Acute Abdominal Pain as the Initial Presentation of an Acquired C1 Inhibitor Deficiency.

Introduction: Acquired angioedema (AAE), a rare cause of adult-onset non-urticarial mucocutaneous angioedema, can present as acute abdomen, a frequent complaint in the emergency room (ER), often leading to unnecessary and potentially harmful procedures. Case Presentation: We report a 47-year-old hypertense male, controlled with an angiotensin converting enzyme inhibitor (ACEI), who presented in the ER with progressively worsening abdominal pain, nausea, and vomiting, and a radiologic workup revealing small intestine thickening, initially diagnosed with ACEI-induced angioedema. However, further investigation revealed low serum levels of C4, C1q, and C1 inhibitors, with an abnormal function of the latter, favoring the diagnosis of AAE instead. The frequent association of this condition with lymphoproliferative disorders encouraged further studies, which unveiled a monoclonal gammopathy IgM/Kappa, representing an increased risk of Waldenström macroglobulinemia, non-Hodgkin lymphoma, and multiple myeloma. Discussion: AAE should be regarded as an important differential diagnosis in patients presenting with acute abdomen in the ER, especially when more common causes are excluded. A correct and early diagnosis may represent a chance for a better prognosis of underlying diseases.

Introdução: O angioedema adquirido (AA), causa rara de angioedema mucocutâneo não urticariforme de início tardio, pode ter como apresentação inicial abdómen agudo, motivo frequente de admissão no serviço de urgência (SU), promovendo frequentemente procedimentos desnecessários e potencialmente prejudiciais. Apresentação do caso: Um homem de 47 anos, hipertenso e controlado com um inibidor da enzima conversora de angiotensina (IECA), recorreu ao SU por um quadro de dor abdominal com agravamento progressivo, náuseas e vómitos. A investigação radiológica inicial revelou espessamento do intestino delgado, culminando num diagnóstico preliminar de angioedema induzido por IECA. No entanto, uma investigação mais aprofundada em regime ambulatório revelou níveis séricos reduzidos de C4, C1q e de inibidor de C1, com função anormal deste último, favorecendo o diagnóstico de AA. A associação frequente desta condição com distúrbios linfoproliferativos incentivou investigação adicional, que revelou uma gamopatia monoclonal IgM/Kappa, representando um risco aumentado de macroglobulinemia de Waldenström, linfoma não-Hodgkin e mieloma múltiplo. Discussão: O AA deve ser considerado um diagnóstico diferencial de abdómen agudo, principalmente após exclusão de causas mais frequentes. Um diagnóstico precoce pode contribuir para um melhor prognóstico da patologia subjacente.

Structural basis for the inhibition of ßFXIIa by garadacimab.

Activated FXII (FXIIa) is the principal initiator of the plasma contact system and can activate both procoagulant and proinflammatory pathways. Its activity is important in the pathophysiology of hereditary angioedema (HAE). Here, we describe a high-resolution cryoelectron microscopy (cryo-EM) structure of the beta-chain from FXIIa (ßFXIIa) complexed with the Fab fragment of garadacimab. Garadacimab binds to ßFXIIa through an unusually long CDR-H3 that inserts into the S1 pocket in a non-canonical way. This structural mechanism is likely the primary contributor to the inhibition of activated FXIIa proteolytic activity in HAE. Garadacimab Fab-ßFXIIa structure also reveals critical determinants of high-affinity binding of garadacimab to activated FXIIa. Structural analysis with other bona fide FXIIa inhibitors, such as benzamidine and C1-INH, reveals a surprisingly similar mechanism of ßFXIIa inhibition by garadacimab. In summary, the garadacimab Fab-ßFXIIa structure provides crucial insights into its mechanism of action and delineates primary and auxiliary paratopes/epitopes.

Extremely Late Diagnosis of Hereditary Angioedema Type I in an Elderly Female.

This case presents an instance of an extremely delayed diagnosis of hereditary angioedema (HAE) type I in an elderly female with no significant past medical history. The patient had a prolonged history of recurrent lip swelling and itchiness dating back to her teenage years, leading to multiple visits to the emergency room (ER). These recurrent episodes were characterized by random onset and accompanied by generalized pruritus and urticaria. During these ER visits, the patient would be inappropriately treated for presumed hypersensitivity reaction due to her confounding environmental allergies presenting with urticaria, complicating and significantly delaying her diagnosis. The patient was adopted, and the family history was unknown. There was no history of medication use suggestive of acquired angioedema. At the time of the visit, she had signs of chronic lip changes and atopy. After an extensive workup, it showed severely low levels of C1 esterase inhibitor and borderline low to normal C4 and C1q, consistent with the diagnosis of HAE type I. Initial treatment with an on-demand C1 esterase inhibitor reduced the recurrence of lip swelling and transitioned to long-term prophylaxis use. Overall, the treatment outcome was generally successful, with less recurrence of lip swelling and ER visits.

