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Clinical and Translational Allergy Jan 2022Hereditary angioedema (HAE), a rare disease that is characterized by painful and recurring non-allergic swelling episodes, is caused by the deficiency or dysfunction of... (Review)
Review
BACKGROUND
Hereditary angioedema (HAE), a rare disease that is characterized by painful and recurring non-allergic swelling episodes, is caused by the deficiency or dysfunction of C1 inhibitor (C1INH) protein. A comprehensive HAE management plan may require long-term prophylaxis (LTP) in addition to on-demand treatment to help "normalize" patients' lives so that they may fully engage in work, school, family, and leisure activities.
AIM
The main objective of this narrative review is to provide an overview of updated guideline recommendations specific to LTP of HAE and discuss clinical considerations and pharmacologic management options, with a focus on C1INH.
MATERIALS AND METHODS
The authors reviewed relevant HAE literature for current recommendations regarding LTP and the role of C1NH.
RESULTS
Acute HAE attacks are treated with on-demand medication; however, there is a consensus that LTP should routinely be considered for risk reduction and prevention of future episodes. The 2017 World Allergy Organization/European Academy of Allergy and Clinical Immunology guidelines recommend that all patients with HAE be evaluated for LTP routinely and the 2020 HAE Association (HAEA) guidelines emphasize that the decision to use LTP should not be based on rigid criteria, but rather should be based on individual patient needs. Both guidelines recommend C1INH as first-line/preferred therapy for LTP in a range of patient types including adults, children/adolescents, and pregnant/lactating patients. The HAEA also recommends the kallikrein inhibitor, lanadelumab, as a first-line option for LTP. HAE pathway-specific agents for LTP have not been associated with notable safety concerns.
DISCUSSION
Plasma-derived C1INH has been available for 40+ years in Europe and impacts multiple targets within the HAE pathway. C1INH has been used for on-demand treatment and LTP. A subcutaneous formulation of plasma-derived C1INH is approved for LTP and produces functional C1INH activity levels consistently above the threshold needed for protection from HAE attacks. Other pathway-specific options for LTP include the plasma kallikrein inhibitors, lanadelumab-flyo and berotralstat, approved for adults and pediatric patients aged ≥12 years. C1INH is approved for adults and pediatric patients aged ≥6 years.
CONCLUSION
Assessing the need for LTP is vital in the ongoing dialogue between clinicians and patients, as both disease-related factors and patient preferences may change over time. Among available options for LTP, plasma-derived C1INH is the broadly recommended first-line option for LTP in patients with HAE, including pregnant/lactating women and pediatric patients (≥6 years).
PubMed: 35079346
DOI: 10.1002/clt2.12092 -
Scientific Reports Nov 2022Horses are seasonal polyoestrous animals, and the photoperiod is the main factor modulating their reproductive activity. There is no consensus on the andrological and...
Horses are seasonal polyoestrous animals, and the photoperiod is the main factor modulating their reproductive activity. There is no consensus on the andrological and biochemical factors that influence breeding seasonality. To assess the involvement of climate in reproduction, Mangalarga Marchador stallions were monitored over 1 year regarding semen quality and seminal plasma proteome. Here, we show that kallikrein (KLKs) proteoforms in seminal plasma are involved in climate conditioning of reproduction. During the breeding season, greater abundance and different types of KLKs occurred simultaneously to lower sperm motility, greater semen volumes and higher concentrations of glucose and cholesterol. Considering that vasodilation due to activation of the kallikrein-kinin system and the consequent inhibition of the renin-angiotensin system may be associated with lower sperm motility, unravelling the involvement of KLK proteoforms in reproductive seasonality is a priority in horse breeding.
