Hereditary angioedema

Short description: Disorder resulting in severe swelling

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Hereditary angioedema (HAE)

Other names| Hereditary angioneurotic edema (HANE),[1] familial angioneurotic edema[2]
Swollen right hand during a hereditary angioedema attack.
Specialty| Hematology
Symptoms| Recurrent attacks of severe swelling[3]
Usual onset| Childhood[3]
Duration| Attacks last a few days (without treatment)[3]
Types| Type I, II, III[3]
Causes| Genetic disorder (autosomal dominant)[3]
Diagnostic method| Measuring C4 and C1-inhibitor levels.[2]
Differential diagnosis| Intestinal obstruction, other types of angioedema[2]
Prevention| plasma kallikrein inhibitors, C1 inhibitor concentrates[1]
Treatment| Supportive care, medications[1]
Medication| C1 inhibitor, ecallantide, icatibant, sebetralstat[1]
Prognosis| 25% risk of death if airway involved (without treatment)[2]
Frequency| ~1 in 50,000[3]

Hereditary angioedema (HAE) is a rare disease that results in recurrent attacks of severe swelling.[3] HAE affects approximately 1 in 50,000 people.[3] The condition is typically first noticed in childhood.[3]

The swelling most commonly affects the arms, legs, face, intestinal tract, and airway.[3] If the intestinal tract is affected, abdominal pain and vomiting may occur.[1] Swelling of the airway can result in its obstruction and can cause trouble breathing.[1] Without treatment, this can cause a risk of death in about 25% of people.[2] With treatment, outcomes are generally good.[2] Without preventive treatment, attacks typically occur every two weeks and last for a few days.[3]

There are three main types of HAE.[3] Types I and II are caused by a mutation in the SERPING1 gene, which encodes the C1 inhibitor protein, and type III, now called HAE with normal C1 inhibitor (HAE-nl-C1INH).[4] Types I and II affect females and males equally,[5] while HAE with normal C1 inhibitor affects females more often than males.[2]

Six known mutations are described in the literature under HAE with normal C1 inhibitor.[4] The result is increased levels of kallikrein activity and bradykinin, which promotes swelling.[3] The condition may be inherited in an autosomal dominant manner or occur as a spontaneous mutation.[3]

Known common HAE triggers are[6]:

* Stress
* Minor trauma
* Anxiety
* Surgery
* Ailments such as colds/flu/other viral infections

People with HAE have also reported exposure to cold and activities that cause mechanical trauma (gardening, hammering, shoveling) can also be triggers.[7] Attacks can often occur without any obvious preceding events or a known trigger.[3]

Diagnosis of HAE types I and II is based on measurement of C4 and C1-inhibitor levels or genetic testing.[8]

Management of HAE involves efforts to prevent attacks and the treatment of attacks if they occur.[1] During an attack, supportive care such as intravenous fluids and airway support may be required.[1] Preventative treatments include C1-inhibitor concentrates and plasma kallikrein inhibitors.[1] Acute treatment options include C1-inhibitor concentrates, bradykinin receptor antagonists like icatibant, and plasma kallikrein inhibitors such as ecallantide and sebetralstat.[9]

The condition was first described in 1888 by Canadian physician William Osler.[10]

## Contents

* 1 Signs and symptoms
* 2 Genetics
* 3 Pathophysiology
* 4 Diagnosis
* 5 Types
* 6 Prevention
* 6.1 Long-term
* 6.2 Short-term
* 7 HAE Attack Management
* 8 Prognosis
* 9 Epidemiology
* 10 Society and culture
* 11 Research
* 12 References
* 13 Further reading
* 14 External links

## Signs and symptoms

People diagnosed with Hereditary Angioedema have recurrent swelling in the extremities, genitals, face, lips, larynx or GI tract.[11]

Swelling involving the respiratory and gastrointestinal systems can cause significant risk and distress. Involvement of respiratory structures, such as the throat or larynx, can cause difficulties in breathing and life-threatening airway obstruction.[11][12] Episodes that attack the gastrointestinal tract can cause a number of complications including vomiting, crampy abdominal pain, diarrhea, and dehydration.[12]