Successful Pregnancy Outcome in a Hereditary Angioedema Patient With Previous Pregnancy Losses: A Proposed Delivery Plan.

This case report underscores the effective implementation of a delivery plan for a pregnant patient, focusing on a successful case study where a cesarean section, preceded by the pre-treatment of intravenous plasma-derived C1 inhibitor, resulted in the delivery of a healthy baby. The proposed delivery plan offers a systematic approach to managing hereditary angioedema during pregnancy. It recommends opting for delivery at an academic center equipped with high-risk obstetric care, obstetric anesthesia, and a level 4 Neonatal Intensive Care Unit. The plan also emphasizes the importance of early admission at the onset of labor and delineates specific protocols for both vaginal and cesarean deliveries.

The Inhibition of Serine Proteases by Serpins Is Augmented by Negatively Charged Heparin: A Concise Review of Some Clinically Relevant Interactions.

Serine proteases are members of a large family of hydrolytic enzymes in which a particular serine residue in the active site performs an essential role as a nucleophile, which is required for their proteolytic cleavage function. The array of functions performed by serine proteases is vast and includes, among others, the following: (i) the ability to fight infections; (ii) the activation of blood coagulation or blood clot lysis systems; (iii) the activation of digestive enzymes; and (iv) reproduction. Serine protease activity is highly regulated by multiple families of protease inhibitors, known collectively as the SERine Protease INhibitor (SERPIN). The serpins use a conformational change mechanism to inhibit proteases in an irreversible way. The unusual conformational change required for serpin function provides an elegant opportunity for allosteric regulation by the binding of cofactors, of which the most well-studied is heparin. The goal of this review is to discuss some of the clinically relevant serine protease-serpin interactions that may be enhanced by heparin or other negatively charged polysaccharides. The paired serine protease-serpin in the framework of heparin that we review includes the following: thrombin-antithrombin III, plasmin-anti-plasmin, C1 esterase/kallikrein-C1 esterase inhibitor, and furin/TMPRSS2 (serine protease Transmembrane Protease 2)-alpha-1-antitrypsin, with the latter in the context of COVID-19 and prostate cancer.

Clinical Experience with Berotralstat in Patients with Hereditary Angioedema with Normal C1-Esterase Inhibitor: A Commented Case Series.

Hereditary angioedema (HAE) is a rare genetic disorder characterized by potentially life-threatening episodes of swelling. Most HAE cases are caused by deficient (type I) or dysfunctional (type II) C1-esterase inhibitor (C1-INH) protein. However, some patients present with a subtype of HAE that is associated with normal plasma levels of functional C1-INH protein and complement component 4 (HAE-nC1INH). Treatment of HAE-nC1INH is driven by clinical experience as robust clinical trial data to inform treatment decisions are lacking in this population. This retrospective case series assessed clinical features and treatment outcomes in 15 patients with HAE-nC1INH who initiated long-term prophylaxis with oral berotralstat 150 mg once daily as part of their disease management pathway. Most patients were female (93%), with a median age of 49 years. All patients experienced abdominal swelling attacks. On average, patients tried a mean of 4 different treatments for their HAE, including berotralstat. Although most patients associated prophylactic and on-demand medications that target the bradykinin pathway with improvements in the frequency and/or severity of attacks, treatment outcomes varied considerably between patients, highlighting the importance of a personalized approach to disease management. In this case series, berotralstat was an effective prophylactic treatment option in most patients with HAE-nC1INH. Further studies are required to demonstrate the potential efficacy, safety, and impact on quality of life of currently approved HAE therapies in patients with HAE-nC1INH.

Vision loss due to atypical bilateral edema of the optic nerve in a patient with hereditary angioedema: A case report.

