Review
The bradykinin-forming cascade and its role in hereditary angioedema

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Objective

To review the mechanisms by which bradykinin is generated in hereditary angioedema (HAE) (C1 inhibitor deficiency), including the role of human plasma proteins and endothelial cells.

Data Sources

Published articles in reviewed journals that address (1) the fundamentals of bradykinin formation, (2) interactions between kinin-forming proteins and endothelial cells, (3) clinical evidence that bradykinin causes swelling in HAE, and (4) therapeutic options focused on inhibition of the plasma kallikrein-kinin cascade.

Study Selection

Historical articles that have made fundamental observations. Recent articles that address evolving concepts of disease pathogenesis and treatment.

Results

C1 inhibitor deficiency causes dysregulation of the plasma bradykinin-forming cascade with overproduction of bradykinin due to uninhibited effects of activated factor XII and plasma kallikrein. Swelling in HAE and production of bradykinin are localized (and may then disseminate); activation along the endothelial cell surface involves cell membrane ligands of factor XII and high-molecular-weight kininogen, release of endothelial cell heat shock protein 90, activation of the high-molecular-weight kininogen–prekallikrein complex, and endothelial cell activation at the B2 receptor. Attacks of swelling may be terminated by treatment with a kallikrein inhibitor or B2 receptor blockade. Replenishing C1 inhibitor can abort attacks of swelling and provide prophylaxis with intravenous administration.

Conclusions

Bradykinin is the mediator of swelling in types I and II HAE and is overproduced because of a deficiency in C1 inhibitor. Inhibition of bradykinin formation by novel agents can provide targeted therapeutic approaches that address the pathophysiologic abnormalities.

Introduction

Hereditary angioedema (HAE) has an incidence of approximately 1 per 50,000 persons due to a mutation of 1 allele of the C1 inhibitor (C1-INH) gene1, 2 on chromosome band 11q12-q13.3 It is inherited as an autosomal dominant disorder, yet as many as 25% of patients present with a new mutation, that is, they have no family history.4 Angioedema is the primary manifestation of this disorder and is defined as swelling due to extravasation of fluid into the interstitium of the deep dermis and subcutaneous tissue. The swelling typically lasts 2 to 5 days, and the tissue returns to normal between episodes.5 An evanescent rash reminiscent of erythema marginatum5 can herald an attack of angioedema in approximately 30% of patients, but there is no associated pruritus or urticaria.

Swelling can occur at virtually any site but most commonly occurs in the face (lips, cheek, and periorbital area), gastrointestinal tract, extremities, penis, and scrotum. Swelling can affect the tongue and pharynx to such a degree that secretions cannot be handled and placement of an airway becomes essential. Laryngeal edema with inspiratory stridor can progress rapidly to cause asphyxiation,6 and tracheostomy may be needed. Abdominal attacks lasting 2 to 4 days are present in more than 90% of patients and are characterized by severe abdominal pain that can be accompanied by nausea, vomiting, and diarrhea. The symptoms may suggest the presence of an acute abdomen, and, if the diagnosis is not recognized, unnecessary surgery may be performed. The cause of these symptoms is edema of the bowel wall,5, 7 with partial or complete luminal obstruction, and ascites may be present.8

Although sudden episodes of swelling can occur seemingly spontaneously, exogenous events, including blunt trauma, infection (particularly infection with concomitant fever), menstruation, and the use of estrogen or angiotensin-converting enzyme inhibitors, may precipitate attacks.9 Progesterone, on the other hand, may be protective.10 The swelling seen in HAE is due to activation of the plasma bradykinin-forming cascade, a complex 3-step process in which there is activation of factor XII (Hageman factor) (Fig 1), conversion of prekallikrein to plasma kallikrein, and digestion of high-molecular-weight kininogen (HK) to release bradykinin. The cascade is activated in vitro by binding of factor XII and a complex of prekallikrein and HK to initiating surfaces (eg, silicates, endotoxin, and uric acid crystals); however, in vivo, trauma to the endothelial cell surface and other tissue may expose initiating surfaces (eg, negatively charged proteins) that activate factor XII and initiate factor XII–dependent cascades.

