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Dong XQ, Zhang YH, Luo J, Li MJ, Ma LQ, Qi YT, Miao YL. Keratin 1 modulates intestinal barrier and immune response via kallikrein kinin system in ulcerative colitis. World J Gastroenterol 2025; 31:102070. [PMID: 39958441 PMCID: PMC11752705 DOI: 10.3748/wjg.v31.i6.102070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Revised: 12/06/2024] [Accepted: 12/19/2024] [Indexed: 01/10/2025] Open
Abstract
BACKGROUND External factors in ulcerative colitis (UC) exacerbate colonic epithelial permeability and inflammatory responses. Keratin 1 (KRT1) is crucial in regulating these alterations, but its specific role in the progression of UC remains to be fully elucidated. AIM To explore the role and mechanisms of KRT1 in the regulation of colonic epithelial permeability and inflammation in UC. METHODS A KRT1 antibody concentration gradient test, along with a dextran sulfate sodium (DSS)-induced animal model, was implemented to investigate the role of KRT1 in modulating the activation of the kallikrein kinin system (KKS) and the cleavage of bradykinin (BK)/high molecular weight kininogen (HK) in UC. RESULTS Treatment with KRT1 antibody in Caco-2 cells suppressed cell proliferation, induced apoptosis, reduced HK expression, and increased BK expression. It further downregulated intestinal barrier proteins, including occludin, zonula occludens-1, and claudin, and negatively impacted the coagulation factor XII. These changes led to enhanced activation of BK and HK cleavage, thereby intensifying KKS-mediated inflammation in UC. In the DSS-induced mouse model, administration of KRT1 antibody mitigated colonic injury, increased colon length, alleviated weight loss, and suppressed inflammatory cytokines such as interleukin (IL)-1, IL-6, tumor necrosis factor-α. It also facilitated repair of the intestinal barrier, reducing DSS-induced injury. CONCLUSION KRT1 inhibits BK expression, suppresses inflammatory cytokines, and enhances markers of intestinal barrier function, thus ameliorating colonic damage and maintaining barrier integrity. KRT1 is a viable therapeutic target for UC.
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Affiliation(s)
- Xiang-Qian Dong
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Yunnan Province Clinical Research Center for Digestive Diseases, Kunming 650032, Yunnan Province, China
| | - Ying-Hui Zhang
- Department of Gastroenterology, Affiliated Hospital of Yunnan University, Kunming 650021, Yunnan Province, China
| | - Juan Luo
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Yunnan Province Clinical Research Center for Digestive Diseases, Kunming 650032, Yunnan Province, China
| | - Mao-Juan Li
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Yunnan Province Clinical Research Center for Digestive Diseases, Kunming 650032, Yunnan Province, China
| | - Lan-Qing Ma
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Yunnan Province Clinical Research Center for Digestive Diseases, Kunming 650032, Yunnan Province, China
| | - Ya-Ting Qi
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Yunnan Province Clinical Research Center for Digestive Diseases, Kunming 650032, Yunnan Province, China
| | - Ying-Lei Miao
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Yunnan Province Clinical Research Center for Digestive Diseases, Kunming 650032, Yunnan Province, China
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Sexton D, Nguyen HQ, Juethner S, Luo H, Zhang Z, Jasper P, Zhu AZX. A quantitative systems pharmacology model of plasma kallikrein-kinin system dysregulation in hereditary angioedema. J Pharmacokinet Pharmacodyn 2024; 51:721-734. [PMID: 38734778 PMCID: PMC11579104 DOI: 10.1007/s10928-024-09919-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Accepted: 04/09/2024] [Indexed: 05/13/2024]
Abstract
Hereditary angioedema (HAE) due to C1-inhibitor deficiency is a rare, debilitating, genetic disorder characterized by recurrent, unpredictable, attacks of edema. The clinical symptoms of HAE arise from excess bradykinin generation due to dysregulation of the plasma kallikrein-kinin system (KKS). A quantitative systems pharmacology (QSP) model that mechanistically describes the KKS and its role in HAE pathophysiology was developed based on HAE attacks being triggered by autoactivation of factor XII (FXII) to activated FXII (FXIIa), resulting in kallikrein production from prekallikrein. A base pharmacodynamic model was constructed and parameterized from literature data and ex vivo assays measuring inhibition of kallikrein activity in plasma of HAE patients or healthy volunteers who received lanadelumab. HAE attacks were simulated using a virtual patient population, with attacks recorded when systemic bradykinin levels exceeded 20 pM. The model was validated by comparing the simulations to observations from lanadelumab and plasma-derived C1-inhibitor clinical trials. The model was then applied to analyze the impact of nonadherence to a daily oral preventive therapy; simulations showed a correlation between the number of missed doses per month and reduced drug effectiveness. The impact of reducing lanadelumab dosing frequency from 300 mg every 2 weeks (Q2W) to every 4 weeks (Q4W) was also examined and showed that while attack rates with Q4W dosing were substantially reduced, the extent of reduction was greater with Q2W dosing. Overall, the QSP model showed good agreement with clinical data and could be used for hypothesis testing and outcome predictions.
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Affiliation(s)
- Dan Sexton
- Takeda Development Center Americas, Inc., Lexington, MA, USA
| | - Hoa Q Nguyen
- Takeda Development Center Americas, Inc., Lexington, MA, USA
| | - Salomé Juethner
- Takeda Development Center Americas, Inc., Lexington, MA, USA
| | | | | | | | - Andy Z X Zhu
- Takeda Development Center Americas, Inc., Lexington, MA, USA.
- Preclinical and Translational Science Department, Takeda Pharmaceutical Company Limited, 35 Landsdowne Street, Cambridge, MA, 02139, USA.
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3
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Sexton D, Faucette R, Rivera-Hernandez M, Kenniston JA, Papaioannou N, Cosic J, Kopacz K, Salmon G, Beauchemin C, Juethner S, Yeung D. A novel assay of excess plasma kallikrein-kinin system activation in hereditary angioedema. FRONTIERS IN ALLERGY 2024; 5:1436855. [PMID: 39391687 PMCID: PMC11464748 DOI: 10.3389/falgy.2024.1436855] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Accepted: 08/20/2024] [Indexed: 10/12/2024] Open
Abstract
Background Cleaved high-molecular-weight kininogen (HKa) is a disease state biomarker of kallikrein-kinin system (KKS) activation in patients with hereditary angioedema due to C1 inhibitor deficiency (HAE-C1INH), the endogenous inhibitor of plasma kallikrein (PKa). Objective Develop an HKa-specific enzyme-linked immunosorbent assay (ELISA) to monitor KKS activation in the plasma of HAE-C1INH patients. Methods A novel HKa-specific antibody was discovered by antibody phage display and used as a capture reagent to develop an HKa-specific ELISA. Results Specific HKa detection following KKS activation was observed in plasma from healthy controls but not in prekallikrein-, high-molecular-weight kininogen-, or coagulation factor XII (FXII)-deficient plasma. HKa levels in plasma collected from HAE-C1INH patients in a disease quiescent state were higher than in plasma from healthy controls and increased further in HAE-C1INH plasma collected during an angioedema attack. The specificity of the assay for PKa-mediated HKa generation in minimally diluted plasma activated with exogenous FXIIa was demonstrated using a specific monoclonal antibody inhibitor (lanadelumab, IC50 = 0.044 µM). Conclusions An ELISA was developed for the specific and quantitative detection of HKa in human plasma to support HAE-C1INH drug development. Improved quantification of the HKa biomarker may facilitate further pathophysiologic insight into HAE-C1INH and other diseases mediated by a dysregulated KKS and may enable the design of highly potent inhibitors targeting this pathway.
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Affiliation(s)
- Dan Sexton
- Takeda Development Center Americas Inc., Cambridge, MA, United States
| | - Ryan Faucette
- Takeda Development Center Americas Inc., Cambridge, MA, United States
| | | | - Jon A. Kenniston
- Takeda Development Center Americas Inc., Cambridge, MA, United States
| | | | - Janja Cosic
- Takeda Development Center Americas Inc., Cambridge, MA, United States
| | - Kris Kopacz
- Takeda Development Center Americas Inc., Cambridge, MA, United States
| | - Gary Salmon
- Charles River Laboratories, Harlow, United Kingdom
| | | | - Salomé Juethner
- Takeda Pharmaceuticals USA, Inc., Lexington, MA, United States
| | - Dave Yeung
- Takeda Development Center Americas Inc., Cambridge, MA, United States
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4
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Christiansen SC, Zuraw BL. Contact System Activation and Bradykinin Generation in Angioedema: Laboratory Assessment and Biomarker Utilization. Immunol Allergy Clin North Am 2024; 44:543-560. [PMID: 38937015 DOI: 10.1016/j.iac.2024.03.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/29/2024]
Abstract
The role of contact system activation has been clearly established in the pathogenesis of hereditary angioedema due to C1 inhibitor deficiency (HAE-C1INH). C1 inhibitor (C1INH)-protease complexes, levels of functional C1INH, plasma kallikrein activation, and cleavage of high-molecular-weight kininogen have each been associated with disease activity. More recently, HAE with normal levels of C1INH (HAE-nl-C1INH) has been recognized. Six genetic mutations have been identified which are linked to HAE-nl-C1INH phenotypes. The majority of individuals with HAE-nl-C1INH fall into the unknown category. There is substantial evidence that bradykinin generation underlies the recurrent attacks of swelling in some of these cohorts.
