Materiały źródłowe

• #1 An overview of angioedema: Pathogenesis and causes – UpToDate

  https://www.uptodate.com/contents/an-overview-of-angioedema-pathogenesis-and-causes/print

  An overview of angioedema: Pathogenesis and causes […] The pathogenesis and causes of angioedema will be reviewed here. […] Angioedema is self-limited, localized swelling of the skin or mucosal tissues, which results from extravasation of fluid into the interstitium due to a loss of vascular integrity.

• #2 Angioedema – Immunology; Allergic Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/immunology-allergic-disorders/allergic-autoimmune-and-other-hypersensitivity-disorders/angioedema

  Angioedema is swelling (usually localized) of the subcutaneous tissues due to increased vascular permeability and extravasation of intravascular fluid. […] Known mediators of increased vascular permeability include the following: Mast cell-derived mediators (eg, histamine, leukotrienes, prostaglandins) […] Bradykinin and complement-derived mediators. […] In bradykinin-mediated angioedema, the dermis is usually spared, so urticaria and pruritus are absent. […] Several causes (eg, calcium channel blockers, fibrinolytic agents) have no identified mechanism; sometimes a cause (eg, muscle relaxants) with a known mechanism is overlooked clinically. […] Acute angioedema is mast cell-mediated in 90% of cases. […] Angiotensin-converting enzyme (ACE) inhibitors cause about 30% of cases of acute angioedema seen in emergency departments.

• #3 Angioedema: Causes, Appearance and Treatment — DermNet

  https://dermnetnz.org/topics/angioedema

  Angioedema is caused by an increase in local capillary permeability and plasma extravasation, usually mediated by mast cells, histamine, or bradykinin release. […] Angioedema is most commonly histamine-mediated; mast cell and basophil stimulation results in histamine release. […] The exact cause depends on the type of angioedema a patient has. […] Decreased C1 inhibitor activity leads to excessive kallikrein, which in turn produces bradykinin, a potent vasodilator. […] If hereditary angioedema is suspected, testing can find low C4 and C1-INH levels (part of the complement system). However, cases of HAE with normal C4 levels have been reported.

• #4 Angioedema – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK538489/

  In describing pathophysiology, angioedema is classified as histamine-mediated angioedema and bradykinin-mediated angioedema. […] Histamine-mediated angioedema is the most common and is secondary to mast-cells and basophil activation. […] Bradykinin-mediated angioedema (hereditary angioedema, acquired C1-inhibitor deficiency and angiotensin-converting enzyme inhibitor-associated angioedema). Allergic reactions and hives do not trigger this condition. C1-inhibitor is a regulator of complement and the contact system; if deficient or dysfunctional it causes activation of the contact system resulting in uncontrolled production of kallikrein leading to proteolysis of high-molecular-weight kininogen and bradykinin, leading to edema by increasing in vascular permeability. […] Genetics: Hereditary angioedema can be secondary to F12 gene, angiopoietin-1, and plasminogen or some unknown gene mutation.

• #5 Angioedema in the emergency department: a practical guide to differential diagnosis and management | International Journal of Emergency Medicine | Full Text

  https://intjem.biomedcentral.com/articles/10.1186/s12245-017-0141-z

  Angioedema is a common presentation in the emergency department (ED). Airway angioedema can be fatal; therefore, prompt diagnosis and correct treatment are vital. […] The most common pathophysiology underlying angioedema is mediated by histamine; however, ED staff must be alert for the less common bradykinin-mediated forms of angioedema. […] Crucially, bradykinin-mediated angioedema does not respond to the same treatment as histamine-mediated angioedema. […] Bradykinin-mediated angioedema can result from many causes, including hereditary defects in C1 esterase inhibitor (C1-INH), side effects of angiotensin-converting enzyme inhibitors (ACEis), or acquired deficiency in C1-INH. […] ED physicians must be aware of the different pathophysiologic pathways that lead to angioedema in order to efficiently and effectively manage these potentially fatal conditions.

• #6 Angioedema – Immunology; Allergic Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/immunology-allergic-disorders/allergic-autoimmune-and-other-hypersensitivity-disorders/angioedema

  Angioedema is swelling (usually localized) of the subcutaneous tissues due to increased vascular permeability and extravasation of intravascular fluid. […] Known mediators of increased vascular permeability include the following: Mast cell-derived mediators (eg, histamine, leukotrienes, prostaglandins) […] Bradykinin and complement-derived mediators. […] In bradykinin-mediated angioedema, the dermis is usually spared, so urticaria and pruritus are absent. […] Several causes (eg, calcium channel blockers, fibrinolytic agents) have no identified mechanism; sometimes a cause (eg, muscle relaxants) with a known mechanism is overlooked clinically. […] Acute angioedema is mast cell-mediated in 90% of cases. […] Angiotensin-converting enzyme (ACE) inhibitors cause about 30% of cases of acute angioedema seen in emergency departments.

• #7 Angioedema – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK538489/

  In describing pathophysiology, angioedema is classified as histamine-mediated angioedema and bradykinin-mediated angioedema. […] Histamine-mediated angioedema is the most common and is secondary to mast-cells and basophil activation. […] Bradykinin-mediated angioedema (hereditary angioedema, acquired C1-inhibitor deficiency and angiotensin-converting enzyme inhibitor-associated angioedema). Allergic reactions and hives do not trigger this condition. C1-inhibitor is a regulator of complement and the contact system; if deficient or dysfunctional it causes activation of the contact system resulting in uncontrolled production of kallikrein leading to proteolysis of high-molecular-weight kininogen and bradykinin, leading to edema by increasing in vascular permeability. […] Genetics: Hereditary angioedema can be secondary to F12 gene, angiopoietin-1, and plasminogen or some unknown gene mutation.

• #8 Angioedema: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/135208-overview

  Angioedema is a result of the fast onset of an increase in local vascular permeability in subcutaneous or submucosal tissue. Histamine and bradykinin are the most recognized vasoactive mediators known to be critical in the pathologic process of angioedema; most cases of angioedema are primarily mediated by 1 of these 2 mediators, though some investigators indicate the possibility that both may be involved in certain cases. […] Other vasoactive mediators are, at least in part, involved in the pathogenesis of various types of angioedema. Leukotrienes, for example, may play an important role in the onset of angioedema that is induced by nonsteroidal anti-inflammatory drugs (NSAIDs). […] For histamine-mediated angioedema (histaminergic angioedema), mast cells and basophils are the primary sources of histamine. The activation of mast cells or basophils with subsequent histamine release may be either mediated or unmediated by immunoglobulin E (IgE).

• #9 Angioedema: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/135208-overview

  Angioedema is a result of the fast onset of an increase in local vascular permeability in subcutaneous or submucosal tissue. Histamine and bradykinin are the most recognized vasoactive mediators known to be critical in the pathologic process of angioedema; most cases of angioedema are primarily mediated by 1 of these 2 mediators, though some investigators indicate the possibility that both may be involved in certain cases. […] Other vasoactive mediators are, at least in part, involved in the pathogenesis of various types of angioedema. Leukotrienes, for example, may play an important role in the onset of angioedema that is induced by nonsteroidal anti-inflammatory drugs (NSAIDs). […] For histamine-mediated angioedema (histaminergic angioedema), mast cells and basophils are the primary sources of histamine. The activation of mast cells or basophils with subsequent histamine release may be either mediated or unmediated by immunoglobulin E (IgE).

• #10 Urticaria and Angioedema: A Practical Approach | AAFP

  https://www.aafp.org/pubs/afp/issues/2004/0301/p1123.html

  Urticaria (i.e., pruritic, raised wheals) and angioedema (i.e., deep mucocutaneous swelling) occur in up to 25 percent of the U.S. population. […] Angioedema, which can occur alone or with urticaria, is characterized by nonpitting, non-pruritic, well-defined, edematous swelling that involves subcutaneous tissues (e.g., face, hands, buttocks, genitals), abdominal organs, or the upper airway (i.e., larynx). […] Chronic urticaria and angioedema tend to be idiopathic, with no identifiable cause, or to be precipitated by a multitude of endogenous or exogenous factors that can be immunologic or nonimmunologic. […] Histamine released from cutaneous mast cells and basophils in response to inciting stimuli is the primary mediator of urticaria. In this process, specific IgE antibodies cross-link the IgE receptors bound to mast cells and stimulate the production of preformed and newly generated inflammatory mediators.

