PLAUR splicing pattern in hereditary angioedema patients' monocytes and macrophages.

BACKGROUND: The PLAUR gene encodes the urokinase-like plasminogen activator receptor (uPAR) and may undergo alternative splicing. Excluding cassette exons 3, 5 and 6 from the transcript results in truncated protein variants whose precise functions have not been elucidated yet. The PLAUR gene is one of several expressed in myeloid cells, where uPAR participates in different cellular processes, including the contact activation system and kallikrein-kinin system, which play an important role in hereditary angioedema (HAE) pathogenesis. A hypothesis about the PLAUR splicing pattern impact on HAE severity was tested. METHODS AND RESULTS: The RT-PCR quantified by capillary electrophoresis was used. Although no significant difference in alternative transcript frequency was observed between healthy volunteers and HAE patients, a significant increase in all cassette exon inclusion variants was revealed during monocyte-to-macrophage differentiation. CONCLUSIONS: PLAUR alternative splicing in monocytes and macrophages neither was different between HAE patients and healthy controls, nor reflected disease severity. However, the results showed an PLAUR splicing pattern was changing during monocyte-to-macrophage differentiation, but the significance of these changes is unknown and awaits future clarification.

A mechanism for hereditary angioedema caused by a lysine 311-to-glutamic acid substitution in plasminogen.

Patients with hereditary angioedema (HAE) experience episodes of bradykinin (BK)-induced swelling of skin and mucosal membranes. The most common cause is reduced plasma activity of C1 inhibitor, the main regulator of the proteases plasma kallikrein (PKa) and factor XIIa (FXIIa). Recently, patients with HAE were described with a Lys311 to glutamic acid substitution in plasminogen (Plg), the zymogen of the protease plasmin (Plm). Adding tissue plasminogen activator to plasma containing Plg-Glu311 vs plasma containing wild-type Plg (Plg-Lys311) results in greater BK generation. Similar results were obtained in plasma lacking prekallikrein or FXII (the zymogens of PKa and FXIIa) and in normal plasma treated with a PKa inhibitor, indicating Plg-Glu311 induces BK generation independently of PKa and FXIIa. Plm-Glu311 cleaves high and low molecular weight kininogens (HK and LK, respectively), releasing BK more efficiently than Plm-Lys311. Based on the plasma concentrations of HK and LK, the latter may be the source of most of the BK generated by Plm-Glu311. The lysine analog ε-aminocaproic acid blocks Plm-catalyzed BK generation. The Glu311 substitution introduces a lysine-binding site into the Plg kringle 3 domain, perhaps altering binding to kininogens. Plg residue 311 is glutamic acid in most mammals. Glu311 in patients with HAE, therefore, represents reversion to the ancestral condition. Substantial BK generation occurs during Plm-Glu311 cleavage of human HK, but not mouse HK. Furthermore, mouse Plm, which has Glu311, did not liberate BK from human kininogens more rapidly than human Plg-Lys311. This indicates Glu311 is pathogenic in the context of human Plm when human kininogens are the substrates.

Biological therapy in hereditary angioedema: transformation of a rare disease.

Introduction: Hereditary angioedema, a disabling condition, with high mortality when untreated, is caused by C1 inhibitor deficiency and other regulatory disorders of bradykinin production or metabolism. This review covers the remarkable progress made in biological therapies for this rare disorder.Areas covered: Over the past 10 years, several evidence-based parenteral treatments have been licensed, including two plasma-derived C1 inhibitor replacement therapies and one recombinant C1 inhibitor replacement for acute treatment of angioedema attacks and synthetic peptides for inhibition of kallikrein or bradykinin B2 receptors, with oral small molecule treatments currently in clinical trial. Moreover, recent advances in prophylaxis by subcutaneous C1 inhibitor to restore near-normal plasma function or by humanized antibody inhibition of kallikrein have resulted in freedom from symptoms for a high proportion of those treated.Expert opinion: This plethora of treatment possibilities has come about as a result of recent scientific advances. Collaboration between patient groups, basic and clinical scientists, physicians, nurses, and the pharmaceutical industry has underpinned this translation of basic science into treatments and protocols. These in their turn have brought huge improvements in prognosis, quality of life and economic productivity to patients, their families, and the societies in which they live.

