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Clinical and Translational Science Mar 2022Factor XII (FXII) is the principal initiator of the plasma contact system and has proinflammatory and prothrombotic activities. This single-center, first-in-human phase... (Randomized Controlled Trial)
Randomized Controlled Trial
Factor XII (FXII) is the principal initiator of the plasma contact system and has proinflammatory and prothrombotic activities. This single-center, first-in-human phase I study aimed to assess the safety and tolerability of single escalating doses of garadacimab, a monoclonal antibody that specifically inhibits activated FXII (FXIIa), in healthy male volunteers. Volunteers were randomized to eight cohorts, with intravenous (i.v.) doses of 0.1, 0.3, 1, 3, and 10 mg/kg and subcutaneous (s.c.) doses of 1, 3, and 10 mg/kg. Six volunteers in each cohort received garadacimab or placebo in a ratio of 2:1. Follow-up for safety lasted 85 days after dosing. Blood samples were collected throughout for pharmacokinetic/pharmacodynamic analysis. Forty-eight volunteers were enrolled: 32 received garadacimab and 16 received placebo. Most volunteers experienced at least one treatment-emergent adverse event (TEAE), predominantly grade 1. No serious TEAEs, deaths, or TEAEs leading to discontinuation were reported. No volunteers tested positive for garadacimab antidrug antibodies. Garadacimab plasma concentrations increased in a dose-dependent manner. Sustained inhibition of FXIIa-mediated kallikrein activity beyond day 28 resulted from 3 and 10 mg/kg garadacimab (i.v. and s.c.). A dose-dependent increase in activated partial thromboplastin time with no change in prothrombin time was demonstrated. Garadacimab (single-dose i.v. and s.c.) was well-tolerated in healthy volunteers. Dose-dependent increases in plasma concentration and pharmacodynamic effects in relevant kinin and coagulation pathways were observed. These results support the clinical development of garadacimab, including in phase II studies in hereditary angioedema and coronavirus disease 2019 (COVID-19).
Topics: Angioedemas, Hereditary; Antibodies, Monoclonal; COVID-19; Dose-Response Relationship, Drug; Double-Blind Method; Factor XIIa; Humans; Male
PubMed: 34859955
DOI: 10.1111/cts.13180 -
Journal of Cardiovascular and Thoracic... 2022The tissue kallikrein-kinin system is an endogenous homeostatic pathway, which its stimulation is associated with cardioprotection. The present study aimed to determine...
The tissue kallikrein-kinin system is an endogenous homeostatic pathway, which its stimulation is associated with cardioprotection. The present study aimed to determine the effect of exercise training on plasma tissue kallikrein (TK) and bradykinin (BK) and their association with cardiac hypertrophy. 22 non-athlete and 22 athlete women were exposed to acute (Bruce test) and chronic (12-week swimming training) exercises. 2D echocardiography was used to evaluate morphological and functional features of the heart. Plasma concentrations of TK and BK were quantified by ELISA. Athletes had significantly higher values of left ventricle end-diastolic diameter index (LVEDDI) and left ventricle mass index (LVMI) than non-athletes. Exercise intervention affected echocardiographic features in neither of the study groups. Chronic exercise training notably increased plasma levels of TK and BK, which increase was more pronounced in the athletes. Plasma TK negatively correlated with LVEDDI (r=-0.64, =0.036 and r=-0.58, =0.027) and LVMI (r=-0.51, =0.032 and r=-0.63, =0.028) in the non-athlete and athlete groups. In opposition, there was a positive correlation between plasma TK and left ventricle ejection fraction in non-athletes (r=0.39, =0.049) and athletes (r=0.53, =0.019). The upregulation of the tissue kallikrein-kinin system may be a protective mechanism against excessive cardiac hypertrophy induced by chronic exercise training.
