Mast cell degranulation and bradykinin-induced angioedema - searching for the missing link.

Initiation of the bradykinin generation cascade is responsible for the occurrence of attacks in some types of angioedema without wheals. Hereditary angioedema due to C1 inhibitor deficiency (HAE-C1-INH) is one such clinical entity. In this paper, we explore the existing evidence that mast cells (MCs) degranulation may contribute to the activation of the kallikrein-kinin system cascade, followed by bradykinin formation and angioedema. We present the multidirectional effects of MC-derived heparin and other polyanions on the major components of the kinin-kallikrein system, particularly on the factor XII activation. Although, bradykinin- and histamine-mediated symptoms are distinct clinical phenomena, they share some common features, such as some similar triggers and a predilection to occur at sites where mast cells reside, namely the skin and mucous membranes. In addition, recent observations indicate a high incidence of hypersensitivity reactions associated with MC degranulation in the HAE-C1-INH patient population. However, not all of these can be explained by IgE-dependent mechanisms. Mast cell-related G protein-coupled receptor-X2 (MRGPRX2), which has recently attracted scientific interest, may be involved in the activation of MCs through a different pathway. Therefore, we reviewed MRGPRX2 ligands that HAE-C1-INH patients may be exposed to in their daily lives and that may affect MCs degranulation. We also discussed the known inter- and intra-individual variability in the course of HAE-C1-INH in relation to factors responsible for possible variability in the strength of the response to MRGPRX2 receptor stimulation. The above issues raise several questions for future research. It is not known to what extent a prophylactic or therapeutic intervention targeting the pathways of one mechanism (mast cell degranulation) may affect the other (bradykinin production), or whether the number of mast cells at a specific body site and their reactivity to triggers such as pressure, allergens or MRGPRX2 agonists may influence the occurrence of HAE-C1-INH attacks at that site.

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.

Aquaporin-1 inhibition exacerbates ischemia-reperfusion-induced lung injury in mouse.

BACKGROUND: Ischemia-reperfusion injury (IRI), which involves severe inflammation and edema, is an inevitable feature of the lung transplantation process and leads to primary graft dysfunction (PGD). The activation of aquaporin 1 (AQP1) modulates fluid transport in the alveolar space. The current study investigated the role of AQP1 in ischemia-reperfusion (IR)-induced lung injury. METHODS: A mouse model of lung IR was established by clamping the left lung hilar for 1 h and released for reperfusion for 24 h. The AQP1 inhibitor acetazolamide (AZA) was administered 3 days before lung ischemia with a dose of 100 mg/kg per day via gavage. Lung injury was evaluated using the ratio of wet-to-dry weight, peripheral bronchial epithelial thickness, degree of angioedema, acute lung injury score, neutrophil infiltration, and cytokine concentrations in bronchoalveolar lavage fluid. RESULTS: Compared with sham treatment, ischemia with no reperfusion (IR 0h) and ischemia with reperfusion for 24 h (IR 24 h) significantly upregulated AQP1 expression, increased the wet/dry weight ratio, angioedema, neutrophil infiltration and cytokine production (interleukin -6 and tumor necrosis factor -α) and thickened the peripheral bronchial epithelium. AZA exacerbated inflammation and pulmonary edema. CONCLUSION: AQP1 may exert a protective effect against IR-induced lung injury, which could be attributed to alleviating pulmonary edema and inflammation. AQP1 upregulation might be a potential application to alleviate lung IRI and decrease the incidence of PGD.

gC1qR Antibody Can Modulate Endothelial Cell Permeability in Angioedema.

