Therapeutic Approaches in Hereditary Angioedema

Antoniu, Sabina A

doi:10.1007/s12016-011-8254-2

Cited by 14 publications

(9 citation statements)

References 44 publications

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“…In addition, in humans, severe lung edema can develop in a rare genetic disorder, hereditary angioedema, that results from bradykinin accumulation due to mutations of the C1 esterase/kallikrein inhibitor 39 . Clinical studies have shown that inhibitors of bradykinin can efficiently treat lung edema in these circumstances 40 . Furthermore, the use of ACE inhibitors provides yet another line of clinical evidence for disturbed lung accumulation of bradykinin that can, on rare occasions, lead to severe outcomes 41,42 .…”

Section: Discussionmentioning

confidence: 99%

SARS-CoV-2 receptor is co-expressed with elements of the kinin–kallikrein, renin–angiotensin and coagulation systems in alveolar cells

Sidarta-Oliveira

Jara

Ferruzzi

et al. 2020

Sci Rep

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SARS-CoV-2, the pathogenic agent of COVID-19, employs angiotensin converting enzyme-2 (ACE2) as its cell entry receptor. Clinical data reveal that in severe COVID-19, SARS-CoV-2 infects the lung, leading to a frequently lethal triad of respiratory insufficiency, acute cardiovascular failure, and coagulopathy. Physiologically, ACE2 plays a role in the regulation of three systems that could potentially be involved in the pathogenesis of severe COVID-19: the kinin–kallikrein system, resulting in acute lung inflammatory edema; the renin–angiotensin system, promoting cardiovascular instability; and the coagulation system, leading to thromboembolism. Here we assembled a healthy human lung cell atlas meta-analysis with ~ 130,000 public single-cell transcriptomes and show that key elements of the bradykinin, angiotensin and coagulation systems are co-expressed with ACE2 in alveolar cells and associated with their differentiation dynamics, which could explain how changes in ACE2 promoted by SARS-CoV-2 cell entry result in the development of the three most severe clinical components of COVID-19.

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Section: Discussionmentioning

confidence: 99%

SARS-CoV-2 receptor is co-expressed with elements of the kinin–kallikrein, renin–angiotensin and coagulation systems in alveolar cells

Sidarta-Oliveira

Jara

Ferruzzi

et al. 2020

Sci Rep

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“…Decreased expression of C1INH or the presence of a dysfunctional C1INH protein can be found in plasma of patients with HAE. Purified or recombinant forms of C1INH have been, therefore, successfully used for the treatment of HAE [152, 153]. C1INH controls the activation of the classical complement pathway by inactivating the proteinases C1r and C1s, and it also regulates the activation of the lectin pathway potentially by inactivating MASPs 1 and 2 [151, 154, 155].…”

Section: Coagulation and Complementmentioning

confidence: 99%

Interactions between coagulation and complement—their role in inflammation

et al. 2011

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The parallel expression of activation products of the coagulation, fibrinolysis, and complement systems has long been observed in both clinical and experimental settings. Several interconnections between the individual components of these cascades have also been described, and the list of shared regulators is expanding. The coexistence and interplay of hemostatic and inflammatory mediators in the same microenvironment typically ensures a successful host immune defense in compromised barrier settings. However, dysregulation of the cascade activities or functions of inhibitors in one or both systems can result in clinical manifestations of disease, such as sepsis, systemic lupus erythematosus, or ischemia–reperfusion injury, with critical thrombotic and/or inflammatory complications. An appreciation of the precise relationship between complement activation and thrombosis may facilitate the development of novel therapeutics, as well as improve the clinical management of patients with thrombotic conditions that are characterized by complement-associated inflammatory responses.

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“…These substances can also be used as prophylaxis. 17 In addition to being an important inhibitor of factor XIIa and kallikrein, C1INH is also the major inhibitor of the proteases C1r and C1s, which belong to the classical complement pathway (Figure 3). Therefore, a deficiency of C1INH or a dysfunctional C1INH protein will lead to uncontrolled activation of the complement and contact system, as well as massive BK release.…”

Section: Hereditary Angioedemamentioning

confidence: 99%

Recent insights into the role of the contact pathway in thrombo-inflammatory disorders

Montfoort

Meijers

2014

Hematology

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The contact pathway of coagulation consists of the proteins factor XI, factor XII, prekallikrein, and high-molecularweight kininogen. Activation of the contact system leads to procoagulant and proinflammatory reactions. The contact system is essential for surface-initiated coagulation, as exemplified by aPTT, but there is probably no role for the contact system in initiating physiologic in vivo coagulation. However, over the last few years, there has been renewed interest, especially because of experimental evidence suggesting that the contact system contributes to thrombosis. Knockout mice deficient in one of the contact proteins were protected against artificially induced thrombosis. Furthermore, inhibiting agents such as monoclonal antibodies, antisense oligonucleotides, and small molecules were found to prevent thrombosis in rodents and primates in both venous and arterial vascular beds. Although it remains to be established whether targeting the contact system will be effective in humans and which of the contact factors is the best target for anticoagulation, it would constitute a promising approach for future effective and safe antithrombotic therapy. Learning Objectives• To understand that the contact system consists of 4 proteins: factor XI, factor XII, PK, and HK • To understand that deficiency of factor XII, PK, or HK is not associated with a bleeding tendency in humans • To understand that targeting the contact system is an effective method to prevent thrombosis in mice •

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Therapeutic Approaches in Hereditary Angioedema

Cited by 14 publications

References 44 publications

SARS-CoV-2 receptor is co-expressed with elements of the kinin–kallikrein, renin–angiotensin and coagulation systems in alveolar cells

SARS-CoV-2 receptor is co-expressed with elements of the kinin–kallikrein, renin–angiotensin and coagulation systems in alveolar cells

Interactions between coagulation and complement—their role in inflammation

Recent insights into the role of the contact pathway in thrombo-inflammatory disorders

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