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Affiliation(s)
- Sandra C Christiansen
- Department of Medicine, University of California San Diego, 9500 Gilman Drive, Mail Code 0732, La Jolla, CA 92093, USA
| | - Bruce L Zuraw
- Department of Medicine, University of California San Diego, 9500 Gilman Drive, Mail Code 0732, La Jolla, CA 92093, USA; Medicine Service, San Diego Veterans Administration Healthcare System, 3350 La Jolla Village Drive, San Diego, CA 92161, USA.
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Zuraw BL, Christiansen SC. Classification, Diagnosis, and Pathology of Angioedema Without Hives. Immunol Allergy Clin North Am 2024; 44:529-541. [PMID: 38937014 DOI: 10.1016/j.iac.2024.03.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/29/2024]
Abstract
A clear disease classification schema coupled with an understanding of the specific mechanisms involved in the different types of angioedema without hives informs the diagnostic assessment. The recommended approach involves several key steps. Foremost is the recognizing of the clinical clues which allow for the differentiation of mast cell-mediated disorders from bradykinin-mediated angioedema. Enhanced vascular permeability related to bradykinin is of critical importance to identify given the implications for disease morbidity and risk of mortality. The ability to efficiently categorize and diagnose all forms of angioedema results in improved patient outcomes.
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Affiliation(s)
- Bruce L Zuraw
- Department of Medicine, University of California San Diego, 9500 Gilman Drive, Mail Code 0732, La Jolla, CA 92093, USA; Medicine Service, San Diego Veterans Administration Healthcare System, 3350 La Jolla Village Drive, San Diego, CA 92161, USA.
| | - Sandra C Christiansen
- Department of Medicine, University of California San Diego, 9500 Gilman Drive, Mail Code 0732, La Jolla, CA 92093, USA
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Lima H, Zheng J, Wong D, Waserman S, Sussman GL. Pathophysiology of bradykinin and histamine mediated angioedema. FRONTIERS IN ALLERGY 2023; 4:1263432. [PMID: 37920409 PMCID: PMC10619149 DOI: 10.3389/falgy.2023.1263432] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Accepted: 09/26/2023] [Indexed: 11/04/2023] Open
Abstract
Angioedema is characterized by swelling localized to the subcutaneous and submucosal tissues. This review provides an overview of angioedema, including the different types, triggers, and underlying pathophysiologic mechanisms. Hereditary and acquired angioedema are caused by dysregulation of the complement and kinin pathways. In contrast, drug-induced and allergic angioedema involve the activation of the immune system and release of vasoactive mediators. Recent advances in the understanding of the pathophysiology of angioedema have led to the development of targeted therapies, such as monoclonal antibodies, bradykinin receptor antagonists, and complement inhibitors, which promise to improve clinical outcomes in patients with this challenging condition. To accurately diagnose and manage angioedema, an understanding of this condition's complex and varied pathophysiology is both necessary and critical.
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Affiliation(s)
- Hermenio Lima
- LEADER Research Inc., Hamilton, ON, Canada
- Department of Medicine, McMaster University, Hamilton, ON, Canada
| | | | - Dennis Wong
- Division of Clinical Immunology and Allergy, Department of Medicine, University of Toronto, Toronto, ON, Canada
| | - Susan Waserman
- Division of Clinical Immunology and Allergy, Department of Medicine, McMaster University, Hamilton, ON, Canada
| | - Gordon L. Sussman
- Department of Medicine and Division of Clinical Immunology & Allergy, University of Toronto, Toronto, ON, Canada
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Duckworth EJ, Murugesan N, Li L, Rushbrooke LJ, Lee DK, De Donatis GM, Maetzel A, Yea CM, Hampton SL, Feener EP. Pharmacological suppression of the kallikrein kinin system with KVD900: An orally available plasma kallikrein inhibitor for the on-demand treatment of hereditary angioedema. Clin Exp Allergy 2022; 52:1059-1070. [PMID: 35278245 PMCID: PMC9544254 DOI: 10.1111/cea.14122] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 02/02/2022] [Accepted: 03/01/2022] [Indexed: 12/21/2022]
Abstract
BACKGROUND Hereditary angioedema (HAE) is a rare genetic disease that leads to recurrent episodes of swelling and pain caused by uncontrolled plasma kallikrein (PKa) activity. Current guidelines recommend ready availability of on-demand HAE treatments that can be administered early upon attack onset. This report describes the pharmacological and pharmacodynamic properties of the novel oral small-molecule PKa inhibitor KVD900 as a potential on-demand treatment for HAE. METHODS Pharmacological properties of KVD900 on PKa and closely related serine proteases were characterized using kinetic fluorogenic substrate activity assays. Effects of KVD900 on PKa activity and kallikrein kinin system activation in whole plasma were measured in the presence of dextran sulphate (DXS)-stimulation using a fluorogenic substrate and capillary immunoassays to quantify high molecular weight kininogen (HK), plasma prekallikrein and Factor XII cleavage. Pharmacodynamic effects of orally administered KVD900 were characterized in plasma samples from six healthy controls in a first in human phase 1 clinical trial and from 12 participants with HAE in a phase 2 clinical trial. RESULTS KVD900 is a selective, competitive and reversible inhibitor of human PKa enzyme with a Ki of 3.02 nM. The association constant (Kon ) of KVD900 for PKa is >10 × 106 M-1 s-1 . Oral administration of KVD900 in a first-in-human clinical trial achieved rapid and near complete inhibition of DXS-stimulated PKa enzyme activity and HK cleavage and reduced plasma prekallikrein and Factor XII activation in plasma. In individuals with HAE, orally administered KVD900 inhibited DXS-stimulated PKa activity in plasma by ≥95% from 45 min to at least 4 h post-dose and provided rapid protection of HK from cleavage. CONCLUSION KVD900 is a fast-acting oral PKa inhibitor that rapidly inhibits PKa activity, kallikrein kinin system activation and HK cleavage in plasma. On-demand administration of KVD900 may provide an opportunity to halt the generation of bradykinin and reverse HAE attacks.
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Affiliation(s)
| | | | - Lily Li
- KalVista PharmaceuticalsCambridgeMassachusettsUSA
| | | | | | | | - Andreas Maetzel
- KalVista PharmaceuticalsCambridgeMassachusettsUSA
- Institute for Health Policy, Management & EvaluationUniversity of TorontoTorontoOntarioCanada
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Gülbahar O, Germenis AE. Rediscovery of a forgotten disease: Hereditary Angioedema. Balkan Med J 2021; 38:68-72. [PMID: 33593720 PMCID: PMC8909243 DOI: 10.5152/balkanmedj.2021.20030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Accepted: 12/13/2020] [Indexed: 12/02/2022] Open
Affiliation(s)
- Okan Gülbahar
- Division of Immunology-Allergy, Department of Internal Medicine, Ege University School of Medicine, İzmir, Turkey
| | - Anastasios E. Germenis
- Department of Immunology and Histocompatibility, School of Medicine, University of Thessaly, Larissa, Greece
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9
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Bova M, Suffritti C, Bafunno V, Loffredo S, Cordisco G, Del Giacco S, De Pasquale TMA, Firinu D, Margaglione M, Montinaro V, Petraroli A, Radice A, Brussino L, Zanichelli A, Zoli A, Cicardi M. Impaired control of the contact system in hereditary angioedema with normal C1-inhibitor. Allergy 2020; 75:1394-1403. [PMID: 31860755 DOI: 10.1111/all.14160] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2019] [Revised: 11/11/2019] [Accepted: 11/21/2019] [Indexed: 01/23/2023]
Abstract
BACKGROUND Hereditary angioedema (HAE) comprises HAE with C1-inhibitor deficiency (C1-INH-HAE) and HAE with normal C1-INH activity (nl-C1-INH-HAE), due to mutations in factor XII (FXII-HAE), plasminogen (PLG-HAE), angiopoietin 1 (ANGPT1-HAE), kininogen 1 genes (KNG1-HAE), or angioedema of unknown origin (U-HAE). The Italian network for C1-INH-HAE (ITACA) created a registry including different forms of angioedema without wheals. OBJECTIVE We analyzed clinical and laboratory features of a cohort of Italian subjects with nl-C1-INH-HAE followed by ITACA to identify specific biomarkers. METHODS A total of 105 nl-C1-INH-HAE patients were studied. Plasma concentrations of cleaved high-molecular-weight kininogen (cHK), vascular endothelial growth factors (VEGFs), angiopoietins (Angs), and secreted phospholipase A2 enzymes (sPLA2 ) were evaluated. RESULTS We identified 43 FXII-HAE patients, 58 U-HAE, and 4 ANGPT1-HAE. We assessed a prevalence of 1:1.4 × 106 for FXII-HAE and 1:1.0 × 106 for U-HAE. cHK levels in U-HAE patients were similar to controls in plasma collected using protease inhibitors cocktail (PIC), but they significantly increased in the absence of PIC. In FXII-HAE patients, cHK levels, in the absence of PIC, were significantly higher than in controls. We found a significant increase of VEGF-A, VEGF-C, and Ang1 levels in U-HAE patients compared to controls. In FXII-HAE, only VEGF-C levels were increased. Ang2 concentrations and sPLA2 activity were not modified. The levels of these mediators in ANGPT1-HAE patients were not altered. CONCLUSIONS Our results suggest that pathogenesis of FXII-, ANGPT1-, and U-HAE moves through an unbalanced control of kallikrein activity, with bradykinin as most likely mediator. VEGFs and Ang1 participate in the pathophysiology of U-HAE increasing the basal vascular permeability.
