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Revista Alergia Mexico (Tecamachalco,... Sep 2023Hereditary angioedema type 1 (HAE1) is an autosomal dominant disorder, characterized by quantitative and qualitative deficiency of C1 inhibitor, excessive production of...
BACKGROUND
Hereditary angioedema type 1 (HAE1) is an autosomal dominant disorder, characterized by quantitative and qualitative deficiency of C1 inhibitor, excessive production of bradykinin and causing recurrent angioedema in varying degrees of severity that affects quality of life and life itself. from the patients. Lanadelumab is a human monoclonal antibody, a specific inhibitor of plasma kallikrein, approved for long-term prophylaxis of HAE1.
CASE REPORT
A 59-year-old female patient, diagnosed with HAE 1 since November 1987, without therapeutic response to danazol, fresh frozen plasma, or C1 inhibitor derived from intravenous plasma, requiring 3 to 9 monthly vials of icatibant acetate due to angioedema. laryngeal, cutaneous and visceral with highly altered quality of life indices. Lanadelumab 300 mg subcutaneously every 14 days was started. At the start of treatment, the AECT1 score was 1 point; AE-Qol2: 57 points, AAS3: 32 points, being followed up at 5, 10 and 12 months. After one year of treatment, the records showed an AECT1 of 19 points; AE-Qol2: 36 points and AAS3: 5 points. The requirement for icatibant acetate has been no more than 3 vials per month.
CONCLUSION
In accordance with the literature, lanadelumab offered a significant decrease in angioedema activity and a significantly positive impact on the pa- tient's quality of life, confirming that lanadelumab is an effective option for long-term HAE prophylaxis. .
Topics: Female; Humans; Middle Aged; Quality of Life; Antibodies, Monoclonal, Humanized; Angioedema; Angioedemas, Hereditary
PubMed: 37933935
DOI: 10.29262/ram.v70i3.1270 -
Cureus Oct 2023Type-1 hypersensitivity reaction represents an acute IgE-mediated reaction that can cause life-threatening conditions, such as anaphylactic shock, angioedema, and airway... (Review)
Review
Type-1 hypersensitivity reaction represents an acute IgE-mediated reaction that can cause life-threatening conditions, such as anaphylactic shock, angioedema, and airway obstruction. Other reactions that can mimic type-1 hypersensitivity reactions include IgE-independent mast cell degranulation, bradykinin-mediated reactions, leukotrienes-mediated reactions, and pseudo-allergies. We use the term pseudo-allergy in this article for histamine-mediated reactions that are mast cell-independent. We did not discuss pseudo-allergic reactions that are not acute or life-threatening, such as celiac disease, Heiner's syndrome, eosinophilic esophagitis, and food protein-induced enterocolitis in our article because the emergency department is not the primary location to diagnose or treat these reactions. Herein, we present some allergic-like reactions that can be life-threatening, such as scombroid food poisoning (SFP), bradykinin-induced angioedema, IgE-independent angioedema, opioid-induced angioedema, and non-steroidal anti-inflammatory drug (NSAID)-induced hypersensitivity and angioedema. These reactions may have different treatments based on their mechanism of reaction. Histamine-mediated reactions, such as SFP, histamine-mediated angioedema, and mast cell degranulation induced by NSAIDs, and opioids can be treated with antihistamines, epinephrine, and corticosteroids. Bradykinin-induced angioedema, including hereditary angioedema and acquired angioedema, can be treated with fresh frozen plasma. Hereditary angioedema can be treated with many FDA-approved targeted medications, such as plasma-derived C1-INH, plasma kallikrein inhibitor (Ecallantide), and selective bradykinin-2 receptor antagonist (Icatibant). However, these targeted agents are not well-studied enough to be used for acquired angioedema. It is crucial for emergency medicine physicians to be familiar with and predict these reactions to prevent misdiagnosis, be prepared to treat these life-threatening conditions appropriately without delay and eliminate patients' exposure to any unnecessary investigations or treatments.