Topics: Horses; Male; Animals; Sperm Motility; Semen Analysis; Kallikreins; Semen; Reproduction; Spermatozoa
PubMed: 36333376
DOI: 10.1038/s41598-022-21350-w -
Pharmaceuticals (Basel, Switzerland) Aug 2020Kinins (peptides related to bradykinin, BK) are formed from circulating substrates, the kininogens, by the action of two proteases, the kallikreins. The only clinical... (Review)
Review
Kinins (peptides related to bradykinin, BK) are formed from circulating substrates, the kininogens, by the action of two proteases, the kallikreins. The only clinical application of a BK receptor ligand, the B receptor antagonist icatibant, is the treatment of the rare hereditary angioedema (HAE) caused by the deficiency of C1-esterase inhibitor (C1-INH). Less common forms of HAE (genetic variants of factor XII, plasminogen, kininogen) are presumably mediated by increased BK formation. Acquired forms of BK-mediated angioedema, such as that associated with angiotensin-I converting enzyme (ACE) inhibition, are also known. Antibody-based analytical techniques are briefly reviewed, and support that kinins are extremely short-lived, prominently cleared by ACE. Despite evidence of continuous activation of the kallikrein-kinin system in HAE, patients are not symptomatic most of the time and their blood or plasma obtained during remission does not generate excessive immunoreactive BK (iBK), suggesting effective homeostatic mechanisms. HAE-C1-INH and HAE-FXII plasmas are both hyperresponsive to fibrinolysis activation. On another hand, we suggested a role for the alternate tissue kallikrein-kinin system in patients with a plasminogen mutation. The role of the BK B receptor is still uncertain in angioedema states. iBK profiles under in vitro stimulation provide fresh insight into the physiopathology of angioedema.
PubMed: 32824891
DOI: 10.3390/ph13090201 -
Hamostaseologie Dec 2021Factor XII (FXII) is a serine protease zymogen produced by hepatocytes and secreted into plasma. The highly glycosylated coagulation protein consists of six domains and... (Review)
Review
Factor XII (FXII) is a serine protease zymogen produced by hepatocytes and secreted into plasma. The highly glycosylated coagulation protein consists of six domains and a proline-rich region that regulate activation and function. Activation of FXII results from a conformational change induced by binding ("contact") with negatively charged surfaces. The activated serine protease FXIIa drives both the proinflammatory kallikrein-kinin pathway and the procoagulant intrinsic coagulation cascade, respectively. Deficiency in FXII is associated with a prolonged activated partial thromboplastin time (aPTT) but not with an increased bleeding tendency. However, genetic or pharmacological deficiency impairs both arterial and venous thrombosis in experimental models. This review summarizes current knowledge of FXII structure, mechanisms of FXII contact activation, and the importance of FXII for diagnostic coagulation testing and thrombosis.
Topics: Blood Coagulation; Blood Coagulation Tests; Factor XII; Humans; Partial Thromboplastin Time; Thrombosis
PubMed: 34592776
DOI: 10.1055/a-1528-0499 -
Microorganisms Sep 2022We aimed to determine the biomarker performance of the proteolytic enzymes cathepsin B (Cat B) and plasma kallikrein (PKa) and transforming growth factor (TGF)-β to...
We aimed to determine the biomarker performance of the proteolytic enzymes cathepsin B (Cat B) and plasma kallikrein (PKa) and transforming growth factor (TGF)-β to detect hepatic fibrosis (HF) in chronic hepatitis C (CHC) patients. We studied 53 CHC patients and 71 healthy controls (HCs). Hepatic-disease stage was determined by liver biopsies, aminotransferase:platelet ratio index (APRI) and Fibrosis (FIB)4. Hepatic inflammation and HF in CHC patients were stratified using the METAVIR scoring system. Cat-B and PKa activities were monitored fluorometrically. Serum levels of TGF-β (total and its active form) were determined using ELISA-like fluorometric methods. Increased serum levels of Cat B and PKa were found (p < 0.0001) in CHC patients with clinically significant HF and hepatic inflammation compared with HCs. Levels of total TGF-β (p < 0.0001) and active TGF-β (p < 0.001) were increased in CHC patients compared with HCs. Cat-B levels correlated strongly with PKa levels (r = 0.903, p < 0.0001) in CHC patients but did not correlate in HCs. Levels of Cat B, PKa and active TGF-β increased with the METAVIR stage of HF. Based on analyses of receiver operating characteristic (ROC) curves, Cat B and PKa showed high diagnostic accuracy (area under ROC = 0.99 ± 0.02 and 0.991 ± 0.007, respectively) for distinguishing HF in CHC patients from HCs. Taken together, Cat B and PKa could be used as circulating biomarkers to detect HF in HCV-infected patients.