Angioedema due to acquired C1-inhibitor deficiency: spectrum and treatment with C1-inhibitor concentrate.

BACKGROUND: Acquired angioedema due to C1-inhibitor (C1-INH) deficiency (AAE-C1-INH) is a serious condition that may result in life-threatening asphyxiation due to laryngeal edema. It is associated with malignant B-cell lymphoma and other disorders. The purpose of this study was to describe the characteristics and associated disorders of patients with AAE-C1-INH and assess the efficacy of plasma-derived C1-INH concentrate (pdC1-INH) in the treatment of AAE-C1-INH. Forty-four patients with AAE-C1-INH from the Angioedema Outpatient Service of Mainz were assessed for associated disorders. In 32 of these patients, the duration of swelling attacks was measured before and after treatment with pdC1-INH (Berinert® (CSL Behring, Marburg, Germany)). The time between injection and complete resolution of symptoms and treatment effectiveness was provided by the patients. RESULTS: The following underlying disorders were present: monoclonal gammopathy of undetermined significance (47.7%), non-Hodgkin lymphoma (27.3%), anti-C1-INH autoantibodies alone (11.4%), and other conditions (4.5%). In 9.1% patients, no associated disorder could be found. AAE-C1-INH led to the detection of lymphoma in 75% of patients with the malignancy. Treatment with pdC1-INH shortened attacks by an average (SD) 54.4 (± 32.8) hours (P < 0.0001). The earlier the attack was treated, the shorter the time between injection and resolution of symptoms (P = 0.0149). A total of 3553 (97.7%) of the 3636 attacks were effectively treated with pdC1-INH as assessed by the patient. The mean (SD) dose per-attack was 787 (± 442) U. pdC1-INH was effective in 1246 (93.8%) of 1329 attacks in 8 patients with anti-C1-INH autoantibodies and in 344 (99.4%) of 346 attacks in 6 patients without autoantibodies. The average (SD) dose per effectively treated attack was 1238.4 (± 578.2) U in patients with anti-C1-INH autoantibodies and 510.2 (± 69.1) U in patients without autoantibodies. CONCLUSIONS: pdC1-INH is highly effective in treating AAE-C1-INH patients and is also effective in the vast majority of attacks in patients with anti-C1-INH autoantibodies. It is fast-acting and reduces attack duration.

Angiopoietin-1 haploinsufficiency affects the endothelial barrier and causes hereditary angioedema.

BACKGROUND: Different mutations of the angiopoietin-1 gene (ANGPT1) have been associated with the occurrence of hereditary angioedema (HAE). OBJECTIVE: The purpose of the study is to clarify whether the ANGPT1 A119S variant plays its role via haploinsufficiency or a dominant negative effect. METHODS: The ability of ANGPT1 A119S variant to affect the endothelial barrier function was assessed by immunocytochemistry. Inter-endothelial gap formation molecules primarily responsible for cell-cell adhesions of HUVECs, vascular endothelial (VE)-cadherin and ß-catenin, and reorganization of the F-actin cytoskeletal were evaluated. RESULTS: In in vitro conditions mimicking the heterozygous state, the p.A119S variant significantly reduced the capability to bind its natural receptor (80.7% of normal), less than the homozygous condition (59.1%). After stimulation of VEGF or bradykinin, the addiction to equimolar amounts of wtANGPT1 and ANGPT1 p.A119S clearly reduced the expression of VE-cadherin on the endothelial cell surface (31% and 24% respectively). Likewise, cell surface expression of ß-catenin was reduced and severe gap formation between adjacent HUVECs developed. In cultured cells, ß-catenin expression was mostly observed along the cell surface. Treatment with equimolar amounts of wtANGPT1 and ANGPT1 p.A119S failed to restore the reorganization of the F-actin cytoskeletal elements. ANGPT1 p.A119S variant in homozygous condition further diminished VE-cadherin and ß-catenin expression and failed to reduce stress fibre formation significantly affecting the endothelial barrier functionality. CONCLUSIONS AND CLINICAL RELEVANCE: Present data show that in a heterozygous state the p.A119S substitution results in a pathogenic loss of function of the protein due to a mechanism of haploinsufficiency. The ANGPT1 reduced ability to counteract the increment of endothelial permeability produced by inducers, such as VEGF and bradykinin, stimulate vascular leakage and reorganization of the F-actin cytoskeletal elements. As a result, a partial impairment of the ANGPT1 functionality, like when dominant mutations occur, represents a pathophysiological cause of HAE.

