C1 Esterase Inhibitor Deficiency Research Articles

A mechanistic model of in vitro plasma activation to evaluate therapeutic kallikrein-kinin system inhibitors.

The kallikrein-kinin system (KKS) is a complex biochemical pathway that plays a crucial role in regulating several physiological processes, including inflammation, coagulation, and blood pressure. Dysregulation of the KKS has been associated with several pathological conditions such as hereditary angioedema (HAE), hypertension, and stroke. Developing an accurate quantitative model of the KKS may provide a better understanding of its role in health and disease and facilitate the rapid and targeted development of effective therapies for KKS-related disorders. Here, we present a novel, detailed mechanistic model of the plasma KKS, elucidating the processes of Factor XII (FXII) activation, the kallikrein feedback loop, cleavage of high molecular weight kininogen leading to bradykinin (BK) production, and the impact of inhibitors. The model incorporates both surface and solution-phase reactions of all proteins in the KKS, describing how binding site concentration affects the rate of surface reactions. The model was calibrated and validated using a variety of published and in-house experimental datasets, which encompass a range of dextran sulphate (DXS) concentrations to initiate contact activation and various KKS inhibitors to block bradykinin production. Our mathematical model showed that a trace amount of activated FXII is required for subsequent FXII activation. The model also reveals a bell-shaped curve relationship between the activation of the KKS and the number of DXS surface binding sites. Simulations of BK generation in healthy and HAE plasma demonstrated the impact of C1 esterase inhibitor (C1inh) deficiency via increased peak BK levels and accelerated formation in HAE plasma. The efficacy of KKS inhibitors, such as CSL312, ecallantide, and C1inh, was also evaluated, with CSL312 showing the most potent inhibition of BK generation. The present model represents a valuable framework for studying the intricate interactions within the plasma KKS and provides a better understanding of the mechanism of action of various KKS-targeted therapies.

Prolonging the circulatory half-life of C1 esterase inhibitor via albumin fusion.

Hereditary Angioedema (HAE) is an autosomal dominant disease characterized by episodic swelling, arising from genetic deficiency in C1-esterase inhibitor (C1INH), a regulator of several proteases including activated Plasma kallikrein (Pka). Many existing C1INH treatments exhibit short circulatory half-lives, precluding prophylactic use. Hexahistidine-tagged truncated C1INH (trC1INH lacking residues 1-97) with Mutated N-linked Glycosylation Sites N216Q/N231Q/N330Q (H6-trC1INH(MGS)), its murine serum albumin (MSA) fusion variant (H6-trC1INH(MGS)-MSA), and H6-MSA were expressed in Pichia pastoris and purified via nickel-chelate chromatography. Following intravenous injection in mice, the mean terminal half-life of H6-trC1INH(MGS)-MSA was significantly increased versus that of H6-trC1INH(MGS), by 3-fold, while remaining ~35% less than that of H6-MSA. The extended half-life was achieved with minimal, but significant, reduction in the mean second order rate constant of Pka inhibition of H6-trC1INH(MGS)-MSA by 33% relative to that of H6-trC1INH(MGS). Our results validate albumin fusion as a viable strategy for half-life extension of a natural inhibitor and suggest that H6-trC1INH(MGS)-MSA is worthy of investigation in a murine model of HAE.

Hereditary Angioedema in Pregnancy: A Case Report and Review of Obstetric Anesthesia Management.

Hereditary angioedema (HAE) is a rare disorder due to C1 esterase inhibitor deficiency, causing recurrent swelling. Pregnancy can exacerbate HAE due to estrogen fluctuations alongside peripartum stress and trauma. We present a pregnant patient with HAE who underwent induction of labor and vaginal delivery with neuraxial anesthesia. Management included C1-inhibitor prophylaxis, 48 hours of postpartum monitoring, and a self-treatment plan at discharge. Angioedema prevention involves timely anesthesia consultation, accessible emergency airway equipment, early neuraxial anesthesia, planned vaginal delivery, and 48 to 72 hours of close postpartum monitoring. Readily available C1-inhibitor and a multidisciplinary approach with these recommendations are crucial for peripartum management.

Long term outcome of C1-esterase inhibitor deficiency.