PURPOSE: To describe a rare case of vision loss due to bilateral edema of the optic nerve in a patient with Hereditary Angioedema, treated with prophylactic C1-esterase inhibitor. METHODS: A 60-year-old Caucasian male affected by Hereditary Angioedema with unknown genetic defect (HAE- UNK) was admitted to our hospital presenting bilateral vision loss (best corrected visual acuity of 20/32 in the right eye and hand motion in the left eye) during an HAE attack. Intravenous administration of C1- esterase inhibitor (C1-INH, 1500 IU, Berinert, CSL Behring) determined the resolution of facial and periorbital swelling, however visual impairment persisted, in contrast with previous attacks experienced by the patient. Fundus examination revealed a vital optic disc without papilledema in both eyes. Magnetic resonance imaging (MRI) of the head and orbits showed bilateral edema of the optic nerve sheath. Treatment with intravenous and oral steroids was ineffective. Subsequently, a prophylactic treatment strategy with subcutaneous C1-esterase inhibitor was started (7000 IU every four days). RESULTS: Complete regression of edema of the optic nerves was observed by imaging at two months of follow-up after chronic treatment with C1-esterase inhibitor (7000 IU every four days). Complete restoration of visual acuity was achieved (BCVA 20/20 in both eyes) and multimodal imaging of the optic nerves demonstrated the absence of anatomical and functional damage. CONCLUSION: Patients affected by HAE may show atypical presentation with edema of the optic nerves without involvement of the optic nerve head. They may significantly benefit from prophylactic and chronic treatment with C1-esterase inhibitor.

Uncovering the true burden of hereditary angioedema due to C1-inhibitor deficiency: A focus on the Asia-Pacific region.

Hereditary angioedema (HAE) due to C1-inhibitor deficiency or dysfunction is a rare genetic disorder that causes recurrent episodes of swelling in various parts of the body. Treatment goals of HAE aim to "normalize" life for all patients; however, lack of diagnostic facilities and limited access to effective treatment options in developing nations cause delays in diagnosis and place a significant burden on patients. In this review, we aim to highlight the burden of disease caused by C1-inhibitor HAE across the Asia-Pacific region, considering its epidemiology, morbidity and mortality, and socioeconomic and psychological impact. We also review the availability of guideline-recommended diagnostic facilities and treatments, and how patients are currently managed. Data were collected from published literature and HAE experts in the region, who provided information regarding diagnosis and management in their countries. Current practice was reviewed against international guidelines, as well as local guidelines/consensus used in Australia, Japan, and China. Suggestions are provided for improving the time to diagnosis in the region, increasing access to guideline-recommended treatments, and providing support to reduce the burden on patients and caregivers. There is an urgent need to improve HAE services and provide access to life-saving treatment in developing countries, and efforts should be made to increase awareness of guideline recommendations in high-income economies that do not currently provide long-term prophylactic treatments.

Tackling the Root Cause of Surface-Induced Coagulation: Inhibition of FXII Activation to Mitigate Coagulation Propagation and Prevent Clotting.

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.

Patient-level indirect treatment comparison of lanadelumab versus pdC1-INH i.v. in hereditary angioedema patients: PATCH study.

BACKGROUND: Hereditary angioedema (HAE) is an autosomal dominant inherited disease in which patients suffer from local attacks primarily affecting skin and gastrointestinal tract, and sometimes even the upper respiratory tract leading to asphyxiation. Since head-to-head trials between authorized treatments are lacking, this study compares efficacy and safety of lanadelumab and intravenous plasma-derived C1-esterase inhibitor (pdC1-INH i.v.) in HAE patients on long-term prophylaxis by means of an indirect treatment comparison. METHODS: Efficacy and safety of lanadelumab against pdC1-INH i.v. were analyzed in a fully prespecified indirect comparison based on individual patient data (n = 231) from the HELP and CHANGE clinical trials. Primary and secondary efficacy endpoints were compared using a generalized linear model for count data. Confounding variables were identified a priori via systematic literature research and validated by clinical experts. Adjustment of confounders was implemented using a conditional regression model. RESULTS: Lanadelumab showed a statistically significant improvement in reduction of HAE attack rates compared to pdC1-INH i.v. across multiple endpoints: Monthly attack rate of patients treated with lanadelumab was less than half compared to pdC1-INH i.v. (Rate ratio: 0.486; 95% CI: 0.253, 0.932). Monthly rate of laryngeal attacks was found to be five times lower for lanadelumab (Rate ratio: 0.2; 95% CI: 0.044, 0.915) and monthly rate of acute treated HAE attacks among lanadelumab patients was about one third of the attack rate of pdC1-INH i.v. patients (Rate ratio: 0.366; 95% CI: 0.185, 0.727). CONCLUSION: This study contributes to current knowledge in the treatment of HAE by indicating a statistically significant reduction of HAE attacks under lanadelumab compared to pdC1-INH i.v.