Some people may experience prodromal symptoms, including tingling, fatigue or weakness at the site of impending edema with one third of people experiencing an erythematous rash (erythema marginatum) as the prodromal symptom.[11] Urticaria is usually not seen in hereditary angioedema, as compared to other causes of angioedema such as histamine induced symptoms.[11]

## Genetics

Because HAE is an autosomal dominant disease, there is no sex difference in transmission and both sexes are equally likely to receive the mutated gene from their parents. The autosomal dominant inheritance pattern with regards to hereditary angioedema requires receipt of only one copy of the mutated C1 inhibitor gene to have symptomatic disease.[13][14][15][16] Further, hereditary angioedema with C1 inhibitor deficiency types 1 and 2 have complete penetrance, meaning all of those who inherit the dysfunctional gene will have symptomatic disease. However, hereditary angioedema with normal C1 inhibitor levels (Type 3 disease) has incomplete penetrance, and men may be asymptomatic carriers despite inheriting a mutated gene.[11]

With regards to the mutations in the SERPING1 gene that is seen in hereditary angioedema types 1 and 2 (hereditary angioedema with C1 inhibitor deficiency), 75% of the cases are due to an autosomal dominant inheritance of a mutated gene and 25% of cases are due to de novo mutations of the egg or sperm, or early in embryological development.[11] Hereditary angioedema type 3 (hereditary angioedema with normal C1 inhibitor levels) is associated with mutations in genes for Factor XII, angiopoietin 1, plasminogen or kininogen 1.[11]

## Pathophysiology

The pathophysiologic mechanisms contributing to bradykinin mediated angioedema in hereditary angioedema have been described. C1 inhibitor usually acts as an inhibitor of the plasma contact system, where it inhibits plasma kallikrein, factor XIIa, and factor XIIf. However, in hereditary angioedema with C1 inhibitor deficiency, C1 inhibitor is either reduced in quantity and function (type 1) or dysfunctional (type 2), this leads to bradykinin disinhibition and bradykinin mediated activation of bradykinin B1 receptor and bradykinin B2 receptor on endothelial cells (cells lining blood vessels).[11] This activation leads to vascular endothelial cadherin (a type of cell adhesion molecule) phosphorylation, internalization and degradation. Cadherin degradation leads to actin cytoskeleton contraction and increased pore size of the vascular endothelial cells. Adherens junctions are also reduced due to bradykinin B1 and B2 receptor activation and vascular endothelial growth factor (VEGF) is also activated. The degradation of these endothelial intercellular barrier junctions mediated by histamine leads to increased vascular permeability, leading to vascular leakage into surrounding tissues and thus causing the characteristic swelling seen in hereditary angioedema.[11] The bradykinin B1 receptor (unlike the B2 receptor) is slowly and only partially desensitized after binding the bradykinin agonist, thus remaining constitutively active long after initial bradykinin exposure which can explain the protracted swelling seen in hereditary angioedema as compared to other causes of angioedema.[11]

## Diagnosis

Template:Complement test comparisons Recognizing HAE is often difficult due to the wide variability in disease expression, with the diagnosis often delayed for years.[11] The course of the disease is diverse and unpredictable, even within a single patient over their lifetime. This disease may be similar in its presentation to other forms of angioedema resulting from allergies or other medical conditions, but it is significantly different in cause and treatment. When HAE is misdiagnosed as an allergy it is most commonly treated with steroids, epinephrine or anti-histamines, drugs that are usually ineffective in treating a HAE episode.[11] Other misdiagnoses have resulted in unnecessary exploratory surgery for patients with abdominal swelling and other HAE patients report that their abdominal pain was wrongly diagnosed as psychosomatic or malingering.[11]

HAE accounts for only a small fraction of all cases of angioedema. To avoid potentially fatal consequences such as upper airway obstruction and unnecessary abdominal surgery, the importance of a correct diagnosis cannot be overemphasized.[17]

## Types

There are three types of hereditary angioedema (HAE). HAE types I and II are both caused by a deficiency of complement C1-inhibitor (C1-INH), a plasma protein that is an important inhibitor of several serine proteases, specially of the complement system and the contact activation/kallikrein-kinin pathway, but also the fibrinolytic system.[18][19][20]