Angioedema is characterized by swelling of the skin or mucous membranes. Overproduction of the vasodilator bradykinin (BK) is an important contributor to the disease pathology, which causes rapid increase in vascular permeability. BK formation on endothelial cells results from high molecular weight kininogen (HK) interacting with gC1qR, the receptor for the globular heads of C1q, the first component of the classical pathway of complement. Endothelial cells are sensitive to blood-flow-induced shear stress and it has been shown that shear stress can modulate gC1qR expression. This study aimed to determine the following: (1) how BK or angioedema patients' (HAE) plasma affected endothelial cell permeability and gC1qR expression under shear stress, and (2) if monoclonal antibody (mAb) 74.5.2, which recognizes the HK binding site on gC1qR, had an inhibitory effect in HK binding to endothelial cells. Human dermal microvascular endothelial cells (HDMECs) grown on Transwell inserts were exposed to shear stress in the presence of HAE patients' plasma. Endothelial cell permeability was measured using FITC-conjugated bovine serum albumin. gC1qR expression and HK binding to endothelial cell surface was measured using solid-phase ELISA. Cell morphology was quantified using immunofluorescence microscopy. The results demonstrated that BK at 1 µg/mL, but not HAE patients' plasma and/or shear stress, caused significant increases in HDMEC permeability. The mAb 74.5.2 could effectively inhibit HK binding to recombinant gC1qR, and reduce HAE patients' plasma-induced HDMEC permeability change. These results suggested that monoclonal antibody to gC1qR, i.e., 74.5.2, could be potentially used as an effective therapeutic reagent to prevent angioedema.

An update on factor XII-driven vascular inflammation.

The plasma protein factor XII (FXII) is the liver-derived zymogen of the serine protease FXIIa that initiates an array of proteolytic cascades. Zymogen activation, enzymatic FXIIa activity and functions are regulated by interactions with cell receptors, negatively charged surfaces, other serine proteases, and serpin inhibitors, which bind to distinct protein domains and regions in FXII(a). FXII exerts mitogenic activity, while FXIIa initiates the pro-inflammatory kallikrein-kinin pathway and the pro-thrombotic intrinsic coagulation pathway, respectively. Growing evidence indicates that FXIIa-mediated thrombo-inflammation plays a crucial role in various pathological states besides classical thrombosis, such as endothelial dysfunction. Consistently, increased FXIIa levels are associated with hypercholesterolemia and hypertriglyceridemia. In contrast, FXII deficiency protects from thrombosis but is otherwise not associated with prolonged bleeding or other adverse clinical manifestations. Here, we review current concepts for FXII(a)-driven vascular inflammation focusing on endothelial hyperpermeability, receptor signaling, atherosclerosis and immune cell activation.

COVID-19 and hereditary angioedema: Incidence, outcomes, and mechanistic implications.

Background: Patients with hereditary angioedema (HAE) have been postulated to be at increased risk for coronavirus disease 2019 (COVID-19) infection due to inherent dysregulation of the plasma kallikrein-kinin system. Only limited data have been available to explore this hypothesis. Objective: To assess the interrelationship(s) between COVID-19 and HAE. Methods: Self-reported COVID-19 infection, complications, morbidity, and mortality were surveyed by using an online questionnaire. The participants included subjects with HAE with C1 inhibitor (C1INH) deficiency (HAE-C1INH) and subjects with HAE with normal C1-inhibitor (HAE-nl-C1INH), and household controls (normal controls). The impact of HAE medications was examined. Results: A total of 1162 participants who completed the survey were analyzed, including: 695 subjects with HAE-C1INH, 175 subjects with HAE-nl-C1INH, and 292 normal controls. The incidence of reported COVID-19 was not significantly different between the normal controls (9%) and the subjects with HAE-C1INH (11%) but was greater in the subjects with HAE-nl-C1INH (19%; p = 0.006). Obesity was positively correlated with COVID-19 across the overall population (p = 0.012), with a similar but nonsignificant trend in the subjects with HAE-C1INH. Comorbid autoimmune disease was a risk factor for COVID-19 in the subjects with HAE-C1INH (p = 0.047). COVID-19 severity and complications were similar in all the groups. Reported COVID-19 was reduced in the subjects with HAE-C1INH who received prophylactic subcutaneous C1INH (5.6%; p = 0.0371) or on-demand icatibant (7.8%; p = 0.0016). The subjects with HAE-C1INH and not on any HAE medications had an increased risk of COVID-19 compared with the normal controls (24.5%; p = 0.006). Conclusion: The subjects with HAE-C1INH who were not taking HAE medications had a significantly higher rate of reported COVID-19 infection. Subcutaneous C1INH and icatibant use were associated with a significantly reduced rate of reported COVID-19. The results implicated potential roles for the complement cascade and tissue kallikrein-kinin pathways in the pathogenesis of COVID-19 in patients with HAE-C1INH.

