Hereditary Angioedema: The Clinical Picture of Excessive Contact Activation

Abstract

Hereditary angioedema is a rare, genetic disorder characterized by painful, debilitating and potentially life-threatening angioedema attacks in subcutaneous and submucosal tissue. While usually unpredictable, attacks can be provoked by a variety of triggers including physical injury and certain medication and are often preceded by prodromal symptoms. Hereditary angioedema has a profound influence on the patients' lives. The fundamental cause of hereditary angioedema in almost all patients is a mutation in the SERPING1 gene leading to a deficiency in C1-inhibitor. Subsequently, the contact activation cascade and kallikrein-kinin pathway are insufficiently inhibited, resulting in excessive bradykinin production triggering vascular leakage. While C1-inhibitor is an important regulator of the intrinsic coagulation pathway, fibrinolytic system and complement cascade, patients do not have an increased risk of coagulopathy, autoimmune conditions or immunodeficiency disorders. Hereditary angioedema is diagnosed based on C1-inhibitor level and function. Genetic analysis is only required in rare cases where hereditary angioedema with normal C1-inhibitor is found. In recent years, new, highly specific therapies have greatly improved disease control and angioedema-related quality of life. This article reviews the clinical picture of hereditary angioedema, the underlying pathophysiology, diagnostic process and currently available as well as investigational therapeutic options.

Drugs of the Kallikrein–Kinin System: An Overview

“…Presently, the therapeutic showcase of the KKS is hereditary angioedema (HAE), a rare disease most often caused by the haplodeficiency of C1INH. Numerous mutations transmitted in an autosomal-dominant manner are known in the corresponding gene SERPING1 [32]. HAE is characterized by recurrent episodes (attacks) of swelling due to fluid extravasation, and limbs, the orofacial and genital areas, and the intestine can be affected.…”

2024 Eberhard F. Mammen Award Announcements: Part I—Most Popular Articles

“…Also worth noting from Table 3 is that two of the papers on the list have not yet as yet been published in an issue, being available only on eFirst within the 2022 to 2023 publication period. 10 18 This, therefore, should be marked as a special achievement for these papers. Similarly, one of the papers derived from a previous Young Investigator award winner.…”

“…Consequently, the most popular papers from each category are identified separately. Tables 3 and 4 respectively list the top 25 downloaded articles from STH in 2023 (from 2022 and 2023 inclusive), as eligible for either the “free access” ( Table 3 ) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 or “general category” ( Table 4 ) 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 awards.…”

Mechanisms involved in hereditary angioedema with normal C1-inhibitor activity

“…Reciprocal activation of PK and FXII is enhanced by a process called contact activation, which occurs when KKS components bind to certain macromolecules or surfaces ( Figure 1C ) ( Colman and Schmaier, 1997 ; Long et al, 2016 ; Schmaier, 2016 ; Petersen et al, 2022 ). A variety of organic (e.g., nucleic acids, glycosaminoglycans) and inorganic (e.g., polyphosphates, silicates) substances support plasma contact activation ( Colman and Schmaier, 1997 ; Long et al, 2016 ; Schmaier, 2016 ; Tillman and Gailani, 2018 ).…”