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Affiliation(s)
- Maria Bova
- Department of Translational Medical Sciences and Center for Basic and Clinical Immunology Research, University of Naples Federico II, Naples, Italy
| | - Chiara Suffritti
- Department of Biomedical and Clinical Sciences Luigi Sacco, University of Milan, Milan, Italy
| | - Valeria Bafunno
- Medical Genetics, Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy
| | - Stefania Loffredo
- Department of Translational Medical Sciences and Center for Basic and Clinical Immunology Research, University of Naples Federico II, Naples, Italy
- Institute of Experimental Endocrinology and Oncology "G. Salvatore", National Research Council, Naples, Italy
| | - Giorgia Cordisco
- Medical Genetics, Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy
| | | | | | - Davide Firinu
- Department of Medical Sciences, University of Cagliari, Cagliari, Italy
| | - Maurizio Margaglione
- Medical Genetics, Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy
| | | | - Angelica Petraroli
- Department of Translational Medical Sciences and Center for Basic and Clinical Immunology Research, University of Naples Federico II, Naples, Italy
| | - Anna Radice
- Department of Allergy, University of Florence, Florence, Italy
| | - Luisa Brussino
- Department of Medical Science, University of Torino, Turin, Italy
| | | | - Alessandra Zoli
- Department of Clinical Immunology, Ospedali Riuniti, Ancona, Italy
| | - Marco Cicardi
- Department of Biomedical and Clinical Sciences Luigi Sacco, University of Milan, Milan, Italy
- IRCCS-ICS Maugeri, Milano, Italy
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Tanaka KA, Mondal S, Morita Y, Williams B, Strauss ER, Cicardi M. Perioperative Management of Patients With Hereditary Angioedema With Special Considerations for Cardiopulmonary Bypass. Anesth Analg 2020; 131:155-169. [DOI: 10.1213/ane.0000000000004710] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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Schmaier AH, Stavrou EX. Factor XII - What's important but not commonly thought about. Res Pract Thromb Haemost 2019; 3:599-606. [PMID: 31624779 PMCID: PMC6781921 DOI: 10.1002/rth2.12235] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2019] [Revised: 04/28/2019] [Accepted: 05/18/2019] [Indexed: 12/20/2022] Open
Abstract
Factor XII (FXII) becomes a serine protease when blood is exposed to artificial medical surfaces or when pathologic surfaces arise in disease states leading to its autoactivation. Initiation of the blood coagulation cascade was the first recognized activity of FXIIa. Blocking FXIIa activity formed on artificial medical surfaces should reduce induced blood coagulation leading to thrombosis. In contrast to FXII enzymatic activities, less is known about zymogen FXII functions. Studies show that zymogen FXII has biologic activity in various cells in vivo. In endothelium, FXII stimulates cell growth and proliferation and, in vivo, neoangiogenesis after injury. In fibroblasts, transforming growth factor-β increases FXII expression, which in turn stimulates fibroblast proliferation, contributing to tissue fibrosis. In neutrophils, FXII stimulates Akt2 to initiate neutrophil adhesion, migration, and chemotaxis, priming events leading to NETosis. Factor FXII deficiency leads to decreased neutrophil recruitment and improved wound healing. In dendritic cells, FXII contributes to neuroinflammation, and its deficiency or pharmacologic inhibition renders mice less susceptible to autoimmune encephalomyelitis. These combined studies indicate that FXII also contributes to multiple components of the inflammatory response. In sum, targeting FXII's biologic activities may provide novel approaches to reduce thrombosis and the inflammatory response in various disease states.
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Affiliation(s)
- Alvin H. Schmaier
- Department of MedicineCase Western Reserve UniversityClevelandOhio
- Department of MedicineUniversity Hospitals Cleveland Medical CenterClevelandOhio
| | - Evi X. Stavrou
- Department of MedicineCase Western Reserve UniversityClevelandOhio
- Department of MedicineVA Northeast Ohio Healthcare SystemClevelandOhio
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12
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Levi M, Cohn DM. The Role of Complement in Hereditary Angioedema. Transfus Med Rev 2019; 33:243-247. [DOI: 10.1016/j.tmrv.2019.08.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2019] [Revised: 08/15/2019] [Accepted: 08/16/2019] [Indexed: 11/28/2022]
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13
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Hereditary Angioedema: Insights into inflammation and allergy. Mol Immunol 2019; 112:378-386. [PMID: 31279849 DOI: 10.1016/j.molimm.2019.06.017] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2019] [Revised: 06/24/2019] [Accepted: 06/24/2019] [Indexed: 11/21/2022]
Abstract
Hereditary Angioedema (HAE) is a rare autosomal recessive bradykinin (BK)-mediated disease characterized by local episodes of non-pitting swelling. Initially considered a complement-mediated disease, novel pathogenic mechanisms uncovered in the last decade have revealed new HAE-associated genes and tight physiological relationships among complement, contact, coagulation, fibrinolysis and inflammation. Uncontrolled production of BK due to inefficient regulation of the plasma contact system, increased activity of contact and coagulation factors or a deficient regulation of BK receptor-triggered intracellular signalling are on the basis of HAE pathology. In this new scenario, HAE can result from different mechanisms that may generate distinct clinical phenotypes of the disease. This review focuses in the recent advances and unsolved challenges in our comprehension of this ever increasingly complex pathology.
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Farfara D, Feierman E, Richards A, Revenko AS, MacLeod RA, Norris EH, Strickland S. Knockdown of circulating C1 inhibitor induces neurovascular impairment, glial cell activation, neuroinflammation, and behavioral deficits. Glia 2019; 67:1359-1373. [PMID: 30882931 DOI: 10.1002/glia.23611] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2018] [Revised: 02/11/2019] [Accepted: 02/19/2019] [Indexed: 12/20/2022]
Abstract
The cross-talk between blood proteins, immune cells, and brain function involves complex mechanisms. Plasma protein C1 inhibitor (C1INH) is an inhibitor of vascular inflammation that is induced by activation of the kallikrein-kinin system (KKS) and the complement system. Knockout of C1INH was previously correlated with peripheral vascular permeability via the bradykinin pathway, yet there was no evidence of its correlation with blood-brain barrier (BBB) integrity and brain function. In order to understand the effect of plasma C1INH on brain pathology via the vascular system, we knocked down circulating C1INH in wild-type (WT) mice using an antisense oligonucleotide (ASO), without affecting C1INH expression in peripheral immune cells or the brain, and examined brain pathology. Long-term elimination of endogenous C1INH in the plasma induced the activation of the KKS and peritoneal macrophages but did not activate the complement system. Bradykinin pathway proteins were elevated in the periphery and the brain, resulting in hypotension. BBB permeability, extravasation of plasma proteins into the brain parenchyma, activation of glial cells, and elevation of pro-inflammatory response mediators were detected. Furthermore, infiltrating innate immune cells were observed entering the brain through the lateral ventricle walls and the neurovascular unit. Mice showed normal locomotion function, yet cognition was impaired and depressive-like behavior was evident. In conclusion, our results highlight the important role of regulated plasma C1INH as it acts as a gatekeeper to the brain via the neurovascular system. Thus, manipulation of C1INH in neurovascular disorders might be therapeutically beneficial.