In HAE type I, there is a quantitative C1-inhibitor deficiency, antigenic as well as functional C1-inhibitor levels in plasma are decreased. This type accounts for approximately 85% of HAE cases with C1-inhibitor deficiency.[11]

In HAE type II, there is a qualitative deficiency, with normal - sometimes even elevated - C1-inhibitor protein levels, but decreased functional C1-inhibitor measurements. This type is seen in approximately 15% of HAE cases with C1-inhibitor deficiency.[20][21]

C1-inhibitor deficiency is caused by mutations of the SERPING1 gene, the gene encoding complement C1-inhibitor. More than 700 different mutations have been described.[21] The SERPING1 gene shows a considerable tendency for de novo mutations. As a result, it is not uncommon to observe patients with primary recurrent angioedema attacks and C1-inhibitor deficiency where both parents are unaffected.[22]

Another type of hereditary angioedema, originally named HAE type III, has been observed.[23][24][25] In contrast to HAE types I and II, this type of the disease is characterized by normal C1-inhibitor measurements. Thus, the term "hereditary angioedema with normal C1-inhibitor" is now generally used for this HAE type. Normal C1 inhibitor level hereditary angioedema is thought to involve various mutations that increased bradykinin activity and cause a decreased threshold for activation of the plasma contact system thus leading to the symptoms of angioedema.[11]

Hereditary angioedema with normal C1-inhibitor is a genetically heterogeneous disorder. Several molecular subtypes have been identified. A first subtype, identified in 2006, is caused by mutations of the F12 gene encoding coagulation factor XII (also known as Hageman factor).[26][27] All four mutations known so far, the two originally described missense mutations in exon 9 as well as the two additional, very rare mutations described later, affect the proline-rich region of coagulation factor XII.[26][27][24] An accelerated activation of the kallikrein-kinin system appears to represent the pathomechanism through that the F12 mutations cause angioedema.[28]

Clinical manifestation of hereditary angioedema due to a F12 mutation occurs preferably, but not exclusively in female mutation carriers. The remarkable estrogen-sensitivity is a characteristic feature of the HAE type caused by a F12 mutation. For example, estrogen-containing oral contraceptives play an important role in triggering angioedema attacks. Exacerbation of symptoms during pregnancy is also a common observation.[29][25] Hereditary angioedema due to Factor XII dysfunction is the most common subtype of type III angioedema.[11]

A second molecular subtype of HAE with normal C1-inhibitor is caused by a mutation of the plasminogen gene, namely a rare missense mutation within the kringle 3 domain of plasminogen, resulting in a novel type of dysplasminogenemia.[30] The mutation creates a new lysine-binding site within the kringle 3 domain and alters the glycosylation of plasminogen.[30] The mutant plasminogen protein has been shown to be a highly efficient kininogenase that directly releases bradykinin from high- and low-molecular-weight kininogen.[31] Tongue swellings are a very frequent and characterizing symptom in patients with hereditary angioedema due to a plasminogen mutation.[30][25]

Very rare observations have suggested that mutations of the following genes may also be responsible for the development of hereditary angioedema with normal C1-inhibitor: angiopoietin 1 [HAE with an angiopoietin 1 (ANGPT1) mutation]; myoferlin [HAE with a myoferlin (MYOF) mutation]; kininogen 1 [HAE with a kininogen 1 (KNG1) mutation]; and heparan sulfate-glucosamine 3-sulfotransferase 6 [HAE with a heparan sulfate-glucosamine 3-sulfotransferase 6 (HS3ST6) mutation].[27][25]

However, for a large proportion of cases with hereditary angioedema with normal C1-inhibitor the genetic cause remains unknown.[11]

## Prevention

Treatment with ACE inhibitors is contraindicated in this condition, as these drugs can lead to bradykinin accumulation, which can precipitate disease episodes.[32][33]

### Long-term

People in whom episodes occur at least once a month or who are at high risk of developing laryngeal edema require long-term prevention. There are several phase III clinical trials addressing HAE prophylaxis and therapy. These have led to the licensing of pdC1INH in many parts of the world; bradykinin receptor antagonists (icatibant) in Europe; kallikrein inhibitors (ecallantide and lanadelumab) in the United States; and recombinant C1-INH replacement therapy (rhC1INH; conestat alfa) in Europe. Tranexamic acid has been shown to be relatively ineffective therapy. Danazol prophylaxis remains an option but therapeutic agents are now being used more for prophylaxis because of danazol's adverse events.[34]