• #11 Angioedema | Concise Medical Knowledge

  https://www.lecturio.com/concepts/angioedema/

  Angioedema may result from 3 primary mechanisms: […] Mast cell-mediated angioedema (most common and associated with urticaria): […] Once activated, mast cells release inflammatory mediators: […] Bradykinin-mediated angioedema (not associated with urticaria): Bradykinin is an inflammatory mediator that can lead to vasodilation and vascular permeability. […] General pathophysiology: Inflammatory mediators increase vascular permeability and dilation of capillaries. […] Extravasation of fluid from vasculature leads to asymmetric edema in the subcutaneous tissue and deep dermis.

• #12 Angioedema – Immunology; Allergic Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/immunology-allergic-disorders/allergic-autoimmune-and-other-hypersensitivity-disorders/angioedema

  Angioedema is swelling (usually localized) of the subcutaneous tissues due to increased vascular permeability and extravasation of intravascular fluid. […] Known mediators of increased vascular permeability include the following: Mast cell-derived mediators (eg, histamine, leukotrienes, prostaglandins) […] Bradykinin and complement-derived mediators. […] In bradykinin-mediated angioedema, the dermis is usually spared, so urticaria and pruritus are absent. […] Several causes (eg, calcium channel blockers, fibrinolytic agents) have no identified mechanism; sometimes a cause (eg, muscle relaxants) with a known mechanism is overlooked clinically. […] Acute angioedema is mast cell-mediated in 90% of cases. […] Angiotensin-converting enzyme (ACE) inhibitors cause about 30% of cases of acute angioedema seen in emergency departments.

• #13 Angioedema – Core EM

  https://coreem.net/core/angioedema/

  Mechanism and Pathophysiology: […] Mast Cell (granulocyte) Mediated […] Mast cell activation (by IgE crosslinking or directly) leads to the generation of mediators (histamine, heparin, leukotriene and prostaglandin D2), which increases vascular permeability. […] IgE Dependent (Type I Hypersensitivity) Reactions […] Pro-inflammatory mediators then act on the mucosa and cause angioedema. These chemicals can recruit other cells, like eosinophils, and may lead to anaphylaxis. […] NSAIDs hinder the formation of prostaglandins within mast cells and other leukocytes. This can cause an abundance of leukotrienes and other pro-inflammatory mediators and precipitate angioedema (Nzeako 2010). […] Bradykinin Mediated […] Plasma globulins called kininogens release bradykinin and cause vascular permeability.

• #14 Azthena logo with the word Azthena

  https://www.news-medical.net/health/Angioedema-Pathophysiology.aspx

  Pathogenesis of the types of angioedema has been studied extensively. […] Evidence shows that there is a C1 esterase inhibitor (C1 INH) deficiency. Normally C1 INH is responsible for regulation of activity of inflammatory mediators like complement component C1. Activation of C1 is the first step in the activation of complements and their role in inflammation. […] If there is a deficiency of C1 INH the mediators of inflammation like bradykinin, kallikrein, and plasmin become overtly active. […] Acquired angioedema also results due to C1 INH deficiency. There are 2 types of acquired angioedema and both have autoimmune mechanisms in their pathology. […] Angiotensin-Converting Enzyme Inhibitors or ACE inhibitors are one of the common drugs that cause angioedemas. This results mainly due to raised levels of bradykinins. […] In these conditions there is a raised level of several cytokines. There is an increased level of the cytokines granulocyte-macrophage colony-stimulating factor, interleukin (IL)-3, IL-5, and IL-6.

• #15 Acquired and Hereditary Angioedema: Pathogenesis and Therapy | SpringerLink

  https://link.springer.com/chapter/10.1007/978-3-642-83360-1_14

  There are two main pathogenetic ways by which angioedema can develop. These pathways are completely different and lead to completely different diseases, which may have angioedema of the skin in common. […] Most cases of cutaneous angioedema develop with involvement of the mast cell and its mediators; especially histamine is considered to play a major role. The exact pathogenesis, however, is not known. […] This type of angioedema is assumed to be related to urticaria for several reasons: Often it appears alternately with urticaria. It responds to antihistaminic drugs. The same causes may provoke either urticaria or angioedema.

• #16 Urticaria and Angioedema: A Practical Approach | AAFP

  https://www.aafp.org/pubs/afp/issues/2004/0301/p1123.html

  Immunologic urticaria and angioedema are a result of IgE antibody-mediated reactions that usually occur within one hour of exposure to the allergen. […] A rarer cause of acute urticaria is a type II hypersensitivity reaction mediated by cytotoxic antibodies and complement activation. […] Urticaria also has been associated with herpes virus, cytomegalovirus, Epstein-Barr virus, and chronic hepatitis infections, and with bacterial, fungal, and parasitic infections. […] Angioedema has been reported in patients taking angiotensin-converting enzyme inhibitors. […] Although most cases of urticaria and angioedema are idiopathic with benign courses, physicians should follow up on factors that might appear inconsequential at first but may prove to be worthy of further evaluation.

• #17 Angioedema – Immunology; Allergic Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/immunology-allergic-disorders/allergic-autoimmune-and-other-hypersensitivity-disorders/angioedema

  Angioedema is swelling (usually localized) of the subcutaneous tissues due to increased vascular permeability and extravasation of intravascular fluid. […] Known mediators of increased vascular permeability include the following: Mast cell-derived mediators (eg, histamine, leukotrienes, prostaglandins) […] Bradykinin and complement-derived mediators. […] In bradykinin-mediated angioedema, the dermis is usually spared, so urticaria and pruritus are absent. […] Several causes (eg, calcium channel blockers, fibrinolytic agents) have no identified mechanism; sometimes a cause (eg, muscle relaxants) with a known mechanism is overlooked clinically. […] Acute angioedema is mast cell-mediated in 90% of cases. […] Angiotensin-converting enzyme (ACE) inhibitors cause about 30% of cases of acute angioedema seen in emergency departments.

• #18 Angioedema • LITFL Medical Blog • CCC Airway

  https://litfl.com/angioedema/

  Angioedema may be histamine-mediated or non-histamine-mediated: […] histamine-mediated angioedema may co-exist with urticaria and is mast-cell mediated […] non-histaminergic (bradykinin-mediated) angioedema tends to be more severe, more prolonged and less responsive to adrenaline […] includes ACEI-related angioedema and both hereditary and acquired C1 esterase inhibitor deficiency.

• #19 Angioedema – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK538489/

  In describing pathophysiology, angioedema is classified as histamine-mediated angioedema and bradykinin-mediated angioedema. […] Histamine-mediated angioedema is the most common and is secondary to mast-cells and basophil activation. […] Bradykinin-mediated angioedema (hereditary angioedema, acquired C1-inhibitor deficiency and angiotensin-converting enzyme inhibitor-associated angioedema). Allergic reactions and hives do not trigger this condition. C1-inhibitor is a regulator of complement and the contact system; if deficient or dysfunctional it causes activation of the contact system resulting in uncontrolled production of kallikrein leading to proteolysis of high-molecular-weight kininogen and bradykinin, leading to edema by increasing in vascular permeability. […] Genetics: Hereditary angioedema can be secondary to F12 gene, angiopoietin-1, and plasminogen or some unknown gene mutation.

• #20 Angioedema – Wikipedia

  https://en.wikipedia.org/wiki/Angioedema

  The underlying mechanism typically involves histamine or bradykinin. […] In hereditary angioedema, bradykinin plays a critical role in all forms of the condition. […] Various mechanisms that interfere with bradykinin production or degradation can lead to angioedema. […] In hereditary angioedema, bradykinin formation is caused by continuous activation of the complement system due to a deficiency in one of its prime inhibitors, C1-esterase. […] The pathogenesis of hereditary angioedema is suspected to be related to unopposed activation of the contact pathway by the initial generation of kallikrein and/or clotting factor XII by damaged endothelial cells. […] The end product of this cascade, bradykinin, is produced in large amounts and is believed to be the predominant mediator leading to increased vascular permeability and vasodilation that induces typical angioedema „attacks”.

