Bradykinin-mediated Angioedema Research Articles

Angiotensin-Converting Enzyme Inhibitors and Other Medications Associated With Angioedema.

Angioedema is a localized swelling of the dermis, subcutaneous tissues, and/or submucosal tissues caused by fluid extravasation into these tissues. Angioedema is associated with certain vasoactive molecules and is typically mediated by histamine or bradykinin. It manifests clinically as facial edema, swelling of the extremities and urogenital area, and potential involvement of the larynx, leading to dyspnea and inspiratory stridor, which can become life-threatening. Histamine-mediated angioedema is associated with urticaria and pruritus and will show classic signs of allergic (type 1 hypersensitivity) reactions. Bradykinin-mediated angioedema is often familial (hereditary angioedema) and is more often associated with gastrointestinal symptoms (abdominal pain, nausea, vomiting, diarrhea), edema of the extremities and trunk, and a lack of urticaria and pruritus. Angiotensin-converting enzyme inhibitors (ACEIs) are a class of medications commonly prescribed for hypertension, heart failure, and diabetic nephropathy. ACEIs are associated with an increased risk of angioedema, which can range from a mild reaction to severe and life-threatening. ACEI-induced angioedema is a bradykinin-mediated reaction that can occur in individuals with a genetic predisposition. Other medications, such as angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs, and certain antibiotics, most notably those in the beta-lactam class, can also cause drug-induced angioedema. The present investigation describes current knowledge of the pathophysiology, epidemiology, clinical manifestations, predisposing factors, and management of drug-induced angioedema.

Bradykinin-Mediated Angioedema Induced by Commonly Used Cardiovascular Drugs

ACE inhibitors, sartans, and sacubitril are among the most important drugs for the prevention of cardiovascular mortality and morbidity. At the same time, they are known to cause non-allergic bradykinin-mediated angioedema, a potentially fatal swelling of the mucosa and/or submucosa and deeper skin without signs of urticaria or pruritus, occurring mainly in the head and neck region. In contrast with hereditary angioedema, which is also mediated by bradykinin, angioedema triggered by these drugs is by far the most common subtype of non-allergic angioedema. The molecular mechanisms underlying this type of angioedema, which are discussed here, are not yet sufficiently understood. There are a number of approved drugs for the prevention and treatment of acute attacks of hereditary angioedema. These include inhibitors of bradykinin synthesis that act as kallkrein inhibitors, such as the parenterally applied plasma pool, and recombinant C1 esterase inhibitor, ecallantide, lanadelumab, and the orally available berotralstat, as well as the bradykinin receptor type 2 antagonist icatibant. In contrast, no diagnostic tools, guidelines, or treatments have yet been approved for the diagnosis and treatment of acute non-allergic drug-induced angioedema, although it is more common and can take life-threatening courses. Approved specific drugs and a structured diagnostic workflow are needed for this emergency diagnosis.

Acute angioedema in Cape Town emergency centres and a suggested algorithm to simplify and improve management.