In 2018, the US Food and Drug Administration (FDA) approved lanadelumab, an injectable monoclonal antibody, to prevent attacks of HAE types I and II in people twelve years of age and older. Lanadelumab inhibits the plasma enzyme kallikrein, which liberates the kinins bradykinin and kallidin from their kininogen precursors and is produced in excess in individuals with HAE types I and II.[35][36]

Berotralstat (Orladeyo) was approved in the US in December 2020, for the prevention of attacks of hereditary angioedema in people twelve years of age and older.[37][38]

In February 2023, the FDA approved the expanded use of lanadelumab (Takhzyro) to prevent attacks of hereditary angioedema in children aged 2 to 12 years of age.[39]

Donidalorsen (Dawnzera) was approved for medical use in the US in August 2025, for the prevention of attacks of hereditary angioedema in people twelve years of age and older.[40]

### Short-term

Short-term prevention is normally administered before surgery or dental treatment. In Germany, C1-INH concentrate is used for this and given 1–1.5 hours before the procedure. In countries where C1-inhibitor concentrate is not available or only available in an emergency (laryngeal edema), high-dose androgen treatment is administered for 5–7 days.[41]

## HAE Attack Management

The aim of acute treatment is to halt progression of the edema as quickly as possible, which can be life-saving, particularly if the swelling is in the larynx. Several C1 inhibitor treatments are available in the US and two C1 inhibitor products are available in Canada. Berinert P (CSL Behring), which is pasteurized, was approved by the US FDA in 2009 for acute attacks. Cinryze, which is nanofiltered, was approved by the FDA in 2008 for prophylaxis. Ruconest is a recombinant C1 inhibitor approved in the US and the EU that does not carry the risk of infectious disease transmission due to human blood-borne pathogens.[42][unreliable medical source?]

Sebetralstat (Ekterly) was approved for medical use in the United States in July 2025.[43] It is an oral (pill) plasma kallikrein inhibitor that is for use in people aged twelve years of age and older.[43]

In Germany, most acute treatment consists of C1 inhibitor concentrate from donor blood, which must be administered intravenously; however, in most European countries, C1 inhibitor concentrate is only available to patients who are participating in special programs. In emergency situations where C1 inhibitor concentrate is not available, fresh frozen plasma (FFP) can be used as an alternative, as it also contains C1 inhibitor.[44]

Other treatment modalities can stimulate the synthesis of C1 inhibitor, or reduce C1 inhibitor consumption. Purified C1 inhibitor, derived from human blood, has been used in the EU since 1979.[39]

The medication ecallantide inhibits plasma kallikrein and was approved by the FDA in the United States for acute attacks in 2009. Icatibant inhibits the bradykinin B2 receptor, and was approved in the EU in 2008 and the US in 2011.[42][unreliable medical source?][45][46]

## Prognosis

About 25% of those affected die in the first two decades of life, mainly due to lack of treatment.[47] In an Italian study, people with HAE had an average life expectancy like that of the general population.[48]

## Epidemiology

Data regarding the epidemiology of angioedema is limited. The incidence of HAE is one in 50,000 worldwide.[3] Mortality rates are estimated at 15–33%, resulting primarily from laryngeal edema and asphyxiation. HAE leads to 15,000–30,000 emergency department visits per year.[49][50]

## Society and culture

There are national associations for HAE patients and their families in a number of countries around the world. Many of these national associations are members of the global organization Hereditary Angioedema International (HAEI). HAEI raises awareness about hereditary angioedema as well as facilitating coordination of research regarding the condition.[51]

The US Hereditary Angioedema Association (HAEA) is a non-profit advocacy organization serving people with HAE and their caregivers. The association is a community of people affected by HAE and their loved ones who are leading the fight in HAE research, advocacy, and finding a cure. Through a passionate commitment to the HAE community, the HAEA offers a wide variety of services and resources that further HAE education, clinical research, community engagement, access to medications, personalized support networks, and a wide range of services to help people living with HAE lead a normal life.[52]