PubMed: 36144371
DOI: 10.3390/microorganisms10091769 -
Pharmaceuticals (Basel, Switzerland) Oct 2020The kallikrein-kinin system (KKS) is proposed to act as a counter regulatory system against the vasopressor hormonal systems such as the renin-angiotensin system (RAS),... (Review)
Review
The kallikrein-kinin system (KKS) is proposed to act as a counter regulatory system against the vasopressor hormonal systems such as the renin-angiotensin system (RAS), aldosterone, and catecholamines. Evidence exists that supports the idea that the KKS is not only critical to blood pressure but may also oppose target organ damage. Kinins are generated from kininogens by tissue and plasma kallikreins. The putative role of kinins in the pathogenesis of hypertension is discussed based on human mutation cases on the KKS or rats with spontaneous mutation in the kininogen gene sequence and mouse models in which the gene expressing only one of the components of the KKS has been deleted or over-expressed. Some of the effects of kinins are mediated via activation of the B and/or B receptor and downstream signaling such as eicosanoids, nitric oxide (NO), endothelium-derived hyperpolarizing factor (EDHF) and/or tissue plasminogen activator (T-PA). The role of kinins in blood pressure regulation at normal or under hypertension conditions remains debatable due to contradictory reports from various laboratories. Nevertheless, published reports are consistent on the protective and mediating roles of kinins against ischemia and cardiac preconditioning; reports also demonstrate the roles of kinins in the cardiovascular protective effects of the angiotensin-converting enzyme (ACE) and angiotensin type 1 receptor blockers (ARBs).
PubMed: 33126450
DOI: 10.3390/ph13110347 -
The Journal of Allergy and Clinical... Apr 2024Hereditary angioedema (HAE) is typically caused by a deficiency of the protease inhibitor C1 inhibitor (C1INH). The absence of C1INH activity on plasma kallikrein and...
Hereditary angioedema (HAE) is typically caused by a deficiency of the protease inhibitor C1 inhibitor (C1INH). The absence of C1INH activity on plasma kallikrein and factor XIIa leads to overproduction of the vasoactive peptide bradykinin, with resulting angioedema. As the primary site of C1INH and prekallikrein production, the liver is recognized as an important therapeutic target in HAE, leading to the development of hepatic-focused treatment strategies such as GalNAc-conjugated antisense technology and gene modification. This report reviews currently available data on hepatic-focused interventions for HAE that have advanced into human trials. Donidalorsen is an investigational GalNAc-conjugated antisense oligonucleotide that binds to prekallikrein mRNA in the liver and reduces the expression of prekallikrein. Phase 2 data with subcutaneous donidalorsen demonstrated a significant reduction in HAE attack rate compared with placebo. Phase 3 trials are underway. ADX-324 is a GalNAc-conjugated short-interfering RNA being investigated in HAE. BMN 331 is an investigational AAV5-based gene therapy vector that expresses wild-type human C1INH and is targeted to hepatocytes. A single intravenous dose of BMN 331 is intended to replace the defective SERPING1 gene and enable patients to produce functional C1INH. A first-in-human phase 1/2 study is ongoing with BMN 331. NTLA-2002 is an investigational in vivo clustered regularly interspaced short palindromic repeats/Cas9-based therapy designed to knock out the prekallikrein-coding KLKB1 gene in hepatocytes; a phase 1/2 study is ongoing. Findings from these and other ongoing studies are highly anticipated with the expectation of expanding the array of treatment options in HAE.
Topics: Humans; Angioedemas, Hereditary; Bradykinin; Complement C1 Inhibitor Protein; Liver; Prekallikrein
PubMed: 38142864
DOI: 10.1016/j.jaip.2023.12.025 -
Orphanet Journal of Rare Diseases Nov 2022Hereditary angioedema (HAE) is a rare autosomal dominant genetic disease characterized by repetitive subcutaneous or submucosal angioedema, activation of the kinin... (Review)
Review
Hereditary angioedema (HAE) is a rare autosomal dominant genetic disease characterized by repetitive subcutaneous or submucosal angioedema, activation of the kinin system, and increased vascular permeability. C1-inhibitor (C1-INH) deficiency, the main mechanism of HAE pathogenesis, occurs when abnormal activation of plasma kallikrein, bradykinin, and factor XII, or mutation of genes such as SERPING1 cause quantitative or functional C1-INH defects. Although androgens are not approved for HAE treatment in many countries, they are widely used in China and Brazil to reduce the frequency and severity of HAE attacks. The long-term adverse effects of androgen treatment are concerning for both physicians and patients. Virilization, weight gain, acne, hirsutism, liver damage, headache, myalgia, hematuria, menstrual disorders, diminished libido, arterial hypertension, dyslipidemia, and anxiety/depression are commonly observed during long-term treatment with androgens. These adverse effects can affect the quality of life of HAE patients and often lead to treatment interruption, especially in women and children. In-depth studies of the pathogenesis of HAE have led to the approval of alternative treatment strategies, including plasma-derived C1 inhibitor, recombinant human C1 inhibitor, plasma Kallikrein inhibitor (ecallantide; lanadelumab), and bradykinin B2 receptor antagonist (icatibant), some of which have achieved satisfactory results with mostly non-serious side effects. Therefore, a new standard of medical care may expand possibilities for the management of HAE in emerging countries.
