WAO Global Hereditary Angioedema
(HAE) Practice Parameter
Timothy J. Craig, DO
Professor of Medicine and Pediatrics
Distinguished Educator
Chief, Allergy, Asthma, and Immunology
Program Director
Director of Clinical Allergy and Respiratory Research
Pennsylvania State University College of Medicine
Hershey, Pennsylvania, USA
WAO Global Hereditary Angioedema Practice Parameter
Chair: Tim Craig, USA
General Advisor: Richard F. Lockey, USA

Steering Committee Members:
 Konrad Bork, Germany
 Tom Bowen, Canada
 Henrik Boysen, Belgium
 Marco Cicardi, Italy
 Henriette Farkas, Hungary
 Anete Grumach, Brazil (SLAAI)
 Connie Katelaris, Australia (APAAACI)
 Hilary Longhurst, UK
 William Lumry, USA (ACAAI)
 Marcus Maurer, Germany (EAACI)
 Bruce Ritchie, Canada
 Bruce Zuraw, USA (AAAAI)
 Emel Aygören Pürsün, Germany
 Inmaculada Martinez-Saguer, Germany
Sponsors of the WAO HAE Program
Company
Financial Supporter
CSL Behring
XX
Dyax
XX
Viropharma
XX
Shire
XX (via Jerini)
Pharming
(did not yet have a
product on the market)
WAO Global Hereditary Angioedema Practice Parameter
OBJECTIVES:
1. Produce an evidence based guideline for care of HAE
patients throughout the world
2. Develop a document that would be a reference for HCP
3. To develop a document that could be used at the bedside
4. Have a document that could be utilized in all countries
5. Develop a guideline that would be approved by the global
allergy community
6. Develop a power point program for use by all members of
the WAO
7. Lastly, and most importantly, to improve care for the
patients with Hereditary Angioedema and to improve access
of therapies to all patients, in all countries around the world.
Is there a need for this?
Active
Cleaved: Inactive
What Is C1-Inhibitor?
Human plasma protein …that mediates inflammation
Key regulator of four
biochemical pathways
1.
2.
3.
4.
Complement
Contact
Fibrinolytic
Coagulation
C1-Inhibitor deficiency
can cause:
– debilitating pain
– disfiguring swelling
– asphyxiation & death
Autosomal Dominant Defect
Crowder JR, Crowder TR. Five generations of angioneurotic
edema. Arch Inter Med 1917; 20:840-52
HAE Is Caused By C1 Inhibitor Mutations
Bissler JJ, et al. Proc Assoc Am Physicians. 1997;109:164-173.
Davis AE 3rd. Annu Rev Immunol. 1988;6:595-628.
Verpy E, et al. Am J Hum Genet. 1996;59:308-319.
Zuraw BL, Herschbach J. J Allergy Clin Immunol. 2000;105:541-546.
C1-INH involved in 3 systems → C1-INH depletion
Factor XIIa
C1-INH
Factor XII
Contact System C1-INH
Prekallikrein
HMW-K
Kallikrein
Increased vascular
permeability 
ANGIOEDEMA
Complement
System
C1rs
Plasminogen
Bradykinin
C1
Plasmin
Fibrinolytic
System
C4
C2
C1INH Null Mice and Vascular Permeability
C1INH gene
B2BKR gene
Evans blue
C1INH therapy
+/+
+/+
No
No
+/+
+/+
Yes
No
-/+/+
Yes
No
Adapted from Han ED, et al. J Clin Invest. 2002;109:1057-1063.
-/+/+
Yes
Yes
-/-/Yes
No
In Vivo Generation of Kinins in HAE
From Nussberger J, et al. J Allergy Clin Immunol. 1999;104:1321-1322; with permission.
How Does BK Cause Angioedema?
Increased vascular permeability
VE-cadherin
Actin stress fibers
Nonstimulated
Stimulated
From Tiruppathi C, et al. Vascul Pharmacol. 2003;39:173-185; with permission.
Common triggers of HAE attacks
Trauma
Menstruation
Angioedem
Angioedema
a attack
Infection
Medications
Stress
Treatment of HAE
• Conceptually divide into
three categories
– Long-term prophylaxis
• Minimize attack frequency and
severity
• Prevent hospitalizations and
emergency room visits
– Short-term prophylaxis
• Prevent attacks after trauma
• Prevent attacks during important life
events
– Treatment of acute attacks
• Terminate ongoing attack
• Prevent morbidity and mortality
Therapeutic Implications
PK
Adapted from Zuraw BL. Immunol Allergy Clin North Am. 2006;26:691-708.
Drug
Advantages
Disadvantages
Best use
Status
Plasmaderived
C1-INH
• Extensive clinical
experience
• Corrects the
fundamental defect
• long half-life
• Infectious risk
• Needs IV access
• Limited supply
• Acute attacks
• Short-term
• Long-term
prophylaxis
• Prodromes
• Berinert P:
approved in EU,
USA, Canada,
Argentina
• Cinryze: approved
in EU, USA
• Cetor in the EU,
Turkey
Recombinant
C1-INH
• Corrects the
fundamental defect
• No human virus
risk
• Scalable supply
• Needs IV access
• Short half-life
• Potential for
allergic reactions
• Acute attacks
• Short
prophylaxis
• Prodrome?
• Rhucin: approved
in the EU
Ecallantide
• More potent than
C1-INH
• No infectious risk
• Subcutaneous
administration
• Antibodies may
cause allergic
reaction or
neutralization
• Short half-life
• Acute attacks
in office
• Kalbitor:
approved in the
USA
Icatibant
• No infectious
risk
• Stable at room
temperature
• Subcutaneous
• Short half-life
• Local pain or
irritation
• Home
treatment of
acute
attacks?
• Firazyr: approved
in EU, USA,
Brazil
In Summary
 Global document is now being evidence
based
 From here it will go to the steering
committee for approval
 Than it will go to WAO leadership
 Finally out to all the Allergy Associations for
their approval
 Power Point slides will go through the same
process
Thank you.
Questions?
tcraig@psu.edu