Angioedema is the most common acute allergic presentation to emergency centres (EC), with hospitalisation rates increasing in high-income countries. Angioedema can complicate with life-threatening laryngeal obstruction. There are no local data; therefore, we aimed to characterise acute angioedema cases presenting to ECs and develop a simple management algorithm. To characterise the clinical presentation, management and outcomes of acute angioedema cases presenting to ECs. Based on these findings, we developed a management algorithm for acute angioedema to improve the care of acute angioedema in South Africa (SA). We conducted a retrospective folder review of all patients admitted to Groote Schuur Hospital (tertiary) and Mitchells Plain District Hospital (secondary) ECs from 1 June 2018 to 31 June 2020. Using ICD-10 coding, folders of adults ≥18 years with possible angioedema presenting to the ECs were screened. An allergist extracted demographics, medical history, management and outcome data for each angioedema event. A total of 142acute angioedema episodes were included, with a median (interquartile range) age of 42 (28- 58) years, and 62% of patients were female. The majority (124/142, 87%) of acute angioedema EC presentations involved swelling above the shoulders, with airway involvement in 20(14%) patients, with two patients requiring intubation. Nineteen (13%) patients required admission, with five (26%) admitted to high care/intensive care. Drug-induced angioedema was the most common cause, with 64/142 (45%) linked to a known offending drug, 42/64 (65.6%) being angiotensin-converting enzyme inhibitor (ACE-I). Critical information to guide angioedema management, including past personal/family allergy history, and duration of angioedema prior to EC visit, was not recorded in 64.7% and 37.8% of EC records, respectively. Unnecessary treatment with corticosteroids or antihistamines occurred in 19/53 (36%) and 16/53 (30%) cases with bradykinin-mediated angioedema ACE-I angioedema and hereditary angioedema). Overall, only 36/142 (25%) of angioedema patients were connected to allergy care. Angioedema is the most common allergy presentation to two ECs in Cape Town, SA. Bradykinin-mediated angioedema secondary to ACE-I therapy is the single most common offender, and was not appropriately managed in more than a third of cases. Based on these findings, we have developed a management algorithm that easily stratifies patients into bradykinin or mast cell-mediated angioedema with a step-by-step management approach that is applicable to the SA context. Ongoing awareness and education on allergy emergencies are required to ensure accurate diagnosis of less common causes of angioedema (particularly bradykinin-mediated angioedema) and linkage to allergy specialist care.

Neurologic and Psychiatric Manifestations of Bradykinin-Mediated Angioedema: Old and New Challenges.

Neurologic manifestations have been occasionally described in patients with bradykinin-mediated angioedema. The existing literature is currently limited to case series and case reports mainly described in the hereditary forms (HAE) concerning central nervous system (CNS) involvement. On the contrary, very little is known about peripheral and autonomic nervous system manifestations. CNS involvement in HAE may present with symptoms including severe headaches, visual disturbance, seizures, and various focal and generalized deficits. In addition, a stroke-like clinical picture may present in HAE patients. In turn, some drugs used in patients with cardiovascular and neurologic disorders, such as recombinant tissue plasminogen activator (r-tPA) and angiotensin-converting enzyme inhibitors (ACEI), may produce medication-induced angioedema, resulting in a diagnostic challenge. Finally, most patients with HAE have higher levels of psychological distress, anxiety, and depression. With this review, we aimed to provide an organized and detailed analysis of the existing literature on neurologic and psychiatric manifestations of HAE to shed light on these potentially invalidating symptoms and lay the foundation for further personalized diagnostic pathways for patients affected by this protean disease.

Concomitant medication in patients with bradykinin-mediated angioedema - there's more than ACE inhibitors.

Bradykinin-mediated angioedema is a rare, non-allergic, potentially life-threatening disease. ACE inhibitor-induced angioedema and hereditary angioedema (HAE) are the two most common presentations. Therapeutic options, pathophysiology and diagnosis continue to be investigated, with considerable progress in HAE over the last few decades. For all patients with bradykinin-mediated angioedema, there are several medications that should be avoided or administered with caution. Some of the triggering medications are well known, while others are suspected or of unknown significance. A common denominator is that there is no approved therapy for bradykinin-mediated angioedema as a drug side effect. Some medications, such as tissue plasminogen activator, have a higher incidence of angioedema with potential airway compromise than ACE inhibitors, although this fact is widely underappreciated. In this review, we aim to summarize what is currently known and recommended about concomitant medication in HAE patients and the interaction of other bradykinin-influencing drugs.

Isolated angioedema due to face mask and other cases of isolated angioedema.

Isolated angioedema can be divided into two groups as mast cell-mediated angioedema and bradykinin-mediated angioedema according to the known mechanisms of occurrence. However, angioedema can also occur with mechanisms whose cause is unknown. Treatment varies according to the mechanism of angioedema formation. In this prospective study, we present the causes of 80 isolated angioedema cases admitted to our clinic during the pandemic period. We would like to emphasize the causes that we found in our cases but which are rare in the literature. For example: angioedema due to allergy to nickel in the mask used during the pandemic period, T cell-mediated angioedema, alpha adrenergic receptor blocker use, and patients diagnosed with collagen tissue disease presenting with angioedema as the first clinical finding.