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Affiliation(s)
- Dorit Farfara
- Patricia and John Rosenwald Laboratory of Neurobiology and Genetics, The Rockefeller University, New York, New York
| | - Emily Feierman
- Patricia and John Rosenwald Laboratory of Neurobiology and Genetics, The Rockefeller University, New York, New York
| | - Allison Richards
- Patricia and John Rosenwald Laboratory of Neurobiology and Genetics, The Rockefeller University, New York, New York
| | - Alexey S Revenko
- Department of Antisense Drug Discovery, IONIS Pharmaceuticals Inc., Carlsbad, California
| | - Robert A MacLeod
- Department of Antisense Drug Discovery, IONIS Pharmaceuticals Inc., Carlsbad, California
| | - Erin H Norris
- Patricia and John Rosenwald Laboratory of Neurobiology and Genetics, The Rockefeller University, New York, New York
| | - Sidney Strickland
- Patricia and John Rosenwald Laboratory of Neurobiology and Genetics, The Rockefeller University, New York, New York
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Busse PJ, Farkas H, Banerji A, Lumry WR, Longhurst HJ, Sexton DJ, Riedl MA. Lanadelumab for the Prophylactic Treatment of Hereditary Angioedema with C1 Inhibitor Deficiency: A Review of Preclinical and Phase I Studies. BioDrugs 2019; 33:33-43. [PMID: 30539362 PMCID: PMC6373397 DOI: 10.1007/s40259-018-0325-y] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Hereditary angioedema (HAE) with C1 esterase inhibitor (C1-INH) deficiency (C1-INH-HAE) is a rare disease characterized by diminished levels or dysfunctional activity of C1-INH, leading to dysregulated plasma kallikrein activity within the kallikrein-kinin pathway. Symptoms manifest as painful, potentially life-threatening swelling of subcutaneous tissues throughout the body and/or submucosal edema in the upper airway or gastrointestinal tract. Attacks recur with unpredictable frequency, intensity, and duration, placing a heavy burden on patients' daily lives. Despite improved availability of medications for on-demand treatment during attacks and prophylaxis of future attacks, unmet needs remain. Lanadelumab, a fully human monoclonal antibody, may help address some of the limitations of existing prophylactic options (e.g., the need for intravenous administration or frequent dosing). Preclinical studies demonstrate that it is highly potent and specifically inhibits plasma kallikrein, and findings from phase Ia and Ib studies suggest this agent is well tolerated and provides sustained inhibition of plasma kallikrein, allowing for less frequent dosing. The phase III HELP Study (NCT02586805) evaluating the efficacy and safety of lanadelumab in preventing HAE attacks has been completed, and its open-label extension (NCT02741596) is ongoing. Lanadelumab is now approved in the USA and Canada for prophylaxis to prevent attacks of HAE in patients aged ≥ 12 years. This review provides an overview of the discovery and clinical development of lanadelumab, from preclinical through phase Ib studies, characterizing its safety/tolerability, efficacy, and pharmacokinetic and pharmacodynamic profiles. It also highlights how this agent may positively impact clinical care of patients with C1-INH-HAE.
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MESH Headings
- Adolescent
- Adult
- Aged
- Aged, 80 and over
- Angioedemas, Hereditary/drug therapy
- Angioedemas, Hereditary/pathology
- Angioedemas, Hereditary/physiopathology
- Angioedemas, Hereditary/prevention & control
- Antibodies, Monoclonal, Humanized/pharmacokinetics
- Antibodies, Monoclonal, Humanized/pharmacology
- Antibodies, Monoclonal, Humanized/therapeutic use
- Clinical Trials, Phase I as Topic
- Drug Evaluation, Preclinical
- Humans
- Middle Aged
- Plasma Kallikrein/antagonists & inhibitors
- Plasma Kallikrein/drug effects
- Young Adult
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Affiliation(s)
- Paula J Busse
- Division of Clinical Immunology and Allergy, Department of Medicine, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, Room 11-20, New York, NY, 10029, USA.
| | - Henriette Farkas
- Hungarian Angioedema Reference Center, 3rd Department of Internal Medicine, Semmelweis University, Kutvolgyi ut 4, Budapest, 1125, Hungary
| | - Aleena Banerji
- Division of Rheumatology, Allergy and Immunology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Cox 201, Boston, MA, 02114, USA
| | - William R Lumry
- Allergy and Asthma Research Associates, 10100 N. Central Expressway, Suite 100, Dallas, TX, 75231, USA
| | - Hilary J Longhurst
- Department of Immunology, Addenbrookes Hospital Cambridge University NHS Foundation Trust, Hills Road, Cambridge, CB2 0QQ, UK
| | | | - Marc A Riedl
- Division of Rheumatology, Allergy and Immunology, University of California, San Diego, 8899 University Center Lane, Suite 230, San Diego, CA, 92122, USA
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Levi M, Cohn DM, Zeerleder S. Hereditary angioedema: Linking complement regulation to the coagulation system. Res Pract Thromb Haemost 2019; 3:38-43. [PMID: 30656274 PMCID: PMC6332742 DOI: 10.1002/rth2.12175] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2018] [Accepted: 11/12/2018] [Indexed: 12/20/2022] Open
Abstract
Congenital deficiency of C1 inhibitor, the main inhibitor of the classic complement system pathway, leads to paroxysmal angioedema (hereditary angioedema) that can be debilitating or life-threatening for affected patients. In the past few years many new insights on the pathogenesis of angioedema formation in the presence of low levels of C1 inhibitor has been accumulated. There is a central role for bradykinin that is released upon activation of the kallikrein-kinin system that is insufficiently controlled by adequate levels of C1 inhibitor. As C1 inhibitor also possesses a central regulatory role of other plasma systems, including the contact activation system of coagulation and the plasminogen-plasmin system that governs endogenous fibrinolysis, it is interesting to observe the effects of C1 inhibitor deficiency on activation of these systems and relevance for hemostasis in vivo and thrombo-embolic disease. Interestingly, and despite significant activation of these pathways, C1 inhibitor deficiency is not at all associated with a hemorrhagic tendency or prothrombotic state. New therapeutic options for treatment of C1 inhibitor efficiency have become available in recent years, including various forms of C1 inhibitor concentrate. Restoration of C1 inhibitor levels in patients with hereditary angioedema has not resulted in thrombotic complications or any other relevant disorder associated with the hemostatic system.
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Affiliation(s)
- Marcel Levi
- Department of MedicineUniversity College London HospitalsNHS Foundation TrustLondonUK
- Cardiometabolic ProgrammeUniversity College London HospitalsNHS Foundation TrustLondonUK
- Department of Vascular MedicineAmsterdam Universities Medical CenterAmsterdamThe Netherlands
| | - Danny M. Cohn
- Department of Vascular MedicineAmsterdam Universities Medical CenterAmsterdamThe Netherlands
| | - Sacha Zeerleder
- Department of Molecular Cell BiologySanquin Research & Landsteiner LaboratoryAmsterdamThe Netherlands
- Department of Hematology and Central Hematology LaboratoryInselspitalBern University HospitalBernSwitzerland
- Department for BioMedical ResearchBern University HospitalBernSwitzerland
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Abstract
Hereditary angioedema (HAE) is a rare genetic disorder primarily caused by mutations in the SERPING1 gene encoding the C1 inhibitor (C1INH) that leads to plasma deficiency, resulting in recurrent attacks of severe swelling. In the current issue of the JCI, Haslund et al. show that in a subset of patients with type I HAE, mutated C1INH encoded by HAE-causing SERPING1 acts upon wildtype (WT) C1INH in a dominant-negative manner and forms intracellular C1INH aggregates. These aggregates lead to a reduction in the levels of secreted functional C1INH, thereby manifesting in the condition that allows the disease state. Interestingly, administration of WT SERPING1 gene is able to restore the levels of secreted C1INH, thereby opening up a novel mechanism justifying gene therapy for HAE.
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18
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De Maat S, Hofman ZLM, Maas C. Hereditary angioedema: the plasma contact system out of control. J Thromb Haemost 2018; 16:1674-1685. [PMID: 29920929 DOI: 10.1111/jth.14209] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2018] [Accepted: 06/11/2018] [Indexed: 01/06/2023]
Abstract
The plasma contact system contributes to thrombosis in experimental models. Even though our standard blood coagulation tests are prolonged when plasma lacks contact factors, this enzyme system appears to have a minor (if any) role in hemostasis. In this review, we explore the clinical phenotype of C1 esterase inhibitor (C1-INH) deficiency. C1-INH is the key plasma inhibitor of the contact system enzymes, and its deficiency causes hereditary angioedema (HAE). This inflammatory disorder is characterized by recurrent aggressive attacks of tissue swelling that occur at unpredictable locations throughout the body. Bradykinin, which is considered to be a byproduct of the plasma contact system during in vitro coagulation, is the main disease mediator in HAE. Surprisingly, there is little evidence for thrombotic events in HAE patients, suggesting mechanistic uncoupling from the intrinsic pathway of coagulation. In addition, it is questionable whether a surface is responsible for contact system activation in HAE. In this review, we discuss the clinical phenotype, disease modifiers and diagnostic challenges of HAE. We subsequently describe the underlying biochemical mechanisms and contributing disease mediators. Furthermore, we review three types of HAE that are not caused by C1-INH inhibitor deficiency. Finally, we propose a central enzymatic axis that we hypothesize to be responsible for bradykinin production in health and disease.