Hereditary angioedema (HAE) is a rare hereditary disorder characterized by episodic swelling and life-threatening airway obstruction caused by laryngeal angioedema. In most HAE patients, reduced level of serum C1-Inhibitor (type-I-HAE) or presence of aberrant C1-Inhibitor (type-II-HAE) result in the lost of regulation of the complementary system and contact activation system with downstream over-activation of bradykinin - the chief mediator leading to angioedema. Type-III HAE (HAE-nl-C1INH) is rare without deficient or dysfunction of C1-Inhibitor, often with genetic aberrant related to the contact activation system. The prevalence of HAE in the population is estimated at 1 in 50,000 individuals, often with early onset, but due to the heterogeneity of the disease, there is frequently a significant delay in diagnosis. Recently, better awareness by physicians, more access to diagnostic tools, better management and prophylaxis has decreased morbidity and mortality. A focus in HAE patient care shift from management of attacks with on-demand medication, to use of prophylaxis to reduce attacks has improved the overall quality of life of patients with HAE. One area in HAE research that has not been emphasized is the long-term consequence of C1-INH deficiency in HAE patients, other than the typical manifestations of HAE, as evidence have emerged linking this disorder with increased risk of cardiovascular diseases, auto-immune disorders, and malignancy. This review aims to gather the current knowledge and evidence of potential consequence of C1-Inhibitor deficiency in HAE aside from angioedema with emphasis in the improvement of long-term care and overall quality of life for HAE patients.

Determinants of Disease Activity in Adults With Hereditary Angioedema due to C1-Esterase Inhibitor Deficiency.

Determinants of Disease Activity in Adults With Hereditary Angioedema due to C1-Esterase Inhibitor Deficiency.

Physician- and patient-reported outcomes by hereditary angioedema type: Data from a real-world study.

Background: Hereditary angioedema (HAE) is a rare genetic condition characterized by painful and often debilitating swelling attacks. Little is known about the differences in outcomes between patients with HAE types I or II (type I: HAE caused by C1 esterase inhibitor deficiency; type II: HAE caused by C1 esterase inhibitor dysfunction), with decreased or dysfunctional C1 esterase inhibitor (C1-INH), and those with normal C1-INH (nC1-INH-HAE). Objective: To compare physician- and patient-reported real-world outcomes in patients with HAE types I/II versus patients with nC1-INH-HAE. Methods: Data were drawn from the Adelphi HAE Disease Specific ProgrammeTM a real-world, cross-sectional survey of HAE-treating physicians and their patients in the United States conducted between July and November 2021. Physicians reported patient disease activity and severity, and recent attack history. Patient-reported outcomes were collected. Bivariate tests used were either the Student's t-test, the Fisher exact test, or Mann-Whitney U test. Results: Physicians (N = 67) provided data on 368 patients (92.4% HAE types I/II and 7.6% nC1-INH-HAE). Physicians reported that a higher proportion of patients with nC1-INH-HAE had moderate or high disease activity and moderate or severe disease severity both at diagnosis and at data collection versus those with HAE types I/II. Patients with nC1-INH-HAE versus patients with HAE types I/II experienced increased attack severity (34.6% versus 4.4%) and hospitalization rate during the most recent attack (39.3% versus 6.6%), and reported lower health status and quality of life, via the European Quality of Life 5 Dimension 5 Level (US tariff) and Angioedema Quality of Life, respectively. On average, 25% of the patients with nC1-INH-HAE reported absenteeism and work or activity impairment due to HAE compared with 2.7% of patients with HAE types I/II. Both patient groups reported improvements in disease activity and severity from diagnosis to the time of data collection. Conclusion: These real-world findings suggest that patients with nC1-INH-HAE have increased disease activity and severity, and experience greater impairment to their quality of life, work, and daily functioning than patients with HAE types I/II. Powered statistical analyses are required to confirm these findings.

