Davis AE. Clin Immunol 2005;114;3–9
Longhurst H. and Cicardi M. Lancet 2012;379:474–81
Overactivation of classical and lectin pathways
does not progress to common pathway and
C3 concentration is typically normal,
probably because reactions occur in fluid phase
Abnormalities in complement pathway are
important in diagnosis, but are
probably not responsible for swellings

Bradykinin can be released from kininogen through 2 distinct pathways
1. Cleaving of HMWK
by plasma kallikrein
2. Cleaving of LMWK
by tissue kallikrein
(Carboxypeptidase N)
(Aminopeptidase P)
(Dipeptidyl-peptidase 4) (Neutral endopeptidase)
3. Bradykinins can be converted to
their des-Arg products by CPN
4. Bradykinins are degraded into
inactive peptides by other kininases B1 BKR is expressed after inflammatory stimuli.
Physiological role is unclear, it might also have a role in
pathogenesis of HAE

Swelling in angioedema results from
increased vascular permeability
Paracellular fluid movement in endothelial cells is restricted by vascular endothelial
cadherin (VE-cadherin) that make up adherens junction
• Extracellular domains link adjacent
endothelial cells
• Intracellular domain binds β-catenin
and p120-catenin, which stabilize
VE-cadherin

1. Activation B2 BKR initiates a signaling cascade in which
phospholipase C increases intracellular Ca2+

2. Intracellular calcium flux activates
• endothelial nitric oxide synthase (eNOS) and phospholipase A2 (PLA2),
which makes vasodilator and permeability-enhancing molecules
• Protein kinase C
3. Protein kinase C:
• Phosphorylates VE-cadherin,
β-catenin and p120-catenin
• Absence of stabilizing catenins,
VE-cadherin is internalized and
degraded
• PKC activates GTPase RhoA,
along with myosin light chain kinase
• Contraction of actin cytoskeleton
that leads to wider gaps between
endothelial cells

Contraction, altogether with a loss of VE-cadherin
adherens junction and vascular dilatation >>
fluid move from vascular to interstitial space

• Autosomal dominant
• More than 280 mutations have been reported in patients with HAE
• Type I HAE mutations, occur throughout SERPING1 gene, and may involve missense, nonsense,
deletion, or insertion mutations. As a consequence, mutant C1INH protein is not secreted.
• Type II HAE mutations, are almost always missense mutations involving region of gene at or near
active site on reactive mobile loop, resulting in secretion of a protein that cannot form
inhibitory complex with its target proteases
• 25% of patients presumably have a de novo mutation of C1INH gene
HAE type I & II are resulted from mutations in SERPING1 gene

G. Dewald and K. Bork. Biochemical and Biophysical Research Communications 2006;343:1286–9
Missense mutations in the coagulation factor XII (Hageman factor)
gene in hereditary angioedema with normal C1 inhibitor
• Hypothesized that abnormal coagulation
factor XII molecule may lead to inappropriate
activation of kinin-forming cascade, therefore
performed a search for mutations in F12 gene
• Screened 20 index patients and
145 German blood donors served as controls
• 2 missense mutations were identified in exon 9
of F12 gene in 6/20 patients
• These mutation were absence in controls
threonine-to-lysine substitution
threonine-to-arginine substitution

Bork K. Immunol Allergy Clin N Am 2013;33:457–70

Zingale LC, et. al. Immunol Allergy Clin North Am 2006;26:669-90
Acquired C1 INH def: Increased catabolism of C1INH
that outstrips normal capacity of host to synthesize C1INH

Picture from www.aaia.ca, access September 2015
Clinical Features
Sites: face, oropharynx, extremities,
abdomen, genitourinary tract
Less frequent: brain, kidney, heart, and joints

Bork k. et. al. American Journal of Medicine 2006;119:267-74
Survey from 221 pts with C1 inhibitor deficiency with 131,110 episodes

