Prekallikrein Activation and High-Molecular-Weight Kininogen Consumption in Hereditary Angioedema

Schapira, Marc; Silver, Lee D.; Scott, Cheryl F.; Schmaier, Alvin H.; Prograis, Lawrence J.; Curd, John G.; Colman, Robert W.

doi:10.1056/nejm198305053081802

Cited by 193 publications

(90 citation statements)

References 31 publications

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“…Loss of control over any of these levels may have severe pathophysiological consequences. For example, deficiency in C1 inhibitor, the major PKa inactivator, is associated with hereditary angioedema, a life-threatening condition with recurrent attacks of edema (16,57,58). The central role of bradykinin in the pathology of this disease has recently been proven by an elegant mouse model, in which targeted deletion of the C1 inhibitor gene resulted in spontaneous vascular leakage.…”

Section: Discussionmentioning

confidence: 99%

Local Bradykinin Formation Is Controlled by Glycosaminoglycans

Renné

Schuh²,

Müller‐Esterl

2005

The Journal of Immunology

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Bradykinin is a potent inflammatory mediator that induces vasodilation, vascular leakage, and pain sensations. This short-lived peptide hormone is liberated from its large precursor protein high molecular weight kininogen (HK) through the contact system cascade involving coagulation factor XII and plasma kallikrein. Although bradykinin release is well established in vitro, the factors and mechanisms controlling bradykinin generation in vivo are still incompletely understood. In this study we demonstrate that binding of HK to glycosaminoglycans (GAGs) of the heparan and chondroitin sulfate type efficiently interferes with bradykinin release in plasma and on endothelial surfaces. Proteolytic bradykinin production on endothelial cells is restored following degradation of cell surface GAG through heparinase. Alternatively, application of HK fragments D3 or light chain, which compete with uncleaved HK for cell binding, promote kininogen proteolysis and bradykinin release. Intravital microscopy revealed that HK fragments increase bradykinin-mediated mesentery microvascular leakage. Topical application of D3 or light chain enhanced bradykinin generation and edema formation in the mouse skin. Our results demonstrate that bradykinin formation is controlled by HK binding to and detachment from GAGs. Separation of the precursor from cell surfaces is a prerequisite for its efficient proteolytic processing. By this means, fragments arising from HK processing propagate bradykinin generation, revealing a novel regulatory level for the kallikrein-kinin system.

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Section: Discussionmentioning

confidence: 99%

Local Bradykinin Formation Is Controlled by Glycosaminoglycans

Renné

Schuh²,

Müller‐Esterl

2005

The Journal of Immunology

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“…Bradykinin causes vasodilation and increased vascular permeability, and since kininogens are consumed during attacks of hereditary angioedema, it has been suggested that kinins, including bradykinin, are responsible for this condition (Schapira et al, 1983). Patients undergoing treatment with ACE inhibitors may develop angioedema (Wood et al, 1987) which characteristically appears shortly after starting treatment.…”

Section: Introductionmentioning

confidence: 99%

The effects of intradermal bradykinin are potentiated by angiotensin converting enzyme inhibitors in hypertensive patients.

Ferner

Wilson

Paterson

et al. 1989

Brit J Clinical Pharma

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1 To test the hypothesis that angiotensin converting enzyme (ACE) inhibitors potentiate the tissue effects of bradykinin, the thickness of weals produced by intradermal injections of bradykinin was measured in 17 hypertensive subjects whose antihypertensive regimen included an ACE inhibitor, and in 12 whose treatment did not. 2 Weal thickness increased linearly with the logarithm of the bradykinin dose in both groups (P < 0.0001). 3 The patients receiving ACE inhibitors showed a mean response of 1.18 ± 0.08 mm (mean ± s.e. mean), compared with a mean response of 0.75 ± 0.08 mm for patients not receiving an ACE inhibitor (P = 0.002). Mean weal response (1.08 ± 0.9 mm) was not significantly different in patients taking captopril (n = 11) compared with that (1.29 ± 0.12 mm) in patients taking enalapril (n = 9). 4 Facial flushing during the experiment occurred in six patients taking ACE inhibitors but none who were not.5 Dermal responses to bradykinin are enhanced in patients taking ACE inhibitors as routine antihypertensive therapy. This study supports the hypothesis that bradykinin may be responsible for some of the adverse effects of these drugs.