Analysis of the relationship between genetic mutation, clinical manifestations and prognosis in hereditary angioedema: scoping review protocol

Hereditary Angioedema (HAE) is a rare and severe genetic autosomal dominant disease of the immune system, caused by a deficiency of C1 esterase inhibitor (C1-INH). Classified into 3 subtypes: HAE with quantitative deficiency of the C1-INH inhibitor, C1-INH dysfunction, and normal C1-INH.The objective is to present a protocol examining the evidence on the relationship between mutations, clinical manifestations and prognosis in AEH. A systematic review will be conducted according to the steps: formulation of the clinical question (PICO), protocol with inclusion and exclusion criteria, conduction of a broad bibliographical search, extraction and summary of the included studies. This systematic review will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Evidence will be obtained from the Pubmed, Embase, Web of Science and Scopus databases in the last 10 years. The selection of descriptors will be conducted using the Health Sciences Descriptors (DeCs), with the Boolean operators “AND and OR”, which will result in a search strategy for each proposed database. The selection will be conducted by two independent reviewers based on pre-determined criteria. In case of any discrepancy between the two reviewers, a third reviewer will mediate the conflict. Each study included will be assessed using the ROBINS-I, for the risk of bias, following the Oxford Evidence Base Center level of evidence and recommendation. Kappa Statistic will be used to assess inter-rater reliability. This systematic review will allow a greater understanding of HAE, and provide scientific evidence for healthcare professionals involved in the diagnosis and treatment of this disease.

Evolution of Guidelines for the Management of Hereditary Angioedema due to C1 Inhibitor Deficiency.

Hereditary angioedema (HAE) is a severe and disabling condition characterized by recurrent episodes of subcutaneous or mucosal swelling in the skin and respiratory and gastrointestinal tracts. HAE due to C1-esterase inhibitor deficiency (C1-INH-HAE) is the most prevalent subtype. The present Iberian study compared C1-INH-HAE treatment guidelines published between 2010 and 2022 to identify the main differences in therapeutic approaches for on-demand treatment and short- and long-term prophylaxis (LTP). HAE guidelines evolved with the availability of new treatments and with a change in the management paradigm towards an individualized, patient-centered approach, where quality of life (QOL) is central. A parallel trend was observed towards increasingly frequent home-based treatment, which potentially facilitates timely interventions, provides greater flexibility and convenience, and is associated with increased QOL, enabling patients to lead more normal lives. Most innovations over the years were made for LTP, together with the advent of new therapies and awareness of patients' needs. Several prophylactic therapies with a high level of evidence became available, although formal head-to-head comparisons are lacking. The treatment goals became more ambitious, ranging from a reduction in the frequency, severity, and duration of attacks to achieving total disease control and normalization of patients' lives. The document also addresses relevant items such as changes in terminology (eg, the introduction of designations as "first-line") and the introduction of patient-reported outcome measures to assess patients' perceptions of their self-experienced QOL and well-being. Unmet needs in the management of C1-INH-HAE are identified.

STAR-0215 is a Novel, Long-Acting Monoclonal Antibody Inhibitor of Plasma Kallikrein for the Potential Treatment of Hereditary Angioedema.

Hereditary angioedema (HAE) is a rare autosomal dominant disorder caused by a deficiency in functional C1 esterase inhibitor (C1-INH), a serpin family protein that blocks the activity of plasma kallikrein. Insufficient inhibition of plasma kallikrein results in the overproduction of bradykinin, a vasoactive inflammatory mediator that produces both pain and unpredictable swelling during HAE attacks, with potentially life-threatening consequences. We describe the generation of STAR-0215, a humanized immunoglobulin G1 (IgG1) antibody with a long circulating half-life (t1/2) that potently inhibits plasma kallikrein activity, with a >1000-fold lower affinity for prekallikrein and no measurable inhibitory activity against other serine proteases. The high specificity and inhibitory effect of STAR-0215 is demonstrated through a unique allosteric mechanism involving N-terminal catalytic domain binding, destabilization of the activation domain, and reversion of the active site to the inactive zymogen state. The YTE (M252Y/S254T/T256E) modified fragment crystallizable (Fc) domain of STAR-0215 enhances pH-dependent neonatal Fc receptor (FcRn) binding, resulting in a prolonged t1/2 in vivo (⁓34 days in cynomolgus monkeys) compared to antibodies without this modification. A single subcutaneous dose of STAR-0215 ({greater than or equal to} 100 mg) was predicted to be active in patients for 3 months or longer, based on simulations using a minimal physiologically based pharmacokinetic (mPBPK) model. These data indicate that STAR-0215, a highly potent and specific antibody against plasma kallikrein with extended t1/2, is a potential agent for long-term preventative HAE therapy administered every 3 months or less frequently. Significance Statement STAR-0215 is a YTE-modified immunoglobulin G1 monoclonal antibody with a novel binding mechanism that specifically and potently inhibits the enzymatic activity of plasma kallikrein and prevents the generation of bradykinin. It has been designed to be a long-lasting prophylactic treatment to prevent attacks of HAE and to decrease the burden of disease and the burden of treatment for people with HAE.