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.

Role of Endothelial G Protein-Coupled Receptor Kinase 2 in Angioedema.

Excessive BK (bradykinin) stimulation is responsible for the exaggerated permeabilization of the endothelium in angioedema. However, the molecular mechanisms underlying these responses have not been investigated. BK receptors are Gq-protein-coupled receptors phosphorylated by GRK2 (G protein-coupled receptor kinase 2) with a hitherto unknown biological and pathophysiological significance. In the present study, we sought to identify the functional role of GRK2 in angioedema through the regulation of BK signaling. We found that the accumulation of cytosolic Ca2+ in endothelial cells induced by BK was sensitive to GRK2 activity, as it was significantly augmented by inhibiting the kinase. Accordingly, permeabilization and NO production induced by BK were enhanced, as well. In vivo, mice with reduced GRK2 levels in the endothelium (Tie2-CRE/GRK2fl+/fl-) exhibited an increased response to BK in terms of vascular permeability and extravasation. Finally, patients with reduced GRK2 levels displayed a severe phenotype of angioedema. Taken together, these findings establish GRK2 as a novel pivotal regulator of BK signaling with an essential role in the pathophysiology of vascular permeability and angioedema.

Proteomic Analysis of the Acid-Insoluble Fraction of Whole Saliva from Patients Affected by Different Forms of Non-histaminergic Angioedema.

We analyzed by bidimensional electrophoresis the acid-insoluble fraction of saliva from three classes of angioedema patients and a healthy control group, highlighting significant variations of several normalized spot volumes. Characterization of the corresponding proteins was performed by in-gel tryptic digestion of the spots, followed by high-resolution HPLC-ESI-MS/MS analysis of tryptic mixtures. By this strategy, 16 differentially-expressed proteins among two or more groups were identified. We found higher concentration of proteins involved in immune response (interleukin-1 receptor antagonist and annexin A1), and of moonlighting proteins acting as plasminogen receptors (glyceraldehyde-3-phosphate dehydrogenase, α-enolase, and annexin A2) in patients affected by the idiopathic non-histaminergic or hereditary angioedema with unknown origin with respect to healthy controls. These data provide new information on the molecular basis of these less characterized types of angioedema. Graphical Abstract Graphical Abstract.

Kallikrein-kinin blockade in patients with COVID-19 to prevent acute respiratory distress syndrome.

COVID-19 patients can present with pulmonary edema early in disease. We propose that this is due to a local vascular problem because of activation of bradykinin 1 receptor (B1R) and B2R on endothelial cells in the lungs. SARS-CoV-2 enters the cell via ACE2 that next to its role in RAAS is needed to inactivate des-Arg9 bradykinin, the potent ligand of the B1R. Without ACE2 acting as a guardian to inactivate the ligands of B1R, the lung environment is prone for local vascular leakage leading to angioedema. Here, we hypothesize that a kinin-dependent local lung angioedema via B1R and eventually B2R is an important feature of COVID-19. We propose that blocking the B2R and inhibiting plasma kallikrein activity might have an ameliorating effect on early disease caused by COVID-19 and might prevent acute respiratory distress syndrome (ARDS). In addition, this pathway might indirectly be responsive to anti-inflammatory agents.