Long-term prophylaxis therapy in patients with hereditary angioedema with C1 inhibitor deficiency.

OBJECTIVE: To review the criteria for long-term prophylaxis therapy in patients with hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE), describe how these criteria have evolved over time, and anticipate how criteria may change in the future with the availability of new C1-INH-HAE treatment options. DATA SOURCES: Treatment guidelines, consensus statements, and expert reviews. STUDY SELECTIONS: Manuscripts that described long-term prophylaxis therapy in patients with C1-INH-HAE were selected. RESULTS: Historically, patients with C1-INH-HAE were considered to be candidates for long-term prophylaxis therapy if they had at least 1 attack per month, had at least 5 days of disability per month because of C1-INH-HAE, or did not sufficiently respond to on-demand treatment. More recently, guidelines and reviews state that thresholds of number of attacks or days of disability are arbitrary and that treatment plans should be individualized to the patient's needs. Furthermore, all patients should have a comprehensive management plan that is reviewed periodically and should have at least 2 doses of on-demand treatment available. Prophylaxis therapy should be discussed as a potential treatment option for each patient; however, the decision for its use will depend on the patient's individual needs and the course of their symptoms. CONCLUSION: The criteria for long-term prophylaxis therapy in C1-INH-HAE have changed with the recognition that treatments should be individualized to the patient's needs and with the availability of new medications that have more favorable benefit-risk profiles, are easier to use, and improve patients' quality of life.

The complex alteration in the network of IL-17-type cytokines in patients with hereditary angioedema.

Hereditary angioedema (HAE) is a rare autosomic-dominant disorder characterized by a deficiency of C1 esterase inhibitor which causes episodic swellings of subcutaneous tissues, bowel walls and upper airways that are disabling and potentially life-threatening. We evaluated n = 17 patients with confirmed HAE diagnosis during attack and remission state and n = 19 healthy subjects. The samples were tested for a panel of IL (Interleukin)-17-type cytokines (IL-1ß, IL-6, IL-10, granulocyte-macrophage colony stimulating factor (GM-CSF), IL-17, IL-21, IL-22, IL-23) and transforming growth factor-beta (TGF-ß) subtypes. Data indicate that there are variations of cytokine levels in HAE subjects comparing the condition during the crisis respect to the value in the remission phase, in particular type 17 signature cytokines are increased, whereas IL-23 is unmodified and TGF-ß3 is significantly reduced. When comparing healthy and HAE subjects in the remission state, we found a significant difference for IL-17, GM-CSF, IL-21, TGF-ß1 and TGF-ß2 cytokines. These results confirm and extend our previous findings indicating that in HAE there is operating an inflammatory activation process, which involves also T helper 17 (Th17) cytokines and TGF-ß isoforms, associated with localized angioedema attacks and characterized by elevated bradykinin levels.

Coagulation factor XII in thrombosis and inflammation.