Each year on 16 May, the HAEi, the HAEA, and the HAE community raise awareness of HAE with the international HAE day.[53][54]

## Research

Based CRISPR/Cas9 technology, a potential one-time gene editing therapy known as NTLA-2002 is being developed for the treatment of HAE. NTLA-2002 is designed to prevent HAE attacks by inactivating the kallikrein B1 (KLKB1) gene, which encodes for prekallikrein, the kallikrein precursor protein.[55][56]

## References

1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 "Hereditary angioedema". 2017. https://rarediseases.info.nih.gov/diseases/5979/hereditary-angioedema.
2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 "Orphanet: Hereditary angioedema". August 2011. http://www.orpha.net/consor/cgi-bin/Disease_Search.php?lng=EN&data_id=12136&Disease_Disease_Search_diseaseGroup=Hereditary-angioedema&Disease_Disease_Search_diseaseType=Pat&Disease(s)/group of diseases=Hereditary-angioedema&title=Hereditary-angioedema&search=Disease_Search_Simple.
3. ↑ 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 3.11 3.12 3.13 3.14 3.15 Reference, Genetics Home (5 July 2017). "hereditary angioedema". https://medlineplus.gov/genetics/condition/hereditary-angioedema/.
4. ↑ 4.0 4.1 Smith, Tukisa D.; Riedl, Marc A. (October 2024). "The future of therapeutic options for hereditary angioedema". Annals of Allergy, Asthma & Immunology 133 (4): 380–390. doi:10.1016/j.anai.2024.04.029. PMID 38679158. https://linkinghub.elsevier.com/retrieve/pii/S1081120624002758.
5. ↑ "Hereditary Angioedema - NORD (National Organization for Rare Disorders)". 2008. https://rarediseases.org/rare-diseases/hereditary-angioedema/.
6. ↑ "US Hereditary Angioedema Association". https://www.haea.org/pages/p/what_is_hae#triggers.
7. ↑ "Attack Triggers". 2022-07-04. https://haei.org/what-is-hae/attack-triggers/.
8. ↑ "Diagnosis". 2015-04-16. https://haei.org/what-is-hae/diagnosis/.
9. ↑ "How can HAE be treated?". 2022-03-04. https://haei.org/what-is-hae/treatment/.
10. ↑ Levin, Alex V.; Enzenauer, Robert W. (2017). The Eye in Pediatric Systemic Disease. Springer. p. 71. ISBN 978-3-319-18389-3. https://books.google.com/books?id=AvIoDwAAQBAJ&pg=PA71.
11. ↑ 11.00 11.01 11.02 11.03 11.04 11.05 11.06 11.07 11.08 11.09 11.10 11.11 11.12 11.13 11.14 11.15 11.16 Busse PJ, Christiansen SC (2020). "Hereditary Angioedema.". N Engl J Med 382 (12): 1136–1148. doi:10.1056/NEJMra1808012. PMID 32187470.
12. ↑ 12.0 12.1 "Hereditary angioedema: a broad review for clinicians". Arch Intern Med 161 (20): 2417–29. November 2001. doi:10.1001/archinte.161.20.2417. PMID 11700154.
13. ↑ "A single nucleotide deletion at the C1 inhibitor gene as the cause of hereditary angioedema: insights from a Brazilian family". Allergy 66 (10): 1384–90. October 2011. doi:10.1111/j.1398-9995.2011.02658.x. PMID 21623829.
14. ↑ "Mutational spectrum of the c1 inhibitor gene in a cohort of Italian patients with hereditary angioedema: description of nine novel mutations". Ann Hum Genet 78 (2): 73–82. March 2014. doi:10.1111/ahg.12052. PMID 24456027.
15. ↑ "Genetic test indications and interpretations in patients with hereditary angioedema". Mayo Clin Proc 81 (7): 958–72. July 2006. doi:10.4065/81.7.958. PMID 16835976.
16. ↑ "Inheritance of Hereditary Angioedema - Patient Information - Shire's Brave Community". http://www.bravecommunity.com/patients/conditions/hereditary-angioedema/information/inheritance.aspx.
17. ↑ "Management of angioedema in the ER". http://caep.ca/sites/caep.ca/files/caep/files/2012_conference_-_management_of_angioedema_in_the_er.pdf.
18. ↑ "A biochemical abnormality in hereditary angioneurotic edema: Absence of serum inhibitor of C' 1-esterase". Am. J. Med. (The American Journal of Medicine) 35 (1): 37–44. July 1963. doi:10.1016/0002-9343(63)90162-1. PMID 14046003.
19. ↑ "Hereditary angioneurotic edema: Two genetic variants". Science 148 (3672): 957–958. 14 May 1965. doi:10.1126/science.148.3672.957. PMID 14277836. Bibcode: 1965Sci...148..957R.