The COVID-19 pandemic represents an unprecedented threat to global health. Millions of cases have been confirmed around the world, and hundreds of thousands of people have lost their lives. Common symptoms include a fever and persistent cough and COVID-19 patients also often experience an excess of fluid in the lungs, which makes it difficult to breathe. In some cases, this develops into a life-threatening condition whereby the lungs cannot provide the body's vital organs with enough oxygen. The SARS-CoV-2 virus, which causes COVID-19, enters the lining of the lungs via an enzyme called the ACE2 receptor, which is present on the outer surface of the lungs' cells. The related coronavirus that was responsible for the SARS outbreak in the early 2000s also needs the ACE2 receptor to enter the cells of the lungs. In SARS, the levels of ACE2 in the lung decline during the infection. Studies with mice have previously revealed that a shortage of ACE2 leads to increased levels of a hormone called angiotensin II, which regulates blood pressure. As a result, much attention has turned to the potential link between this hormone system in relation to COVID-19. However, other mouse studies have shown that ACE2 protects against a build-up of fluid in the lungs caused by a different molecule made by the body. This molecule, which is actually a small fragment of a protein, lowers blood pressure and causes fluid to leak out of blood vessels. It belongs to a family of molecules known as kinins, and ACE2 is known to inactivate certain kinins. This led van de Veerdonk et al. to propose that the excess of fluid in the lungs seen in COVID-19 patients may be because kinins are not being neutralized due to the shortage of the ACE2 receptor. This had not been hypothesized before, even though the mechanism could be the same in SARS which has been researched for the past 17 years. If this hypothesis is correct, it would mean that directly inhibiting the receptor for the kinins (or the proteins that they come from) may be the only way to stop fluid leaking into the lungs of COVID-19 patients in the early stage of disease. This hypothesis is unproven, and more work is needed to see if it is clinically relevant. If that work provides a proof of concept, it means that existing treatments and registered drugs could potentially help patients with COVID-19, by preventing the need for mechanical ventilation and saving many lives.

Angioedema as a systemic disease.

Angioedema is a clinical entity defined as self-limiting edema localized in the deeper layers of the skin and mucosa and lasting for several days. Angioedema can be provoked by bradykinin and/or mast cell mediators, including histamine. Four types of acquired and three types of hereditary angioedema have been identified. The most obvious form of angioedema associated with other systemic disease is acquired angioedema due to C1-inhibitor deficiency. It is characterized by acquired consumption of C1 inhibitor and various underlying disorders, such as multiple myeloma, chronic lymphocytic leukemia, rectal carcinoma, and non-Hodgkin lymphoma. Suspected cases need an accurate differential diagnosis to exclude all other types of acquired and hereditary angioedema.

Diagnostic biologique des angioedèmes bradykiniques : les recommandations du CREAK.

Bradykinin mediated angioedema (BK-AE) can be associated either with C1Inhibitor deficiency (hereditary and acquired forms), either with normal C1Inh (hereditary form and drug induced AE as angiotensin converting enzyme inhibitors…). In case of high clinical suspicion of BK-AE, C1Inh exploration must be done at first: C1Inh function and antigenemy as well as C4 concentration. C1Inh deficiency is significant if the tests are below 50 % of the normal values and controlled a second time. In case of C1Inh deficiency, you have to identify hereditary from acquired forms. C1q and anti-C1Inh antibody tests are useful for acquired BK-AE. SERPING1 gene screening must be done if a hereditary angioedema is suspected, even if there is no family context (de novo mutation 15 %). If a hereditary BK-AE with normal C1Inh is suspected, F12 and PLG gene screening is suitable.

Angioedema Due to Bradykinin Dysregulation.

Angioedema is an acute swelling of the deeper layers of the skin or mucosa resulting from a transient increase in vascular permeability. Angioedema can occur in the absence or presence of hives, be hereditary or acquired, and be caused by various potential mediators, including histamine and bradykinin. Bradykinin-mediated angioedema can be difficult to diagnose but is responsible for a disproportionate percentage of the serious morbidity and mortality associated with angioedema. Our understanding of the basic biology of angioedema has dramatically expanded over recent years. The classification of angioedema has correspondently undergone major changes. Optimal management of patients with angioedema requires that an accurate diagnosis be established and that treatment be tailored to the patient's specific form of angioedema. In this article, we review the biology of bradykinin-mediated angioedema as well as the clinical approach to the evaluation of angioedema with a focus on bradykinin-mediated angioedema. Recognizing how the underlying pathophysiology and mechanisms of bradykinin dysregulation contribute to angioedema can help guide the clinical approach to the patient.