Combinations of proinflammatory and procoagulant reactions are the unifying principle for a variety of disorders affecting the cardiovascular system. The factor XII-driven contact system starts coagulation and inflammatory mechanisms via the intrinsic pathway of coagulation and the bradykinin-producing kallikrein-kinin system, respectively. The biochemistry of the contact system in vitro is well understood; however, its in vivo functions are just beginning to emerge. Challenging the concept of the coagulation balance, targeting factor XII or its activator polyphosphate, provides protection from thromboembolic diseases without interfering with hemostasis. This suggests that the polyphosphate/factor XII axis contributes to thrombus formation while being dispensable for hemostatic processes. In contrast to deficiency in factor XII providing safe thromboprotection, excessive FXII activity is associated with the life-threatening inflammatory disorder hereditary angioedema. The current review summarizes recent findings of the polyphosphate/factor XII-driven contact system at the intersection of procoagulant and proinflammatory disease states. Elucidating the contact system offers the exciting opportunity to develop strategies for safe interference with both thrombotic and inflammatory disorders.

Angioedema deaths in the United States, 1979-2010.

BACKGROUND: Hospital admission data indicate that the angioedema incidence has increased during the past several decades. Little is known about mortality trends. OBJECTIVES: To count the number of deaths associated with angioedema in the United States, investigate correlations with age, sex, race, and other contributory causes, and analyze trends from 1979 to 2010. METHODS: All US death certificates in which angioedema was listed as an underlying or contributing cause of death during 1979 to 2010 were analyzed. Age-adjusted mortality rates were analyzed by age, sex, and race. Other conditions designated as the underlying cause of death were investigated. RESULTS: From 1979 to 2010, there were 5,758 deaths in which angioedema was listed as a contributing cause. The age-adjusted death rate for hereditary angioedema decreased from 0.28 (95% confidence interval [CI] 0.25-0.32) to 0.06 (95% CI 0.05-0.08) per million persons per year. Conversely, mortality for angioedema increased from 0.24 (95% CI 0.21-0.27) to 0.34 (95% CI 0.31-0.37) per million. Blacks constituted 55% of angioedema deaths that were associated with use of angiotensin-converting enzyme inhibitors. On death certificates that listed hereditary angioedema as the underlying cause of death, cancer (frequently lymphoma or leukemia) was the second most commonly listed cause. CONCLUSION: Angioedema-associated deaths were very rare from 1979 to 2010. Hereditary angioedema deaths became even more so, whereas nonhereditary angioedema deaths increased. Risks associated with angiotensin-converting enzyme inhibitors were higher in blacks. Lack of specific coding for acquired angioedema most likely explains the observed association between cancer and hereditary angioedema. In the future, more granular coding systems may help distinguish hereditary from acquired angioedema.

Current update on cellular and molecular mechanisms of hereditary angioedema.

OBJECTIVE: To provide an update on the molecular mechanisms of hereditary angioedema (HAE). DATA SOURCES: MEDLINE and PubMed databases were searched to identify pertinent articles using the following key terms: hereditary angioedema, angioedema, C1 inhibitor, bradykinin, contact system, factor XII, mechanism, pathophysiology, severity, permeability, and estrogen. STUDY SELECTIONS: Articles were selected based on their relevance to the subject matter. RESULTS: Although the biochemical basis of "classic" HAE is known to result from C1 esterase inhibitor (C1INH) deficiency, a new form, HAE with normal C1INH, has been identified. HAE types I and II are caused by mutations in the SERPING1 gene that result in decreased plasma levels of functional C1INH. In HAE with normal C1INH, mutations in the F12 gene have been identified in a subset of individuals, but the genetic defect remains unknown in most patients. The primary mediator of swelling in HAE is bradykinin, a product of the plasma contact system that increases vascular permeability. HAE disease severity is highly variable and may be influenced by polymorphisms in other genes and other factors, such as hormones, trauma, stress, and infection. CONCLUSION: Hereditary angioedema is a heterogeneous disorder with a complex pathophysiology. Implicated genes include SERPING1 and FXII in patients with HAE from C1INH deficiency and HAE with normal C1INH levels, respectively. Disease severity is highly variable.