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Affiliation(s)
- S De Maat
- Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
| | - Z L M Hofman
- Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
| | - C Maas
- Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
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Cicardi M, Zuraw BL. Angioedema Due to Bradykinin Dysregulation. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE 2018; 6:1132-1141. [DOI: 10.1016/j.jaip.2018.04.022] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/12/2018] [Revised: 04/25/2018] [Accepted: 04/25/2018] [Indexed: 01/08/2023]
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The Complex Interaction Between Polycystic Ovary Syndrome and Hereditary Angioedema: Case Reports and Review of the Literature. Obstet Gynecol Surv 2018; 72:417-424. [PMID: 28715060 DOI: 10.1097/ogx.0000000000000457] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Importance Hereditary angioedema (HAE) is a rare but severe disease, with high risk of death, and attacks have been associated to high estrogen levels. Polycystic ovary syndrome (PCOS) is a common hyperandrogenic condition, which is frequently treated with combined oral contraceptives. Objective The aim of this study was to describe 2 clinical cases of young women diagnosed as having PCOS who developed HAE attacks after the introduction of combined estrogen-progestin pills to treat PCOS symptoms. Evidence Acquisition Literature review of sex hormones' role in genesis of HAE attacks and possible mechanisms involved. Results In the cases reported, after initiation of combined contraceptives, patients presented with facial swelling with airway involvement (laryngeal edema) and abdominal pain. They had a familial history of angioedema and normal C1 inhibitor (C1-INH) levels, leading to the diagnosis of HAE with normal C1-INH (HAEnC1-INH) or HAE type III. After suspension of exogenous estrogen, patients remained asymptomatic from HAE. Conclusions and Relevance HAEnC1-INH is an estrogen-dependent form of HAE. It is well established that exogenous estrogen triggers attacks of all types of HAE. However, this is the first description of the association between PCOS and HAE, in which PCOS could be masking HAE symptoms. We propose that PCOS might have a protective role regarding HAE attacks, because of its particular hormonal features, that is, hyperandrogenism and relative stable levels of estradiol. The use of combined estrogen-progestin compounds in women with PCOS and HAE must be avoided, and treatment must be individualized.
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Schmaier AH. Plasma Prekallikrein: Its Role in Hereditary Angioedema and Health and Disease. Front Med (Lausanne) 2018; 5:3. [PMID: 29423395 PMCID: PMC5788901 DOI: 10.3389/fmed.2018.00003] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2017] [Accepted: 01/09/2018] [Indexed: 11/13/2022] Open
Abstract
Plasma prekallikrein (PK) has a critical role in acute attacks of hereditary angioedema (HAE). Unlike C1 inhibitor, its levels fall during HAE attacks with resultant cleaved high-molecular-weight kininogen. Cleavage of high-molecular-weight kininogen liberates bradykinin, the major biologic peptide that promotes the edema. How prekallikrein initially becomes activated in acute attacks of HAE is not known. PK itself is negatively associated with cardiovascular disease. High prekallikrein is associated with accelerated vascular disease in diabetes and polymorphisms of prekallikrein that reduce high-molecular-weight kininogen binding are associated with protection from cardiovascular events. Prekallikrein-deficient mice have reduced thrombosis risk and plasma kallikrein (PKa) inhibition is associated with reduced experimental gastroenterocolitis and arthritis in rodents. In sum, prekallikrein and its enzyme PKa are major targets in HAE providing much opportunity to improve the acute and chronic management of HAE. PKa inhibition also may be a target to ameliorate cardiovascular disease, thrombosis risk, and inflammation as in enterocolitis and arthritis.
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Affiliation(s)
- Alvin H Schmaier
- Hematology and Oncology Division, Department of Medicine, University Hospitals Cleveland Medical Center, Case Western Reserve University, Cleveland, OH, United States
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22
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Björkqvist J, Sala-Cunill A, Renné T. Hereditary angioedema: a bradykinin-mediated swelling disorder. Thromb Haemost 2017; 109:368-74. [DOI: 10.1160/th12-08-0549] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2012] [Accepted: 11/08/2012] [Indexed: 11/05/2022]
Abstract
SummaryEdema is tissue swelling and is a common symptom in a variety of diseases. Edema form due to accumulation of fluids, either through reduced drainage or increased vascular permeability. There are multiple vascular signalling pathways that regulate vessel permeability. An important mediator that increases vascular leak is the peptide hormone bradykinin, which is the principal agent in the swelling disorder hereditary angioedema. The disease is autosomal dominant inherited and presents clinically with recurrent episodes of acute swelling that can be life-threatening involving the skin, the oropharyngeal, laryngeal, and gastrointestinal mucosa. Three different types of hereditary angiodema exist in patients. The review summarises current knowledge on the pathophysiology of hereditary angiodema and focuses on recent experimental and pharmacological findings that have led to a better understanding and new treatments for the disease.
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Hereditary angioedema: Assessing the hypothesis for underlying autonomic dysfunction. PLoS One 2017; 12:e0187110. [PMID: 29107952 PMCID: PMC5673184 DOI: 10.1371/journal.pone.0187110] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2017] [Accepted: 10/13/2017] [Indexed: 11/19/2022] Open
Abstract
Background Attacks of Hereditary Angioedema due to C1-inhibitor deficiency (C1-INH-HAE)are often triggered by stressful events/hormonal changes. Objective Our study evaluates the relationship between autonomic nervous system (ANS) and contact/complement system activation. Methods Twenty-three HAE patients (6 males, mean age 47.5±11.4 years) during remission and 24 healthy controls (8 males, mean age 45.3±10.6 years) were studied. ECG, beat-by-beat blood pressure, respiratory activity were continuously recorded during rest (10’) and 75-degrees-head-up tilt (10’). C1-INH, C4, cleaved high molecular weight kininogen (cHK) were assessed; in 16 patients and 11 controls plasma catecholamines were also evaluated. Spectral analysis of heart rate variability allowed extraction of low-(LF) and high-(HF) frequency components, markers of sympathetic and vagal modulation respectively. Results HAE patients showed higher mean systolic arterial pressure (SAP) than controls during both rest and tilt. Tilt induced a significant increase in SAP and its variability only in controls. Although sympathetic modulation (LFnu) increased significantly with tilt in both groups, LF/HF ratio, index of sympathovagal balance, increased significantly only in controls. At rest HAE patients showed higher noradrenaline values (301.4±132.9 pg/ml vs 210.5±89.6pg/ml, p = 0.05). Moreover, in patients tilt was associated with a significant increase in cHK, marker of contact system activation (49.5 ± 7.5% after T vs 47.1 ± 7.8% at R, p = 0.01). Conclusions Our data are consistent with altered ANS modulation in HAE patients, i.e. increased sympathetic activation at rest and blunted response to orthostatic challenge. Tilt test-induced increased HK cleavage suggests a link between stress and bradykinin production.
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2D-LC–MS/MS to measure cleaved high-molecular-weight kininogen in human plasma as a biomarker for C1-INH-HAE. Bioanalysis 2017; 9:1477-1491. [DOI: 10.4155/bio-2017-0105] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Aim: C1-INH-HAE is caused by activation of plasma kallikrein which subsequently cleaves high-molecular-weight kininogen (HMWK) to generate bradykinin and cHMWK. Materials & methods: A novel ion-pair 2D LC–MS/MS assay was developed to measure the 46 kDa cHMWK in plasma as a biomarker for C1-INH-HAE. The sample preparation included sodium dodecyl sulfate denaturation, methanol crash, chymotryptic digestion and peptide enrichment by solid phase extraction. Results: The LLOQ was 200 ng/ml. The overall cHMWK recovery combining crash and digestion was 57.5%. The precision of the method was ≤12.7% and accuracy ≤-13.8%. Conclusion: A reagent-free LC–MS assay has been developed for the quantitation of 46 kDa cHMWK, which was shown to be elevated in plasma of C1-INH-HAE patients due to C1-INH deficiency relative to that of healthy subjects.
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Christiansen SC, Zuraw BL. Laboratory Approaches for Assessing Contact System Activation. Immunol Allergy Clin North Am 2017; 37:527-539. [DOI: 10.1016/j.iac.2017.04.008] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
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Abstract
Remarkable progress in understanding the pathophysiology and underlying mechanisms of hereditary angioedema has led to the development of effective treatment for this disorder. Progress in three separate areas has catalyzed our understanding of hereditary angioedema. The first is the recognition that HAE type I and type II result from a deficiency in the plasma level of functional C1 inhibitor. This observation has led to a detailed understanding of the SERPING1 mutations responsible for this deficiency as well as the molecular regulation of C1 inhibitor expression and function. The second is that the fundamental cause of swelling is enhanced contact system activation leading to increased generation of bradykinin. Substantial progress has been made in defining the parameters regulating bradykinin generation and catabolism as well as the receptors that transduce the biologic effects of kinins. The third is the understanding that tissue swelling in hereditary angioedema primarily involves the function of endothelial cell adherens junctions. This knowledge is driving increased attention to the role of endothelial biology in determining disease activity in hereditary angioedema. While there has been considerable progress made, large gaps still remain in our knowledge. Important areas that remain poorly understood include the factors that lead to very low plasma functional C1 inhibitor levels, the triggers of contact system activation in hereditary angioedema, and the role of the bradykinin B1 receptor. The phenotypic variability of hereditary angioedema has been extensively documented but never understood. The mechanisms discussed in this chapter likely contribute to this variability. Future progress in understanding these mechanisms should provide new means to improve the diagnosis and treatment of hereditary angioedema.