Section snippets

Classification of HAE

HAE has been divided into 3 types, 2 of which are attributable to mutant C1-INH. Type I HAE has a very low serum level of C1-INH protein, with C1-INH function correspondingly low, and is seen in approximately 85% of patients.6, 9 Type II HAE accounts for approximately 15% of cases. This latter group has a mutation that allows gene transcription and messenger RNA translation to proceed, but the protein produced is inactive. The total C1-INH protein level typically is normal or even elevated,11

Diminished C1-INH Levels and Attacks of Swelling

The functional C1-INH level in patients with type I or II HAE should be approximately 50% if the one normal gene is functioning properly. Yet, blood levels are typically less than that, and, when functional levels are 30% or less, there is insufficient inhibition of bradykinin-forming enzymes, and an attack of swelling becomes likely. This reduction of expected C1-INH levels is due to multiple mechanisms. First, C1-INH is an activatable inhibitor, that is, C1-INH is cleaved by the enzyme that

Constituents of the Plasma Bradykinin-Forming Cascade

The conditions requisite for the generation of bradykinin in normal human plasma are an initiating surface, factor XII, prekallikrein, and HK. Factor XII circulates as a single-chain proenzyme of 80 kDa with no detectable enzymatic activity.25 It slowly autoactivates when bound to initiating, polyanionic surfaces,26 with conversion to factor XIIa (molecular weight of 80 kDa) and subsequent digestion to factor XIIf (molecular weight of 30 kDa). In the presence of plasma kallikrein, there is

Activation of the Plasma Bradykinin-Forming Cascade

Binding of factor XII to macromolecular surfaces does not create any active site, but the bound factor XII autoactivates.39 The concentration of enzyme (factor XIIa) continuously increases, and the reaction rate accelerates until the concentration of substrate (factor XII) becomes limiting and then slows down.26 This initiating step is inhibited by C1-INH (Fig 3).40

As factor XIIa is produced, it converts prekallikrein to plasma kallikrein and also factor XI to factor XIa (Fig 3). The latter

C1-INH as a Control Protein of Complement and Bradykinin Formation

After C1-INH levels were identified to be abnormal in patients with HAE, the action of C1-INH on enzymes other than C1 was considered. It was next shown to bind to the active site of plasma kallikrein45 and, therefore, to block the ability of plasma kallikrein to cleave HK and to activate factor XII. Next, C1-INH was identified as the only significant plasma inhibitor for factor XIIa and factor XIIf46; thus, it controls virtually all of the reactions of the plasma bradykinin-forming cascade (

Bradykinin as the Mediator of HAE

The first report of an inhibitor deficiency in HAE antedates the discovery of C1-INH deficiency when Landerman et al49 described deficiencies in “serum globulin permeability factor” and in plasma kallikrein noted when plasma was diluted. The serum globulin permeability factor turned out to be factor XIIf.50 The next reports of the mediator of swelling were of a trypsin-sensitive, kininlike molecule derived from C2 or, more specifically, by plasmin cleavage of C2b.51 Augmented skin reactivity of

Activation Along the Surface of Endothelial Cells

Although sampling of any random blood vessel demonstrates elevated levels of bradykinin and kinin-forming enzymes in HAE, it is clear that bradykinin formation predominantly occurs locally, at the site of swelling.61 The reasons for this localization are not yet clear but may be related to the fact that the natural initiating surface in the body seems to be endothelial cells with surface “receptors” that bind all the constituents of the bradykinin-forming cascade. The bradykinin-forming cascade

Special Consideration of Fibrinolysis

Plasmin is assumed to have a role in the pathogenesis of HAE because antifibrinolytic agents, such as ε-aminocaproic acid84 and tranexamic acid,85 have been shown to be effective therapeutic modalities (although less so than attenuated androgens), but neither has been approved by the US Food and Drug Administration for the treatment of HAE. Plasma kallikrein can convert plasminogen to plasmin directly or indirectly33 by activating the small amount of plasma prourokinase to urokinase. Urokinase,

Targeted Treatment of HAE

In the past, acute episodes of swelling were treated with supportive measures because no agent was available for this purpose.5, 6, 89 Fresh-frozen plasma administration can be effective90; however, its use is controversial because marked exacerbation of symptoms has been reported6 as prekallikrein and HK are also being replenished. Because activation proceeds much faster than does inactivation (seconds vs minutes), symptoms may worsen before they get better.

Prophylactic therapy has used

Conclusions

Bradykinin is the mediator of the swelling of HAE. Fluid-phase interaction of factor XII, prekallikrein, and HK produces bradykinin in an uncontrolled manner when C1-INH is absent. However, new data suggest that activation along the endothelial cell surface may relate to the fact that bradykinin formation starts as a local phenomenon at the site of swelling and may then spread to become more generalized. The endothelial cell may be an active participant and not simply the site of formation of

Acknowledgments

Editorial assistance in the development of this manuscript was provided by Publication Connexion. We acknowledge the Medical Affairs Department of Dyax Corp for their assistance in defining the unmet educational need that this article addresses.

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    Disclosures: Authors have nothing to disclose.

    Funding Source: This study was financially supported by Dyax Corp.

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