PubMed: 36398053
DOI: 10.34172/jcvtr.2022.28 -
The Journal of Heart and Lung... Oct 2021Primary graft dysfunction (PGD) is the leading cause of early mortality after heart transplant. Pre-transplant predictors of PGD remain elusive and its etiology remains...
BACKGROUND
Primary graft dysfunction (PGD) is the leading cause of early mortality after heart transplant. Pre-transplant predictors of PGD remain elusive and its etiology remains unclear.
METHODS
Microvesicles were isolated from 88 pre-transplant serum samples and underwent proteomic evaluation using TMT mass spectrometry. Monte Carlo cross validation (MCCV) was used to predict the occurrence of severe PGD after transplant using recipient pre-transplant clinical characteristics and serum microvesicle proteomic data. Putative biological functions and pathways were assessed using gene set enrichment analysis (GSEA) within the MCCV prediction methodology.
RESULTS
Using our MCCV prediction methodology, decreased levels of plasma kallikrein (KLKB1), a critical regulator of the kinin-kallikrein system, was the most predictive factor identified for PGD (AUROC 0.6444 [0.6293, 0.6655]; odds 0.1959 [0.0592, 0.3663]. Furthermore, a predictive panel combining KLKB1 with inotrope therapy achieved peak performance (AUROC 0.7181 [0.7020, 0.7372]) across and within (AUROCs of 0.66-0.78) each cohort. A classifier utilizing KLKB1 and inotrope therapy outperforms existing composite scores by more than 50 percent. The diagnostic utility of the classifier was validated on 65 consecutive transplant patients, resulting in an AUROC of 0.71 and a negative predictive value of 0.92-0.96. Differential expression analysis revealed a enrichment in inflammatory and immune pathways prior to PGD.
CONCLUSIONS
Pre-transplant level of KLKB1 is a robust predictor of post-transplant PGD. The combination with pre-transplant inotrope therapy enhances the prediction of PGD compared to pre-transplant KLKB1 levels alone and the resulting classifier equation validates within a prospective validation cohort. Inflammation and immune pathway enrichment characterize the pre-transplant proteomic signature predictive of PGD.
Topics: Adult; Aged; Cardiomyopathies; Cohort Studies; Extracellular Vesicles; Female; Heart Transplantation; Humans; Logistic Models; Machine Learning; Male; Middle Aged; Plasma Kallikrein; Predictive Value of Tests; Primary Graft Dysfunction; Proteomics; ROC Curve; Risk Factors
PubMed: 34330603
DOI: 10.1016/j.healun.2021.07.001 -
Journal of Bone and Mineral Research :... Mar 2022Fibrodysplasia ossificans progressiva (FOP) is a progressive, debilitating genetic disease in which skeletal muscle and connective tissue is episodically replaced by...
Fibrodysplasia ossificans progressiva (FOP) is a progressive, debilitating genetic disease in which skeletal muscle and connective tissue is episodically replaced by heterotopic bone. Discovery of surrogate biomarkers of disease (genotype)-related and flare-up-associated activity of FOP in a readily accessible matrix, such as plasma, would facilitate an understanding of the complex pathophysiology of FOP, aid patient care, and provide a valuable tool for the development and monitoring of potential therapeutics. In a case-control study, using a carefully collected and curated set of plasma samples from 40 FOP patients with the classic ACVR1 mutation and 40 age- and sex-matched controls, we report the identification of disease-related and flare-up-associated biomarkers of FOP using a multiplex analysis of 113 plasma-soluble analytes. Adiponectin (implicated in hypoxia, inflammation, and heterotopic ossification) as well as tenascin-C (an endogenous activator of innate immune signaling through the TLR4 pathway and a substrate for kallikrein-7) were highly correlated with FOP genotype, while kallikrein-7 was highly correlated with acute flare-up status. Plasma-soluble biomarkers for FOP support a flare-up-related acute inflammatory phase of disease activity superimposed on a genotypic background of chronic inflammation. © 2021 American Society for Bone and Mineral Research (ASBMR).