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Soni P, Kumar V, Alliu S, Shetty V. Hereditary angioedema (HAE): a cause for recurrent abdominal pain. BMJ Case Rep 2016; 2016:bcr-2016-217196. [PMID: 27873761 DOI: 10.1136/bcr-2016-217196] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
A 44-year-old Hispanic woman presented to the emergency room with a 2-day history of sudden onset of severe cramping left lower quadrant abdominal pain associated with ∼20 episodes diarrhoea. Abdominal CT scan exhibited bowel wall oedema and acute extensive colitis. On the basis of the preliminary diagnosis of acute abdomen, the patient was admitted under the surgical team and treated for acute colitis. Since her family history was significant for hereditary angioedema (HAE), complement studies were performed which revealed low complement C4 levels and abnormally low values of C1q esterase inhibitor. Thus, the diagnosis of HAE type I was established. This case report summarises that the symptoms of HAE are often non-specific, hence making the underlying cause difficult to diagnose.
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Affiliation(s)
- Parita Soni
- Department of Internal Medicine, Maimonides Medical Center, Brooklyn, New York, USA
| | - Vivek Kumar
- Department of Internal Medicine, Maimonides Medical Center, Brooklyn, New York, USA
| | - Samson Alliu
- Department of Internal Medicine, Maimonides Medical Center, Brooklyn, New York, USA
| | - Vijay Shetty
- Department of Cardiology, Maimonides Medical Center, Brooklyn, New York, USA
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Hofman ZL, Relan A, Zeerleder S, Drouet C, Zuraw B, Hack CE. Angioedema attacks in patients with hereditary angioedema: Local manifestations of a systemic activation process. J Allergy Clin Immunol 2016; 138:359-66. [DOI: 10.1016/j.jaci.2016.02.041] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2015] [Revised: 01/31/2016] [Accepted: 02/18/2016] [Indexed: 11/17/2022]
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Bork K, Witzke G. Shortened Activated Partial Thromboplastin Time May Help in Diagnosing Hereditary and Acquired Angioedema. Int Arch Allergy Immunol 2016; 170:101-7. [DOI: 10.1159/000447695] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2016] [Accepted: 06/15/2016] [Indexed: 11/19/2022] Open
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Diagnostic and therapeutic management of hereditary angioedema due to C1-inhibitor deficiency: the Italian experience. Curr Opin Allergy Clin Immunol 2016; 15:383-91. [PMID: 26106828 DOI: 10.1097/aci.0000000000000186] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
PURPOSE OF REVIEW Hereditary angioedema (HAE) due to C1-inhibitor (C1-INH) deficiency (C1-INH-HAE) is a rare disease, with a reported prevalence of about 1 : 50 000. C1-INH-HAE causes disabling symptoms, which may be life-threatening if swelling affects upper airways. Diagnostic procedures are now well established and the role of bradykinin as the main mediator of plasma outflow eliciting angioedema formation has been clearly elucidated. RECENT FINDINGS Increased understanding of the pathogenesis of C1-INH-HAE allowed in recent years the development of new drugs targeted to inhibit bradykinin synthesis (Ecallantide) or activity (Icatibant). At the same time, a recombinant C1-INH concentrate (Ruconest) was produced from the milk of transgenic rabbits and two plasma-derived C1-INHs (Berinert, Cinryze) underwent controlled trials to obtain marketing authorization. In 2012, an Italian network for C1-INH-HAE (ITACA) was established by physicians of 17 HAE reference centres to collect data from Italian patients and to homogenize and improve the diagnostic and therapeutic approach to the disease. SUMMARY Although there is a widespread agreement on therapeutic goals and treatment of C1-INH-HAE acute attacks, different approaches to prophylaxis are still present among HAE experts. The clinical experience of ITACA on a large population of C1-INH-HAE patients followed for several years may help in identifying the most effective strategies for the management of the disease.
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Schmaier AH. The contact activation and kallikrein/kinin systems: pathophysiologic and physiologic activities. J Thromb Haemost 2016; 14:28-39. [PMID: 26565070 DOI: 10.1111/jth.13194] [Citation(s) in RCA: 271] [Impact Index Per Article: 30.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2015] [Accepted: 10/29/2015] [Indexed: 12/31/2022]
Abstract
The contact activation system (CAS) and kallikrein/kinin system (KKS) are older recognized biochemical pathways that include several proteins that skirt the fringes of the blood coagulation, fibrinolytic, complement and renin-angiotensin fields. These proteins initially were proposed as part of the hemostatic pathways because their deficiencies are associated with prolonged clinical assays. However, the absence of bleeding states with deficiencies of factor XII (FXII), prekallikrein (PK) and high-molecular-weight kininogen indicates that the CAS and KKS do not contribute to hemostasis. Since the discovery of the Hageman factor 60 years ago much has been learned about the biochemistry, cell biology and animal physiology of these proteins. The CAS is a pathophysiologic surface defense mechanism against foreign proteins, organisms and artificial materials. The KKS is an inflammatory response mechanism. Targeting their activation through FXIIa or plasma kallikrein inhibition when blood interacts with the artificial surfaces of modern interventional medicine or in acute attacks of hereditary angioedema restores vascular homeostasis. FXII/FXIIa and products that arise with PK deficiency also offer novel ways to reduce arterial and venous thrombosis without an effect on hemostasis. In summary, there is revived interest in the CAS and KKS due to better understanding of their activities. The new appreciation of these systems will lead to several new therapies for a variety of medical disorders.
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Affiliation(s)
- A H Schmaier
- Department of Medicine, Case Western Reserve University, Cleveland, OH, USA
- University Hospitals Case Medical Center, Cleveland, OH, USA
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Björkqvist J, de Maat S, Lewandrowski U, Di Gennaro A, Oschatz C, Schönig K, Nöthen MM, Drouet C, Braley H, Nolte MW, Sickmann A, Panousis C, Maas C, Renné T. Defective glycosylation of coagulation factor XII underlies hereditary angioedema type III. J Clin Invest 2015; 125:3132-46. [PMID: 26193639 DOI: 10.1172/jci77139] [Citation(s) in RCA: 120] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2014] [Accepted: 06/04/2015] [Indexed: 12/15/2022] Open
Abstract
Hereditary angioedema type III (HAEIII) is a rare inherited swelling disorder that is associated with point mutations in the gene encoding the plasma protease factor XII (FXII). Here, we demonstrate that HAEIII-associated mutant FXII, derived either from HAEIII patients or recombinantly produced, is defective in mucin-type Thr309-linked glycosylation. Loss of glycosylation led to increased contact-mediated autoactivation of zymogen FXII, resulting in excessive activation of the bradykinin-forming kallikrein-kinin pathway. In contrast, both FXII-driven coagulation and the ability of C1-esterase inhibitor to bind and inhibit activated FXII were not affected by the mutation. Intravital laser-scanning microscopy revealed that, compared with control animals, both F12-/- mice reconstituted with recombinant mutant forms of FXII and humanized HAEIII mouse models with inducible liver-specific expression of Thr309Lys-mutated FXII exhibited increased contact-driven microvascular leakage. An FXII-neutralizing antibody abolished bradykinin generation in HAEIII patient plasma and blunted edema in HAEIII mice. Together, the results of this study characterize the mechanism of HAEIII and establish FXII inhibition as a potential therapeutic strategy to interfere with excessive vascular leakage in HAEIII and potentially alleviate edema due to other causes.
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Schmaier AH. Thrombosis Prevention without Anticoagulation. Front Med (Lausanne) 2015; 1:12. [PMID: 25705625 PMCID: PMC4335402 DOI: 10.3389/fmed.2014.00012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2014] [Accepted: 04/27/2014] [Indexed: 11/21/2022] Open
Affiliation(s)
- Alvin H Schmaier
- Division of Hematology and Oncology, Department of Internal Medicine, University Hospitals Case Medical Center, Case Western Reserve University , Cleveland, OH , USA
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Caccia S, Suffritti C, Cicardi M. Pathophysiology of Hereditary Angioedema. PEDIATRIC ALLERGY, IMMUNOLOGY, AND PULMONOLOGY 2014; 27:159-163. [PMID: 25538858 PMCID: PMC4268578 DOI: 10.1089/ped.2014.0425] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/23/2014] [Accepted: 10/10/2014] [Indexed: 02/05/2023]
Abstract
The genetic deficiency of the C1 inhibitor is responsible for hereditary angioedema (HAE), which is a disease transmitted as an autosomal dominant trait. More than 200 point mutations in the C1 inhibitor gene have been found to be associated with HAE. Patients with this disease suffer from recurrent angioedema, which is mediated by bradykinin derived from activation of the contact system. This system is physiologically controlled at several steps by the C1 inhibitor. In this review, we describe known mechanisms for the development of angioedema in patients with C1 inhibitor deficiency.