• #21 Hereditary Angioedema Mechanism of Disease & Pathogenesis

  https://www.discoverhae.com/hcp/hae-mechanism-of-disease

  Most cases of hereditary angioedema (HAE) are caused by a deficiency or dysfunction of C1 esterase inhibitor (C1-INH), resulting in the inability to regulate the contact system. C1-INH inhibits plasma kallikrein and coagulation factor XIIa. In the absence of functional C1-INH, activated factor XII (factor XIIa) activates prekallikrein to form kallikrein, which can then rapidly activate factor XII, resulting in a positive feedback loop. […] HAE attacks are initiated when the kallikrein-kinin cascade is activated. […] In response to this activation, plasma kallikrein activity increases the cleavage of high-molecular-weight kininogen (HMWK) to produce bradykinin. […] Excessive bradykinin, after binding to bradykinin B2 receptors, causes an increase in blood vessel permeability. This allows fluid to pass through the blood vessel walls, causing subcutaneous or submucosal swelling.

• #22 Bradykinin-induced angioedema in the emergency department | International Journal of Emergency Medicine | Full Text

  https://intjem.biomedcentral.com/articles/10.1186/s12245-022-00408-6

  The contact pathway is initiated when factor XII (or Hageman factor) binds to damaged tissue and converts to factor XIIa, which then converts prekallikrein to plasma kallikrein. Finally, kallikrein cleaves HMWK to form bradykinin, which binds B2 receptors on the vascular endothelium, triggering vasodilation and increased permeability. […] Bradykinin-induced angioedema may be hereditary, acquired or drug induced. […] Bradykinin binds the bradykinin B2 receptor on the vascular endothelium, stimulating substance P release and inducing angioedema. […] C1 esterase inhibitor (C1-INH), which acts as a brake on the complement system, blocks bradykinin overproduction via the contact system. […] Hereditary angioedema (HAE) arises from mutations in the gene encoding C1-INH, reducing its expression (type I) or function (type II).

• #23 Hereditary Angioedema: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/135604-overview

  C1-INH is a member of the serpin family of protease inhibitors, as are alpha-antitrypsin, antithrombin III, and angiotensinogen. These proteins stoichiometrically inactivate their target proteases by forming stable, one-to-one complexes with the protein to be inhibited. […] Deficiencies in C1-INH allow unchecked activation of the classic complement pathway and other biochemical systems including the bradykinin system. Patients can present with any combination of painless, nonpruritic, nonpitting swelling of the skin (cutaneous angioedema); severe abdominal pain; or acute airway obstruction. […] Evidence is now overwhelming that bradykinin is the mediator responsible for capillary leakage. Researchers have demonstrated activation of the kinin system with increased blood bradykinin levels associated with clinical flares. Bradykinin is an important inflammatory mediator formed by the action of the plasma enzyme kallikrein on the substrate high molecular weight kininogen that causes neutrophil chemotaxis, capillary dilation with plasma leakage, and smooth muscle relaxation, and it has been linked to other forms of angioedema.

• #24 Hereditary Angioedema: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/135604-overview

  C1-INH is a member of the serpin family of protease inhibitors, as are alpha-antitrypsin, antithrombin III, and angiotensinogen. These proteins stoichiometrically inactivate their target proteases by forming stable, one-to-one complexes with the protein to be inhibited. […] Deficiencies in C1-INH allow unchecked activation of the classic complement pathway and other biochemical systems including the bradykinin system. Patients can present with any combination of painless, nonpruritic, nonpitting swelling of the skin (cutaneous angioedema); severe abdominal pain; or acute airway obstruction. […] Evidence is now overwhelming that bradykinin is the mediator responsible for capillary leakage. Researchers have demonstrated activation of the kinin system with increased blood bradykinin levels associated with clinical flares. Bradykinin is an important inflammatory mediator formed by the action of the plasma enzyme kallikrein on the substrate high molecular weight kininogen that causes neutrophil chemotaxis, capillary dilation with plasma leakage, and smooth muscle relaxation, and it has been linked to other forms of angioedema.

• #25 Azthena logo with the word Azthena

  https://www.news-medical.net/health/Angioedema-Pathophysiology.aspx

  Pathogenesis of the types of angioedema has been studied extensively. […] Evidence shows that there is a C1 esterase inhibitor (C1 INH) deficiency. Normally C1 INH is responsible for regulation of activity of inflammatory mediators like complement component C1. Activation of C1 is the first step in the activation of complements and their role in inflammation. […] If there is a deficiency of C1 INH the mediators of inflammation like bradykinin, kallikrein, and plasmin become overtly active. […] Acquired angioedema also results due to C1 INH deficiency. There are 2 types of acquired angioedema and both have autoimmune mechanisms in their pathology. […] Angiotensin-Converting Enzyme Inhibitors or ACE inhibitors are one of the common drugs that cause angioedemas. This results mainly due to raised levels of bradykinins. […] In these conditions there is a raised level of several cytokines. There is an increased level of the cytokines granulocyte-macrophage colony-stimulating factor, interleukin (IL)-3, IL-5, and IL-6.

• #26 Hereditary Angioedema

  https://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/allergy/hereditary-angioedema/

  Hereditary angioedema arises from gene mutations that encode an important protease known as C1 inhibitor belonging to a serine superfamily of proteins. […] The principal mediator involved in HAE during episodes of swelling is bradykinin, a byproduct of the plasma contact system. The C1 inhibitor plays a significant role in the complement cascade, coagulation, and contact systems. […] In the setting of C1 inhibitor deficiency (type I HAE) or C1 inhibitor dysfunction (type II HAE), increased levels of bradykinin lead to recurrent episodes of angioedema. […] Deficiencies in either quantitative or functional levels of C1 inhibitor lead to increased production of bradykinin, the main mediator of recurrent episodes of swelling.

• #27 Angioedema – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK538489/

  In describing pathophysiology, angioedema is classified as histamine-mediated angioedema and bradykinin-mediated angioedema. […] Histamine-mediated angioedema is the most common and is secondary to mast-cells and basophil activation. […] Bradykinin-mediated angioedema (hereditary angioedema, acquired C1-inhibitor deficiency and angiotensin-converting enzyme inhibitor-associated angioedema). Allergic reactions and hives do not trigger this condition. C1-inhibitor is a regulator of complement and the contact system; if deficient or dysfunctional it causes activation of the contact system resulting in uncontrolled production of kallikrein leading to proteolysis of high-molecular-weight kininogen and bradykinin, leading to edema by increasing in vascular permeability. […] Genetics: Hereditary angioedema can be secondary to F12 gene, angiopoietin-1, and plasminogen or some unknown gene mutation.

• #28 Hereditary Angioedema Mechanism of Disease & Pathogenesis

  https://www.discoverhae.com/hcp/hae-mechanism-of-disease

  Most cases of hereditary angioedema (HAE) are caused by a deficiency or dysfunction of C1 esterase inhibitor (C1-INH), resulting in the inability to regulate the contact system. C1-INH inhibits plasma kallikrein and coagulation factor XIIa. In the absence of functional C1-INH, activated factor XII (factor XIIa) activates prekallikrein to form kallikrein, which can then rapidly activate factor XII, resulting in a positive feedback loop. […] HAE attacks are initiated when the kallikrein-kinin cascade is activated. […] In response to this activation, plasma kallikrein activity increases the cleavage of high-molecular-weight kininogen (HMWK) to produce bradykinin. […] Excessive bradykinin, after binding to bradykinin B2 receptors, causes an increase in blood vessel permeability. This allows fluid to pass through the blood vessel walls, causing subcutaneous or submucosal swelling.

• #29 Hereditary angioedema – Wikipedia

  https://en.wikipedia.org/wiki/Hereditary_angioedema

  Hereditary angioedema (HAE) is a disorder that results in recurrent attacks of severe swelling. The swelling most commonly affects the arms, legs, face, intestinal tract, and airway. If the intestinal tract is affected, abdominal pain and vomiting may occur. Swelling of the airway can result in its obstruction and trouble breathing. Without preventive treatment, attacks typically occur every two weeks and last for a few days. […] There are three main types of HAE. Types I and II are caused by a mutation in the SERPING1 gene, which encodes the C1 inhibitor protein, and type III now called HAE with Normal C1 esterase. The result is increased levels of bradykinin, which promotes swelling. The condition may be inherited in an autosomal dominant manner or occur as a new mutation. […] The pathophysiologic mechanisms contributing to bradykinin mediated angioedema in hereditary angioedema have been described. C1 inhibitor usually acts as an inhibitor of the plasma contact system. However, in hereditary angioedema with C1 inhibitor deficiency, C1 inhibitor is either reduced in quantity and function (type 1) or dysfunctional (type 2), this leads to bradykinin disinhibition and bradykinin mediated activation of bradykinin B1 receptor and bradykinin B2 receptor on endothelial cells (cells lining blood vessels). This activation leads to vascular endothelial cadherin (a type of cell adhesion molecule) phosphorylation, internalization and degradation. Cadherin degradation leads to actin cytoskeleton contraction and increased pore size of the vascular endothelial cells. Adherens junctions are also reduced due to bradykinin B1 and B2 receptor activation and vascular endothelial growth factor (VEGF) is also activated. The degradation of these endothelial intercellular barrier junctions mediated by histamine leads to increased vascular permeability, leading to vascular leakage into surrounding tissues and thus causing the characteristic swelling seen in hereditary angioedema. […] Normal C1 inhibitor level hereditary angioedema is thought to involve various mutations that increased bradykinin activity and cause a decreased threshold for activation of the plasma contact system thus leading to the symptoms of angioedema.