Hereditary angioedema and COVID-19 during pregnancy: Two case reports

Hereditary angioedema and COVID-19 during pregnancy: Two case reports

A Comprehensive Review of Bradykinin-Induced Angioedema Versus Histamine-Induced Angioedema in the Emergency Department.

Angioedema (AE) is a condition that is frequently encountered in the emergency department (ED). It is a rare condition with localized, asymmetrical swelling of the skin and/or mucosa that is frequently nonpruritic and primarily affects locations with loose connective tissue. Physicians must have a thorough understanding of this condition since it can cause fatal airway compromise, which might be the presenting symptom. Histamine-mediated AE is the most common type of AE seen in EDs. However, ED physicians must be on the lookout for the less common bradykinin-mediated types of AEas these do not respond to the same therapy as histamine-mediated AE. Hospitals may lack specialized drugs or protocols, and many ED staff may be unable to identify or treat bradykinin-mediated AE. It is crucial to understand the pathophysiology of the various kinds of AE in order to optimize treatment. The goal of this review paper is to provide an overview of the pathophysiology, clinical manifestations, and treatment options for bradykinin and histamine-induced AE in the ED.

PERSISTENT ANGIOEDEMA AFTER COVID-19 VACCINATION: IS BRADYKININ TO BLAME?

<h3>Introduction</h3> Bradykinin-mediated angioedema (BMA) represents a subtype of angioedema that presents with nonpruritic, non-pitting swelling of the skin and mucosal surfaces. <h3>Case Description</h3> A 32-year-old female presented to the Emergency Department (ED) for recurrent lip and tongue swelling after receiving the Janssen vaccination one day prior. She was treated with epinephrine with transient improvement and discharged on steroids and antihistamines. She returned to the ED multiple times and was ultimately hospitalized for recurrent angioedema. She would be trialed on additional antihistamine medications, including omalizumab, without relief. She presented to our ED and was treated with epinephrine, antihistamines, and steroids. Her labs, including C4, C1INH, C1q, tryptase, were unremarkable. She was given a dose of icatibant with immediate resolution of her angioedema. <h3>Discussion</h3> This case illustrates a unique presentation of BMA following the Janssen SARS-CoV-2 vaccine. Given this patient's persistent angioedema and lack of sustained clinical response to antihistamines, corticosteroids, and epinephrine, the diagnosis of BMA was made. A search for an underlying etiology, including evaluation for hereditary, acquired, and medication-induced angioedema was unremarkable. This led to a diagnosis of idiopathic bradykinin-mediated angioedema. This case questions whether there is a particular facet of the SARS-CoV-2 vaccine, specifically, responsible for increased bradykinin levels. Homology of the bradykinin motif has been found in the SARS-CoV-2 spike protein; therefore, the antibody response to the SARS-CoV-2 protein may potentially cross-react with bradykinin protein. It is plausible that immune stimulation to the COVID-19 vaccine and subsequent generation of SARS-CoV-2 specific antibodies may have led to excess bradykinin production in our patient.

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.

Classification and Treatment of Angioedema without Wheals: A Spanish Delphi Consensus.

Problems in the definition and classification of angioedema, leading to difficulties in its diagnosis and treatment, have been identified; therefore, an improvement in the current classification of angioedema is required. The aim of this study was to propose a practical classification of angioedema without wheals that helps to establish a differential diagnosis and take appropriate therapeutic decisions. An initial proposal of classification of angioedema without wheals was agreed by a scientific committee of experts and was subsequently validated by a panel of experts by means of consensus based on the Delphi methodology. Forty-five items on the classification, diagnosis, and treatment of angioedema without wheals were proposed for the survey. Most items (93.8%) were agreed after two rounds. All panelists agreed with the proposed classification, as well as with most of the clinical and treatment characteristics. The angioedema without wheals classification established three groups: histamine-mediated, bradykinin-mediated, and unknown mechanism angioedema. The clinical characteristics of the proposed types of angioedema were also agreed, except for the allergic histamine-mediated and unknown mechanism angioedema, which generated debate. Regarding treatments, although there was broad agreement with the proposed items, a lack of knowledge about some treatments in this pathology was observed. The proposed classification of angioedema without wheals was accepted with a high degree of agreement; however, knowledge of available treatments needs to be increased and the definition of angioedema of unknown mechanism needs to be improved.