Picture from www.aaia.ca, access September 2015
Clinical Features
Sites: face, oropharynx, extremities,
abdomen, genitourinary tract
Less frequent: brain, kidney, heart, and joints
Course: gradual worsening over the first 24 hrs,
followed by an even slower recovery
over the next 48 -72 hrs
Variability in attack kinetics can be seen
Severity is highly variable and
can not be predicted at onset
Frequency: twice per week to less than 1/yr
Onset: 50% of patients begins before age of 10 yrs
Worsening of symptoms around puberty
Occasionally, begin in late teens or
early adulthood
Although some patients appear to decreased symptoms as they age,
others continue to experience HAE attacks throughout their lives

US Hereditary Angioedema Association
Erythema marginatum
Serpiginous, nonpruritic rash, characterized by red rings that
appear on trunk and appendages
Prodromal symptoms
Precede an attack by several hours or
day in up to 50% of patients
Erythema marginatum, localized tingling,
and a sense of skin tightness
Others include fatigue, malaise,
flu-like symptoms,
irritability, mood changes, hyperactivity,
thirst, and nausea

Shiber JR. N Engl J Med 2005;353:e15
Angioedema of arytenoids; lisinopril
In HAE:
• Mortality rate due to laryngeal angioedema of approximately 30%
• More than half experience at least one laryngeal attack
• All patients are at risk for potential laryngeal attack
irrespective of prior disease severity

Severe abdominal pain with
intractable nausea and vomiting, and
“third spacing” of fluid can induce hypotension
Capsule endoscopy during abdominal attack
Pain intensity during severe abdominal attack
Symptoms are at maximum intensity for up to 24 h
before spontaneously resolving in a further day

Cicardi M. and Zanichelli A. Immunol Allergy Clin N Am 2013;33:449–56

Caballero T. et. al. J Investig Allergol Clin Immunol 2011;21:422-41
Triggers factors

Hereditary angioedema with
normal C1 INH
• More likely to affect females, men tend to
have milder symptoms
• Less likely to manifest before puberty
• Tend to have fewer attacks
• Higher percentage of facial and tongue
episodes
• No definitive lab to confirm
• Diagnosis is one of exclusion

Bork K, et. al. Allergy 2015;70:1004-12
Hereditary angioedema with normal C1-INH
with versus without specific F12 gene mutations
HAE-FXII
(n=69)
HAE-unknown
(n=196)
Male: female 1: 68 1: 6.3
Mean age at onset
(yr)
20.3 29.6
Impact of OC &
pregnancy
Higher -
Incidence of
asphyxiation due to
angioedema
Similar Similar
No abnormalities were found for C1-INH protein, C1q, alpha2-macroglobulin,
antithrombin III, and angiotensin-converting enzyme

Acquired C1 INH deficiency
• Onset at a relatively older age
• Lack of family history

Non-histaminergic idiopathic
angioedema
• Lack of response to usual treatments for mast
cell–dependent angioedema

Laboratory criteria
After first year of age:
• C1 inhibitor antigen concentration <50% of normal
values obtained on 2 separate occasions
• C1 inhibitor function <50% (chromogenic assay) or
<84% (ELISA assay; of normal values obtained on two
separate occasions
Mutation in C1-inhibitor gene that modifies protein
synthesis or function

Bradykinin-mediated angioedema
• Slower evolution
• Longer duration
• Lack of urticaria
• Failure to respond to
antihistamines or corticosteroids
C4 level is an excellent screening tool
for C1INH deficiency in patients > 1 year
• Reduced C4 level even between attacks
in at least 95% of patients
• Increasing to virtually 100% during
attack
Normal C4 level during an attack strongly
suggests a diagnosis other than C1INH deficiency