• #30 Hereditary Angioedema Mechanism of Disease & Pathogenesis

  https://www.discoverhae.com/hcp/hae-mechanism-of-disease

  In the classical complement pathway, insufficient or defective C1-INH also results in diminished levels of proteins such as C4, a useful biomarker in the diagnosis of HAE. […] HAE Types I and II are caused by a genetic mutation in the SERPING1 gene, which codes for C1-INH. […] HAE is an autosomal dominant genetic disorder, so a person with HAE has a 50% chance of passing it down to offspring.

• #31 Hereditary Angioedema: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/135604-overview

  C1-INH is a member of the serpin family of protease inhibitors, as are alpha-antitrypsin, antithrombin III, and angiotensinogen. These proteins stoichiometrically inactivate their target proteases by forming stable, one-to-one complexes with the protein to be inhibited. […] Deficiencies in C1-INH allow unchecked activation of the classic complement pathway and other biochemical systems including the bradykinin system. Patients can present with any combination of painless, nonpruritic, nonpitting swelling of the skin (cutaneous angioedema); severe abdominal pain; or acute airway obstruction. […] Evidence is now overwhelming that bradykinin is the mediator responsible for capillary leakage. Researchers have demonstrated activation of the kinin system with increased blood bradykinin levels associated with clinical flares. Bradykinin is an important inflammatory mediator formed by the action of the plasma enzyme kallikrein on the substrate high molecular weight kininogen that causes neutrophil chemotaxis, capillary dilation with plasma leakage, and smooth muscle relaxation, and it has been linked to other forms of angioedema.

• #32 Hereditary angioedema: Classification, pathogenesis, and diagnosi…: Ingenta Connect

  https://www.ingentaconnect.com/contentone/ocean/aap/2011/00000032/00000006/art00006

  Hereditary angioedema (HAE) is a rare autosomal dominant genetic disorder associated with a deficiency in C1 inhibitor. […] Decreased C1 inhibitor activity leads to inappropriate activation of multiple pathways, including the complement and contact systems and the fibrinolysis and coagulation systems. […] Reduced C1 inhibitor activity results in increased activation of plasma kallikrein-kinin system proteases and increased bradykinin levels. Bradykinin is felt to be the main mediator of symptoms in HAE. […] The treatment of HAE has improved significantly in recent years with the availability of several safe and effective therapies. […] This review will provide an update on the classification, pathophysiology, clinical presentation, and diagnosis of HAE.

• #33 Hereditary Angioedema

  https://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/allergy/hereditary-angioedema/

  Hereditary angioedema arises from gene mutations that encode an important protease known as C1 inhibitor belonging to a serine superfamily of proteins. […] The principal mediator involved in HAE during episodes of swelling is bradykinin, a byproduct of the plasma contact system. The C1 inhibitor plays a significant role in the complement cascade, coagulation, and contact systems. […] In the setting of C1 inhibitor deficiency (type I HAE) or C1 inhibitor dysfunction (type II HAE), increased levels of bradykinin lead to recurrent episodes of angioedema. […] Deficiencies in either quantitative or functional levels of C1 inhibitor lead to increased production of bradykinin, the main mediator of recurrent episodes of swelling.

• #34 Hereditary Angioedema: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/135604-overview

  There is no question that a relatively small subgroup of patients with HAE with normal C1 inhibitor have a factor XII mutation and it is presumed that this mutation is of importance in initiation of attacks. This may be closely related to endothelial cell activation and the initiation of attacks but further research is clearly needed.

• #35 Hereditary angioedema – Wikipedia

  https://en.wikipedia.org/wiki/Hereditary_angioedema

  Hereditary angioedema (HAE) is a disorder that results in recurrent attacks of severe swelling. The swelling most commonly affects the arms, legs, face, intestinal tract, and airway. If the intestinal tract is affected, abdominal pain and vomiting may occur. Swelling of the airway can result in its obstruction and trouble breathing. Without preventive treatment, attacks typically occur every two weeks and last for a few days. […] There are three main types of HAE. Types I and II are caused by a mutation in the SERPING1 gene, which encodes the C1 inhibitor protein, and type III now called HAE with Normal C1 esterase. The result is increased levels of bradykinin, which promotes swelling. The condition may be inherited in an autosomal dominant manner or occur as a new mutation. […] The pathophysiologic mechanisms contributing to bradykinin mediated angioedema in hereditary angioedema have been described. C1 inhibitor usually acts as an inhibitor of the plasma contact system. However, in hereditary angioedema with C1 inhibitor deficiency, C1 inhibitor is either reduced in quantity and function (type 1) or dysfunctional (type 2), this leads to bradykinin disinhibition and bradykinin mediated activation of bradykinin B1 receptor and bradykinin B2 receptor on endothelial cells (cells lining blood vessels). This activation leads to vascular endothelial cadherin (a type of cell adhesion molecule) phosphorylation, internalization and degradation. Cadherin degradation leads to actin cytoskeleton contraction and increased pore size of the vascular endothelial cells. Adherens junctions are also reduced due to bradykinin B1 and B2 receptor activation and vascular endothelial growth factor (VEGF) is also activated. The degradation of these endothelial intercellular barrier junctions mediated by histamine leads to increased vascular permeability, leading to vascular leakage into surrounding tissues and thus causing the characteristic swelling seen in hereditary angioedema. […] Normal C1 inhibitor level hereditary angioedema is thought to involve various mutations that increased bradykinin activity and cause a decreased threshold for activation of the plasma contact system thus leading to the symptoms of angioedema.

• #36 Angioedema – Immunology; Allergic Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/immunology-allergic-disorders/allergic-autoimmune-and-other-hypersensitivity-disorders/angioedema

  Angioedema is swelling (usually localized) of the subcutaneous tissues due to increased vascular permeability and extravasation of intravascular fluid. […] Known mediators of increased vascular permeability include the following: Mast cell-derived mediators (eg, histamine, leukotrienes, prostaglandins) […] Bradykinin and complement-derived mediators. […] In bradykinin-mediated angioedema, the dermis is usually spared, so urticaria and pruritus are absent. […] Several causes (eg, calcium channel blockers, fibrinolytic agents) have no identified mechanism; sometimes a cause (eg, muscle relaxants) with a known mechanism is overlooked clinically. […] Acute angioedema is mast cell-mediated in 90% of cases. […] Angiotensin-converting enzyme (ACE) inhibitors cause about 30% of cases of acute angioedema seen in emergency departments.

• #37 Why Do ACE Inhibitors Cause Angioedema? | Mt. Laurel, NJ

  https://www.beckerentandallergy.com/blog/ace-inhibitors-cause-angioedema

  Angiotensin-converting enzyme (ACE) inhibitors are a class of medications widely used to treat various health conditions. […] However, they can cause angioedema, a serious side effect characterized by the localized swelling of the deep dermis, subcutaneous, or submucosal tissue. […] This post aims to provide an in-depth understanding of why ACE inhibitors cause angioedema while covering the mechanisms involved in angiotensin-converting enzyme inhibitor-induced angioedema. […] ACE inhibitors can, unfortunately, lead to a serious side effect known as angioedema. This condition is characterized by rapid skin swelling, mucous membranes, and submandibular tissues. […] The development of angioedema from ACE inhibitors results from the medications impact on a peptide called bradykinin. […] ACE inhibitors block the degradation of bradykinin, leading to its accumulation in the body. This build-up of bradykinin in tissues, a phenomenon also known as ACE-I-induced angioedema triggers vasodilation, or the widening of blood vessels. This process, in turn, leads to fluid extravasation into deep tissues, which causes swelling.