20. ↑ 20.0 20.1 "C1-inhibitor deficiency and angioedema". Mol. Immunol. (Molecular Immunology) 38 (2–3): 161–173. August 2001. doi:10.1016/s0161-5890(01)00040-2. PMID 11532278.
21. ↑ 21.0 21.1 "SERPING1 mutation update: Mutation spectrum and C1 Inhibitor phenotypes". Hum. Mutat. (Human Mutation) 41 (1): 38–57. January 2020. doi:10.1002/humu.23917. PMID 31517426.
22. ↑ "Frequent de novo mutations and exon deletions in the C1inhibitor gene of patients with angioedema". J. Allergy Clin. Immunol. (The Journal of Allergy and Clinical Immunology) 106 (6): 1147–1154. December 2000. doi:10.1067/mai.2000.110471. PMID 11112899.
23. ↑ "Hereditary angioedema with normal C1-inhibitor activity in women". Lancet (The Lancet) 356 (9225): 213–217. 15 July 2000. doi:10.1016/S0140-6736(00)02483-1. PMID 10963200.
24. ↑ 24.0 24.1 "An update on the genetics and pathogenesis of hereditary angioedema". Genes Dis. (Genes & Diseases) 7 (1): 75–83. March 2020. doi:10.1016/j.gendis.2019.07.002. PMID 32181278.
25. ↑ 25.0 25.1 25.2 25.3 "Managing Diagnosis, Treatment, and Burden of Disease in Hereditary Angioedema Patients with Normal C1-Esterase Inhibitor". J Asthma Allergy (Journal of Asthma and Allergy) 16: 447–460. 22 April 2023. doi:10.2147/JAA.S398333. PMID 37124440.
26. ↑ 26.0 26.1 "Missense mutations in the coagulation factor XII (Hageman factor) gene in hereditary angioedema with normal C1 inhibitor". Biochem. Biophys. Res. Commun. (Biochemical-and-Biophysical-Research-Communications) 343 (4): 1286–1289. 19 May 2006. doi:10.1016/j.bbrc.2006.03.092. PMID 16638441. Bibcode: 2006BBRC..343.1286D.
27. ↑ 27.0 27.1 27.2 "The Genetics of Hereditary Angioedema: A Review". J. Clin. Med. (Journal of Clinical Medicine) 10 (9): 2023. 9 May 2021. doi:10.3390/jcm10092023. PMID 34065094.
28. ↑ "Mechanisms involved in hereditary angioedema with normal C1-inhibitor activity". Front. Physiol. (Frontiers in Physiology) 14. 23 May 2023. doi:10.3389/fphys.2023.1146834. PMID 37288434.
29. ↑ "Hereditary angioedema with normal C1 inhibitor and factor XII mutation: a series of 57 patients from the French National Center of Reference for Angioedema". Clin. Exp. Immunol. (Clinical & Experimental Immunology) 185 (3): 332–337. September 2016. doi:10.1111/cei.12820. PMID 27271546.
30. ↑ 30.0 30.1 30.2 "A missense mutation in the plasminogen gene, within the plasminogen kringle 3 domain, in hereditary angioedema with normal C1 inhibitor". Biochem Biophys Res Commun (Biochemical-and-Biophysical-Research-Communications) 498 (1): 193–198. 25 March 2018. doi:10.1016/j.bbrc.2017.12.060. PMID 29548426. Bibcode: 2018BBRC..498..193D.
31. ↑ "A mechanism for hereditary angioedema caused by a lysine 311-to-glutamic acid substitution in plasminogen". Blood. (Blood) 139 (18): 2816–2829. 5 May 2022. doi:10.1182/blood.2021012945. PMID 35100351.
32. ↑ "Pathways of bradykinin degradation in blood and plasma of normotensive and hypertensive rats". Am. J. Physiol. Heart Circ. Physiol. 280 (5): H2182–8. May 2001. doi:10.1152/ajpheart.2001.280.5.H2182. PMID 11299220.
33. ↑ "Inactivation of bradykinin by angiotensin-converting enzyme and by carboxypeptidase N in human plasma". Am. J. Physiol. Heart Circ. Physiol. 278 (4): H1069–74. April 2000. doi:10.1152/ajpheart.2000.278.4.H1069. PMID 10749699.
34. ↑ Hereditary angioedema: beyond international consensus - circa December 2010 - The Canadian Society of Allergy and Clinical Immunology Dr. David McCourtie Lecture
35. ↑ "FDA Approves Takhzyro (lanadelumab-flyo) for Hereditary Angioedema". https://www.drugs.com/newdrugs/fda-approves-takhzyro-lanadelumab-flyo-hereditary-angioedema-4809.html.
36. ↑ "FDA OKs New Prophylactic Drug for Rare Hereditary Angioedema". https://www.medscape.com/viewarticle/901177.
37. ↑ "Drug Trials Snapshot: Orladeyo". 3 December 2020. https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshot-orladeyo. This article incorporates text from this source, which is in the public domain.