Wagenaar-Bos I. et. al. Journal of Immunological Methods 2008;338:14–20
Functional C1-Inhibitor diagnostics in hereditary angioedema:
Assay evaluation and recommendations
Obj: evaluated performance of fC1- Inh assays in 15 different laboratories that are specialised in HAE diagnostics
Chromogenic assay in 13 labs
ELISA in 2 different labs
• Chromogenic assay measures inhibition activity of
target protease C1s by C1-Inh in the plasma sample to be tested
• ELISA assay detects complexes formed between C1Inh and
C1r or C1s following activation of C1
• Chromogenic assay:
PPV 98 %
NNV 100 %
• fC1-Inh is more stable in plasma than in serum and
samples should be stored at or below −20 °C

Cugno M. et. al. Allergy 2009:64:254–7
Plasma biomarkers of acute attacks in patients with
angioedema due to C1-inhibitor deficiency
Background: coagulation and fibrinolysis systems are activated during attack
Obj: To investigate whether markers of thrombin generation (prothrombin fragment F1 + 2)
and of fibrin degradation (D-dimer) can be used to diagnostic of angioedema from
C1-INH deficiency, especially in abdominal attacks
Participants: 28 pts with C1-INH deficiency during acute attacks and remission
35 pts without C1-INH deficiency during abdominal colics
20 healthy subjects
During acute angioedema attacks, patients with C1-INH deficiency
have high prothrombin fragment F1 + 2 and D-dimer levels

Syndrome C4 Level C1INH
Antigen
C1INH
Function
C1q Level
Type I HAE Low Low Low Normal
Type II HAE Low Normal Low Normal
HAE with normal
C1INH
Normal Normal Normal Normal
Acquired C1INH
deficiency
Low Low Low Low
ACE-I–associated Normal Normal Normal Normal
Nonhistaminergic
idiopathic
Normal Normal Normal Normal

A focused parameter update: Hereditary angioedema, acquired C1 inhibitor deficiency, and angiotensin-converting enzyme inhibitor–associated angioedema. J Allergy Clin Immunol 2013;131:1491-3
Treatment
• Acute treatment (on demand)
• Prophylaxis
- short term
- long term
All patients with HAE have a management plan

From www.aaia.ca, access September 2015

Castelli R. et. al. Immunopharmacology and Immunotoxicology 2013;35:181–90
FFP

Earlier an attack is treated, less fluid will have moved from
plasma space into interstitial tissue, resulting in less morbidity
and faster recovery

Nanofiltered C1 inhibitor concentrate
• C1 inhibitor was purified from plasma by
a combination of cryoprecipitation,
ion-exchange chromatography, and
polyethylene glycol precipitation
• The resulting C1 inhibitor fraction was
pasteurized, double nanofiltered with the use
of 15-nm Planova filters and lyophilized
Zuraw BL. et al. N Engl J Med 2010;363:513-22

Zuraw BL. et al. N Engl J Med 2010;363:513-22
2 RCT: 1. Compared nanofiltered C1 inh with placebo for
treatment of acute attack of angioedema
Primary end point: time to onset of relief
2. Crossover trial compared prophylactic twice-weekly
injections of nanofiltered C1 inh with placebo
during two 12-week periods
Primary end point: number of attacks
22 subjects
Results:
1st study: median time 2 hrs in C1 INH group
4 hrs in placebo group
(p = 0.02)
2nd study: number of attacks /12 wks 6.26 in C1 INH
12.7 in placebo
(p < 0.001)
C1 INH significant reduced severity and duration of
attacks, open-label rescue therapy, total number of
days with swelling

Frank MM. Immunol Allergy Clin N Am 2013;33:495–503
Reduced in;
- Severity
- Shorter duration of attacks
- Lower total no. of days
of swelling
- Fewer on-demand C1-inhibitor
However, do not completely
abolish attacks

Ecallantide
• Recombinant protein kallikrein antagonist that
is synthesised in Pichia pastoris
• In 3 double-blind placebo-controlled studies,
ecallantide was better than placebo in
improving symptoms
• Subcutaneous formulation of ecallantide
improves convenience