• #38 ACE inhibitor-induced angioedema

  https://dermnetnz.org/topics/ace-inhibitor-induced-angioedema

  ACE inhibitor-induced angioedema is due to the inhibition of bradykinin degradation resulting in elevated plasma bradykinin. […] It is important to note ACE inhibitor-induced angioedema does not involve histamine. […] ACE inhibitor-induced angioedema is a bradykinin-mediated angioedema, so must be distinguished from histamine-mediated angioedemas.

• #39 Angioedema – assessment and treatment | Tidsskrift for Den norske legeforening

  https://tidsskriftet.no/en/2012/11/angioedema-assessment-and-treatment

  Angioedema has numerous hereditary, acquired and iatrogenic causes. […] The majority of angioedema patients have accompanying urticaria. Pathophysiologically, angioedemas are divided into histaminergic and non-histaminergic forms. […] Angioedema is a potentially life-threatening condition and should be assessed and treated systematically. It is important to remember that angioedema is either histaminergic or non-histaminergic, as the treatment of the two types is different. […] Histaminergic angioedema occurs when mast cells and basophil granulocytes release histamine and other vasoactive molecules. […] Non-histaminergic angioedema may be triggered by bradykinin and complement-derived mediators. […] ACE inhibitor treatment reduces the conversion of angiotensin I to angiotensin II and inhibits the degradation of bradykinin. An accumulation of bradykinin is therefore considered to be the most significant cause of angioedema induced by ACE inhibitor drugs. […] Patients with hereditary angioedema are deficient in C1INH or there are deficiencies in the functional activity of C1INH, which ultimately increases the amount of bradykinin. […] Autoimmune thyroid disease may present with angioedema.

• #40 :: Clinical and Experimental Emergency Medicine

  https://www.ceemjournal.org/m/journal/view.php?doi=10.15441/ceem.23.051

  Approximately 0.7% of patients taking angiotensin-converting enzyme inhibitors (ACEIs) develop ACEI-induced angioedema (ACEI-IA). […] The pathophysiology of angioedema involves a rapid increase in vascular permeability and subsequent submucosal edema. With ACE inhibition, the reduced kininase II mediated degradation of substance P and bradykinin causes excessive vasodilation and plasma extravasation. […] The mechanism of action for TXA in the treatment of ACEI-IA is not well understood. However, blockage of plasmin activation by TXA contributes to its antifibrinolytic effect and is an important step in amplifying kallikrein (a precursor of bradykinin) activation. TXA prevents fibrin-induced inflammatory peptides and decreases the conversion of kininogen into bradykinin. […] Further research is needed to clarify the exact mechanisms by which TXA exerts its therapeutic effects in this population.

• #41 Why Do ACE Inhibitors Cause Angioedema? | Mt. Laurel, NJ

  https://www.beckerentandallergy.com/blog/ace-inhibitors-cause-angioedema

  Angiotensin-converting enzyme (ACE) inhibitors are a class of medications widely used to treat various health conditions. […] However, they can cause angioedema, a serious side effect characterized by the localized swelling of the deep dermis, subcutaneous, or submucosal tissue. […] This post aims to provide an in-depth understanding of why ACE inhibitors cause angioedema while covering the mechanisms involved in angiotensin-converting enzyme inhibitor-induced angioedema. […] ACE inhibitors can, unfortunately, lead to a serious side effect known as angioedema. This condition is characterized by rapid skin swelling, mucous membranes, and submandibular tissues. […] The development of angioedema from ACE inhibitors results from the medications impact on a peptide called bradykinin. […] ACE inhibitors block the degradation of bradykinin, leading to its accumulation in the body. This build-up of bradykinin in tissues, a phenomenon also known as ACE-I-induced angioedema triggers vasodilation, or the widening of blood vessels. This process, in turn, leads to fluid extravasation into deep tissues, which causes swelling.

• #42 Use of Tranexamic Acid Prevents Intubation in ACE Inhibitor-Induced Angioedema

  https://clinmedjournals.org/articles/ijccem/international-journal-of-critical-care-and-emergency-medicine-ijccem-7-127.php?jid=ijccem

  Angiotensin-converting enzyme inhibitors (ACE-I) are medications within the antihypertensive class that are used by nearly 108 million patients worldwide. A rare but possibly life-threatening adverse effect of ACE-I is angioedema, which occurs due to elevated levels of bradykinin. […] The development of ACE-I induced angioedema (ACE-AE) originates with kallikrein, which cleaves high molecular weight kininogen to generate bradykinin. […] Angioedema presents as asymmetric swelling of the face, lips, larynx, genitalia, or extremities. It occurs due to elevated levels of bradykinin, leading to vasodilation of blood vessels, increased vascular permeability, and plasma extravasation into the submucosal tissue. […] A more novel approach in the acute management of ACE-AE involves TXA. As seen in Figure 1, TXA inhibits the conversion of plasminogen to plasmin, which is responsible for activating factor XII to factor XIIa. Factor XIIa stimulates kallikrein activation and cleaves kininogen, which produces bradykinin. By reducing the amount of bradykinin, TXA can improve ACE-AE and prevent impending intubation.

• #43 Angioedema due to acquired C1-Inhibitor deficiency | British Society for Immunology

  https://www.immunology.org/public-information/bitesized-immunology/immune-dysfunction/angioedema-due-acquired-c1-inhibitor

  Acquired angioedema (AAE) due to deficiency of C1-inhibitor is a relatively infrequently occurring but serious disorder, resulting in severe, sometimes life-threatening, episodes of angioedema. […] The main causes of acquired C1-inhibitor deficiency are lymphoproliferative disease and autoimmune disease. Most cases of acquired C1-inhibitor deficiency are associated with an underlying B-cell disorder, ranging from auto-immune anti-C1-inhibitor auto-antibodies to lymphoproliferative disease (usually a low grade or splenic marginal zone lymphoma). There are two mechanisms which can lead to this condition: consumption due to complement activation, or (rarely) due to an autoantibody directed against C1-inhibitor. […] A better understanding of the pathogenesis of lymphoproliferative disorders causing acquired C1-inhibitor deficiency may lead to more targeted and effective treatment modalities.

• #44 Angioedema due to acquired C1-Inhibitor deficiency | British Society for Immunology

  https://www.immunology.org/public-information/bitesized-immunology/immune-dysfunction/angioedema-due-acquired-c1-inhibitor

  Acquired angioedema (AAE) due to deficiency of C1-inhibitor is a relatively infrequently occurring but serious disorder, resulting in severe, sometimes life-threatening, episodes of angioedema. […] The main causes of acquired C1-inhibitor deficiency are lymphoproliferative disease and autoimmune disease. Most cases of acquired C1-inhibitor deficiency are associated with an underlying B-cell disorder, ranging from auto-immune anti-C1-inhibitor auto-antibodies to lymphoproliferative disease (usually a low grade or splenic marginal zone lymphoma). There are two mechanisms which can lead to this condition: consumption due to complement activation, or (rarely) due to an autoantibody directed against C1-inhibitor. […] A better understanding of the pathogenesis of lymphoproliferative disorders causing acquired C1-inhibitor deficiency may lead to more targeted and effective treatment modalities.

• #45 Angioedema due to acquired C1-Inhibitor deficiency | British Society for Immunology

  https://www.immunology.org/public-information/bitesized-immunology/immune-dysfunction/angioedema-due-acquired-c1-inhibitor

  Acquired angioedema (AAE) due to deficiency of C1-inhibitor is a relatively infrequently occurring but serious disorder, resulting in severe, sometimes life-threatening, episodes of angioedema. […] The main causes of acquired C1-inhibitor deficiency are lymphoproliferative disease and autoimmune disease. Most cases of acquired C1-inhibitor deficiency are associated with an underlying B-cell disorder, ranging from auto-immune anti-C1-inhibitor auto-antibodies to lymphoproliferative disease (usually a low grade or splenic marginal zone lymphoma). There are two mechanisms which can lead to this condition: consumption due to complement activation, or (rarely) due to an autoantibody directed against C1-inhibitor. […] A better understanding of the pathogenesis of lymphoproliferative disorders causing acquired C1-inhibitor deficiency may lead to more targeted and effective treatment modalities.

• #46 The Role of the Plasminogen Activation System in Angioedema: Novel Insights on the Pathogenesis

  https://www.mdpi.com/2077-0383/10/3/518

  The main physiological functions of plasmin, the active form of its proenzyme plasminogen, are blood clot fibrinolysis and restoration of normal blood flow. […] Recently, the link between PA system and angioedema has been a subject of scientific debate. Angioedema is defined as localized and self-limiting edema of subcutaneous and submucosal tissues, mediated by bradykinin and mast cell mediators. […] In this review we aimed to summarize the recent advances in the AE pathogenesis, focusing on the role of the plasminogen activation (PA) system. […] The pathogenesis of angioedema (AE) reflects an intricate relationship among the coagulation system, the contact system, and the fibrinolytic system. Uncontrolled activation of these pathways triggers endothelial cell activation, increased vascular permeability, edema, and inflammation.