38. ↑ "Orladeyo: FDA-Approved Drugs". https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&varApplNo=214094.
39. ↑ 39.0 39.1 "U.S. FDA Approves Takeda's Takhzyro (lanadelumab-flyo) to Prevent Hereditary Angioedema (HAE) Attacks in Children 2 Years of Age and Older". Takeda (Press release). Retrieved 6 February 2023.
40. ↑ "Dawnzera (donidalorsen) approved in the U.S. as first and only RNA-targeted prophylactic treatment for hereditary angioedema" (Press release). Ionis Pharmaceuticals. 21 August 2025. Retrieved 22 August 2025 - via Business Wire.
41. ↑ Xu, Y.-Y.; Buyantseva, L. V.; Agarwal, N. S.; Olivieri, K.; Zhi, Y.-X.; Craig, T. J. (April 2013). "Update on treatment of hereditary angioedema". Clinical & Experimental Allergy 43 (4): 395–405. doi:10.1111/cea.12080. ISSN 0954-7894. PMID 23517035. https://onlinelibrary.wiley.com/doi/10.1111/cea.12080.
42. ↑ 42.0 42.1 Morgan
43. ↑ 43.0 43.1 "KalVista Pharmaceuticals Announces FDA Approval of Ekterly (sebetralstat), First and Only Oral On-demand Treatment for Hereditary Angioedema" (Press release). Kalvista. 7 July 2025. Retrieved 9 July 2025 - via Business Wire.
44. ↑ Xu, Y.-Y.; Buyantseva, L. V.; Agarwal, N. S.; Olivieri, K.; Zhi, Y.-X.; Craig, T. J. (April 2013). "Update on treatment of hereditary angioedema". Clinical & Experimental Allergy 43 (4): 395–405. doi:10.1111/cea.12080. ISSN 0954-7894. PMID 23517035. https://onlinelibrary.wiley.com/doi/10.1111/cea.12080.
45. ↑ "Firazyr- icatibant acetate injection, solution". 19 January 2024. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ed6657ca-ab68-477a-9968-e12dc928b540.
46. ↑ AG J (2008-07-15). "Jerini Receives European Commission Approval for Firazyr (Icatibant) in the Treatment of HAE". GlobeNewswire News Room (Press release). Retrieved 2025-07-24.
47. ↑ Varga, Lilian; Farkas, Henriette (1 November 2008). "Treatment of type I and II hereditary angioedema with Rhucin, a recombinant human C1 inhibitor". Expert Review of Clinical Immunology 4 (6): 653–661. doi:10.1586/1744666X.4.6.653. ISSN 1744-666X. PMID 20477114.
48. ↑ Perego, Francesca; Gidaro, Antonio; Zanichelli, Andrea; Cancian, Mauro; Arcoleo, Francesco; Senter, Riccardo; Bova, Maria; Pasquale, Tiziana De et al. (2020-05-01). "Life expectancy in Italian patients with hereditary angioedema due to C1-inhibitor deficiency". The Journal of Allergy and Clinical Immunology: In Practice 8 (5): 1772–1774. doi:10.1016/j.jaip.2020.01.007. ISSN 2213-2198. PMID 31954853. https://www.jaci-inpractice.org/article/S2213-2198(20)30046-5/fulltext.
49. ↑ From the: Pinnacle Health System, Harrisburg Hospital, Department of Internal Medicine, 111 South Front Street, Harrisburg, PA 17101, Update on treatment for her
50. ↑ "Update on treatment of hereditary angioedema" Buyantseva, Larisa, Sardana, Niti and Craig, Timothy
51. ↑ "HAEi website". http://www.haei.org/.
52. ↑ "- HAEA". https://www.haea.org/.
53. ↑ Chapman, Mary (5 May 2022). "HAE Awareness Day 'Stepping Up' With Activity Challenges, Storytelling". https://angioedemanews.com/2022/05/05/activities-afoot-more-hae-awareness-day-may-16/.
54. ↑ Inouye, Daniel K. (31 January 2012). "S.Res.286 - 112th Congress (2011-2012): A resolution recognizing May 16, 2012, as Hereditary Angioedema Awareness Day and expressing the sense of the Senate that more research and treatments are needed for Hereditary Angioedema.". http://www.congress.gov/.
55. ↑ "CRISPR-Cas9 in Vivo Gene Editing of KLKB1 for Hereditary Angioedema". The New England Journal of Medicine 390 (5): 432–441. February 2024. doi:10.1056/NEJMoa2309149. PMID 38294975.
56. ↑ "Intellia Therapeutics Announces Initiation of HAELO Phase 3 Study of NTLA-2002, an Investigational In Vivo CRISPR Gene Editing Treatment for Hereditary Angioedema (HAE)". 7 October 2024. https://ir.intelliatx.com/news-releases/news-release-details/intellia-therapeutics-announces-initiation-haelo-phase-3-study.