Bradykinin-Mediated Angioedema Following Tenecteplase Administration in an Acute Ischemic Stroke.

HomeStrokeVol. 53, No. 10Bradykinin-Mediated Angioedema Following Tenecteplase Administration in an Acute Ischemic Stroke No AccessCase ReportRequest AccessFull TextAboutView Full TextView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toNo AccessCase ReportRequest AccessFull TextBradykinin-Mediated Angioedema Following Tenecteplase Administration in an Acute Ischemic Stroke Arnaud Lapostolle, MD, David Weisenburger-Lile, MD, Marion Yger, MD, Sonia Alamowitch, MD and Olivier Fain, MD Arnaud LapostolleArnaud Lapostolle Correspondence to: Arnaud Lapostolle, MD, AP-HP, Department of Neurology, Saint-Antoine Hospital, Paris, France. Email E-mail Address: [email protected] https://orcid.org/0000-0002-0736-8866 AP-HP, Department of Neurology, Saint-Antoine Hospital, Paris, France (A.L., M.Y.). Search for more papers by this author , David Weisenburger-LileDavid Weisenburger-Lile Department of Neurology, Stroke Center, Foch Hospital, Suresnes, France (D.W.-L.). Search for more papers by this author , Marion YgerMarion Yger AP-HP, Department of Neurology, Saint-Antoine Hospital, Paris, France (A.L., M.Y.). Search for more papers by this author , Sonia AlamowitchSonia Alamowitch AP-HP, Service des Urgences Cérébro-Vasculaires, Hôpital Pitié-Salpêtrière, Hôpital Saint-Antoine, CRSA, INSERM, UMRS 938 Sorbonne Université, Paris, France STARE team, iCRIN, ICM, Paris, France (S.A.). Search for more papers by this author and Olivier FainOlivier Fain Department of Internal Medicine, Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Assistance Publique - Hôpitaux de Paris, Hôpital Saint-Antoine, Paris, France (O.F.). UPMC University Paris 06, Paris, France (O.F.). Sorbonne Universités, UPMC University Paris 06, INSERM U938, Centre de Recherche Saint-Antoine (CRSA), Paris, France (O.F.). Search for more papers by this author Originally published7 Sep 2022https://doi.org/10.1161/STROKEAHA.122.040052Stroke. 2022;53:e446–e447"Bradykinin-Mediated Angioedema Following Tenecteplase Administration in an Acute Ischemic Stroke." Stroke, 53(10), pp. e446–e447FootnotesFor Sources of Funding and Disclosures, see page e447.Correspondence to: Arnaud Lapostolle, MD, AP-HP, Department of Neurology, Saint-Antoine Hospital, Paris, France. Email arnaud.[email protected]fr

Large Predominance of Off-Label Prescriptions of C1-Inhibitor Concentrates and Icatibant in a Real-Life Setting: A Retrospective Clinical Study.

