Hereditary angioedema: Pathophysiology (HAE type I, HAE type II, and HAE nC1-INH)

2020 ◽  
Vol 41 (6) ◽  
pp. S14-S17 ◽  
Author(s):  
H. James Wedner
Keyword(s):  
Serine Protease ◽  
Hereditary Angioedema ◽  
Normal Activity ◽  
Genetic Alterations ◽  
Type I ◽  
Factor Xii ◽  
Kinin System ◽  
Major Pathway ◽  
Major Mechanism ◽  
Kallikrein Kinin System

The pathophysiology of hereditary angioedema (HAE) in virtually all cases is the result of the uncontrolled production of the vasoactive peptide bradykinin. C1 inhibitor (C1-INH) is a serine protease inhibitor, which, under normal circumstances, is the regulator of critical enzymes that are active in the cascades that result in bradykinin generation. In the classic forms of HAE, C1-INH is not produced in sufficient quantities (<40% of normal) or the function is <40% of normal activity. The major pathway for the production of bradykinin is the “contact system,” also known as the kallikrein-kinin system. This system begins with the activation of factor XII (FXII) to FXIIa, by a variety of physiologic and pathologic stimuli. FXIIa is a serine protease that binds to surfaces and cleaves prekallikrein to the active serine protease kallikrein. Kallikrein then cleaves high-molecular-weight kininogen to release the nonapeptide bradykinin. Bradykinin binds to the bradykinin β2 receptor, which increases vascular permeability and allows the flow of fluids into the extracellular space and results in angioedema. The two major enzymes generated in this cascade FXIIa and kallikrein are inhibited by C1-INH, which is the major regulator of this cascade. Failure to adequately control the production of bradykinin is thus the major mechanism for HAE. Several other types of HAE in which C1-INH is not decreased (HAE nlC1-INH) have been described. The alterations in FXII and plasminogen (also a serine protease inhibited by C1-INH) like with classic HAE are the result of dysregulation of bradykinin generation. Only genetic alterations in angiopoietin-1 may not be related to bradykinin generation, rather related to the control of the effect of bradykinin on the vascular endothelium.

scholarly journals Molecular genetic diagnosis of hereditary angioedema

2021 ◽  
Vol 18 (1) ◽  
pp. 25-35
Author(s):  
I. E. Guryanova ◽  
Yu. S. Zharankova ◽  
E. A. Polyakova ◽  
V. V. Pugacheva ◽  
K. Ya. Skapavets ◽  
...  
Keyword(s):  
Hereditary Angioedema ◽  
Molecular Genetic ◽  
Genetic Diagnosis ◽  
Unknown Origin ◽  
Normal Activity ◽  
Type I ◽  
Factor Xii ◽  
C1 Inhibitor Deficiency ◽  
Serping1 Gene ◽  
Deficiency Type

Hereditary angioedema (HAE) is a rare genetic condition currently subdivided into two groups: HAE due to C1-inhibitor deficiency (Type I) or dysfunction (Type II) (C1-INH-HAE) and HAE with normal activity of C1‐INH (nC1- INH-HAE). C1-INH-HAE is estimated to occur in approximately 99 % of cases HAE and is caused by sequence variants in the SERPING1 gene. The prevalence of nC1-INH-HAE is extremely low and accounts for about 1 % of all cases of HAE. nC1-INH-HAE currently subdivided on HAE, due to mutations in factor XII (FXII-HAE), plasminogen (PLG-HAE), angiopoietin 1 (ANGPT1-HAE), kininogen 1 gene (KNG1-HAE), or angioedema of unknown origin (U-HAE).The amplicons of the entire coding regions and splice-sites of 18 genes from 24 patients (18 female) belonging to 17 families were analyzed by Next Generation Sequencing (NGS). The median age of patients was 33.5, of onset ‒ 16 years. 15 patients had a family history of edema.We identified seven C1-INH-HAE patients and variants were detected in the SERPING1 gene. For three patients (members of the same family), a heterozygous variant was found deep in the intron of the SERPING1 gene, which is likely to affect protein synthesis. We identified two patients with changes in the PLAUR gene, which may be associated with the manifestation of symptoms angioedema. Six patients showed abnormalities in the genes AGT and KNG1, which can probably explain their early hypertension, which could provoke the appearance of edema.

scholarly journals Management of Patients with Hereditary Angioedema During the COVID-19 Pandemic

2021 ◽  
Vol 19 (3) ◽  
pp. 166-173
Author(s):  
Eray YILDIZ ◽  
Şevket ARSLAN ◽  
Fatih ÇÖLKESEN ◽  
Filiz Sadi AYKAN ◽  
Recep EVCEN ◽  
...  
Keyword(s):  
Hereditary Angioedema ◽  
Clinical Symptoms ◽  
Type I ◽  
Type Ii ◽  
Kinin System ◽  
Beneficial Effects ◽  
Phone Calls ◽  
History Of ◽  
Kallikrein Kinin System