Topics: Activin Receptors, Type I; Biomarkers; Case-Control Studies; Humans; Inflammation; Kallikreins; Myositis Ossificans
PubMed: 34954853
DOI: 10.1002/jbmr.4492 -
The Yale Journal of Biology and Medicine Mar 2020Kinins are proinflammatory peptides that are formed in the skin by the enzymatic action of tissue kallikrein (KLK1) on kininogens. Tissue kallikrein is produced by... (Review)
Review
Kinins are proinflammatory peptides that are formed in the skin by the enzymatic action of tissue kallikrein (KLK1) on kininogens. Tissue kallikrein is produced by eccrine sweat glands and also by cells of the and other skin appendages. Kinin formation may be favored during inflammatory skin disorders when plasma constituents, including kininogens, extravasate from venules and capillaries, which have increased permeability in response to the plethora of inflammatory mediators generated in the course of acute inflammation. By activating either kinin B1 or B2 receptors, kinins modulate keratinocyte differentiation, which relays on activation of several signaling systems that follows receptor stimulation. Participation of the kinin B1 receptor in wound healing is still a matter of controversy though some studies indicate that B1 receptor stimulation regulates keratinocyte migration by controlling metalloproteases 2 and 9 production and by improving wound closure in a mouse model. Development of more stable kinin B1 receptor agonists may be beneficial to modulate wound healing, especially if we take into account that the B1 receptor is up-regulated by inflammation and by cytokines generated in the inflamed microenvironment.
Topics: Homeostasis; Humans; Keratinocytes; Kinins; Receptors, Peptide; Signal Transduction; Skin; Tissue Kallikreins; Wound Healing
PubMed: 32226346
DOI: No ID Found -
Dermatology and Therapy Oct 2021The goal of this article is to discuss the importance of differentiating hereditary angioedema (HAE) from other types of angioedema, describe advances in HAE management,...
OBJECTIVE
The goal of this article is to discuss the importance of differentiating hereditary angioedema (HAE) from other types of angioedema, describe advances in HAE management, especially long-term prophylaxis (LTP), and offer practical recommendations for dermatologists.
COMMENTARY
While HAE is rare, dermatologists are likely to encounter patients with this condition at some point over the course of their clinical practice due to the fact that HAE episodes typically involve subcutaneous swelling and sometimes erythema marginatum. HAE is characterized by recurrent episodes of painful and/or disabling bradykinin-mediated angioedema. Unfortunately, HAE is commonly mistaken for other conditions such as allergic and other mast cell-mediated angioedema, but has very different treatment requirements. Delayed diagnosis of HAE can result in years of avoidable debilitating symptoms, inappropriate treatment, potentially unnecessary invasive intervention, and reduced quality of life, and can be life threatening. Thus, timely identification of HAE is essential to ensure appropriate clinical management. Patients with HAE have either deficiency or dysfunction of the C1 inhibitor (C1INH) protein that inhibits proteases in the contact, complement, and fibrinolytic systems. Pathway-specific HAE treatments include C1INH replacement, kallikrein inhibitors, and bradykinin receptor antagonists. Treatment options for managing acute attacks include C1INH replacement (plasma-derived or recombinant formulations), icatibant (kallikrein inhibitor), and ecallantide (bradykinin B2 receptor antagonist). In the past 5 years, several new options for LTP have been approved, including a subcutaneous plasma-derived C1INH formulation and two kallikrein inhibitors (lanadelumab; berotralstat). Optimal management of HAE entails the creation of a comprehensive management plan that addresses both acute and long-term patient needs and includes input from an HAE expert and the patient/caregivers.
PubMed: 34460082
DOI: 10.1007/s13555-021-00593-x -
Frontiers in Pharmacology 2023The kallikrein kinin system (KKS) is an established pharmacological target for the treatment and prevention of attacks in hereditary angioedema (HAE). Proteolytic...