C1-inhibitor (C1INH) concentrates and the selective bradykinin B2 receptor antagonist icatibant are approved only for treating hereditary angioedema with C1INH deficiency. Yet, they are regularly prescribed off label in other types of bradykinin-mediated angioedema including angiotensin-converting enzyme inhibitor (ACEi)-related and undetermined angioedema. We conducted a retrospective chart review of inpatient prescriptions of C1INH concentrates and icatibant between 2016 and 2020 in the University Hospital of Angers. The first outcome was the proportion of prescriptions with explicit indication. Then, we determined the compliance of prescriptions with European Medicines Agency approvals and the French bradykinin-mediated angioedema reference center guidelines. Finally, we estimated the economic impact of inappropriate prescribing. The therapeutic indication was explicit in 90.4% of prescriptions (n=66/73). Only 17.8% of prescriptions were for hereditary angioedema with C1INH deficiency, while 31.5% were for ACEi-related and 28.7% for undetermined angioedema. However, most off-label prescriptions were consistent with the French bradykinin-mediated angioedema reference center guidelines (73.3%). We estimated that 13% of drug expenditures were potentially excessive. The predominance of off-label prescriptions may be explained by the infrequency of hereditary angioedema and the absence of approved alternatives in other types of bradykinin-mediated angioedema. Most attacks were related to ACEis. Epinephrine was rarely prescribed as first-line therapy in attacks of unknown origin. Given the high prices of these drugs, we advocate the development of a readily available management algorithm of angioedema to reduce inappropriate prescriptions in our center. In addition, we think that the drug prescription circuit should be redesigned to ensure the traceability of prescribed vials in the dispensing areas.

Urticaria and angioedema in children and adolescents: diagnostic challenge.

Urticaria diagnosis may be challenging in children since it can be triggered or related to numerous conditions. In this paper, we reviewed the main aspects regarding the diagnosis of urticaria in the pediatric population. Acute urticaria is often due to viral infections. However, other culprits, including foods, insect stings, drugs, contrast media, vaccination, latex, and medical diseases, may account for acute patterns. Laboratory tests and confirmatory allergy tests should be individualized and guided by history. Chronic urticaria (CU) is defined when hives and/or angioedema last for more than 6 weeks. The most common type of chronic urticaria in children is chronic spontaneous urticaria (CSU). Chronic inducible urticaria (CindU) is less common but is important to diagnose in order to manage appropriately and reduce the risk of severe reactions. Inducible forms in children are often diagnosed with specific provocation tests similar to the tests used in adults. Given that chronic urticaria could rarely be a presentation of vasculitis, systemic-onset juvenile idiopathic arthritis, or auto-inflammatory syndromes, it is important to rule out these conditions. It is crucial to differentiate cases of chronic urticaria from mastocytosis and Bradykinin-mediated angioedema, given that treatment may differ. The management of chronic urticaria in children has improved over the last decade because of the development of both clear management guidelines and new effective drugs. It is crucial to increase awareness for appropriate diagnosis and new available treatment to improve the management of chronic urticaria in children.

Emerging drugs for the treatment of hereditary angioedema due to C1-inhibitor deficiency

ABSTRACT Introduction Hereditary angioedema due to C1-inhibitor (C1-INH-HAE) is a rare disease characterized by unpredictable swelling attacks that may be life-threatening when affecting the upper airways. Understanding the pathophysiology of HAE and the mechanism of bradykinin-mediated angioedema allowed the development of new therapies for the treatment of HAE: clinical trials are ongoing to expand the number of drugs available for on-demand treatment and prophylaxis. Areas covered Authors discuss the products that have been used to treat this disease for many years and present the most recently marketed products and those which are under development. Expert opinion Significant therapeutic progress has been made in HAE. In particular, drugs targeting specific molecules involved in the angioedema formation were developed and studies with new drugs are ongoing. In the coming years, more effective therapies with easier administration route options for on-demand treatment and long-term prophylaxis will be available to treat this disease and the variety of patients. Gene therapy strategies may offer a definitive treatment. High costs of current and new drugs may be a limiting factor for their availability, especially in developing countries.

Angioedema Without Wheals: Challenges in Laboratorial Diagnosis.