Objective: The aim of this study was to determine the clinical course and treatment outcomes of patients with hereditary angioedema (HAE) after infection with coronavirus disease 2019 (COVID-19). Materials and Methods: Thirty-nine patients with HAE were included in this study. These patients were regularly followed up over phone calls since the first COVID-19 case was seen in our country. Patients were asked to visit the hospital if there was a history of contact with a confirmed COVID-19 patient or if the patient developed clinical symptoms of COVID-19.Results: There were 21 (54%) patients with type I HAE, and 18 (46%) with type II HAE. All patients received treatment for angioedema attacks (C1-inhibitor [C1-INH], icatibant), and seven (20%) received long-term prophylaxis (danazol). Treatment for attacks was continued for all patients during the pandemic. Patients taking danazol were switched to long-term prophylaxis using the C1-INH concentrate. Eleven (28%) patients with HAE developed COVID-19 during this study. Only one patient had severe COVID-19. Six patients (54.5%) were diagnosed with type II HAE, and five (45.5%) were diagnosed with type I HAE. The most common COVID-19 symptoms were fever (7/11; 64%) and myalgia (6/11; 55%). Mild angioedema attacks were experienced by 36% (4/11) of the HAE patients diagnosed with COVID-19. Icatibant was used in all patients.Conclusion: Agents used for HAE block the kallikrein-kinin system and may be useful in the treatment of COVID-19. Considering their beneficial effects on COVID-19, it is recommended that HAE patients should continue the use of agents blocking the kallikrein-kinin system. Keywords: COVID-19, hereditary angioedema, kallikrein-kinin system, bradykinin, C1-INH

Kallikrein–kinin system and fibrinolysis in hereditary angioedema due to factor XII gene mutation Thr309Lys

2009 ◽  
Vol 20 (5) ◽  
pp. 325-332 ◽  
Author(s):  
Konrad Bork ◽  
Rouven Kleist ◽  
Jochen Hardt ◽  
Günther Witzke
Keyword(s):  
Gene Mutation ◽  
Hereditary Angioedema ◽  
Factor Xii ◽  
Kinin System ◽  
Kallikrein Kinin System

scholarly journals Treatment of Hereditary Angioedema

2021 ◽  
Vol 31 (1) ◽  
pp. 1-16
Author(s):  
T Caballero
Keyword(s):  
Hereditary Angioedema ◽  
New Drugs ◽  
Current Therapy ◽  
Factor Xii ◽  
Short Term ◽  
Kinin System ◽  
C1 Esterase Inhibitor ◽  
Kallikrein Kinin System ◽  
Esterase Inhibitor

Hereditary angioedema due to C1-esterase inhibitor deficiency (C1-INH-HAE) is a rare autosomal dominant disease. In the last decade, new drugs and new indications for old drugs have played a role in the management of C1-INH-HAE. This review examines current therapy for C1-INH-HAE and provides a brief summary of drugs that are under development. Increased knowledge of the pathophysiology of C1-INH-HAE has been crucial for advances in the field, with inhibition of the kallikrein-kinin system (plasma kallikrein, activated factor XII) as a key area in the discovery of new drugs, some of which are already marketed for treatment of C1-INH-HAE. Pharmacological treatment is based on 3 pillars: treatment of acute angioedema attacks (on-demand treatment), short-term (preprocedure) prophylaxis, and long-term prophylaxis. The 4 drugs that are currently available for the treatment of acute angioedema attacks (purified plasma-derived human C1 esterase inhibitor concentrate, icatibant acetate, ecallantide, recombinant human C1 esterase inhibitor) are all authorized for self-administration, except ecallantide. Purified plasma-derived human C1 esterase inhibitor concentrate is the treatment of choice for short-term prophylaxis. Tranexamic acid, danazol, intravenous and subcutaneous nanofiltered purified plasma-derived human C1 esterase inhibitor concentrate, and lanadelumab can be used for long-term prophylaxis. New drugs are being investigated, mainly as long-term prophylaxis, and are aimed at blocking the kallikrein-kinin system by means of antiprekallikrein, antikallikrein, and anti–activated FXII action.

KALLIKREIN-KININ SYSTEM IN PATIENTS WITH SHOCK. COMPARISON BETWEEN SEPTIC AND CARDIOGENIC SHOCK

1987 ◽  
Author(s):  
F Martínez-Brotóns ◽  
J R Oncins ◽  
J Mestres ◽  
V Amargós ◽  
C Reynaldo
Keyword(s):  
Septic Shock ◽  
Cardiogenic Shock ◽  
Hemodynamic Instability ◽  
Factor Xii ◽  
Kinin System ◽  
Normal Limits ◽  
Α2 Macroglobulin ◽  
At Iii ◽  
Functional Measure ◽  
Kallikrein Kinin System