PubMed: 37927771
DOI: 10.7759/cureus.46536 -
The World Allergy Organization Journal Nov 2023In hereditary angioedema (HAE) due to C1-inhibitor deficiency (C1-INH-HAE), bradykinin-mediated submucosal and/or subcutaneous angioedema dominates the clinical picture....
BACKGROUND
In hereditary angioedema (HAE) due to C1-inhibitor deficiency (C1-INH-HAE), bradykinin-mediated submucosal and/or subcutaneous angioedema dominates the clinical picture. The deficiency of C1-inhibitor can lead to the over-activation of the complement system. Complement plays an important role in all types of hypersensitivity reactions. On the other hand, during the degranulation of mast cells, heparin is also released amongst other substances. Heparin can activate the plasma kinin-kallikrein system, leading to bradykinin generation. These observations suggest a possible connection between C1-INH-HAE and mast cell-mediated hypersensitivity reactions.
OBJECTIVE
To assess the occurrence of hypersensitivity reactions in the Hungarian C1-INH-HAE population.
METHODS
Patients filled out a questionnaire of 112 questions, either online or on paper. The questions were about hypersensitivity and C1-INH-HAE symptoms, the relation between these 2, general health, and demographic data. The study protocol was approved by the institutional review board of Semmelweis University, Budapest, and informed consent was obtained from the participants.
RESULTS
One hundred and six patients (64 female, 42 male, median age 46 years) responded, with 63.2% having hypersensitivity. Hypersensitivity was provoked by pollen in 25.5% of patients, by contact sensitivity in 22.6%, by food in 21.7%, by insect sting in 19.8%, by pet in 15.1%, by drug in 14.2%, by dust mite in 5.7%, and by mold in 1.9%. In 11 patients, hypersensitivity symptoms appeared after the diagnosis of C1-INH-HAE. Six hypersensitive patients experienced improvement in their symptoms; 42 remained the same, but none experienced worsening after the diagnosis of C1-INH-HAE. In 7.8% of the hypersensitive patients, a C1-INH-HAE attack worsened the hypersensitivity symptoms, while 15.7% of the hypersensitive patients experienced a C1-INH-HAE attack provoked by contact with the provoking factor.
CONCLUSION
While 63.2% of our C1-INH-HAE patients have reported hypersensitivity symptoms, Eurostat's latest data puts the prevalence of self-reported allergies in Hungary at 19.3%. Since in our experience most Hungarian patients report hypersensitivity reactions as allergies, this may support a possible connection between the 2 diseases, but further molecular studies are needed.
PubMed: 37920275
DOI: 10.1016/j.waojou.2023.100833 -
The Analyst Nov 2023Angiotensin and kinin metabolic pathways are reported to be altered by many diseases, including COVID-19. Monitoring levels of these peptide metabolites is important for...
Angiotensin and kinin metabolic pathways are reported to be altered by many diseases, including COVID-19. Monitoring levels of these peptide metabolites is important for understanding mechanisms of disease processes. In this paper, we report dimethyl labeling of amines in peptides by addition of formaldehyde to samples and deutero-formaldehyde to internal standards to generate nearly identical isotopic standards with 4 / units larger per amine group than the corresponding analyte. We apply this approach to rapid, multiplexed, absolute LC-MS/MS quantitation of renin angiotensin system (RAS) and kallikrein-kinin system (KKS) peptides in human blood serum. Limits of detection (LODs) were obtained in the low pg mL range with 3 orders of magnitude dynamic ranges, appropriate for determinations of normal and elevated levels of the target peptides in blood serum and plasma. Accuracy is within ±15% at concentrations above the limit of quantitation, as validated by spike-recovery in serum samples. Applicability was demonstrated by measuring RAS and KKS peptides in serum from COVID-19 patients, but is extendable to any class of peptides or other small molecules bearing reactive -NH groups.
Topics: Humans; Renin-Angiotensin System; Kallikrein-Kinin System; Chromatography, Liquid; Serum; COVID-19; Tandem Mass Spectrometry; Peptides; Formaldehyde; Isotopes
PubMed: 37850419
DOI: 10.1039/d3an00943b -
Journal of Thrombosis and Haemostasis :... Jan 2024In plasma, high molecular weight kininogen (HK) is either free or bound to prekallikrein (PK) or factor (F) XI (FXI). During contact activation, HK is thought to anchor...