Threshold-stimulated kallikrein activity distinguishes bradykinin- from histamine-mediated angioedema.

BACKGROUND: The lack of specific biomarkers makes the diagnosis of hereditary angioedema (HAE) with normal levels of C1-inhibitor (C1INH) protein (HAE-nl-C1INH) and idiopathic non-histaminergic angioedema (INHA) difficult. Confirming or excluding these diagnoses is a significant challenge for clinicians evaluating patients with angioedema. OBJECTIVE: To develop a reliable biomarker that would aid the diagnosis of HAE-nl-C1INH and INHA. METHODS: A total of 154 consecutive patients referred for angioedema at a single centre were enrolled and evaluated. Subjects were clinically phenotyped based on clinical history and response to treatment by clinicians blinded to laboratory assay results. Plasma kallikrein activity was measured by the cleavage of the fluorometric substrate Z-Phe-Arg-AMC-HCL in plasma samples stimulated ex vivo with submaximal doses of dextran sulphate. RESULTS: Stimulated plasma kallikrein activity (mean relative fluorescence units/min ± SD) was significantly increased in both HAE-nl-C1INH (1804 ± 600) and INHA (1579 ± 371) subjects compared to non-swelling controls (171 ± 46) and histaminergic angioedema (133 ± 30) subjects. Using a threshold cut-off based on the normal controls, HAE-nl-C1INH and INHA subjects could be differentiated from histaminergic angioedema subjects with high sensitivity (negative predictive value 86%-89%) and specificity (positive predictive value 80%-100%). CONCLUSION AND CLINICAL RELEVANCE: The stimulated kallikrein activity assay allows differentiation of bradykinin- from histamine-mediated angioedema. The assay could feasibly be considered as a potential clinical tool for the diagnosis of bradykinin-mediated angioedema.

Epidemiology of Bradykinin-mediated angioedema: a systematic investigation of epidemiological studies.

BACKGROUND: Bradykinin-mediated angioedema (Bk-AE) can be life-threatening and requires specific targeted therapies. Knowledge of its epidemiology may help optimize its management. METHODS: We systematically searched the medical literature to identify abstracts of interest indexed between 1948 and March, 2016. We used published national survey data on the proportion of the population treated with angiotensin-converting enzyme inhibitors (ACEI) to derive estimates of the population prevalence of ACEI-AE in the USA, Germany and France. For hereditary angioedema (C1-INH-HAE) and C1-inhibitor related acquired angioedema (C1-INH-AAE), publications had to contain original epidemiologic data collection within a defined geographical area. Hereditary angioedema with normal C1-INH was not included in the analysis due to lack of clearly defined criteria. RESULTS: We identified 4 relevant publications on the prevalence of ACEI-AE, 6 on the prevalence of C1-INH-HAE, and 1 on the prevalence of C1-INH-AAE. The 1st year cumulative incidence of ACEI-AE was estimated to vary between 0.12 (population-based analyses) and 0.30 (meta-analyses of clinical trials) per 100 patient-years. The population prevalence of ACEI-AE was modeled to vary between 7 and 26 in 100,000. The prevalence of C1-INH-HAE was estimated to vary between 1.1 and 1.6 per 100,000. The prevalence of C1-INH-AAE was estimated to be 0.15 per 100,000 in one epidemiological investigation of AAE in Denmark. CONCLUSIONS: Epidemiological evidence on Bk-AE is limited to North America and Europe. ACEI-AE is more common than C1-INH-HAE (~ 10:1), which is more common than C1-INH-AAE (~ 10:1). More studies are needed to comprehensively assess the epidemiological burden of Bk-AE.

Idiopathic Nonhistaminergic Acquired Angioedema Versus Hereditary Angioedema.

