Plasmin is a natural trigger for bradykinin production in patients with hereditary angioedema with factor XII mutations

Maat, Steven de; Björkqvist, Jenny; Suffritti, Chiara; Wiesenekker, Chantal P; Nagtegaal, Willem; Koekman, Cornelis A.; Dooremalen, Sanne van; Pasterkamp, Gérard; Groot, Philip G. de; Cicardi, Marco; Renné, Thomas; Maas, Coen

doi:10.1016/j.jaci.2016.02.021

Cited by 154 publications

(155 citation statements)

References 56 publications

(45 reference statements)

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“…FXII is a protease involved in the activation of the coagulation and contact systems and these mutations found in F12 gene in patients with FXII-HAE have been shown to produce hyperactivability of coagulation factor FXII, with the consequent activation of the contact system [43].…”

Section: Other Forms Of Angioedema With Activation Of the Contact Systemmentioning

confidence: 99%

Pathophysiology of Bradykinin-Mediated Angioedema: The Role of the Complement System

Palomo¹,

Caballero²

2017

A Comprehensive Review of Urticaria and Angioedema

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The "complement system" is one of the efector pathways of the immune system against microorganisms and tumor cells. The complement system can be activated through three major pathways: classical, lectin, and alternative. The sequential activation through the generation of complex enzymes from inactive zymogens produces a cascade in which a capable enzyme generates a large number of active downstream molecules.C1 inhibitor (C1-INH) is a serine protease inhibitor (serpin) that regulates the following closely interrelated proteolytic pathways: complement system, coagulation system, contact system, and ibrinolysis system. The absence or malfunction of C1-INH results in the presence of atacks of angioedema (AE) due to uncontrolled activation of the contact system, with the generation of bradykinin (BK), a vasoactive peptide released from high-molecular-weight kininogen (HMWK). Some drugs that inhibit the catabolism of BK have been implicated in the development of AE. These include angiotensin-converting enzyme inhibitors (ACEIs), dipeptidyl peptidase IV (DPP-IV) inhibitors, aminopeptidase P (APP) inhibitors, and neutral endopeptidase (NEP) inhibitors.We describe in this chapter the biochemistry pathways implicated in the pathophysiology of bradykininergic angioedema (BK-AE) and the role of the complement system in the prototype of BK-AE, in hereditary angioedema with C1-INH deiciency (C1-INH-HAE), and also in acquired angioedema with C1-INH deiciency (C1-INH-AAE).

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Section: Other Forms Of Angioedema With Activation Of the Contact Systemmentioning

confidence: 99%

Pathophysiology of Bradykinin-Mediated Angioedema: The Role of the Complement System

Palomo¹,

Caballero²

2017

A Comprehensive Review of Urticaria and Angioedema

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“…Recent studies confirmed these findings, and showed that the change in protein glycosylation introduced new sites for potential cleavage. 18 The variants caused accelerated FXII activation by plasmin, thereby interrupting the balance between activation and inhibition of the contact system in solution. As a result, the FXIImutants escaped C1inh inactivation during activation by plasmin.…”

Section: Mutational Spectrummentioning

confidence: 99%

“…21 For the deletion variant, the anticipated functional consequences have been demonstrated experimentally. 18 For the duplication, no functional investigations have yet been performed.…”

Section: Mutational Spectrummentioning

confidence: 99%

Clinical Utility Gene Card for hereditary angioedema with normal C1 inhibitor (HAEnC1)

et al. 2017

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“…Plasmin activates the kallikrein-kinin system (KKS). 6 The KKS includes the plasma proteins PPK and FXII. 7 When the KKS is activated, PPK and FXII are converted to the enzymes PKal and FXIIa (see figure, red arrows).…”

mentioning

confidence: 99%

“…BK induces vasodilatation and increases vascular permeability and edema formation. 6,7 Infusion of tPA into patients with myocardial infarction increases PKal and BK generation. 8 Local production of BK in a stroke patient receiving tPA could contribute to loss of blood vessel and blood-brain barrier integrity, leading to tissue damage and increased risk of hemorrhagic transformation.…”

mentioning

confidence: 99%

Making thrombolysis safer in stroke

Gailani

2017

Blood

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Plasmin is a natural trigger for bradykinin production in patients with hereditary angioedema with factor XII mutations

Abstract: Our findings indicate a new pathway for bradykinin formation in patients with HAE, in which FXII is cleaved and activated by plasmin. This should lead to the identification of new markers for diagnosis and targets for treatment.

Cited by 154 publications

References 56 publications

Pathophysiology of Bradykinin-Mediated Angioedema: The Role of the Complement System

Pathophysiology of Bradykinin-Mediated Angioedema: The Role of the Complement System

Clinical Utility Gene Card for hereditary angioedema with normal C1 inhibitor (HAEnC1)

Making thrombolysis safer in stroke

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