Ecallantide
However, administration outside a healthcare
facility is not recommended;
187 pts given to sc. ecallantide
• 4% had hypersensitivity events, including
anaphylaxis in 2%
• 8% of participants developed antibodies to
either P. pastoris or ecallantide itself

Van Veen HA. et. al. Journal of Biotechnology 2012;162:319–26
Recombinant human C1 inhibitor
Transgenic rabbits harbor the genomic C1INH gene
rhC1INH expresses in milk
Harvest and purification
Therapeutic application of C1-Inh in inflammatory diseases like sepsis, acute myocardial infarction and
vascular leakage syndrome seems promising, but large doses may be required.
Therefore, a high-yield recombinant expression system for C1-Inh is very interesting.
Bos I. et. al. Biochimica et Biophysica Acta 2003;1648:75– 83
Pichia pastoris
Picture from 2013.igem.org, access September 2015
Different glycosylation results in a much reduced half-life of mean 3 h compared
with 24 h or more for plasma-derived C1 inhibitors

Craig T. et. al. WAO Journal 2012;5:182–99
They all appear to be highly effective, but data allowing direct comparisons are lacking

Craig T. et. al. WAO Journal 2012;5:182–99
Plasma occasionally induce an acute exacerbation, presumably
because plasma contains uncleaved HMWK in addition to C1INH
Management of oropharyngeal-laryngeal attacks is
primarily on maintaining the patency of airway

Prophylactic treatment
• Short term
Protect against the likelihood of experiencing attacks after
a stimulus known to precipitate attacks
• Long term
Decrease frequency or severity of attacks

Long-term prophylaxis
Not all patients require, decision to provide
must be individualized;
• Attack frequency and severity
• Location of attacks
• Access to acute care
• Presence of comorbid conditions
• Patient preference
Need for long-term prophylaxis may change in
a particular patient over time

Optimal dose should be based on clinical response,
rather than on C1INH level or C4 level

-Both efficacy and side effects of
androgens are dose-related
-If androgens are used, dosage must
be titrated to lowest dose that provides
effective control of attacks
-Caution should be exercised if dose
> 200 mg/day for long-term prophylaxis
Relative contraindications:
- Children
- Breast or prostate cancer
- Preexisting hepatic dysfunction
- Pregnant

Antifibrinolytic agents are effective and relatively safe
but generally is less effective than androgen

Tourangeau LM, et. al. Int Arch Allergy Immunol 2011;157:417-24
Background: C1INH is most effective when administered early. Home infusion of C1INH allows for the earliest
possible intervention since patients can initiate therapy at first sign of symptoms
Method: 39 subjects with HAE utilizing 2 groups : one receiving on demand C1INH therapy in medical facility and
the other self-managing on-demand C1INH therapy in home setting under supervision of a treating physician
A registered nurse provided training in the majority of cases. Physician supervised the process
Duration: 8 wks
Safety and Efficacy of Physician-Supervised
Self-Managed C1 Inhibitor Replacement Therapy
Results
- Attack frequency was similar
- Significant decreases in
attack duration (p < 0.0001)
pain medication use (p < 0.0001)
attack severity (p < 0.005)
in subjects who received C1INH at home
- Home group experienced more frequent
injection-related side effects
- Clinic group noted more severe adverse
events from C1INH
Severity of attacks Duration of attacks

Adjunctive strategies
• Avoid ACE-I drugs
• Avoid birth control pills containing estrogen
and estrogen replacement therapy
• Lifestyle modifications to address triggers
such as stress

Treatment of HAE with normal C1 INH
• No controlled treatment studies
• May respond to many of the same drugs as in
patients with HAE due to reduced C1INH
• Some had improved on long-term prophylactic
therapy with danazol, progesterone, or
tranexamic acid

Treatment of acquired C1 INH
deficiency
• Treatment of underlying disorder
• C1INH autoantibodies require a higher dose of
pdC1INH or are even resistant to pdC1INH
• Retuximab has induced remission in a small
group of patients with acquired C1INH
deficiency, C1INH autoantibodies, and severe
frequent attacks
• Antifibrinolytics appears to be more effective
than androgens for long-term prophylaxis