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“…30 Incubation of HAE plasma ex vivo was shown to generate bradykinin. 31,32 Furthermore, the contact system is activated in vivo during attacks of angioedema in HAE patients, [33][34][35] and increased levels of bradykinin have been measured in plasma during attacks of angioedema. 36 Contact system activation was also shown to cleave C1 inhibitor into a nonfunctional form, 11 and the plasma level of cleaved nonfunctional C1 inhibitor is increased during attacks of angioedema in HAE patients.…”

Section: What Is the Primary Mediator Of Swelling In Hae?mentioning

confidence: 99%

The Pathophysiology of Hereditary Angioedema

Zuraw

2010

World Allergy Organization Journal

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Abstract:Hereditary angioedema (HAE) causes recurrent episodes of angioedema that may be very severe and are frequently associated with significant morbidity and even mortality. Understanding the pathophysiology of this disease is crucial for proper diagnosis and management of these patients. HAE is caused by mutations in the SERPING1 gene that result in decreased plasma levels of functional C1 inhibitor. A large number of different mutations have been described that result in HAE. About 15% of patients have a mutation at or near the active site of the reactive mobile loop, resulting in a protein that lacks functional activity (type II HAE). Type I HAE is caused by a diverse range of mutations, some of which cause the nascent protein to misfold and thus to be unable to enter the secretory pathway. The primary mediator of swelling in HAE is bradykinin, a product of the plasma contact system. Bradykinin induces increased vascular permeability by activating the bradykinin B2 receptor, which results in phosphorylation of vascular endothelial cadherin. The regulation of both the bradykinin B2 receptor and peptidases that degrade bradykinin may influence HAE disease severity. HAE results from mutations in the SERPING1 gene that lead to a loss of functional C1 inhibitor. Attacks of angioedema result from generation of bradykinin, which acts on bradykinin B2 receptors to enhance vascular permeability.Key Words: HAE, C1 inhibitor, contact system, bradykinin, plasma kallikrein, Hageman factor (WAO Journal 2010; 3:S25-S28) I n 1888, William Osler described a familial form of angioedema associated with significant morbidity and mortality. 1 He called this disease hereditary angio-neurotic edema (HANE), a name that has subsequently been shortened to hereditary angioedema (HAE). The prevalence of HAE is not known for certain, but has been estimated to range from 1:30,000 to 1:80,000 in the general population without any known sex, ethnic, or racial differences. 2 HAE is clinically characterized by recurrent episodes of angioedema that typically involve the extremities, gastrointestinal tract, face, oropharynx, larynx, or external genitalia. Patients with HAE experience discrete episodes of nonpruritic nonpitting angioedema at these sites. 2,3 HAE attacks are classically distinguished from allergic or idiopathic angioedema by their longer duration (typically 72-96 hours), absence of accompanying urticaria and failure to respond to antihistamines or corticosteroid therapy.Most often, patients with HAE become symptomatic during childhood. Fifty percent of HAE patients first experience a swelling episode before age 10, with some patients manifesting angioedema as early as 1 year of age. 4,5 Most patients then experience a worsening of symptoms around puberty. 3 Occasionally, patients with HAE do not begin to show evidence of angioedema until their late teens or early adulthood. Rare patients with HAE have been reported who never experience angioedema, but are identified through screening family members of a symptomatic patient. 5...

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Prekallikrein Activation and High-Molecular-Weight Kininogen Consumption in Hereditary Angioedema

Cited by 193 publications

References 31 publications

Local Bradykinin Formation Is Controlled by Glycosaminoglycans

Local Bradykinin Formation Is Controlled by Glycosaminoglycans

The effects of intradermal bradykinin are potentiated by angiotensin converting enzyme inhibitors in hypertensive patients.

The Pathophysiology of Hereditary Angioedema

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