• #47 The Role of the Plasminogen Activation System in Angioedema: Novel Insights on the Pathogenesis

  https://www.mdpi.com/2077-0383/10/3/518

  The fibrinolytic system is associated at several levels with bradykinin-forming cascade, as shown in Figure 2. […] To complicate the picture of the intricate molecular network of the PA system is the multiple relationships with the complement system. […] In addition to these considerations, different alterations of the PA system in patients with AE, detected by laboratory tests and genetic analysis, have been described in literature. […] The first data that correlate fibrinolytic system to AE pathophysiology date back to 1985, when Nilsson T. et al. showed a constantly fibrinolysis activation during acute attacks in patients with hereditary angioedema with C1-INH deficiency (C1-INH-HAE). […] Currently, the model of “plasminflammation” has been proposed as a key pathway driving HAE pathogenesis.

• #48 The Role of the Plasminogen Activation System in Angioedema: Novel Insights on the Pathogenesis

  https://www.mdpi.com/2077-0383/10/3/518

  The main physiological functions of plasmin, the active form of its proenzyme plasminogen, are blood clot fibrinolysis and restoration of normal blood flow. […] Recently, the link between PA system and angioedema has been a subject of scientific debate. Angioedema is defined as localized and self-limiting edema of subcutaneous and submucosal tissues, mediated by bradykinin and mast cell mediators. […] In this review we aimed to summarize the recent advances in the AE pathogenesis, focusing on the role of the plasminogen activation (PA) system. […] The pathogenesis of angioedema (AE) reflects an intricate relationship among the coagulation system, the contact system, and the fibrinolytic system. Uncontrolled activation of these pathways triggers endothelial cell activation, increased vascular permeability, edema, and inflammation.

• #49 The Role of the Plasminogen Activation System in Angioedema: Novel Insights on the Pathogenesis

  https://www.mdpi.com/2077-0383/10/3/518

  Several recent evidences have highlighted the central role of the PA system in the unregulated production of the inflammatory mediator bradykinin in HAE-1 and HAE-2 forms. […] Important evidence highlighting the role of the PA system in HAE pathogenesis is the use of antifibrinolytic drugs for prophylaxis and management of acute attacks. […] The therapeutic benefits arising from targeting the PA system support the active role of plasminogen activation in the pathogenesis of classical forms of HAE. […] The engagement of mutant plasminogen is reported as a critical step in the disease mechanisms. Mutant plasminogen is more accessible to plasminogen activators (such as uPA and tPA), with subsequent excessive plasmin-mediated generation of vasoactive bradykinin peptide in affected tissues.

• #50 The Role of the Plasminogen Activation System in Angioedema: Novel Insights on the Pathogenesis

  https://www.mdpi.com/2077-0383/10/3/518

  Several recent evidences have highlighted the central role of the PA system in the unregulated production of the inflammatory mediator bradykinin in HAE-1 and HAE-2 forms. […] Important evidence highlighting the role of the PA system in HAE pathogenesis is the use of antifibrinolytic drugs for prophylaxis and management of acute attacks. […] The therapeutic benefits arising from targeting the PA system support the active role of plasminogen activation in the pathogenesis of classical forms of HAE. […] The engagement of mutant plasminogen is reported as a critical step in the disease mechanisms. Mutant plasminogen is more accessible to plasminogen activators (such as uPA and tPA), with subsequent excessive plasmin-mediated generation of vasoactive bradykinin peptide in affected tissues.

• #51 Use of Tranexamic Acid Prevents Intubation in ACE Inhibitor-Induced Angioedema

  https://clinmedjournals.org/articles/ijccem/international-journal-of-critical-care-and-emergency-medicine-ijccem-7-127.php?jid=ijccem

  Angiotensin-converting enzyme inhibitors (ACE-I) are medications within the antihypertensive class that are used by nearly 108 million patients worldwide. A rare but possibly life-threatening adverse effect of ACE-I is angioedema, which occurs due to elevated levels of bradykinin. […] The development of ACE-I induced angioedema (ACE-AE) originates with kallikrein, which cleaves high molecular weight kininogen to generate bradykinin. […] Angioedema presents as asymmetric swelling of the face, lips, larynx, genitalia, or extremities. It occurs due to elevated levels of bradykinin, leading to vasodilation of blood vessels, increased vascular permeability, and plasma extravasation into the submucosal tissue. […] A more novel approach in the acute management of ACE-AE involves TXA. As seen in Figure 1, TXA inhibits the conversion of plasminogen to plasmin, which is responsible for activating factor XII to factor XIIa. Factor XIIa stimulates kallikrein activation and cleaves kininogen, which produces bradykinin. By reducing the amount of bradykinin, TXA can improve ACE-AE and prevent impending intubation.

• #52 The Role of the Plasminogen Activation System in Angioedema: Novel Insights on the Pathogenesis

  https://www.mdpi.com/2077-0383/10/3/518

  The main physiological functions of plasmin, the active form of its proenzyme plasminogen, are blood clot fibrinolysis and restoration of normal blood flow. […] Recently, the link between PA system and angioedema has been a subject of scientific debate. Angioedema is defined as localized and self-limiting edema of subcutaneous and submucosal tissues, mediated by bradykinin and mast cell mediators. […] In this review we aimed to summarize the recent advances in the AE pathogenesis, focusing on the role of the plasminogen activation (PA) system. […] The pathogenesis of angioedema (AE) reflects an intricate relationship among the coagulation system, the contact system, and the fibrinolytic system. Uncontrolled activation of these pathways triggers endothelial cell activation, increased vascular permeability, edema, and inflammation.

• #53 The Role of the Plasminogen Activation System in Angioedema: Novel Insights on the Pathogenesis

  https://www.mdpi.com/2077-0383/10/3/518

  The main physiological functions of plasmin, the active form of its proenzyme plasminogen, are blood clot fibrinolysis and restoration of normal blood flow. […] Recently, the link between PA system and angioedema has been a subject of scientific debate. Angioedema is defined as localized and self-limiting edema of subcutaneous and submucosal tissues, mediated by bradykinin and mast cell mediators. […] In this review we aimed to summarize the recent advances in the AE pathogenesis, focusing on the role of the plasminogen activation (PA) system. […] The pathogenesis of angioedema (AE) reflects an intricate relationship among the coagulation system, the contact system, and the fibrinolytic system. Uncontrolled activation of these pathways triggers endothelial cell activation, increased vascular permeability, edema, and inflammation.

• #54 The Role of the Plasminogen Activation System in Angioedema: Novel Insights on the Pathogenesis

  https://www.mdpi.com/2077-0383/10/3/518

  The role of the complement system in the generation of immunologic and/or allergic disease is of particular interest. […] The cross talk between the fibrinolytic system and the complement system amplifies the inflammatory process with the release of mighty inflammation mediators. […] The several scientific evidences described in this paper highlight the loop in which the PA system, the contact system that generates bradykinin, and the complement system are connected.

• #55 Angioedema – EMCrit Project

  https://emcrit.org/ibcc/angioedema/

  Angioedema may be divided into histamine-mediated versus bradykinin-mediated etiologies. This is an essential differentiation, because the treatment for these two entities is entirely different. […] Bradykinin angioedema involves a vicious spiral involving plasmin, XIIa, and kallekrine as shown above. These proteins enzymatically activate one another, leading to an explosion of inflammatory kallekrine activity. This leads to the generation of bradykinin, which causes edema. […] Allergy-type therapies (steroid, antihistamine, epinephrine) do not work for bradykinin-mediated angioedema. These therapies should only be used if there is confusion about whether the angioedema could be histamine-mediated. […] C1-inhibitor inhibits XIIa and kallikrein, perhaps the two most important enzymes involved in bradykinin generation. Based on its ability to inhibit multiple enzymes which are centrally placed in the spiral of kallikrein activation, this drug would be predicted to be very useful in bradykinin-induced angioedema.