A Comprehensive Management Approach in Pediatric and Adolescent Patients With Hereditary Angioedema.

Hereditary angioedema (HAE) is a rare autosomal-dominant disorder; most cases are characterized by low plasma levels of C1 esterase inhibitor (C1-INH). Clinical manifestations of HAE due to C1-INH deficiency include unpredictable, acute, recurrent episodes of nonpruritic swelling that can affect the face, trunk, limbs, and the respiratory, gastrointestinal, and genitourinary tracts. Attacks can be disfiguring, disabling, painful, and even life-threatening if laryngeal swelling occurs. Symptoms of HAE generally manifest in childhood. Effective medications are available and approved to treat HAE in children. However, evidence informing use of these medications in pediatric clinical practice is limited. Hereditary angioedema management plans are critical to optimize outcomes and should address on-demand treatment for acute attacks and plans to prevent potentially fatal laryngeal attacks. The plan should also comprise a holistic approach to address nonclinical aspects of HAE, including quality of life (QoL) and psychological issues. This article provides an overview of HAE management principles that health care providers can apply to treat pediatric patients to improve their QoL.

Burden of illness seen in hereditary angioedema in Japanese patients: Results from a patient reported outcome survey.

Hereditary angioedema (HAE) is a potentially life-threatening rare disease, which is mainly caused by the deficiency or dysfunction of C1-esterase inhibitor, and characterized by spontaneous, recurrent episodes of edema in various parts of the body including internal organs and the laryngeal area. Delayed diagnosis and treatment increase the burdens and risks of this condition. The current study aimed to understand the burden of illness for HAE patients in Japan before and after diagnosis through a patient reported outcome survey. A survey instrument was distributed to 121 adult patients with HAE by a patient organization via HAE treating physicians between July and November in 2016. Seventy patients (57.9%) returned the questionnaire. Patients reported high levels of medical resource utilization, including emergency procedures and services. Episodes of receiving laparotomy were somewhat less after diagnosis with HAE than before, but no apparent difference in episodes of tracheotomy between before and after the diagnosis. The economic burden, including direct and indirect medical costs, was highest before diagnosis, but still perceived as substantial after diagnosis. Patients reported disruption of work and school life, with 40% reporting that they miss 10 or more days from work or education per year. Sixty percent of patients reported that HAE affected their daily activities. We concluded that HAE is associated with considerable physical, social, economic and psycho-social burdens even after diagnosis, and that higher attack frequency is associated with a heavy disease burden for patients in Japan.

Analysis of the Association of Allergic Disease in Pediatric Patients with Hereditary Angioedema

Hereditary angioedema (HAE) is a rare autosomal dominant disease that is derived from the deficiency or dysfunction of C1 esterase inhibitor (C1-INH). In studies about the diseases that can accompany hereditary angioedema, allergic diseases occur more frequently compared to the healthy population but no studies on this issue have been carried out. This study was conducted in order to determine the frequency of the comorbidity of atopic sensitivity and allergic diseases in patients with hereditary angioedema. 32 patients who were diagnosed with hereditary angioedema in the Paediatric Allergy Polyclinic of Mersin City Hospital between 2019 and 2021 were included in the study. In these patients, the information about the existence of atopic diseases was obtained from their files and recorded. While asthma was observed in 6 (18.8%), allergic rhinitis in 18 (46.9%), and urticaria in 2 (6.2%) patients, dermatitis was not observed in any of the patients. While Fx5 test was positive in 5 (15.6%) patients, inhalant allergen mix sps IgE was positive in 7 (25.9%) patients. The IgE value was above 100 in 12 (52.2%) patients, and the eosinophil level was above 4% in 16 (50%) patients. In conclusion, we speculate in this study that the association of atopic disease and atopic sensitivity is observed more frequently in patients with angioedema than in the healthy population. However, a study with a larger sample is necessary to confirm this finding.

New medications to mitigate attacks of hereditary angioedema: does one size fit all?