Diagnosis during pregnancy
• Rare for HAE-C1-INH manifestations to
present for the first time during pregnancy
• C1-INH testing for diagnosing should be
interpreted with caution because C1-INH
decrease during pregnancy in relation to the
increase in plasma volume
• Testing for C1-INH should be repeated
postpartum to confirm diagnosis

Prenatal diagnosis
• Is rarely requested
• No clear genotype-phenotype correlation
• It can only be performed if disease-causing
mutation of affected parent is known
• Genetic testing for specific mutation is performed
with cells from a chorion villus sample taken after
GA 10th wk or from an amniotic fluid sample
extracted after GA 15th wk. A chorion villus
sample is preferable.
• Preimplantation genetic diagnosis (PGD) might be
more attractive

HAE in neonates and infant
Diagnosis
• C1-INH level in umbilical blood of neonates is
approximately 2/3 of normal adult
• C1 INH reaches levels for mature adults at 6 - 36
months
• C4 reaches levels at 2-3 yrs
• False-positive and false-negative HAE-C1-INH test
results can occur in infants < 12 months, additional
tests to confirm should be performed at a later age
• Genetic testing might be a safer and more direct way,
however disease-causing mutation in family must be
known

Clinical course
• Pregnancy can mitigate, aggravate, or have no
effect on HAE
• Frequency of attacks during previous
pregnancies is not useful for predicting events
in later pregnancies
• Early onset of HAE-INH is associated with
more frequent and more severe attacks during
pregnancy
• Abdominal attacks occur more frequently

Labor and delivery (1)
• Attacks can occur immediately or within
48 hrs of delivery, however rarely
• 80- 90% of births are vaginal deliveries, rate of
cesarean section is not higher than in general
population (2008-2010)

• Routine prophylaxis before uncomplicated
deliveries is not recommended, but pdhC1INH
should be readily available
• Short-term prophylaxis is recommended when
HAE-C1-INH is severe and frequently recurrent
during 3rd trimester or medical history of
genital edema caused by mechanical trauma

• pdhC1INH is recommended if forceps delivery
or vacuum extraction is performed
• After delivery, patients with marked perineal
swelling or other postpartum complications
should be considered at higher risk for acute
attacks, closely monitored for 72 hours after
delivery, and treated with pdhC1INH when
necessary

• Epidural anesthesia is recommended for
cesarean sections to avoid endotracheal
trauma
• STP is recommended with pdhC1INH

Treatment
• pdhC1INH is the first line
• Antifibrinolytics can be administered if C1-INH
is not available
• Androgen are contraindicated

Prophylaxis
• pdhC1INH appears to be safe and effective during
pregnancy and lactation
• Treatment is usually administered during the 2nd half of
pregnancy
• Tranexamic acid is excreted into breast milk, therefore
not recommended during breast-feeding
• It is not known whether anabolic steroids are excreted
into breast milk. Because of their potential side effects
in children, it is recommended that mother cease
breast-feeding before commencing androgen therapy

When they want to pregnant…
Before attempting conception
• Tranexamic acid should be stopped several days
(half-life 2-8 hours)
• Androgen should be discontinued 2 months (half-life
9.44 hours)
• pdhC1INH might continue during conception,
pregnancy, and delivery
• Ecallantide, Icatibant and rhC1INH have no data on use
during pregnancy, and should be avoided before
attempting conception Patients should stop taking
them 1 wk prior

Contraception
• Estrogens should be avoided
• Barrier methods, intrauterine devices, and
progestins can be used

Take home messages
• HAE-C1-INH is a treatable disease with a
highly variable phenotype
• Effective management of hereditary
angioedema requires careful physician-patient
collaboration, with regular reassessments of
patient status and individualization of therapy
based on age, gender, comorbidity, and
patient preference

Hereditary angioedema and bradykinin-mediated angioedema

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