Recombinant C1 inhibitor in the prevention of severe COVID-19: a randomized, open-label, multi-center phase IIa trial.

Background: Conestat alfa (ConA), a recombinant human C1 inhibitor, may prevent thromboinflammation. Methods: We conducted a randomized, open-label, multi-national clinical trial in which hospitalized adults at risk for progression to severe COVID-19 were assigned in a 2:1 ratio to receive either 3 days of ConA plus standard of care (SOC) or SOC alone. Primary and secondary endpoints were day 7 disease severity on the WHO Ordinal Scale, time to clinical improvement within 14 days, and safety, respectively. Results: The trial was prematurely terminated because of futility after randomization of 84 patients, 56 in the ConA and 28 in the control arm. At baseline, higher WHO Ordinal Scale scores were more frequently observed in the ConA than in the control arm. On day 7, no relevant differences in the primary outcome were noted between the two arms (p = 0.11). The median time to defervescence was 3 days, and the median time to clinical improvement was 7 days in both arms (p = 0.22 and 0.56, respectively). Activation of plasma cascades and endothelial cells over time was similar in both groups. The incidence of adverse events (AEs) was higher in the intervention arm (any AE, 30% with ConA vs. 19% with SOC alone; serious AE, 27% vs. 15%; death, 11% vs. 0%). None of these were judged as being related to the study drug. Conclusion: The study results do not support the use of ConA to prevent COVID-19 progression. Clinical trial registration: https://clinicaltrials.gov, identifier NCT04414631.

Could it be hereditary angioedema?-Perspectives from different medical specialties.

Hereditary angioedema (HAE) is a rare autosomal dominant disease, with patients often suffering with associated symptoms for many years before receiving a correct diagnosis. The symptoms greatly impact a patient's quality of life (QoL) and include excruciating abdominal pain and angioedema of the skin and submucosa. Angioedema of the larynx represents a significant mortality risk in undiagnosed patients, and a large proportion of patients with HAE receive incorrect diagnoses and undergo unnecessary surgery. HAE-specific treatments can control and prevent acute life-threatening episodes, in addition to improving QoL, emphasizing the value of early diagnosis for patients. Diagnostic delay may be due to a lack of HAE awareness by healthcare professionals and the similarity of HAE symptoms with those of more common conditions, complicating differential diagnosis. The multifaceted nature of the condition may result in visits to one of many different medical settings, for example: the Emergency Room, pediatrics, general practice, otolaryngology, gastroenterology, and dermatology. Therefore, it is crucial that physicians in multiple healthcare specialties are aware of the disease to ensure that patients with HAE receive a timely diagnosis. Using patient cases from various medical specialties, this review highlights the necessity for cross-specialty awareness of HAE and outlines the essential information for the various healthcare professionals that may encounter a patient with HAE symptoms, in order to effectively treat and/or diagnose HAE.

The Price of a Life: Unveiling the Struggle of Living With Hereditary Angioedema.

Hereditary angioedema (HAE) is a rare, potentially life-threatening genetic condition characterized by recurrent episodes of localized swelling in various body tissues. Despite advancements in the management and prevention of HAE, high costs limit accessibility to these medications and remain a significant hurdle for many patients. This case report illustrates the implications and life-threatening consequences of the affordability crisis associated with HAE medications. To the authors' knowledge, this case also highlights the first reported case of cocaine serving as an HAE trigger.

Hereditary Angioedema.

The authors present the case of a 22-year-old female who reported having a persistent sore throat. The patient had a history of recurring episodes of hereditary angioedema and arrived at the emergency department with her C1-esterase inhibitor. The epidemiology, clinical presentation, and treatment strategies are presented.

Managing Diagnosis, Treatment, and Burden of Disease in Hereditary Angioedema Patients with Normal C1-Esterase Inhibitor.

