Managing Diagnosis, Treatment, and Burden of Disease in Hereditary Angioedema Patients with Normal C1-Esterase Inhibitor

Figures & data

Figure 1 Mutations in genes linked to some forms of HAE-nI-C1-INH and their roles within the fibrinolytic and kallikrein/kinin systems.^20,21,24,25 Adapted from Bork K, Machnig T, Wulff K, Witzke G, Prusty S, Hardt J. Clinical features of genetically characterized types of hereditary angioedema with normal C1 inhibitor: a systematic review of qualitative evidence. Orphanet J Rare Dis. 2020;15(1):289. Creative Commons.²¹

Abbreviations: ANGPT1, angiopoietin-1; ANGPT1, angiopoietin-1 gene; B2R, bradykinin B2 receptor; C1-INH, C1-esterase inhibitor; FXII, coagulation factor XII; FXII, coagulation factor XII gene; FXIIa, activated coagulation factor XII; FXIIf, coagulation factor XII fragment; HAE-nI-C1-INH, hereditary angioedema with normal C1-esterase inhibitor levels; HMWK, high molecular weight kininogen; HS3ST6, heparan sulfate glucosamine 3-O-sulfotransferase-6; HS3ST6, heparan sulfate glucosamine 3-O-sulfotransferase-6 gene; KNG1, kininogen-1 gene; MYOF, myoferlin gene; PAI, plasminogen activator inhibitor; PLG, plasminogen; PLG, plasminogen gene; scuPA, single-chain urokinase-type plasminogen activator; Syn2, syndecan-2; Tie2, tyrosine-protein kinase; tPA, tissue plasminogen activator; uPA, urokinase-type plasminogen activator; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor.

Table 1 Summary of Genes That Have Been Identified to Contain Mutations in Patients with HAE-nI-C1-INH and the Proposed Roles of Such Mutations in Angioedema

Gene	Proposed Role of Mutations in Angioedema
FXII	FXII is a serine protease that becomes activated by contact with negatively charged surfaces and plasma kallikrein. Plasma kallikrein itself is generated from prekallikrein by activated FXII (FXIIa). Identified mutations in this gene to date may play a role in the binding of FXII to negatively charged surfaces, thus influencing contact activation and facilitating inappropriate activation of FXII.^Citation15
ANGPT1	Mutations identified to date in ANGPT1 indicate that ANGPT1 forms fewer multimers and has a reduced binding capacity toward its receptor in the mutated versus the wild-type form. This change affects the ability of ANGPT1 to modulate the increase in endothelial permeability that is induced by VEGF and bradykinin, thus stimulating vascular leakage.^Citation16,Citation26
PLG	It has been proposed that mutations in PLG may lead to structural changes in the protein that increase its affinity for surfaces and/or may make it more accessible to tPA and uPA, which are activators of PLG. This could lead to a subsequent increase in activation of the fibrinolytic system, thus stimulating an increase in bradykinin production.^Citation17 Furthermore, it has been reported that mutations in PLG can lead to increased bradykinin production independently of kallikrein and FXII and that this occurs through direct cleavage of kininogens (including HMWK) by the mutated PLG.^Citation24
KNG1	It has been proposed that the identified mutation in KNG1 may cause alteration to the N-terminal cleavage site of bradykinin, which could change the process of inactivation of bradykinin by aminopeptidase-2 and angiotensin-converting enzyme. This would lead to bradykinin having an increased half-life and, thus, higher than normal activity.^Citation18
MYOF	MYOF is known to modulate VEGF signaling by altering VEGFR-2 levels. It has been proposed that the identified mutations in MYOF could alter VEGF-mediated intracellular signaling cascades by increasing the ability of myoferlin to localize VEGFR-2 to the membrane in response to VEGF stimuli, which may lead to vascular leakage.^Citation19
HS3ST6	It has been proposed that mutated HS3ST6 is unable to perform the last step of Syn2 O-sulfation, which either affects the binding of HMWK on the endothelial cell surface or its internalization via endocytosis. As a consequence, HMWK uses alternative interaction partners on the endothelial cell surface without undergoing endocytosis and is, therefore, more prone to cleavage by kallikrein, resulting in overproduction of bradykinin and enhanced formation of angioedema.^Citation20