## Further reading

* "Hereditary Angioedema". N. Engl. J. Med. 382 (12): 1136–48. March 2020. doi:10.1056/NEJMra1808012. PMID 32187470.

## External links

* v
* t
* e

Lymphoid and complement disorders causing immunodeficiency

Primary|

| Antibody/humoral
(B)|

| Hypogammaglobulinemia|

* X-linked agammaglobulinemia
* Transient hypogammaglobulinemia of infancy

|

Dysgammaglobulinemia|

* IgA deficiency
* IgG deficiency
* IgM deficiency
* Hyper IgM syndrome (1
* 2
* 3
* 4
* 5)
* Wiskott–Aldrich syndrome
* Hyper-IgE syndrome

Other|

* Common variable immunodeficiency
* ICF syndrome

T cell deficiency
(T)|

* thymic hypoplasia: hypoparathyroid (Di George's syndrome)
* euparathyroid (Nezelof syndrome
* Ataxia–telangiectasia)

peripheral: Purine nucleoside phosphorylase deficiency

* Hyper IgM syndrome (1)

Severe combined
(B+T)|

* x-linked: X-SCID
autosomal: Adenosine deaminase deficiency
* Omenn syndrome
* ZAP70 deficiency
* Bare lymphocyte syndrome

Acquired|

* HIV/AIDS

Leukopenia:
Lymphocytopenia|

* Idiopathic CD4+ lymphocytopenia

Complement
deficiency|

* C1-inhibitor (Angioedema/Hereditary angioedema)
* Complement 2 deficiency/Complement 4 deficiency
* MBL deficiency
* Properdin deficiency
* Complement 3 deficiency
* Terminal complement pathway deficiency
* Paroxysmal nocturnal hemoglobinuria
* Complement receptor deficiency

Template:Disorders of globin and globulin proteins

Classification|

* ICD-10: D84.1 (ILDS D84.110)
* ICD-9-CM: 277.6
* OMIM: 106100
* MeSH: D054179
* DiseasesDB: 1821

|

External resources|

* MedlinePlus: 001456
* eMedicine: article/1048994
* Orphanet: 91378

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