The kallikrein kinin system (KKS) is an established pharmacological target for the treatment and prevention of attacks in hereditary angioedema (HAE). Proteolytic activities of FXIIa and single-chain Factor XII (FXII) zymogen contribute to KKS activation and thereby may play roles in both initiating and propagating HAE attacks. In this report, we investigated the effects of potent small molecule FXIIa inhibitors on FXIIa and single chain FXII enzymatic activities, KKS activation, and angioedema in mice. We examined the effects of 29 structurally distinct FXIIa inhibitors on enzymatic activities of FXIIa and a mutant single chain FXII with R334A, R343A and R353A substitutions (rFXII-T), that does not undergo zymogen conversion to FXIIa, using kinetic fluorogenic substrate assays. We examined the effects of a representative FXIIa inhibitor, KV998086, on KKS activation and both carrageenan- and captopril-induced angioedema in mice. FXIIa inhibitors designed to target its catalytic domain also potently inhibited the enzymatic activity of rFXII-T and the pICs of these compounds linearly correlated for rFXIIa and rFXII-T ( = 0.93). KV998086, a potent oral FXIIa inhibitor (IC = 7.2 nM) inhibited dextran sulfate (DXS)-stimulated generation of plasma kallikrein and FXIIa, and the cleavage of high molecular weight kininogen (HK) in human plasma. KV998086 also inhibited rFXII-T mediated HK cleavage ( < 0.005) in plasma from FXII knockout mice supplemented with rFXII-T and stimulated with polyphosphate or DXS. Orally administered KV998086 protected mice from 1) captopril-induced Evans blue leakage in colon and laryngotracheal tissues and 2) blocked carrageenan-induced plasma HK consumption and paw edema. These findings show that small molecule FXIIa inhibitors, designed to target its active site, also inhibit the enzymatic activity of FXII zymogen. Combined inhibition of FXII zymogen and FXIIa may thereby suppress both the initiation and amplification of KKS activation that contribute to hereditary angioedema attacks and other FXII-mediated diseases.
PubMed: 38178859
DOI: 10.3389/fphar.2023.1287487 -
Journal of Neurochemistry Aug 2019Temporal lobe epilepsy (TLE) is a chronic disease, characterized by severe and refractory seizures, triggered in the hippocampus and/or amygdala, disrupting the...
Temporal lobe epilepsy (TLE) is a chronic disease, characterized by severe and refractory seizures, triggered in the hippocampus and/or amygdala, disrupting the blood-brain barrier. This disruption can sustain, or aggravate, the epileptic condition. The aim of this study was to evaluate the activation of the kallikrein-kinin system in patients with TLE, as it relates to the maintenance of blood-brain barrier. Human hippocampal sclerotic tissues removed after surgery for seizure control, plasma, and serum were used in the following assays: immunostaining for white blood cells in the TLE hippocampus, C-reactive protein in serum, quantification of plasma kallikrein (PKal) and cathepsin B (CatB) activity in serum and plasma, quantification of C1-inhibitor, analysis of high-molecular-weight kininogen (H-kininogen) fragments, and activation of plasma prekallikrein for comparison with healthy controls. Infiltration of white blood cells in the sclerotic hippocampus and a significant increase in the neutrophil/lymphocyte ratio in the blood of TLE patients were observed. High levels of C-reactive protein (TLE = 1.4 ± 0.3 µg/mL), PKal (TLE = 5.4 ± 0.4 U/mL), and CatB (TLE = 4.9 ± 0.4 U/mL) were also evident in the serum of TLE patients comparing to controls. A strong linear correlation was observed between active CatB and PKal in the serum of TLE patients (r = 0.88). High levels of cleaved H-kininogen and free PKal, and low levels of C1-inhibitor (TLE = 188 ± 12 µg/mL) were observed in the serum of TLE patients. Our data demonstrated that the plasma kallikrein-kinin system is activated in patients with TLE. OPEN SCIENCE BADGES: This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/.