Hereditary angioedema has received renewed attention in the past two decades, with the elucidation of the biochemical pathways resulting in bradykinin overproduction in patients with congenital C1esterase inhibitor (C1INH) deficiency, leading to recurrent attacks of tissue swelling due to uncontrolled vascular permeability. 1 Busse PJ Christiansen SC Hereditary angioedema. N Engl J Med. 2020; 382: 1136-1148 Crossref PubMed Scopus (132) Google Scholar Oedema attacks affecting the lingual or laryngeal area can become lethal as a result of asphyxiation. 2 Minafra FG Gonçalves TR Alves TM Pinto JA The mortality from hereditary angioedema worldwide: a review of the real-world data literature. Clin Rev Allergy Immunol. 2022; 62: 232-239 Crossref PubMed Scopus (4) Google Scholar Several new treatments have emerged, 143 years after Quincke's first description of hereditary angioedema and 15 years after the introduction of the first specific bradykinin B2 receptor inhibitor (icatibant). These drugs specifically target crucial steps in the kallikrein–kinin (contact) cascade downstream of bradykinin production. 3 Fijen LM Bork K Cohn DM Current and prospective targets of pharmacologic treatment of hereditary angioedema types 1 and 2. Clin Rev Allergy Immunol. 2021; 61: 66-76 Crossref PubMed Scopus (0) Google Scholar Many of these agents have shown their efficacy and safety in acute (on-demand) treatment and prophylaxis of hereditary angioedema attacks, saving lives and revolutionising patients’ quality of life. 4 Lumry WR Settipane RA Hereditary angioedema: epidemiology and burden of disease. Allergy Asthma Proc. 2020; 41: S08-S Crossref Google Scholar These modalities fit well into the modern paradigm in hereditary angioedema treatment, supporting patients’ autonomy, recommending self-administration, and reducing reliance on hospital emergency rooms, health-care providers, and medical points of care. 5 Maurer M Magerl M Betschel S et al. The international WAO/EAACI guideline for the management of hereditary angioedema—the 2021 revision and update. Allergy. 2022; 77: 1961-1990 Crossref PubMed Scopus (32) Google Scholar An investigational oral plasma kallikrein inhibitor for on-demand treatment of hereditary angioedema: a two-part, randomised, double-blind, placebo-controlled, crossover phase 2 trialOral administration of sebetralstat was well tolerated and led to rapid suppression of plasma kallikrein activity, resulting in increased time to use of conventional attack treatment and faster symptom relief versus placebo. Based on these results, a phase 3 trial to evaluate the efficacy and safety of two dose levels of sebetralstat in adolescent and adult participants with hereditary angioedema has been initiated ( NCT05259917 ). Full-Text PDF

Diagnostic value of copy number identification of the SERPING1 gene in patients with different types of hereditary angioedema associated with C1-esterase inhibitor deficiency

Diagnostic value of copy number identification of the SERPING1 gene in patients with different types of hereditary angioedema associated with C1-esterase inhibitor deficiency

The validity and reliability of a Thai version of the Angioedema Control Test: Which recall period is preferable?

The Angioedema Control Test (AECT) is a questionnaire that monitors disease control in patients with angioedema, with a recall period of 4 weeks (AECT-4wk) or 3 months (AECT-3mo). This study investigated the psychometric properties of a Thai version of the AECT. Of 54 patients, 46, 5, 2, and 1 had recurrent angioedema with chronic spontaneous urticaria, hereditary angioedema, idiopathic histaminergic angioedema, and acquired angioedema due to C1 esterase inhibitor deficiency, respectively. The AECT, Angioedema Activity Score (AAS), Dermatology Life Quality Index (DLQI), Angioedema Quality of Life Questionnaire (AE-QoL), and anchors for disease control (numeric rating scale [NRS] and patient global assessment-Likert scale [PatGA-LS]) were used. The patients rated the efficacy of their treatment. Fifty-four and 47 patients completed the AECT-4wk and AECT-3mo, respectively. Both AECT versions showed significant correlations with disease activity (AAS, r = 0.6-0.8), disease control (NRS and PatGA-LS, r = 0.7-0.9), and quality of life impairment (DLQI and AE-QoL, r = 0.6-0.8). Higher correlations were found for the AECT-4wk than for the AECT-3mo. Excellent internal consistency (alpha = 0.98 and 0.97, respectively) and intraclass correlation (0.96 and 0.94, respectively) were found. A cutoff ≥ 10 was confirmed to identify patients with well-controlled disease for both AECT versions (AUCs = 0.89 and 0.97). The Thai version of the AECT is a valid and reliable tool for clinical practice. Due to the shorter recall period, the AECT-4wk may be more accurate than, and preferable to, the AECT-3mo. A cutoff ≥ 10 should be used to identify patients with well-controlled disease.