BACKGROUND
In plasma, high molecular weight kininogen (HK) is either free or bound to prekallikrein (PK) or factor (F) XI (FXI). During contact activation, HK is thought to anchor PK and FXI to surfaces, facilitating their conversion to the proteases plasma kallikrein and FXIa. Mice lacking HK have normal hemostasis but are resistant to injury-induced arterial thrombosis.
OBJECTIVES
To identify amino acids on the HK-D6 domain involved in PK and FXI binding and study the importance of the HK-PK and HK-FXI interactions to coagulation.
METHODS
Twenty-four HK variants with alanine replacements spanning residues 542-613 were tested in PK/FXI binding and activated partial thromboplastin time clotting assays. Surface-induced FXI and PK activation in plasma were studied in the presence or absence of HK. Kng1 mice lacking HK were supplemented with human or murine HK and tested in an arterial thrombosis model.
RESULTS
Overlapping binding sites for PK and FXI were identified in the HK-D6 domain. HK variants with defects only in FXI binding corrected the activated partial thromboplastin time of HK-deficient plasma poorly compared to a variant defective only in PK-binding. In plasma, HK deficiency appeared to have a greater deleterious effect on FXI activation than PK activation. Human HK corrected the defect in arterial thrombus formation in HK-deficient mice poorly due to a specific defect in binding to mouse FXI.
CONCLUSION
Clinical observations indicate FXI is required for hemostasis, while HK is not. Yet, the HK-FXI interaction is required for contact activation-induced clotting in vitro and in vivo suggesting an important role in thrombosis and perhaps other FXI-related activities.
Topics: Animals; Humans; Mice; Kininogen, High-Molecular-Weight; Factor XI; Prekallikrein; Blood Coagulation; Thrombosis
PubMed: 37813198
DOI: 10.1016/j.jtha.2023.09.027 -
The Journal of Allergy and Clinical... May 2023We report an approximately 80% reduction in angioedema attacks with lanadelumab, a mAb targeting plasma kallikrein, in a case of hereditary angioedema with normal C1...
We report an approximately 80% reduction in angioedema attacks with lanadelumab, a mAb targeting plasma kallikrein, in a case of hereditary angioedema with normal C1 inhibitor levels. This finding supports a central pathophysiologic role for kallikrein in hereditary angioedema with normal C1 levels and supports the need for prospective studies of lanadelumab use with this condition.
PubMed: 37780787
DOI: 10.1016/j.jacig.2023.100087 -
Biochemical and Biophysical Research... Nov 2023Bradykinin has a wide variety of physiological functions, including vasodilation and blood pressure reduction. However, the physiological roles of bradykinin are not...
Bradykinin has a wide variety of physiological functions, including vasodilation and blood pressure reduction. However, the physiological roles of bradykinin are not fully understood. We used the CRISPR/Cas9 method to generate BKK1 and BKK2 mutant mice, targeting the BK portion of mouse kininogen1 and kininogen2 genes, respectively. The BKK1 and BKK2 mutant mice had about 50% reductions in plasma low molecular weight kininogen and trypsin-released BK, compared to wild mice. Both BKK1 and BKK2 mice had significantly elevated systolic blood pressure compared to WT mice. These results suggest that plasma LKNG is a source of KNG in the vascular kallikrein-kinin system and contributes to maintaining lower systolic blood pressure.
Topics: Mice; Animals; Bradykinin; Hypertension; Blood Pressure; Kallikreins
PubMed: 37757669
DOI: 10.1016/j.bbrc.2023.09.059 -
Clinical and Translational Allergy Sep 2023Hereditary angioedema (HAE) with C1-inhibitor deficiency (HAE-C1-INH) is characterized by recurrent, debilitating episodes of swelling. Sebetralstat, an investigational...