Angioedema is a prevailing symptom in different diseases, frequently occurring in the presence of urticaria. Recurrent angioedema without urticaria (AE) can be hereditary (HAE) and acquired (AAE), and several subtypes can be distinguished, although clinical presentation is quite similar in some of them. They present with subcutaneous and mucosal swellings, affecting extremities, face, genitals, bowels, and upper airways. AE is commonly misdiagnosed due to restricted access and availability of appropriate laboratorial tests. HAE with C1 inhibitor defect is associated with quantitative and/or functional deficiency. Although bradykinin-mediated disease results mainly from disturbance in the kallikrein–kinin system, traditionally complement evaluation has been used for diagnosis. Diagnosis is established by nephelometry, turbidimetry, or radial immunodiffusion for quantitative measurement of C1 inhibitor, and chromogenic assay or ELISA has been used for functional C1-INH analysis. Wrong handling of the samples can lead to misdiagnosis and, consequently, mistaken inappropriate approaches. Dried blood spot (DBS) tests have been used for decades in newborn screening for certain metabolic diseases, and there has been growing interest in their use for other congenital conditions. Recently, DBS is now proposed as an efficient tool to diagnose HAE with C1 inhibitor deficiency, and its use would improve the access to outbound areas and family members. Regarding HAE with normal C1 inhibitor, complement assays’ results are normal and the genetic sequencing of target genes, such as exon 9 of F12 and PLG, is the only available method. New methods to measure cleaved high-molecular-weight kininogen and activated plasma kallikrein have emerged as potential biochemical tests to identify bradykinin-mediated angioedema. Validated biomarkers of kallikrein–kinin system activation could be helpful in differentiating mechanisms of angioedema. Our aim is to focus on the capability to differentiate histaminergic AE from bradykinin-mediated AE. In addition, we will describe the challenges developing specific tests like direct bradykinin measurements. The need for quality tests to improve the diagnosis is well represented by the variability of results in functional assays.

Nailfold Videocapillaroscopy Findings in Bradykinin-Mediated Angioedema.

Hereditary angioedema with C1-inhibitor deficiency (C1-INH-HAE) and acquired angioedema related to angiotensin-converting enzyme (ACE) inhibitors (ACEI-AAE) are types of bradykinin-mediated angioedema without wheals characterized by recurrent swelling episodes. Recent evidence suggests that a state of "vascular preconditioning" predisposes individuals to attacks, although no data are available on possible structural alterations of the vessels. Objective: This study aims to compare the features of nailfold capillaries to highlight possible structural anomalies between patients affected by C1-INH-HAE and controls and between patients with ACEI-AAE and hypertensive controls. We used nailfold videocapillaroscopy (NVC) to assess the following: apical, internal, and external diameter; loop length; intercapillary distance; and capillary density, distribution, and morphology. Plasma levels of vascular endothelial growth factor (VEGF) A, VEGF-C, angiopoietin (Ang) 1, and Ang2 were also measured. Compared with healthy controls (n=28), C1-INH-HAE patients (n = 34) were characterized by significant structural alterations of the capillaries, such as greater intercapillary distance (216 vs 190 μm), increased apical, internal, and external diameter (28 vs 22 μm; 22 vs 20 μm; and 81 vs 65 μm, respectively), decreased density (4 vs 5 capillaries/mm2), more irregular capillary distribution, and more tortuous morphology. Apical diameter was enlarged in patients with ≥12 attacks per year. In ACEI-AAE patients, NVC showed no alterations with respect to hypertensive controls. NVC performed in 2 C1-INH-HAE patients during attacks showed no changes compared with the remission phase. We detected major structural capillary alterations in C1-INH-HAE patients, thus confirming the involvement of microcirculation in the pathogenesis of angioedema.