Alterations of the kallikrein-kinin system (KKS) consistent with activation and increased consumption have been reported in septic patients and it has been suggested that this activation could contribute to the development of septic shock. As similar alterations have been found in other critically ill patients, many of them prone to shock, we wonder if activation of the KKS could be a consequence rather than a cause of the hemodynamic instability. To answer this question we compared 12 patients with septic shock (8 fatal) with 10 cases of cardiogenic shock secondary to myocardial infarction (8 fatal) as a model of non septic shock. In adition 25 episodes of uncomplicated sepsis and 10 intra-intensive care unit controls were studied. A functional measure of factor XII, high molecular weight kininogen (HMWK) (coagulative methods), prekallikrein (PK), Cl-inhibitor (Cl-INH), α2-macroglobulin (α2-M)- Antithrombin III (AT-III) and kallikrein inhibitor activity (KIA) (chromogenic methods) was performedRESULTS: Patients with septic shock, specially in fatal cases, showed a highly significant decrease in activities of factor XII (P<0.001), PK (P<0.0001), HMWK (P<0.005), α2-M (P<0.001), AT-III (P<0.0001) and KIA (P<0.005). Cl-INH activity was increased in uncomplicated sepsis (P<0.001) but came back to normal or was slightly decreased in septic shock. Components and inhibitors of the KKS were within normal limits in all patients with cardiogenic shock.Our findings support the idea of a contribution of the KKS to the development of septic shock but this system neither seems to play a role in the pathogenesis of cardiogenic shock nor to be altered as a consequence of it.

Changes in Plasma Prekallikrein, High and Low Molecular Weight Kininogens in Disseminated Intravascular Coagulation

1979 ◽  
Author(s):  
M. Yokouchi ◽  
K. Kosaka ◽  
T. Seki ◽  
M. Ogawara ◽  
R. Miura ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Disseminated Intravascular Coagulation ◽  
Marked Decrease ◽  
Normal Values ◽  
Low Molecular Weight ◽  
Factor Xii ◽  
Kinin System ◽  
Intravascular Coagulation ◽  
Plasma Factor ◽  
Kallikrein Kinin System

Changea in components in kallikrein-kinin system have been studied in 15 cases with disseminated Intravascular coagulation (DIC). Nine out of the total cases had infection and six cases had malignancy as primary diseases. Plasma prekallikrein (FKK) was determined by a radiochemical assay using 3H-TAME according to Imanari et al.(1974). High and low molecular weight kininogens (HMWK and LMWK) were bioassayed according to Uchida and Katori (in press). If plasma factor XII, measured in each case, was less than 50 % of normal, values of PKK and HMWK in examined plasma were caliculated from those in 1:1 mixture of examined plasma and normal plasma. All of PKK, HMWK and LMWK Showed moderate to marked decrease in every case with DIC. The values for PKK, HMWK and LMWK were 0.23 0.07 TAME unit/ml (normally 0.620.13), 0,20 0.07 ug(bradykinin equiv.)/ml (normally 0.66 0.14) and 1.24 0.44 ug/ml (normally 2.57 0.41), respectively. There was a significant correlation between PKK and antithrombin III levels (r=0.66, P 0.001) in those cases with DIC. PKK was also directly correlated with HMWK and factor XII. Decrease in PKK and HMWK may be chiefly due to consumption. The mechanism for reduction In LMWK, however, remains to be determined. It may be concluded that plasma prekallikrein, high and low molecular weight kininogens decrease in DIC.

scholarly journals Kallikrein–Kinin System Suppresses Type I Interferon Responses: A Novel Pathway of Interferon Regulation

2018 ◽  
Vol 9 ◽  
Author(s):  
Alecia Seliga ◽  
Michael Hweemoon Lee ◽  
Nicole C. Fernandes ◽  
Viviana Zuluaga-Ramirez ◽  
Marta Didukh ◽  
...  
Keyword(s):  
Type I Interferon ◽  
Type I ◽  
Kinin System ◽  
Kallikrein Kinin System ◽  
Interferon Responses

Activation of Kallikrein-Kinin System in Human Plasma with Purified Serine Protease from Dermatophagoides farinae

1990 ◽  
Vol 91 (1) ◽  
pp. 80-85 ◽  
Author(s):  
Katsunobu Takahashi ◽  
Takashi Aoki ◽  
Shoichi Kohmoto ◽  
Hiroyuki Nishimura ◽  
Yoh Kodera ◽  
...  
Keyword(s):  
Human Plasma ◽  
Serine Protease ◽  
Kinin System ◽  
Kallikrein Kinin System

C1-inhibitor polymers activate the FXII-dependent kallikrein–kinin system: Implication for a role in hereditary angioedema

2015 ◽  
Vol 1850 (6) ◽  
pp. 1336-1342 ◽  
Author(s):  
Daniel Elenius Madsen ◽  
Johannes Jakobsen Sidelmann ◽  
Daniel Biltoft ◽  
Jørgen Gram ◽  
Soren Hansen
Keyword(s):  
Hereditary Angioedema ◽  
C1 Inhibitor ◽  
Kinin System ◽  
Kallikrein Kinin System
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