BACKGROUND: The mechanism of idiopathic nonhistaminergic acquired angioedema (InH-AAE) has not yet been precisely elucidated. This condition is characterized by recurrent angioedema without wheals. OBJECTIVE: To study the clinical features of InH-AAE, and to make, for the first time, independent comparisons with hereditary angioedema of unknown origin (U-HAE), as well as with hereditary angioedema with C1-inhibitor deficiency (C1-INH-HAE). METHODS: We compared the clinical parameters of 46 patients with InH-AAE with those of 27 patients suffering from U-HAE, as well as of 73 patients with C1-INH-HAE. RESULTS: The mean age at the onset of symptoms was 36 years in InH-AAE, 13 years in C1-INH-HAE, and 29 years in U-HAE. More than 12 edematous episodes occurred over a year in 56% of patients with InH-AAE, in 59% of those with C1-INH-HAE, and in 48% of those with U-HAE. Edema of the extremities, of the upper airways, and of the gastrointestinal tract was more common in patients with C1-INH-HAE (92%, 51%, and 75%, respectively). These manifestations occurred less frequently in patients with InH-AAE (54%, 28%, and 20%) and in patients with U-HAE (37%, 29%, and 20%). By contrast, facial edema occurred in only 15% of patients with C1-INH-HAE, but in 67% of patients with InH-AAE and in 59% of patients with U-HAE. CONCLUSIONS: The clinical manifestations of patients with InH-AAE were different from those of patients with C1-INH-HAE. This may indicate different processes underlying edema formation in these disease forms. The close resemblance of the clinical manifestations in InH-AAE and U-HAE might suggest a similarity between the pathophysiology of these conditions.

The Clinical Evaluation of Angioedema.

The clinical evaluation of angioedema is reliant on obtaining a thorough patient and family history with an assessment of risk factors and presenting symptoms unique to each subtype. It is important to distinguish between angioedema with and without urticaria as a primary step in the evaluation; thereafter, laboratory parameters and investigations allow for subsequent stratification. There is a significant disease burden associated with angioedema and thus it is essential for health care practitioners to establish a prompt and accurate diagnosis, and a comprehensive care plan that addresses the patient's physical and mental well-being alike.

Angiotensin-converting Enzyme Inhibitor and Other Drug-associated Angioedema.

Nonsteroidal antiinflammatory agents, ß-lactam antibiotics, non-ß lactam antibiotics, and angiotensin-converting enzyme inhibitors are the most common classes of drugs that cause angioedema. Drug-induced angioedema is known to occur via mechanisms mediated by histamine, bradykinin, or leukotriene, and an understanding of these mechanisms is crucial in guiding therapeutic decisions. Nonallergic angioedema occurs in patients with genetic variants that affect metabolism or synthesis of bradykinin, substance P, prostaglandins, or leukotrienes, or when patients are taking drugs that have synergistic mechanisms. The mainstay in treatment of nonallergic drug-induced angioedema is cessation of the offending agents.

Histaminergic Angioedema.

Angioedema is frequently categorized into histamine- or bradykinin-mediated disease. It is critical to determine the underlying mediator of symptoms as it directs treatment. Histaminergic angioedema is the most frequent cause of angioedema. It is classified as either acute (lasting <6 weeks) or chronic (symptoms >6 weeks). It is further classified into angioedema presenting with or without urticaria. Some patients with acute angioedema may have disease that becomes chronic. Mast cells and basophils are central to the underlying pathophysiology of histamine-mediated angioedema. The underlying treatments of histamine-mediated angioedema are antihistamines, corticosteroids, and epinephrine.

Laboratory Approaches for Assessing Contact System Activation.

Hereditary angioedema (HAE) is a rare autosomal dominant disease clinically characterized by recurrent, often unpredictable attacks of subcutaneous and mucosal swelling. Acute episodes are debilitating, painful, disfiguring, and potentially fatal. HAE type I and type II result from a deficiency in the plasma level of functional C1 inhibitor. HAE with normal levels of C1 inhibitor has been recognized. There is evidence that contact activation underlies the recurrent attacks of swelling. This article reviews laboratory parameters to detect contact system activation and implications for diagnosis of HAE and other forms of bradykinin-mediated angioedema.