• #56 Angioedema – Immunology; Allergic Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/immunology-allergic-disorders/allergic-autoimmune-and-other-hypersensitivity-disorders/angioedema

  Angioedema is swelling (usually localized) of the subcutaneous tissues due to increased vascular permeability and extravasation of intravascular fluid. […] Known mediators of increased vascular permeability include the following: Mast cell-derived mediators (eg, histamine, leukotrienes, prostaglandins) […] Bradykinin and complement-derived mediators. […] In bradykinin-mediated angioedema, the dermis is usually spared, so urticaria and pruritus are absent. […] Several causes (eg, calcium channel blockers, fibrinolytic agents) have no identified mechanism; sometimes a cause (eg, muscle relaxants) with a known mechanism is overlooked clinically. […] Acute angioedema is mast cell-mediated in 90% of cases. […] Angiotensin-converting enzyme (ACE) inhibitors cause about 30% of cases of acute angioedema seen in emergency departments.

• #57 Cross-Reactivity of ACE Inhibitor–Induced Angioedema with ARBs

  https://www.uspharmacist.com/article/cross-reactivity-of-ace-inhibitorinduced-angioedema-with-arbs

  Angioedema is a localized, noninflammatory, nonpruritic swelling of the skin characterized by a buildup of fluid in the interstitial tissue. It can also involve the lips, tongue, intestine, and other peripheral tissues, particularly those containing less connective tissue. […] The common cellular mechanism among these causes appears to be activation of the complement system and/or other pro-inflammatory cytokines such as prostaglandins and histamine, which can result in rapid vasodilatation and edema. […] It has been theorized that ACE inhibitor-mediated angioedema results from an elevation in bradykinin levels, similar to cough. […] Elevated bradykinin levels in the peripheral tissues results in rapid fluid accumulation. Currently, this is the most accepted theory for why ACE inhibitors cause angioedema, but it has not been definitively proven.

• #58 Angioedema secondary to amlodipine and lisinopril: a documented progression | BMJ Case Reports

  https://casereports.bmj.com/content/12/9/e232019

  A 50-year-old man with a polycystic kidney disease, awoke from sleep with unilateral jaw swelling. […] Given the patients presenting features in combination with lack of therapeutic response, the presumptive diagnosis of angioedema was made. […] The presentation of non-heretidary, non-allergic angioedema is often attributed to medications such as ACE inhibitors. Excess bradykinin, causes increased vasodilation and capillary permeability, resulting in the presenting oedema. ACE inhibitors block the ACE, preventing the secondary function of bradykinin degredation. More recently, calcium channel blockers have also been implicated in angioedema; however, the mechanism is still unknown. […] Given the increased frequency of this patients facial oedema, following introduction of amlodipine his angioedema was attributed to a combination of two precipitating agents and mechanisms: amlodipine and lisinopril.

• #59 Angioedema – Core EM

  https://coreem.net/core/angioedema/

  Mechanism and Pathophysiology: […] Mast Cell (granulocyte) Mediated […] Mast cell activation (by IgE crosslinking or directly) leads to the generation of mediators (histamine, heparin, leukotriene and prostaglandin D2), which increases vascular permeability. […] IgE Dependent (Type I Hypersensitivity) Reactions […] Pro-inflammatory mediators then act on the mucosa and cause angioedema. These chemicals can recruit other cells, like eosinophils, and may lead to anaphylaxis. […] NSAIDs hinder the formation of prostaglandins within mast cells and other leukocytes. This can cause an abundance of leukotrienes and other pro-inflammatory mediators and precipitate angioedema (Nzeako 2010). […] Bradykinin Mediated […] Plasma globulins called kininogens release bradykinin and cause vascular permeability.

• #60

  https://www.aaaai.org/allergist-resources/ask-the-expert/answers/old-ask-the-experts/dpp

  Angioedema associated with DPP-4 inhibitors, including sitagliptin, has been reported in a number of publications. […] The true incidence of angioedema due to DPP-4 inhibitors is unknown, but given the role of DPP-4 in bradykinin and substance P degradation, and evidence of variable DPP-4 expression in humans (whether genetically determined or due to external factors such as immunosuppressants), a very plausible mechanism exists for non-histaminergic angioedema associated with this class of medications. […] That said, since C1INH lab results are normal, the Factor XII mutation analysis is the remaining readily available commercial test that could most definitively confirm a mechanism of angioedema. […] The natural history of DPP-4 inhibitor associated angioedema is poorly defined and while it appears to be less common and severe than ACE-I associated angioedema, it’s possible that similar to ACE-I associated angioedema symptoms could recur sporadically for a few months following medication discontinuation in some patients.

• #61 Cross-Reactivity of ACE Inhibitor–Induced Angioedema with ARBs

  https://www.uspharmacist.com/article/cross-reactivity-of-ace-inhibitorinduced-angioedema-with-arbs

  One theory is that stimulation of the angiotensin II receptor activates the bradykinin-prostaglandin-nitric oxide cascade, resulting in bradykinin-mediated side effects from both ARBs and ACE inhibitors; however, the angiotensin II function has not been fully elucidated. […] Further study is needed on the mechanism for angioedema jointly induced by these agents. […] It is possible that there are common pathways for ACE inhibitor and ARB-induced angioedema beyond bradykinin that have yet to be discovered.

• #62 Angioedema in the emergency department: a practical guide to differential diagnosis and management | International Journal of Emergency Medicine | Full Text

  https://intjem.biomedcentral.com/articles/10.1186/s12245-017-0141-z

  To ensure appropriate treatment and management, determination of whether the angioedema is mediated by histamine or bradykinin is essential. […] With the current lack of a reliable point-of-care test to distinguish the two pathophysiologies, ED physicians should familiarize themselves with available indicators to help guide treatment decisions.

• #63 Angioedema – assessment and treatment | Tidsskrift for Den norske legeforening

  https://tidsskriftet.no/en/2012/11/angioedema-assessment-and-treatment

  Angioedema has numerous hereditary, acquired and iatrogenic causes. […] The majority of angioedema patients have accompanying urticaria. Pathophysiologically, angioedemas are divided into histaminergic and non-histaminergic forms. […] Angioedema is a potentially life-threatening condition and should be assessed and treated systematically. It is important to remember that angioedema is either histaminergic or non-histaminergic, as the treatment of the two types is different. […] Histaminergic angioedema occurs when mast cells and basophil granulocytes release histamine and other vasoactive molecules. […] Non-histaminergic angioedema may be triggered by bradykinin and complement-derived mediators. […] ACE inhibitor treatment reduces the conversion of angiotensin I to angiotensin II and inhibits the degradation of bradykinin. An accumulation of bradykinin is therefore considered to be the most significant cause of angioedema induced by ACE inhibitor drugs. […] Patients with hereditary angioedema are deficient in C1INH or there are deficiencies in the functional activity of C1INH, which ultimately increases the amount of bradykinin. […] Autoimmune thyroid disease may present with angioedema.

• #64 Angioedema – Immunology; Allergic Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/immunology-allergic-disorders/allergic-autoimmune-and-other-hypersensitivity-disorders/angioedema

  The cause of chronic ( 6 weeks) angioedema is usually unknown. […] Hereditary angioedema and acquired angioedema are disorders that are characterized by abnormal complement responses and caused by deficiency or dysfunction of C1 inhibitor. […] Symptoms are those of bradykinin-mediated angioedema. […] For ACE inhibitor-related angioedema, occasionally fresh frozen plasma and C1 inhibitor concentrate may be used. […] For bradykinin-mediated angioedema, epinephrine, corticosteroids, and antihistamines have not been shown to be effective. […] Angioedema due to ACE inhibitor use usually resolves about 24 to 48 hours after stopping the medication.

• #65 Angioedema – EMCrit Project

  https://emcrit.org/ibcc/angioedema/

  Angioedema may be divided into histamine-mediated versus bradykinin-mediated etiologies. This is an essential differentiation, because the treatment for these two entities is entirely different. […] Bradykinin angioedema involves a vicious spiral involving plasmin, XIIa, and kallekrine as shown above. These proteins enzymatically activate one another, leading to an explosion of inflammatory kallekrine activity. This leads to the generation of bradykinin, which causes edema. […] Allergy-type therapies (steroid, antihistamine, epinephrine) do not work for bradykinin-mediated angioedema. These therapies should only be used if there is confusion about whether the angioedema could be histamine-mediated. […] C1-inhibitor inhibits XIIa and kallikrein, perhaps the two most important enzymes involved in bradykinin generation. Based on its ability to inhibit multiple enzymes which are centrally placed in the spiral of kallikrein activation, this drug would be predicted to be very useful in bradykinin-induced angioedema.