Hereditary angioedema (HAE) is a rare, chronic, and debilitating genetic disorder characterized by recurrent and unpredictable swelling episodes that primarily affect the subcutaneous and/or submucosal tissues of the extremities, larynx, face, abdomen, and genitals. Most cases of HAE are caused by mutations in the serpin family G member 1 gene (SERPING1), which encodes C1-esterase inhibitor (C1-INH) protein. Mutations in SERPING1 lead to deficient (type I HAE-C1-INH) or dysfunctional (type II HAE-C1-INH) C1-INH protein and subsequent dysregulation of the kallikrein-bradykinin cascade. However, some patients present with a third type of HAE (HAE-nI-C1-INH), which was first described in the year 2000 and is characterized by an absence of mutations in SERPING1. Although mutations in the coagulation factor XII, angiopoietin-1, plasminogen, kininogen-1, myoferlin, and heparan sulfate-glucosamine 3-O-sulfotransferase-6 genes have been identified in some patients with HAE-nI-C1-INH, genetic cause is still unknown in many cases, hindering full elucidation of the pathology of this HAE subtype. Diagnosis of HAE-nI-C1-INH is also further complicated by the fact that patients typically demonstrate normal plasma levels of C1-INH and complement component 4 protein and normal C1-INH functionality during laboratory analysis. Therefore, we review the challenges associated with diagnosing, treating, and living with HAE-nI-C1-INH. We conclude that raising awareness of the presenting features of HAE-nI-C1-INH within the clinical setting and among the general public is critical to aid earlier suspicion and diagnosis of the disease. Furthermore, adopting an individualized approach to HAE-nI-C1-INH treatment is essential to help address the current and significant unmet needs in this patient population.

Hereditary angioedema in cardiac surgery: Perioperative management considerations for a rare disease.

INTRODUCTION: Hereditary Angioedema is a rare disease caused by C1 esterase inhibitor deficiency leading to diffuse and potentially life-threatening oedema formation. Preventing attacks is critical, particularly for patients undergoing cardiac surgery. CASE REPORT: We report a case of a 71-years-old woman with a history of Hereditary Angioedema scheduled for open-heart surgery on Cardiopulmonary Bypass. Multidisciplinar teamwork and patient-targeted strategy were crucial to obtain a favorable outcome. DISCUSSION: Cardiac surgery is a major stressor for Angioedema attacks because of Complement cascade and inflammatory response activation leading to potential life-threatening oedema formation. In literature only few cases of complex open heart surgery under Cardiopulmonary Bypass are described. CONCLUSION: Continuous updating and multidisciplinarity are key elements to manage patients with Hereditary Angioedema in cardiac surgery in order to reduce morbidity and mortality.

Hereditary Angioedema with Normal C1 Esterase Inhibitor Refractory to Long-Term Prophylaxis: A Case Report.

Hereditary angioedema (HAE) was classically thought to be related to a deficiency in the C1 esterase inhibitor (C1-INH). However, HAE with a normal C1 esterase inhibitor (HAE nC1-INH) is a rare disease that has been recently characterized. In this case, we describe a woman with a 21-year history of angioedema who, in the last two years, has experienced severe exacerbations that led to the formal diagnosis of HAE nC1-INH. The patient has been treated with current HAE long-term prophylaxis (LTP) and on-demand therapies but is still experiencing severe, frequent attacks. Our case describes the timeline of this patient's presentation and provides valuable insight into the presentation and management of HAE nC1-INH.

Immunogenicity and Safety of Anti-SARS-CoV-2 mRNA Vaccines in a Cohort of Patients with Hereditary Angioedema.

Many factors may trigger hereditary angioedema (HAE) attacks. This study aims to gain insights into the benefits and potential risks of COVID-19 vaccination in HAE patients, focusing particularly on the possibility of triggering attacks. We enrolled 31 patients with HAE undergoing two doses of the SARS-CoV-2 mRNA Comirnaty-BioNTech/Pfizer vaccine. To evaluate the possible influence of the vaccine on disease control and attack frequency, we administered the angioedema control test (AECT) 4-week version before (T0), 21 days after the first dose (T1), and between 21 and 28 days after the second dose (T2). Despite 5 patients (16.1%) experiencing attacks within 72 h of the first dose administration, no significant variation in attack frequency was observed before and after vaccination [F(2,60) = 0.123; p = 0.799]. In addition, patients reported higher AECT scores at T1 and T2 compared to T0 [F(2,44) = 6.541; p < 0.05; post hoc p < 0.05)], indicating that the disease was rather more controlled after vaccinations than in the previous period. All patients showed a positive serological response to the vaccine without significant differences from healthy controls (U = 162; p = 0.062). These observations suggest that the vaccine administration is safe and effective in HAE patients.