Abbreviations: ANGPT1, angiopoietin-1; ANGPT1, angiopoietin-1 gene; FXII, coagulation factor XII; FXII, coagulation factor XII gene; FXIIa, activated coagulation factor XII; HAE-nI-C1-INH, hereditary angioedema with normal C1-esterase inhibitor levels; HMWK, high molecular weight kininogen; HS3ST6, heparan sulfate glucosamine 3-O-sulfotransferase-6; HS3ST6, heparan sulfate-glucosamine 3-O-sulfotransferase-6 gene; KNG1, kininogen-1 gene; MYOF, myoferlin; MYOF, myoferlin gene; PLG, plasminogen; PLG, plasminogen gene; Syn2, syndecan-2; tPA, tissue plasminogen activator; uPA, urokinase-type plasminogen activator; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor.

Figure 2 Diagnostic algorithms for (a) HAE-C1-INH and (b) HAE-nI-C1-INH, based on the known clinical and genetic characteristics of the diseases. Presence of the supportive evidence shown in the boxes with blue outlines is not required for a confirmed diagnosis of HAE.^1,45,46

Notes: *A lack of efficacy of high-dose antihistamine therapy (eg, cetirizine at 40 mg/day or the equivalent) should be documented for at least one month or for an interval that is expected to be associated with three or more angioedema attacks, whichever is longer. ^45,46

Required evidence for diagnosis,

Supportive evidence for diagnosis (not essential for diagnosis).

Abbreviations: ANGPT1, angiopoietin-1 gene; C1-INH, C1-esterase inhibitor; C4, complement component 4; CT, computed tomography; FXII, coagulation factor XII gene; HAE, hereditary angioedema; HAE-C1-INH, hereditary angioedema due to C1-esterase inhibitor deficiency or dysfunction; HAE-nI-C1-INH, hereditary angioedema with normal C1-esterase inhibitor levels; KNG1, kininogen-1 gene; MRI, magnetic resonance imaging; PLG, plasminogen gene; SERPING1, serpin family G member 1 gene.

Table 2 Proposed Mode of Action of Treatments Offered to Patients with HAE-nI-C1-INH

Treatment	Mode of Action
Berotralstat	Berotralstat is an oral inhibitor of plasma kallikrein activity that prevents cleavage of HMWK and suppresses the release of bradykinin after activation of the contact system.^Citation44,Citation55
C1-INH concentrate	Administration of C1-INH concentrate increases plasma levels of the C1-INH protein, helping to regulate the cascade systems involved in the production of bradykinin during HAE attacks.^Citation44
Danazol	Danazol is an attenuated androgen that increases the synthesis of C1-INH by the liver and enhances the activity of plasma aminopeptidase P. Aminopeptidase P is known to catabolize bradykinin.^Citation2
Desogestrel	Desogestrel is an antigonadotropic progestin that prevents pregnancy by suppressing ovulation. The exact mode of action of progestins in HAE is unclear.^Citation54,Citation56 However, progestins are known to reduce serum levels of estrogen by suppression of the hypothalamic–pituitary–ovarian axis,^Citation57,Citation58 and exposure to estrogens can be a trigger for swelling attacks in patients with HAE-nI-C1-INH.^Citation9,Citation21,Citation31–34
Ecallantide	Ecallantide inhibits the activity of kallikrein, preventing cleavage of HMWK to bradykinin and further activation of FXII.^Citation2,Citation44
Icatibant	Icatibant prevents binding of bradykinin to the bradykinin B2 receptor, thus moderating vasodilation and vascular permeability.^Citation2,Citation44
Lanadelumab	Lanadelumab is a monoclonal antibody inhibitor of plasma kallikrein.^Citation2,Citation44
Tranexamic acid	Tranexamic acid is an antifibrinolytic that competitively inhibits the activation of PLG, reducing its conversion to plasmin and decreasing the incidence of fibrinolysis.^Citation2

Abbreviations: C1-INH, C1-esterase inhibitor; FXII, coagulation factor XII; HAE, hereditary angioedema; HAE-nI-C1-INH, hereditary angioedema with normal C1-esterase inhibitor levels; HMWK, high molecular weight kininogen; PLG, plasminogen.

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