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Affiliation(s)
- Sonia Caccia
- Department of Biotechnologies and Translational Medicine, University of Milan, Milan, Italy
| | - Chiara Suffritti
- Department of Biomedical and Clinical Sciences L.Sacco, University of Milan, Milan, Italy
| | - Marco Cicardi
- Department of Biomedical and Clinical Sciences L.Sacco, University of Milan, Milan, Italy
- Department of Medicine, Luigi Sacco Hospital, Milan, Italy
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Suffritti C, Zanichelli A, Maggioni L, Bonanni E, Cugno M, Cicardi M. High-molecular-weight kininogen cleavage correlates with disease states in the bradykinin-mediated angioedema due to hereditary C1-inhibitor deficiency. Clin Exp Allergy 2014; 44:1503-14. [DOI: 10.1111/cea.12293] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2013] [Revised: 01/31/2014] [Accepted: 02/10/2014] [Indexed: 11/29/2022]
Affiliation(s)
- C. Suffritti
- Department of Biomedical and Clinical Sciences Luigi Sacco; University of Milan, Ospedale Luigi Sacco; Milan Italy
| | - A. Zanichelli
- Department of Biomedical and Clinical Sciences Luigi Sacco; University of Milan, Ospedale Luigi Sacco; Milan Italy
| | - L. Maggioni
- Department of Biomedical and Clinical Sciences Luigi Sacco; University of Milan, Ospedale Luigi Sacco; Milan Italy
| | - E. Bonanni
- Department of Biomedical and Clinical Sciences Luigi Sacco; University of Milan, Ospedale Luigi Sacco; Milan Italy
| | - M. Cugno
- Department of Internal Medicine; IRCCS Fondazione Ospedale Maggiore Policlinico Mangiagalli Regina Elena; University of Milan; Milan Italy
| | - M. Cicardi
- Department of Biomedical and Clinical Sciences Luigi Sacco; University of Milan, Ospedale Luigi Sacco; Milan Italy
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Zanichelli A, Mansi M, Periti G, Cicardi M. Therapeutic management of hereditary angioedema due to C1 inhibitor deficiency. Expert Rev Clin Immunol 2014; 9:477-88. [DOI: 10.1586/eci.13.22] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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Ghannam A, Defendi F, Charignon D, Csopaki F, Favier B, Habib M, Cichon S, Drouet C. Contact System Activation in Patients with HAE and Normal C1 Inhibitor Function. Immunol Allergy Clin North Am 2013; 33:513-33. [PMID: 24176216 DOI: 10.1016/j.iac.2013.07.007] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
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Defendi F, Charignon D, Ghannam A, Baroso R, Csopaki F, Allegret-Cadet M, Ponard D, Favier B, Cichon S, Nicolie B, Fain O, Martin L, Drouet C. Enzymatic assays for the diagnosis of bradykinin-dependent angioedema. PLoS One 2013; 8:e70140. [PMID: 23940538 PMCID: PMC3734293 DOI: 10.1371/journal.pone.0070140] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2013] [Accepted: 06/20/2013] [Indexed: 01/11/2023] Open
Abstract
Background The kinins (primarily bradykinin, BK) represent the mediators responsible for local increase of vascular permeability in hereditary angioedema (HAE), HAE I-II associated with alterations of the SERPING1 gene and HAE with normal C1-Inhibitor function (HAE-nC1INH). Besides C1-Inhibitor function and concentration, no biological assay of kinin metabolism is actually available to help physicians for the diagnosis of angioedema (AE). We describe enzymatic tests on the plasma for diagnosis of BK-dependent AE. Methods The plasma amidase assays are performed using the Pro-Phe-Arg-p-nitroanilide peptide substrate to evaluate the spontaneous amidase activity and the proenzyme activation. We analyzed data of 872 patients presenting with BK-dependent AE or BK-unrelated diseases, compared to 303 controls. Anti-high MW kininogen (HK) immunoblot was achieved to confirm HK cleavage in exemplary samples. Reproducibility, repeatability, limit of blank, limit of detection, precision, linearity and receiver operating characteristics (ROC) were used to calculate the diagnostic performance of the assays. Results Spontaneous amidase activity was significantly increased in all BK-dependent AE, associated with the acute phase of disease in HAE-nC1INH, but preserved in BK-unrelated disorders. The increase of the amidase activity was associated to HK proteolysis, indicating its relevance to identify kininogenase activity. The oestrogens, known for precipitating AE episodes, were found as triggers of enzymatic activity. Calculations from ROC curves gave the optimum diagnostic cut-off for women (9.3 nmol⋅min−1⋅mL−1, area under curve [AUC] 92.1%, sensitivity 80.0%, and specificity 90.1%) and for men (6.6 nmol·min−1⋅mL−1, AUC 91.0%, sensitivity 87.0% and specificity 81.2%). Conclusion The amidase assay represents a diagnostic tool to help physicians in the decision to distinguish between BK-related and –unrelated AE.
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Affiliation(s)
- Federica Defendi
- Centre de Référence des Angioedèmes à Kinines, CREAK, Grenoble, France.
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Zuraw BL, Bernstein JA, Lang DM, Craig T, Dreyfus D, Hsieh F, Khan D, Sheikh J, Weldon D, Bernstein DI, Blessing-Moore J, Cox L, Nicklas RA, Oppenheimer J, Portnoy JM, Randolph CR, Schuller DE, Spector SL, Tilles SA, Wallace D. A focused parameter update: Hereditary angioedema, acquired C1 inhibitor deficiency, and angiotensin-converting enzyme inhibitor–associated angioedema. J Allergy Clin Immunol 2013; 131:1491-3. [DOI: 10.1016/j.jaci.2013.03.034] [Citation(s) in RCA: 127] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2012] [Revised: 03/11/2013] [Accepted: 03/14/2013] [Indexed: 11/26/2022]
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Castelli R, Zanichelli A, Cicardi M, Cugno M. Acquired C1-inhibitor deficiency and lymphoproliferative disorders: a tight relationship. Crit Rev Oncol Hematol 2013; 87:323-32. [PMID: 23490322 DOI: 10.1016/j.critrevonc.2013.02.004] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2012] [Revised: 01/11/2013] [Accepted: 02/14/2013] [Indexed: 11/18/2022] Open
Abstract
Angioedema due to the acquired deficiency of C1-inhibitor is a rare disease known as acquired angioedema (AAE), which was first described in a patient with high-grade lymphoma and is frequently associated with lymphoproliferative diseases, including expansion of B cell clones producing anti-C1-INH autoantibodies, monoclonal gammopathy of uncertain significance (MGUS) and non-Hodgkin lymphoma (NHL). AAE is clinically similar to hereditary angioedema (HAE), and is characterized by recurrent episodes of sub-cutaneous and sub-mucosal edema. It may affect the face, tongue, extremities, trunk and genitals. The involvement of the gastrointestinal tract causes bowel sub-occlusion with severe pain, vomiting and diarrhea, whereas laryngeal edema can be life-threatening. Unlike those with HAE, AAE patients usually have late-onset symptoms, do not have a family history of angioedema and present variable response to treatment due to the hyper-catabolism of C1-inhibitor. Reduced C1-inhibitor function leads to activation of the classic complement pathway with its consumption and activation of the contact system leading to the generation of the vasoactive peptide bradykinin, which increases vascular permeability and induces angioedema. Lymphoprolipherative diseases and AAE are tightly linked with either angioedema or limphoprolyferation being the first symptom. Experimental data indicate that neoplastic tissue and/or anti-C1-inhibitor antibodies induce C1-inhibitor consumption, and this is further supported by the observation that cytotoxic treatment of the lymphoproliferative diseases associated with AAE variably reverses the complement impairment and leads to a clinical improvement in angioedema symptoms.