[Several new treatment possibilities of hereditary angio-oedema]. / Flere nye behandlingsmuligheder ved hereditært angioødem.

Hereditary angio-oedema (HAE) is a rare genetic disease caused by deficiency of complement C1 inhibitor. It is characterised by recurrent episodes of subcutaneous or submucosal oedema typically involving the extremities, bowel, face or larynx. Within the latest years it has become evident that the active mediator of HAE attacks is an increased level of bradykinin and various new treatment modalities have been developed. The aim of this paper is to give an update from the Danish HAE Comprehensive Care Centre on current treatment possibilities and address some of the challenges when diagnosing HAE.

Hereditary angioedema: treatment, management, and precautions in patients presenting for dental care.

Hereditary angioedema (HAE) is a nonhistamine-mediated process causing edema of the tissues of the upper airway, dermis, and subcutaneous tissue. As such it does not respond well to epinephrine, antihistamines, or glucocorticoids. Instead it is treated with attenuated androgenic hormones, episolone aminocaproic acid (EACA), or tranexamic acid, C1 esterase inhibitor, and fresh-frozen plasma. Medical or surgical management of the airway may be necessary in an acute situation. Minor trauma, such as that associated with dental procedures and psychologic stress, may precipitate an attack; however, swelling may not manifest itself for 12-48 hours after a procedure. Symptoms of angioedema may be exacerbated in these patients if they are given an angiotensin-converting enzyme inhibitor. This paper reviews this entity and presents 2 patients who presented for acute care with dental/oral surgical complaints.

[Hereditary angioedema: a case series and bibliographic update]. / Angioedema hereditario: serie de casos y actualización de la bibliografía.

BACKGROUND: Hereditary angioedema is an autosomal dominant inherited condition that is characterized by the local development of edema of the skin, subcutaneous tissue, and the walls of almost any organ, including the gastrointestinal and upper respiratory tracts. OBJECTIVE: To describe the clinical characteristics, diagnosis and treatment of six controlled patients with hereditary angioedema. PATIENTS AND METHODS: This paper presents clinical characteristics of six patients, four of them members of the same family, and two, isolated, non-family related cases. This contribution is a review of the latest literature related to diagnosis and treatment of hereditary angioedema. RESULTS: Hereditary angioedema is a rare clinical entity that has a complicated manifestation profile that requires to discard a wide series of differential diagnosis. Deeper knowledge of its genetics and physiopathology will allow us to explore new treatment alternatives in addition to those already available. CONCLUSIONS: By diffusion of isolated cases or familial cases series, as presented in this paper, the disease recognition and timely treatment will be reached.

Studies of the mechanisms of bradykinin generation in hereditary angioedema plasma.

BACKGROUND: Factor XII-dependent bradykinin formation is thought to be responsible for the swelling associated with the various forms of C1 inhibitor deficiency, and complement activation is augmented during attacks of swelling. OBJECTIVES: To further elucidate the interactions of the kinin-forming cascade that lead to complement activation during attacks of swelling and to determine whether fibrinolysis is augmented as well. METHODS: We compared spontaneous and kaolin-induced activation of normal plasma with the plasma of patients with hereditary angioedema. RESULTS: Hereditary angioedema plasma demonstrated augmented factor XII activation, production of factor XIIf, prekallikrein activation, and high-molecular-weight kininogen cleavage, and, as a result, bradykinin formation was markedly increased. Baseline levels of C4a and plasmin-alpha 2 antiplasmin complexes increased, and, on activation with kaolin, levels increased further. CONCLUSIONS: All parameters indicative of activation of the bradykinin-forming cascade are activated in hereditary angioedema plasma vs normal plasma. Production of factor XIIf, demonstrated for the first time in whole plasma, may be responsible for C1 activation based on C4a production. The factor XII-dependent fibrinolytic cascade is also activated.