HPR131 Benefit Package of Universal Coverage Scheme for Hereditary Angioedema (HAE) Caused by C1 Esterase Inhibitor Deficiency (C1-INH)

HPR131 Benefit Package of Universal Coverage Scheme for Hereditary Angioedema (HAE) Caused by C1 Esterase Inhibitor Deficiency (C1-INH)

PD50 Value Of Healthcare Journey For Patients With Rare Diseases In The Brazilian Public Healthcare System: Methods And Preliminary Results

IntroductionImplementing value-based healthcare (VBHC) services requires the ability to assess and integrate evolution of patient-centered outcomes (PCO), clinical/epidemiological data and resource consumption. Aligned with Porter’s framework of value, the “Value of Healthcare Journey for Patients With Rare Diseases Project” (JAV-RARAS) was implemented to evaluate the value of the healthcare journey of patients with rare diseases (RD) in the Brazilian Public Healthcare System (SUS). The goal of this project is to identify the value (clinical outcomes and costs) associated with the management of RD in the SUS.MethodsPatients diagnosed with eight pre-defined RD under active clinical follow-up in SUS medical centers were invited. Retrospective data on diagnosis and assistance carried out after diagnosis were collected from medical records. Prospective follow-up of one year will be collected through validated clinical questionnaires on three visits, with an average interval of 6 months. Clinical outcomes include exams and disease-specific features, quality of life, productivity loss, treatment adherence and satisfaction. Total cost of patient’s journey in each medical center will be assessed through Time-Driven Activity-Based Costing method. All data collection is being carried out through the Think Patient Value (TPValue®), a computerized management support system, based on Porter’s paradigm of value.ResultsThirty-five medical centers currently assisting patients with RD were enrolled, representing all macro-regions in Brazil: Midwest (n=4), North (n=5), Northeast (n=10), South (n=5) and Southeast (n=11). Recruitment started in March, and until November 2021, 28 centers had reported retrospective data of at least one RD. So far, JAV-RARAS recruited patients with osteogenesis imperfecta (number of patients=106), phenylketonuria (n=52), familial amyloidotic polyneuropathy (n=32), classical homocystinuria (n=25), Prader–Willi syndrome (n=30), acromegaly (n=33), hereditary angioedema associated with C1 esterase-inhibitor deficiency (n=42) and mucopolysaccharidosis type-II (n=17).ConclusionsFuture results of JAV-Raras real-world evidence study will bring PCO and costs according to Porter’s Value, bringing insights for decision-makers in SUS. This study was funded by National Council for Scientific and Technological Development –CNPq and Ministry of Health of Brazil –MoH.

EE681 Costs of Treating Acute Hereditary Angioedema (HAE) Attacks With C1 Inhibitors in Five Central and Eastern European Countries

Hereditary angioedema (HAE) is a rare genetic disease caused by the deficiency or dysfunction of C1 esterase inhibitor (C1-INH), and characterized by recurring episodes of severe swelling, which can be life-threatening. Frequency and severity of attacks vary. Replacement C1-INH therapies provide effective relief; however, there is a lack of comparative data on economic outcomes in Central and Eastern European countries (CEE).

C1 Inhibitor Deficiency Results in Increased Activation of Coagulation and Enhanced Venous Thrombosis