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Affiliation(s)
- Roberto Castelli
- Department of Pathophysiology and Transplantation, Internal Medicine Section, University of Milan, Italy
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Castelli R, Zanichelli A, Cugno M. Therapeutic options for patients with angioedema due to C1-inhibitor deficiencies: from pathophysiology to the clinic. Immunopharmacol Immunotoxicol 2012; 35:181-90. [DOI: 10.3109/08923973.2012.726627] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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Hack CE, Relan A, van Amersfoort ES, Cicardi M. Target levels of functional C1-inhibitor in hereditary angioedema. Allergy 2012; 67:123-30. [PMID: 21923668 DOI: 10.1111/j.1398-9995.2011.02716.x] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
BACKGROUND Hereditary angioedema (HAE) is a heterozygous deficiency of first component of complement-inhibitor (C1INH). Insufficient C1INH activity leads to uncontrolled activation of plasma cascade systems, which results in acute angioedema attacks in patients with HAE. Plasma-derived or recombinant C1INH products are approved for the treatment of such angioedema attacks. The target level of C1INH activity needed to achieve optimal efficacy, however, remains unknown. We determined the plasma level of C1INH associated with optimal clinical efficacy in the treatment of angioedema attacks. METHODS Efficacy and pharmacokinetic data were reviewed from recently published placebo-controlled randomized trials in the treatment of HAE with either plasma-derived or recombinant C1INH products, tested at various doses. RESULTS A dose-dependent effect was observed on time to the beginning of relief of symptoms, on time to resolution of symptoms, and on the response rate within 4 h. Optimal efficacy of C1INH therapy is achieved at doses ≥50 U/kg. This dose increases plasma C1INH activity in almost all patients to values ≥0.7 U/ml (70% of normal), the lower limit of the normal range. The differences in half-lives of the various C1INH products do not have an obvious effect on clinical efficacy. CONCLUSION A review of the efficacy and pharmacokinetic data from recently published controlled studies in the treatment of HAE attacks suggests that efficacy of C1INH therapy is optimal when C1INH activity levels are restored to the normal range.
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Affiliation(s)
- C E Hack
- Department of Dermatology/Allergology, Rheumatology and Immunology, University Medical Center Utrecht, Utrecht, the Netherlands.
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Abstract
Background Laryngeal angioedema may be associated with significant morbidity and even mortality. Because of the potential severity of attacks, both allergists and otolaryngologists must be knowledgeable about the recognition and treatment of laryngeal angioedema. This study describes the clinical characteristics and pathophysiology of bradykinin-mediated angioedema. Methods A literature review was conducted concerning the clinical characteristics and pathophysiology of types I and II hereditary angioedema (HAE), type III HAE, acquired C1 inhibitor (C1INH) deficiency, and angiotensin-converting enzyme (ACE) inhibitor–associated angioedema. Results The diagnosis of type I/II HAE is relatively straightforward as long as the clinician maintains a high index of suspicion. Mutations in the SERPING1 gene result in decreased secretion of functional C1INH and episodic activation of plasma kallikrein and Hageman factor (FXII) of the plasma contact system with cleavage of high molecular weight kininogen and generation of bradykinin. In contrast, there are no unequivocal criteria for making a diagnosis of type III HAE, although a minority of these patients may have a mutation in the factor XII gene. Angioedema attacks and mediator of swelling in acquired C1INH deficiency are similar to those in type I or II HAE; however, it occurs on a sporadic basis because of excessive consumption of C1INH in patients who are middle aged or older. ACE inhibitor–associated angioedema should always be considered in any patient taking an ACE inhibitor who experiences angioedema. ACE is a kininase, which when inhibited is thought to result in increased bradykinin levels. Bradykinin acts on vascular endothelial cells to enhance vascular permeability. Conclusion Laryngeal swelling is not infrequently encountered in bradykinin-mediated angioedema. Novel therapies are becoming available that for the first time provide effective treatment for bradykinin-mediated angioedema. Because the characteristics and treatment of these angioedemas are quite distinct from each other and from histamine-mediated angioedema, it is crucial that the physician be able to recognize and distinguish these swelling disorders.
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Affiliation(s)
- Bruce L. Zuraw
- Department of Medicine, University of California, San Diego, and San Diego Veteran's Affairs Medical Center, La Jolla, California
| | - Sandra C. Christiansen
- Department of Allergy, Kaiser Permanente and University of California, San Diego, California
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Abstract
Abstract
Three single nucleotide polymorphisms (SNPs) were recently found to be associated with activated partial thromboplastin time (aPTT). Because shortened aPTT levels have been observed in patients experiencing venous thrombosis (VT), we investigated the effects of these 3 aPTT-associated SNPs, rs2731672, rs9898, and rs710446, on the risk of VT in a sample of 1110 healthy patients and 1542 patients with VT. Among the 3 tested SNPs, only rs710446 was associated with VT risk; the rs710446-C allele was associated with an increased risk of VT (odds ratio 1.196, 95% confidence interval 1.071-1.336, P = .0012). This association also was observed in an independent sample of 590 controls and 596 patients (odds ratio 1.171, 95% confidence interval 0.889-1.541, P = .059). We also confirmed that the rs710446-C allele was associated with decreased aPTT levels, making this nonsynonymous Ile581Thr variant a new genetic risk factor for VT.
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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.
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Affiliation(s)
- Bruce L Zuraw
- Department of Medicine, University of California San Diego and San Diego Veteran's Affairs Medical Center, La Jolla, Cal
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Zuraw BL. HAE therapies: past present and future. ALLERGY, ASTHMA, AND CLINICAL IMMUNOLOGY : OFFICIAL JOURNAL OF THE CANADIAN SOCIETY OF ALLERGY AND CLINICAL IMMUNOLOGY 2010; 6:23. [PMID: 20667126 PMCID: PMC2921104 DOI: 10.1186/1710-1492-6-23] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 05/21/2010] [Accepted: 07/28/2010] [Indexed: 11/10/2022]
Abstract
Advances in understanding the pathophysiology and mechanism of swelling in hereditary angioedema (HAE) has resulted in the development of multiple new drugs for the acute and prophylactic treatment of patients with HAE. This review will recap the past treatment options, review the new current treatment options, and discuss potential future treatment options for patients with HAE.
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Affiliation(s)
- Bruce L Zuraw
- Department of Medicine, University of California San Diego and San Diego Veteran's Affairs Medical Center, La Jolla, CA, USA.
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Levy JH, Freiberger DJ, Roback J. Hereditary angioedema: current and emerging treatment options. Anesth Analg 2010; 110:1271-80. [PMID: 20418292 DOI: 10.1213/ane.0b013e3181d7ac98] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Angioedema can result from allergic, hereditary, and acquired conditions. Hereditary angioedema (HAE) attacks are disabling at the time of occurrence and can be life threatening; they often result in hospitalization and intensive care unit admission. Although there are several variants of HAE, they share a final common pathway: unopposed activation of multiple kinins and mediators including kallikrein and bradykinin. This leads to increased vascular permeability, which in turn produces the edema after which the condition is named. Older treatment options licensed in the United States, anabolic steroids and antifibrinolytics, have troublesome side effect profiles and may not reverse a severe acute attack. In Europe, C1 esterase inhibitor (C1-INH) concentrates have been used since 1974 for both preventing and terminating attacks. Two of these have now been licensed in the United States for use in HAE patients, one for prophylaxis and the other for treating acute abdominal and facial HAE attacks. The first kinin pathway modulator, ecallantide, has also been licensed recently in the United States for treating HAE attacks. The objective of this article is to describe HAE and review the available options for managing patients, as well as different drugs currently under investigation. Specific attention is given to the perioperative management of patients with HAE.
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Affiliation(s)
- Jerrold H Levy
- FAHA, Department of Anesthesiology, Emory University Hospital, Atlanta, GA 30322, USA.
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Joseph K, Tholanikunnel TE, Kaplan AP. Treatment of episodes of hereditary angioedema with C1 inhibitor: serial assessment of observed abnormalities of the plasma bradykinin-forming pathway and fibrinolysis. Ann Allergy Asthma Immunol 2010; 104:50-4. [PMID: 20143645 DOI: 10.1016/j.anai.2009.11.014] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
BACKGROUND Hereditary angioedema (HAE) is typically the result of a deficiency of C1 inhibitor (C1-INH) with gene defects that lead to diminished plasma levels or the production of a dysfunctional protein. Replacement therapy with C1-INH has been shown to be effective in ameliorating episodes of swelling. We have reported elevated baseline levels of bradykinin, C4a, and plasmin-alpha2-antiplasmin complexes in the plasma of patients with HAE compared with the plasma of healthy controls. The production of factor XII fragment on in vitro activation of plasma with HAE has also been observed. OBJECTIVE To perform serial assessment of abnormalities of the bradykinin-forming pathway and fibrinolysis in patients with HAE after treatment of episodes of swelling with intravenous C1-INH. METHODS We obtained samples of plasma from 9 patients with HAE at a quiescent period (baseline), during an attack of swelling, and at 1, 4, and 12 hours after termination of an infusion of C1-INH. Factor XIIa, kallikrein, and plasmin were each measured by cleavage of synthetic substrates specific for each item. RESULTS Each enzyme was strikingly elevated at baseline compared with the levels in pooled healthy plasma, and there was a progressive decline of activity to normal for factor XIIa and plasmin. Kallikrein decreased in 7 of the 9 patients at 1 hour and then decreased in all patients. Bradykinin levels were elevated at the outset in all patients, increased prominently during an attack of swelling, decreased to baseline after 1 hour, and then decreased toward normal by 4 and 12 hours. CONCLUSION The plasma levels of factor XIIa, kallikrein, and bradykinin decreased when measured serially subsequent to the infusion of nanofiltered C1-INH.
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Affiliation(s)
- Kusumam Joseph
- Division of Rheumatology and Clinical Immunology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
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