Topics: Child; Humans; Female; Angioedemas, Hereditary; Androgens; Plasma Kallikrein; Quality of Life; Complement C1 Inhibitor Protein; Bradykinin B2 Receptor Antagonists
PubMed: 36324138
DOI: 10.1186/s13023-022-02536-x -
Frontiers in Medicine 2022The pathophysiology of preeclampsia is not fully understood. Disturbances in the contact system are associated with preeclampsia. Few studies have investigated the...
OBJECTIVE
The pathophysiology of preeclampsia is not fully understood. Disturbances in the contact system are associated with preeclampsia. Few studies have investigated the association between preeclampsia and alterations in the contact system in plasma. This study aims to elucidate whether this basic biological system is affected in preeclampsia using new methods focusing on the dynamic interactions and total capacity of the contact system in blood.
DESIGN
Cross-sectional study matching women with preeclampsia and controls without preeclampsia regarding age, pregestational body mass index, and gestational age at onset of the disease.
SETTING
Two Danish University hospitals.
SAMPLE
A cohort of 117 women with preeclampsia and 117 controls.
METHODS
The turnover and capacity of the contact system were determined with new methods. Paired -test, Wilcoxon signed-pairs signed rank test, Mann-Whitney or Chi-test were applied, as appropriate.
MAIN OUTCOME MEASUREMENTS
Kallikrein generation (peak kallikrein concentration and endogenous kallikrein potential), coagulation factor XII, prekallikrein, H-kininogen, cleaved H-kininogen, and complement C1 esterase inhibitor.
RESULTS
The endogenous kallikrein potential, peak kallikrein concentration, prekallikrein and cleaved H-kininogen were significantly lower in women with preeclampsia compared to the controls, ≤ 0.005, whereas the concentration of coagulation factor XII, H-kininogen and complement C1 esterase inhibitor was not significantly different, > 0.05.
CONCLUSION
This study demonstrates significant reduction in kallikrein generating capacity, prekallikrein and cleaved H-kininogen indicating that the contact system is affected in preeclampsia suggesting a link to the pathophysiology of the disease.
PubMed: 35733874
DOI: 10.3389/fmed.2022.896811 -
Journal of Thrombosis and Haemostasis :... Jun 2023During plasma contact activation, factor XII (FXII) binds to surfaces through its heavy chain and undergoes conversion to the protease FXIIa. FXIIa activates...
BACKGROUND
During plasma contact activation, factor XII (FXII) binds to surfaces through its heavy chain and undergoes conversion to the protease FXIIa. FXIIa activates prekallikrein and factor XI (FXI). Recently, we showed that the FXII first epidermal growth factor-1 (EGF1) domain is required for normal activity when polyphosphate is used as a surface.
OBJECTIVES
The aim of this study was to identify amino acids in the FXII EGF1 domain required for polyphosphate-dependent FXII functions.
METHODS
FXII with alanine substitutions for basic residues in the EGF1 domain were expressed in HEK293 fibroblasts. Wild-type FXII (FXII-WT) and FXII containing the EGF1 domain from the related protein Pro-HGFA (FXII-EGF1) were positive and negative controls. Proteins were tested for their capacity to be activated, and to activate prekallikrein and FXI, with or without polyphosphate, and to replace FXII-WT in plasma clotting assays and a mouse thrombosis model.
RESULTS
FXII and all FXII variants were activated similarly by kallikrein in the absence of polyphosphate. However, FXII with alanine replacing Lys, Lys, and Lys (FXII-Ala) or Lys, His, and Lys (FXII-Ala) were activated poorly in the presence of polyphosphate. Both have <5% of normal FXII activity in silica-triggered plasma clotting assays and have reduced binding affinity for polyphosphate. Activated FXIIa-Ala displayed profound defects in surface-dependent FXI activation in purified and plasma systems. FXIIa-Ala reconstituted FXII-deficient mice poorly in an arterial thrombosis model.
CONCLUSION
FXII Lys, Lys, Lys, and Lys form a binding site for polyanionic substances such as polyphosphate that is required for surface-dependent FXII function.
Topics: Humans; Animals; Mice; Factor XII; Prekallikrein; Polyphosphates; HEK293 Cells; Factor XI; Thrombosis; Factor XIIa
PubMed: 36863563
DOI: 10.1016/j.jtha.2023.02.014