• #66 Angioedema in the emergency department: a practical guide to differential diagnosis and management | International Journal of Emergency Medicine | Full Text

  https://intjem.biomedcentral.com/articles/10.1186/s12245-017-0141-z

  To ensure appropriate treatment and management, determination of whether the angioedema is mediated by histamine or bradykinin is essential. […] With the current lack of a reliable point-of-care test to distinguish the two pathophysiologies, ED physicians should familiarize themselves with available indicators to help guide treatment decisions.

• #67 Angioedema in the emergency department: a practical guide to differential diagnosis and management | International Journal of Emergency Medicine | Full Text

  https://intjem.biomedcentral.com/articles/10.1186/s12245-017-0141-z

  Angioedema is mediated by several mechanisms, including histamine and bradykinin. […] The mechanism of a third type of HAE with normal C1-INH concentrations and function is not yet fully understood. […] Another cause of bradykinin-mediated angioedema is associated with ACEis. […] Angiotensin-converting enzyme is one of the two enzymes that degrade bradykinin; ACEis can cause accumulation of bradykinin that results in angioedema (ACEi-induced angioedema). […] Response to treatment with antihistamines, corticosteroids, and epinephrine may distinguish histamine- and bradykinin-mediated angioedema. […] Although response or lack of response to treatment is not an appropriate diagnostic measure in the ED, the effect of treatment can be a useful clinical clue for follow-up and subsequent diagnosis.

• #68 Angioedema Center – Current and Ongoing Basic Research

  https://www.angioedemacenter.com/research.php

  Elucidating the Mechanism of Gain of Toxic Function from Mutant C1 Inhibitor Proteins in Hereditary Angioedema […] The reason for the much lower C1INH level in most patients has been a mystery. […] This provides a possible explanation for the low C1INH levels in HAE and therefore for the severity of the disease. […] The concept that acquired defects in secretion of wildtype C1INH may influence disease severity provides a novel basis for understanding HAE, and an opportunity to explore new molecular therapeutic interventions. […] In HAE-C1INH, the mediator of swelling has been shown to be bradykinin that is generated through activation of the contact system. […] Increased generation of a small peptide called bradykinin from blood proteins has been proven to be the cause of swelling attacks in patients with hereditary angioedema.

• #69 Angioedema Center – Current and Ongoing Basic Research

  https://www.angioedemacenter.com/research.php

  Evidence has accumulated that a second bradykinin receptor (B1 receptor) may also be involved; however, little is known about the bradykinin B1 receptor in angioedema. […] The information from these experiments will likely be useful in helping us know how to better manage patients with hereditary angioedema and could lead to new approaches to the treatment of the disease. […] The factors that determine severity of HAE remain poorly understood. […] By studying SNPs on DNA isolated from blood cells, they are hoping to better understand and predict which patients will have mild, moderate or severe HAE. […] Correcting the mutation could result in a cure for HAE.

• #70 FDA Drug Approval Decisions Expected in June 2025 – The Cardiology Advisor

  https://www.thecardiologyadvisor.com/news/fda-drug-approval-decisions-expected-in-june-2025/

  Sebetralstat is an oral plasma kallikrein inhibitor designed to target the kallikrein-kinin system cascade. […] Findings showed patients experienced significantly faster symptom relief from HAE attacks with sebetralstat 300mg (P .0001) and 600mg (P =.0013) compared with placebo. […] The oral medication allowed for early treatment (median 11.5 minutes); median time to beginning of symptom relief was 1.29 hours.

• #71 Pathogenesis of Hereditary Angioedema : The Role of the Bradykinin-Forming Cascade – EM consulte

  https://www.em-consulte.com/article/1129956/pathogenesis-of-hereditary-angioedema-the-role-of-

  Hereditary angioedema (HAE) is an autosomal-dominant disorder owing to mutations in the C1 inhibitor gene. […] When functional levels drop beyond 40% of normal, attacks of swelling are likely to occur due to overproduction of bradykinin. […] Therapies include C1 inhibitor replacement for prophylaxis or acute therapy, whereas inhibition of kallikrein or blockade at the bradykinin receptor level can interrupt acute episodes of swelling. […] Bradykinin is the mediator of swelling in hereditary angioedema types I and II. […] The pathway(s) of bradykinin formation in types I and II hereditary angioedema. […] Vasopermeability owing to bradykinin. […] Assembly and activation of the bradykinin-forming cascade on endothelial cells.

• #72 Frontiers | Genetic and Immunological Insights into Angioedema Without Wheals

  https://www.frontiersin.org/research-topics/58194/pathogenesis-and-diagnosis-of-angioedema-without-wheals—have-we-revealed-all-secret-paths/articles

  Angioedema without wheals (AE) is a distinct clinical condition characterized by self-limiting and localized edema that occurs without the presence of urticaria. […] Despite advancements in understanding the pathogenesis of AE, there remain significant gaps in knowledge, particularly concerning the genetic and immunological underpinnings of the condition. […] This research topic aims to explore the pathogenesis and diagnosis of angioedema without wheals, with the objective of uncovering the underlying mechanisms and improving patient management. […] By testing hypotheses related to the immunological pathways involved in AE, this research seeks to enhance the understanding of the condition and provide a foundation for more accurate and timely diagnosis and treatment. […] To gather further insights into the pathogenesis and diagnosis of angioedema without wheals, we welcome articles addressing, but not limited to, the following themes: – Immunological mechanisms underlying AE.

• #73 Angioedema | Concise Medical Knowledge

  https://www.lecturio.com/concepts/angioedema/

  Angioedema may result from 3 primary mechanisms: […] Mast cell-mediated angioedema (most common and associated with urticaria): […] Once activated, mast cells release inflammatory mediators: […] Bradykinin-mediated angioedema (not associated with urticaria): Bradykinin is an inflammatory mediator that can lead to vasodilation and vascular permeability. […] General pathophysiology: Inflammatory mediators increase vascular permeability and dilation of capillaries. […] Extravasation of fluid from vasculature leads to asymmetric edema in the subcutaneous tissue and deep dermis.

• #74 Angioedema : Emergency Care BC

  https://emergencycarebc.ca/clinical_resource/clinical-summary/angioedema/

  There are essentially two distinct types of angioedema based on pathogenesis: histamine mediated and non-histamine (bradykinin) mediated. […] Pathogenesis: Increased vascular permeability leading to extravascular fluid leak into subcutaneous sand submucosal tissues most notably face, lips, mouth, uvula, larynx, throat, genitalia, and bowel wall.

• #75 Angioedema in the emergency department: a practical guide to differential diagnosis and management | International Journal of Emergency Medicine | Full Text

  https://intjem.biomedcentral.com/articles/10.1186/s12245-017-0141-z

  Angioedema is a common presentation in the emergency department (ED). Airway angioedema can be fatal; therefore, prompt diagnosis and correct treatment are vital. […] The most common pathophysiology underlying angioedema is mediated by histamine; however, ED staff must be alert for the less common bradykinin-mediated forms of angioedema. […] Crucially, bradykinin-mediated angioedema does not respond to the same treatment as histamine-mediated angioedema. […] Bradykinin-mediated angioedema can result from many causes, including hereditary defects in C1 esterase inhibitor (C1-INH), side effects of angiotensin-converting enzyme inhibitors (ACEis), or acquired deficiency in C1-INH. […] ED physicians must be aware of the different pathophysiologic pathways that lead to angioedema in order to efficiently and effectively manage these potentially fatal conditions.

• #76 Bradykinin-induced angioedema in the emergency department | International Journal of Emergency Medicine | Full Text

  https://intjem.biomedcentral.com/articles/10.1186/s12245-022-00408-6

  Acute airway angioedema commonly occurs through two distinct mechanisms: histamine- and bradykinin-dependent. […] Poor recognition of the bradykinin-dependent pathway leads to treatment errors in the emergency department (ED), despite the availability of multiple pharmacologic options for hereditary angioedema (HAE) and other forms of bradykinin-induced angioedema. […] Here, we consider the pathophysiology and clinical features of bradykinin-induced angioedema, and we present a systematic literature review exploring the effectiveness of the available therapies for managing such cases. […] Bradykinin-induced angioedema should be considered if this standard treatment is not effective, despite proper dosing and regard of beta-adrenergic blockade. […] Therapeutics currently approved for HAE appear as promising options for this and other forms of bradykinin-induced angioedema encountered in the ED.

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