ALTEPLASE-ASSOCIATED ANGIOEDEMA: NEW TREATMENT OPTIONS

TOPIC: Critical Care TYPE: Medical Student/Resident Case Reports INTRODUCTION: Alteplase (recombinant tissue plasminogen activator or tPA) has revolutionized the management of acute ischemic stroke since its FDA approval in 1995. Intracerebral bleed is the most known and feared complication after tPA administration. tPA-associated orolingual angioedema (TAOA) is a less common but potentially fatal complication of tPA. We report a patient who developed hemi-orolingual angioedema after receiving tPA. CASE PRESENTATION: A 79-year-old female presented with sudden onset right-sided weakness with initial National Institutes of Health Stroke Scale score of 4. CT head was negative for intracranial bleed and a CT angiogram with perfusion of the head showed occlusion of P2 segment of the left posterior cerebral artery. She received tPA bolus followed by infusion and was transferred to the intensive care unit. She developed right hemi-orolingual angioedema without evidence of airway compromise one and half hours after tPA initiation. Administration of intravenous corticosteroids and antihistamines failed to improve angioedema. She was subsequently treated with 2 units of fresh frozen plasma (FFP) with complete resolution of swelling within 2 hours. DISCUSSION: Alteplase cleaves plasminogen to plasmin which degrades thrombus-bound fibrin. Plasmin also activates the kinin and complement pathways causing increased bradykinin and histamine release respectively. Bradykinin-mediated vasodilation appears to be the primary cause of TAOA. TAOA has an incidence of 0.2-5.1%. It usually develops hemi-lingually and tends to be contralateral to the ischemic side possibly due to autonomic dysfunction from insular cortex ischemia. However, this may not always be true since our patient had contralateral angioedema without insular cortex involvement. Initial management includes corticosteroids and antihistamines which are less effective for bradykinin-mediated angioedema. FFP contains kininase 2 which degrades bradykinin and hence is effectively used off label for angiotensin-converting enzyme inhibitor-induced angioedema. As TAOA also follows the bradykinin pathway, we treated our patient with FFP. To our knowledge, this is the first-ever case of TAOA treated with FFP. Other potential treatment options include C1 esterase inhibitor, icatibant (bradykinin receptor antagonist), and ecallantide (kallikrein inhibitor) which are being used for hereditary angioedema and need to be studied for TAOA. CONCLUSIONS: TAOA is a life-threatening complication that typically occurs in the first 4 hours after tPA administration. Physicians should be aware of this uncommon side effect for early recognition and treatment. Treatment targeting the bradykinin pathway like FFP might be more effective and needs further investigation. REFERENCE #1: Rathbun KM. Angioedema after thrombolysis with tissue plasminogen activator: an airway emergency. Oxf Med Case Reports. 2019;2019(1):omy112. Published 2019 Jan 24. doi:10.1093/omcr/omy11 REFERENCE #2: Hemi-orolingual angioedema and ACE inhibition after alteplase treatment of stroke. M. D. Hill, T. Lye, H. Moss, P. A. Barber, A. M. Demchuk, N. J. Newcommon, T. L. Green, C. Kenney, A. Cole–Haskayne, A. M. Buchan. Neurology May 2003, 60 (9) 1525-1527; DOI: 10.1212/01.WNL.0000058840.66596.1A DISCLOSURES: No relevant relationships by Robert Caldera, source=Web Response No relevant relationships by Kristin Fless, source=Web Response No relevant relationships by Bilal Khan, source=Web Response No relevant relationships by Nirav Mistry, source=Web Response No relevant relationships by Vagram Ovnanian, source=Web Response No relevant relationships by Fariborz Rezai, source=Web Response No relevant relationships by Aditi Saha, source=Web Response No relevant relationships by Sohaib Tariq, source=Web Response No relevant relationships by Lalithaa Thirunavukarasu Murugan, source=Web Response No relevant relationships by Paul Yodice, source=Web Response

Recognition and Management of Hereditary Angioedema: Best Practices for Dermatologists.

ObjectiveThe 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.CommentaryWhile 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.

Angioedema and Fatty Acids.

Angioedema is a life-threatening emergency event that is associated with bradykinin and histamine-mediated cascades. Although bradykinin-mediated angioedema currently has specific therapeutic options, angioedema is sometimes intractable with current treatments, especially histamine-mediated angioedema, suggesting that some other mediators might contribute to the development of angioedema. Fatty acids are an essential fuel and cell component, and act as a mediator in physiological and pathological human diseases. Recent updates of studies revealed that these fatty acids are involved in vascular permeability and vasodilation, in addition to bradykinin and histamine-mediated reactions. This review summarizes each fatty acid’s function and the specific receptor signaling responses in blood vessels, and focuses on the possible pathogenetic role of fatty acids in angioedema.