Topics: Adult; Cathepsin B; Epilepsy, Temporal Lobe; Female; Hippocampus; Humans; Inflammation; Kallikrein-Kinin System; Kallikreins; Male; Middle Aged
PubMed: 31206169
DOI: 10.1111/jnc.14793 -
Blood Mar 2020In this issue of , Noubouossie et al provide new insights into potential mechanisms for thromboinflammatory complications associated with red blood cell (RBC)...
In this issue of , Noubouossie et al provide new insights into potential mechanisms for thromboinflammatory complications associated with red blood cell (RBC) transfusions. By using leukoreduced RBC units to isolate RBC microvesicles (RBC-MVs), they document that RBC-MVs activate factor IX (FIX) via 2 distinct pathways: (1) the canonical intrinsic pathway in which activated FXII (FXIIa) activates FIX in an FXI-dependent manner and (2) a noncanonical pathway in which plasma kallikrein directly activates FIX, which ultimately results in thrombin generation.
Topics: Blood Coagulation Tests; Cell-Derived Microparticles; Erythrocytes; Factor IX
PubMed: 32135018
DOI: 10.1182/blood.2020004985 -
Alzheimer's Research & Therapy Aug 2022Low levels of plasma apolipoprotein E (apoE) and presence of the APOE ε4 allele are associated with an increased risk of Alzheimer's disease (AD). Although the...
BACKGROUND
Low levels of plasma apolipoprotein E (apoE) and presence of the APOE ε4 allele are associated with an increased risk of Alzheimer's disease (AD). Although the increased risk of AD in APOE ε4-carriers is well-established, the protein levels have received limited attention.
METHODS
We here report the total plasma apoE and apoE isoform levels at baseline from a longitudinally (24 months) followed cohort including controls (n = 39), patients with stable amnestic mild cognitive impairment during 24 months follow up (MCI-MCI, n = 30), patients with amnestic MCI (aMCI) that during follow-up were clinically diagnosed with AD with dementia (ADD) (MCI-ADD, n = 28), and patients with AD with dementia (ADD) at baseline (ADD, n = 28). We furthermore assessed associations between plasma apoE levels with cerebrospinal fluid (CSF) AD biomarkers and α-synuclein, as well as both CSF and plasma neurofilament light chain (NfL), YKL-40 and kallikrein 6.
RESULTS
Irrespective of clinical diagnosis, the highest versus the lowest apoE levels were found in APOE ε2/ε3 versus APOE ε4/ε4 subjects, with the most prominent differences exhibited in females. Total plasma apoE levels were 32% and 21% higher in the controls versus MCI-ADD and ADD patients, respectively. Interestingly, MCI-ADD patients exhibited a 30% reduction in plasma apoE compared to MCI-MCI patients. This decrease appeared to be associated with brain amyloid-β (Aβ) pathology regardless of disease status as assessed using the Amyloid, Tau, and Neurodegeneration (A/T/N) classification. In addition to the association between low plasma apoE and low levels of CSF Aβ, lower apoE levels were also related to higher levels of CSF total tau (t-tau) and tau phosphorylated at Threonine 181 residue (p-tau) and NfL as well as a worse performance on the mini-mental-state-examination. In MCI-ADD patients, low levels of plasma apoE were associated with higher levels of CSF α-synuclein and kallikrein 6. No significant correlations between plasma apoE and the astrocytic inflammatory marker YKL40 were observed.
CONCLUSIONS
Our results demonstrate important associations between low plasma apoE levels, Aβ pathology, and progression from aMCI to a clinical ADD diagnosis.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Apolipoprotein E3; Apolipoprotein E4; Apolipoproteins E; Biomarkers; Cognitive Dysfunction; Female; Humans; Kallikreins; Peptide Fragments; alpha-Synuclein; tau Proteins
PubMed: 36002891
DOI: 10.1186/s13195-022-01058-9