BACKGROUND
Hereditary angioedema (HAE) with C1-inhibitor deficiency (HAE-C1-INH) is characterized by recurrent, debilitating episodes of swelling. Sebetralstat, an investigational oral plasma kallikrein inhibitor, demonstrated promising efficacy for on-demand treatment of HAE-C1-INH in a phase 2 trial. We describe the multipronged approach informing the design of KONFIDENT, a phase 3 randomized, placebo-controlled, three-way crossover trial evaluating the efficacy and safety of sebetralstat in patients aged ≥12 years with HAE-C1-INH.
METHODS
To determine an optimal endpoint to measure the beginning of symptom relief in KONFIDENT, we engaged patients with HAE on clinical outcome measures and subsequently conducted analyses of phase 2 outcomes. Sample size was determined via a simulation-based approach using phase 2 data.
RESULTS
Patient interviews revealed a strong preference (71%) for the Patient Global Impression of Change (PGI-C) over other measures and indicated a rating of "A Little Better" as a clinically meaningful milestone. In phase 2, a rating of "A Little Better" demonstrated agreement with attack severity improvement and resolution on the Patient Global Impression of Severity and had better sensitivity than "Better." Simulations indicated that 84 patients completing treatment would ensure at least 90% power for assessing the primary endpoint of time to beginning of symptom relief defined as a PGI-C rating of at least "A Little Better" for two time points in a row.
CONCLUSIONS
Patient feedback and phase 2 data support PGI-C as the primary outcome measure in the phase 3 KONFIDENT trial evaluating sebetralstat, which has the potential to be the first oral on-demand treatment for HAE-C1-INH attacks.
PubMed: 37746795
DOI: 10.1002/clt2.12288 -
Macromolecular Bioscience Feb 2024Factor XII (FXII) is a zymogen present in blood that tends to adsorb onto the surfaces of blood-contacting medical devices. Once adsorbed, it becomes activated,...
Factor XII (FXII) is a zymogen present in blood that tends to adsorb onto the surfaces of blood-contacting medical devices. Once adsorbed, it becomes activated, initiating a cascade of enzymatic reactions that lead to surface-induced coagulation. This process is characterized by multiple redundancies, making it extremely challenging to prevent clot formation and preserve the properties of the surface. In this study, a novel modulatory coating system based on C1-esterase inhibitor (C1INH) functionalized polymer brushes, which effectively regulates the activation of FXII is proposed. Using surface plasmon resonance it is demonstrated that this coating system effectively repels blood plasma proteins, including FXII, while exhibiting high activity against activated FXII and plasma kallikrein under physiological conditions. This unique property enables the modulation of FXII activation without interfering with the overall hemostasis process. Furthermore, through dynamic Chandler loop studies, it is shown that this coating significantly improves the hemocompatibility of polymeric surfaces commonly used in medical devices. By addressing the root cause of contact activation, the synergistic interplay between the antifouling polymer brushes and the modulatory C1INH is expected to lay the foundation to enhance the hemocompatibility of medical device surfaces.
Topics: Blood Coagulation; Factor XII; Factor XIIa; Polymers
PubMed: 37742317
DOI: 10.1002/mabi.202300321 -
Frontiers in Physiology 2023Human plasma kallikrein (PKa) is obtained by activating its precursor, prekallikrein (PK), historically named the Fletcher factor. Human PKa and tissue kallikreins are... (Review)
Review
Human plasma kallikrein (PKa) is obtained by activating its precursor, prekallikrein (PK), historically named the Fletcher factor. Human PKa and tissue kallikreins are serine proteases from the same family, having high- and low-molecular weight kininogens (HKs and LKs) as substrates, releasing bradykinin (Bk) and Lys-bradykinin (Lys-Bk), respectively. This review presents a brief history of human PKa with details and recent observations of its evolution among the vertebrate coagulation proteins, including the relations with Factor XI. We explored the role of Factor XII in activating the plasma kallikrein-kinin system (KKS), the mechanism of activity and control in the KKS, and the function of HK on contact activation proteins on cell membranes. The role of human PKa in cell biology regarding the contact system and KSS, particularly the endothelial cells, and neutrophils, in inflammatory processes and infectious diseases, was also approached. We examined the natural plasma protein inhibitors, including a detailed survey of human PKa inhibitors' development and their potential market.
PubMed: 37711466
DOI: 10.3389/fphys.2023.1188816