Enzymatic pathways in the pathogenesis of hereditary angioedema: The role of C1 inhibitor therapy

SummaryHereditary angioedema (HAE) patients experience recurrent episodes of angioedema attacks that can be painful, disfiguring and even life-threatening. The disorder results from a mutation in the gene that controls the synthesis of C1-inhibitor (C1INH). C1INH is a major regulator of activation of the contact system. It is often assumed that attacks results from uncontrolled local activation of the contact system with subsequent formation of bradykinin. To evaluate the involvement of inflammatory reactions in HAE, we analysed C-reactive protein (CRP) levels. HAE patients included in a clinical database of recombinant human C1-inhibitor (rhC1INH) studies were evaluated. For the current study we analysed CRP levels when patients were asymptomatic, during a clinical attack and in a follow-up period, and correlated these with the clinical manifestations of the attack. Data from 68 HAE patients were analysed and included CRP levels on 273 occasions. While asymptomatic, 20% of the patients analysed had increased CRP. At the onset of the attack (P = 0·049) and during the next 24 h CRP rose significantly (P = 0·002) in patients with an abdominal location, and post-attack levels were significantly higher in these patients than in patients with attacks at other locations (P = 0·034). In conclusion, CRP levels are elevated in a substantial proportion of asymptomatic HAE patients. Levels of CRP increase significantly during an abdominal attack. These data suggest low-grade systemic inflammatory reactions in HAE patients as well as a triggering event for attacks that starts prior to symptom onset.

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“…Of these, the contact system is generally considered the most important for the pathogenesis of the angioedema attacks [5,6].…”

Section: Introductionmentioning

confidence: 99%

C-reactive protein levels in hereditary angioedema

Hofman

Relan

Hack

2014

Clinical and Experimental Immunology

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“…C1-Inh is a 110-kDa glycoprotein that regulates activation of the complement cascade and fibrinolysis [11]. Its main function is to inhibit the C1r, C1s, MASP-1 and MASP-2 proteases and halt activation of the cascade.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, it functions to inhibit proteases of the contact system (plasma kallikrein and activated Hageman factor XIIa and XIIf), which are responsible for the clinical course in HAE. Finally, it exerts inhibitory effects on plasmin and protease Xia (coagulation pathways) [11]. It is considered a suicide protein whose mechanism of action is to form 1:1 stoichiometric complexes with the proteases, thus allowing its clearance and inactivation [11].…”

Section: Discussionmentioning

confidence: 99%

“…Finally, it exerts inhibitory effects on plasmin and protease Xia (coagulation pathways) [11]. It is considered a suicide protein whose mechanism of action is to form 1:1 stoichiometric complexes with the proteases, thus allowing its clearance and inactivation [11]. The clinical result of the C1Inh deficiency is a state of constant activation of the complement, coagulation and contact systems, with the consequential action of consumption of the uncontrolled complement, interference in the coagulation system and increase in the amount of bradykinins, the latter being responsible for stimulating B2 receptors NSAID consumption is a factor associated with poor control; however, hypersensitivity to aspirin has not been reported as a crisis-triggering factor [17].…”

Section: Discussionmentioning

confidence: 99%

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Hypersensitivity to Aspirin as a Factor for Poor Control in Hereditary Angioedema

García-López¹,

Vargas-Camaño²,

Alcázar-Casarín³

et al. 2017

JBM

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Background: Hereditary angioedema (HAE) is a primary immunodeficiency disorder characterized by C1 complement inhibitor deficiency and unregulated activation of complement. Aspirin hypersensitivity is related to an increase in the amount of leukotrienes with eosinophil and mast cell activation and increased levels of glandular kallikrein with upregulated local conversion of bradykinin. Both conditions can be present in the same patient. Objectives: We present five patients with HAE; they were all being treated in similar ways according to the therapeuthic options available in our institute (danazol). However, three of them had recurrent episodes of angioedema; in these cases, it was identified aspirin hypersensitivity as a cause of poor disease control. A review of the literature is included. Case Presentation: We present the cases of four females and one male (age range 21 -58 years) with type I HAE. Subjects were all ISSSTE beneficiaries (state workers) treated at the National Medical Center "20 de Noviembre". Aspirin hypersensitivity was identified in three patients. Elimination of NSAIDs along with dietary elimination of high salicylate-containing foods improved control of angioedema crisis (severe and/ or recurrent episodes). Discussion: Aspirin hypersensitivity was identified as a factor for poor control in our patients with HAE. Such cases improved with dietary elimination of high salicylate-containing foods and avoidance of NSAIDs. Conclusions: This is the first report of patients with HAE and aspirin hypersensitivity as a cause of poor control. We recommend a deliberate search of these comorbidities, especially in cases of poor disease control. Further studies are needed to continue the investigation on this topic.

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“…Increased bradykinin levels increase vascular permeability and extravasation, manifesting as edema (Figure 2)[1,28-30]. This is an important differentiating feature of HAE when compared with allergic reactions, which are primarily mediated by histamine.…”

Section: Clinical Presentationmentioning

confidence: 99%

Hereditary Angioedema Caused By C1-Esterase Inhibitor Deficiency: A Literature-Based Analysis and Clinical Commentary on Prophylaxis Treatment Strategies

Gower¹,

Busse²,

Aygören‐Pürsün³

et al. 2011

World Allergy Organization Journal

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Hereditary angioedema (HAE) caused by C1-esterase inhibitor deficiency is an autosomal-dominant disease resulting from a mutation in the C1-inhibitor gene. HAE is characterized by recurrent attacks of intense, massive, localized subcutaneous edema involving the extremities, genitalia, face, or trunk, or submucosal edema of upper airway or bowels. These symptoms may be disabling, have a dramatic impact on quality of life, and can be life-threatening when affecting the upper airways. Because the manifestations and severity of HAE are highly variable and unpredictable, patients need individualized care to reduce the burden of HAE on daily life. Although effective therapy for the treatment of HAE attacks has been available in many countries for more than 30 years, until recently, there were no agents approved in the United States to treat HAE acutely. Therefore, prophylactic therapy is an integral part of HAE treatment in the United States and for selected patients worldwide. Routine long-term prophylaxis with either attenuated androgens or C1-esterase inhibitor has been shown to reduce the frequency and severity of HAE attacks. Therapy with attenuated androgens, a mainstay of treatment in the past, has been marked by concern about potential adverse effects. C1-esterase inhibitor works directly on the complement and contact plasma cascades to reduce bradykinin release, which is the primary pathologic mechanism in HAE. Different approaches to long-term prophylactic therapy can be used to successfully manage HAE when tailored to meet the needs of the individual patient.

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Enzymatic pathways in the pathogenesis of hereditary angioedema: The role of C1 inhibitor therapy

Cited by 99 publications

References 53 publications

C-reactive protein levels in hereditary angioedema

C-reactive protein levels in hereditary angioedema

Hypersensitivity to Aspirin as a Factor for Poor Control in Hereditary Angioedema

Hereditary Angioedema Caused By C1-Esterase Inhibitor Deficiency: A Literature-Based Analysis and Clinical Commentary on Prophylaxis Treatment Strategies

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