Introduction: C1 esterase inhibitor (C1INH) is a broad acting serine protease inhibitor that functions as a major endogenous inhibitor of activated factor (F) XII, FXI and kallikrein of the contact system. Congenital deficiency for C1INH results in hereditary angioedema (HAE) that can cause potentially life-threatening episodes of bradykinin induced swelling. Patients with HAE have increased circulating markers of activation of coagulation, however, the effect of this procoagulant state on thrombosis remains unclear. Methods: Contact pathway triggered thrombin generation was assessed in citrated plasma from patients with HAE (n=19) or age and sex matched healthy controls (n=20) using calibrated automated thrombography. The association between HAE and risk of composite arterial thromboembolism (ATE) and composite venous thromboembolism (VTE) was analyzed in a registry-based study of HAE patients (n=239) and age and sex matched controls (n=2383) with data analyzed by conditional logistic regression. Markers of activation of coagulation were measured in the plasma of C1INH deficient mice or wildtype littermate controls. C1INH deficient mice or wildtype littermate controls were evaluated in the inferior vena cava stenosis model of venous thrombosis and the carotid artery ferric chloride model of arterial thrombosis. Hemostasis was assessed in C1INH deficient mice or wildtype littermate controls using a tail transection model. Results: Plasma from patients with HAE supported significantly increased intrinsic pathway-initiated thrombin generation compared to healthy controls reflected by significantly reduced lagtime and increased peak. Furthermore, the enhanced thrombin generation negatively correlated with residual plasma levels of C1INH activity. Given that enhanced plasma thrombin generation has been associated with an increased risk of VTE in the general population the association between HAE and VTE was further explored. HAE was found to be associated with a significantly increased risk of composite VTE (OR 3.57, 95% CI 2.16-5.81, P<0.0001) but not composite ATE (OR 1.20, 95% CI 0.81-2.09, P=0.278). Consistent with this finding the cumulative incidence of composite VTE, but not ATE, was significantly higher in patients with HAE compared to controls. C1INH deficient mice had significantly increased plasma levels of coagulation markers prothrombin fragment 1+2, thrombin-antithrombin complexes and D-dimer at baseline compared to wildtype littermate controls. In addition, C1INH deficient mice exhibited enhanced venous thrombus formation in the inferior vena cava stenosis model compared to wildtype littermate controls evidenced by increased thrombus weight. Interestingly, loss of C1INH had no effect on venous thrombus composition. Arterial thrombus formation in the carotid artery ferric chloride model was not significantly different between C1INH deficient mice and wildtype controls.Further, hemostasis, assessed using a tail transection model, did not differ significantly between C1INH deficient mice and wildtype littermate controls. Conclusions: Plasma from patients with HAE supported significantly increased contact pathway-initiated thrombin generation that was dependent on the degree of C1INH deficiency. HAE was found to be associated with a selective increase in the risk of composite VTE but not composite ATE. C1INH deficient mice had evidence of increased basal activation of coagulation consistent with impaired endogenous anticoagulant activity. Further, C1INH deficient mice exhibited increased venous thrombus formation but not arterial thrombus formation phenocopying findings in humans with HAE. This work strongly suggests that plasma C1INH is an important endogenous anticoagulant regulating basal activation of coagulation and providing selective protection against venous thrombus formation.

A CURIOUS CASE OF ACQUIRED ANGIOEDEMA: DIAGNOSIS AND MANAGEMENT OF C1-INH-AAE WITHOUT AN UNDERLYING CONDITION

<h3>Introduction</h3> Angioedema results from localized fluid extravasation into interstitial tissues mediated by mast cells, bradykinin, and other undescribed mechanisms. Recurrent bradykinin-mediated angioedema is most often hereditary, though can rarely be acquired due to autoantibody production. We present a case of acquired C1 esterase inhibitor deficiency (C1-INH-AAE) requiring tracheotomy, and review additional evaluation and maintenance therapy following diagnosis. <h3>Case Description</h3> An 80-year-old woman with multiple comorbidities was referred after two episodes of facial angioedema without clear triggers, including severe recurrence involving her oropharynx that required tracheotomy. Family history was negative, and both losartan and NSAIDs were previously discontinued. Initial evaluation following episode demonstrated indeterminate C1 inhibitor functional assay, low quantitative C1 inhibitor, and borderline C4 level; C1-INH-AAE was subsequently confirmed with C1 esterase autoantibody evaluation. She was prescribed icatibant rescue therapy and started on cetirizine and prednisone 5mg every other day without further recurrence of oropharyngeal symptoms. No evidence of underlying oncologic or rheumatologic process was found on extensive evaluation. During ongoing management over 5 years, tracheotomy was taken down, daily antihistamine was discontinued, and prednisone has been successfully titrated for symptoms associated with local tissue damage and iron deficiency anemia. <h3>Discussion</h3> C1-INH-AAE is a rare cause of recurrent angioedema which presents in older age and is often associated with underlying lymphoproliferative, malignant, or autoimmune disease. Our case reminds that acquired angioedema should be considered in older adults with negative family history, however had no evidence of commonly associated conditions on extensive evaluation. Her subsequent course also offers insight into management of triggers and maintenance therapy.