The international WAO/EAACI guideline for the management of hereditary angioedema—The 2021 revision and update

Hereditary angioedema (HAE) is a rare and disabling disease for which early diagnosis and effective therapy are critical. This revision and update of the global WAO/EAACI guideline on the diagnosis and management of HAE provides up-to-date guidance for the management of HAE. For this update and revision of the guideline, an international panel of experts reviewed the existing evidence, developed 28 recommendations, and established consensus by an online DELPHI process. The goal of these recommendations and guideline is to help physicians and their patients in making rational decisions in the management of HAE with deficient C1 inhibitor (type 1) and HAE with dysfunctional C1 inhibitor (type 2), by providing guidance on common and important clinical issues, such as: (1) How should HAE be diagnosed? (2) When should HAE patients receive prophylactic on top of on-demand treatment and what treatments should be used? (3) What are the goals of treatment? (4) Should HAE management be different for special HAE patient groups such as children or pregnant/breast-feeding women? and (5) How should HAE patients monitor their disease activity, impact, and control? It is also the intention of this guideline to help establish global standards for the management of HAE and to encourage and facilitate the use of recommended diagnostics and therapies for all patients

The international WAO/EAACI guideline for the management of hereditary angioedema - The 2021 revision and update.

Hereditary Angioedema (HAE) is a rare and disabling disease for which early diagnosis and effective therapy are critical. This revision and update of the global WAO/EAACI guideline on the diagnosis and management of HAE provides up-to-date guidance for the management of HAE. For this update and revision of the guideline, an international panel of experts reviewed the existing evidence, developed 28 recommendations, and established consensus by an online DELPHI process. The goal of these recommendations and guideline is to help physicians and their patients in making rational decisions in the management of HAE with deficient C1-inhibitor (type 1) and HAE with dysfunctional C1-inhibitor (type 2), by providing guidance on common and important clinical issues, such as: 1) How should HAE be diagnosed? 2) When should HAE patients receive prophylactic on top of on-demand treatment and what treatments should be used? 3) What are the goals of treatment? 4) Should HAE management be different for special HAE patient groups such as children or pregnant/breast feeding women? 5) How should HAE patients monitor their disease activity, impact, and control? It is also the intention of this guideline to help establish global standards for the management of HAE and to encourage and facilitate the use of recommended diagnostics and therapies for all patients

The Role of Complement in Hereditary Angioedema

Low levels of C1 inhibitor, the main inhibitor of the classic complement system, result in paroxysmal angioedema attacks that can be incapacitating or even life-threatening in affected individuals. Molecular defects in the gene for C1 inhibitor cause hereditary angioedema. In recent years, new insights in the pathways leading to angioedema due to a deficiency of C1 inhibitor have been gathered. Bradykinin, which is formed upon activation of the kallikrein-kinin system under insufficient regulation by C1 inhibitor, plays a crucial role. Whereas C1 inhibitor also occupies a central mediatory role in other plasma systems, such as the contact activation system of coagulation and the fibrinolytic plasminogen-plasmin system, a C1 inhibitor deficiency may also cause enhanced activation of these pathways. Novel therapeutic modalities for treatment and prevention of hereditary angioedema are now available, such as different forms of C1 inhibitor concentrate and novel agents that interfere in the kallikrein-kinin system

Current and Prospective Targets of Pharmacologic Treatment of Hereditary Angioedema Types 1 and 2

Hereditary angioedema (HAE) is a rare disease that causes episodic attacks of subcutaneous and submucosal edema, which can be painful, incapacitating, and potentially fatal. These attacks are mediated by excessive bradykinin production, as a result of uncontrolled activation of the plasma kallikrein/kinin system, which is caused by a C1 esterase inhibitor deficiency or dysfunction in HAE types 1 and 2, respectively. For many years, treatment options were limited to therapies with substantial adverse effects, insufficient efficacy, or difficult routes of administration. Increased insights in the pathophysiology of HAE have paved the way for the development of new therapies with fewer side effects. In the last two decades, several targeted novel therapeutic strategies for HAE have been developed, for both long-term prophylaxis and on demand treatment of acute attacks. This article reviews the advances in the development of more effective and convenient treatment options for HAE and their anticipated effects on morbidity, mortality, and quality of life. The emergence of these improved treatment options will presumably change current HAE guidelines, but adherence to these recommendations may become restricted by high treatment costs. It will therefore be essential to determine the indications and identify the patients that will benefit most from these newest treatment generations. Ultimately, current preclinical research into gene therapies may eventually lead the way towards curative treatment options for HAE. In conclusion, an increasing shift towards the use of highly effective long-term prophylaxis is anticipated, which should drastically abate the burden on patients with hereditary angioedema

Thrombophilia and venous thromboembolism: implications for testing

In the last decades, the knowledge on the etiology of venous thromboembolism (VTE) has increased tremendously. In approximately half of patients presenting with VTE, one or more thrombophilic defects can be identified. This has led to widespread testing for thrombophilia, despite the fact that, at present, it is unclear whether this should have therapeutic consequences. Here we review the currently established hereditary and acquired thrombophilic defects, and focus on the pros and cons of testing in the setting of VTE. Thrombophilia is defined as a disorder associated with an increased tendency to venous thromboembolism (VTE). Thrombophilia can be acquired, such as in patients with cancer, or congenital, in which case a defect in the coagulation system is hereditary. Egeberg was the first to use the term thrombophilia in 1965, when he described a Norwegian family that had a remarkable tendency to VTE, based on a deficiency of antithrombin. Since then, various laboratory abnormalities, both hereditary and acquired, have been discovered that increase the risk of VTE. This article reviews the currently established thrombophilic abnormalities and discusses the potential usefulness and implications of testing for thrombophili

Hereditary angioedema: Linking complement regulation to the coagulation system

Congenital deficiency of C1 inhibitor, the main inhibitor of the classic complement system pathway, leads to paroxysmal angioedema (hereditary angioedema) that can be debilitating or life-threatening for affected patients. In the past few years many new insights on the pathogenesis of angioedema formation in the presence of low levels of C1 inhibitor has been accumulated. There is a central role for bradykinin that is released upon activation of the kallikrein-kinin system that is insufficiently controlled by adequate levels of C1 inhibitor. As C1 inhibitor also possesses a central regulatory role of other plasma systems, including the contact activation system of coagulation and the plasminogen-plasmin system that governs endogenous fibrinolysis, it is interesting to observe the effects of C1 inhibitor deficiency on activation of these systems and relevance for hemostasis in vivo and thrombo-embolic disease. Interestingly, and despite significant activation of these pathways, C1 inhibitor deficiency is not at all associated with a hemorrhagic tendency or prothrombotic state. New therapeutic options for treatment of C1 inhibitor efficiency have become available in recent years, including various forms of C1 inhibitor concentrate. Restoration of C1 inhibitor levels in patients with hereditary angioedema has not resulted in thrombotic complications or any other relevant disorder associated with the hemostatic system