Hereditary angioedema with C1 inhibitor (C1-INH) deficit: the strength of recognition (51 cases).

Hereditary angioedema (HAE) is a rare autosomal dominant disease due to C1 esterase inhibitor deficiency (C1-INH). The disease is characterized by subcutaneous and submucosal edema in the absence of urticaria due to the accumulation of bradykinin. This descriptive study aimed to evaluate the clinical characteristics of patients with a confirmed diagnosis of HAE referred to our Outpatient Clinic between December 2009 and November 2017. Fifty-one patients (38 F, 13 M) with a mean age of 32 years (range: 7-70 y) were included. Family history of HAE was reported in 70% (36/51) of the cases; 33/46 patients became symptomatic by 18 years of age. The median time between onset of symptoms and diagnosis was 13 years (3 mo-50 y). The most frequent triggering factors for attacks were stress (74.4%), trauma (56.4%), and hormonal variations (56%). The main symptoms were subcutaneous edema in 93.5% (43/46) of patients, gastrointestinal symptoms in 84.8% (39/46), and obstruction in the upper airways in 34.8% (16/46). Hospitalization occurred in 65.2%, of whom 13.3% had to be transferred to the Intensive Care Unit. Prophylactic treatment was instituted in 87% (40/46) of patients, and 56.5% (26/46) required additional treatment to control attacks. Owing to our data collection over a period of 8 years, a significant number of patients were identified by this HAE reference center. Despite early recognition and prophylactic treatment, a high percentage of patients were hospitalized. HAE is still diagnosed late, reinforcing the need for more reference centers specialized in diagnosis and educational projects for health professionals.

Hereditary angioedema with C1 inhibitor (C1-INH) deficit: the strength of recognition (51 cases)

Hereditary angioedema (HAE) is a rare autosomal dominant disease due to C1 esterase inhibitor deficiency (C1-INH). The disease is characterized by subcutaneous and submucosal edema in the absence of urticaria due to the accumulation of bradykinin. This descriptive study aimed to evaluate the clinical characteristics of patients with a confirmed diagnosis of HAE referred to our Outpatient Clinic between December 2009 and November 2017. Fifty-one patients (38 F, 13 M) with a mean age of 32 years (range: 7-70 y) were included. Family history of HAE was reported in 70% (36/51) of the cases; 33/46 patients became symptomatic by 18 years of age. The median time between onset of symptoms and diagnosis was 13 years (3 mo-50 y). The most frequent triggering factors for attacks were stress (74.4%), trauma (56.4%), and hormonal variations (56%). The main symptoms were subcutaneous edema in 93.5% (43/46) of patients, gastrointestinal symptoms in 84.8% (39/46), and obstruction in the upper airways in 34.8% (16/46). Hospitalization occurred in 65.2%, of whom 13.3% had to be transferred to the Intensive Care Unit. Prophylactic treatment was instituted in 87% (40/46) of patients, and 56.5% (26/46) required additional treatment to control attacks. Owing to our data collection over a period of 8 years, a significant number of patients were identified by this HAE reference center. Despite early recognition and prophylactic treatment, a high percentage of patients were hospitalized. HAE is still diagnosed late, reinforcing the need for more reference centers specialized in diagnosis and educational projects for health professionals.

Complement, Kinins, and Hereditary Angioedema: Mechanisms of Plasma Instability when C1 Inhibitor is Absent.

Plasma of patients with types I and II hereditary angioedema is unstable if incubated in a plastic (i.e., inert) vessel at 37 °C manifested by progressively increasing formation of bradykinin. There is also a persistent low level of C4 in 95 % of patients even when they are symptomatic. These phenomena are due to the properties of the C1r subcomponent of C1, factor XII, and the bimolecular complex of prekallikrein with high molecular weight kininogen (HK). Purified C1r auto-activates in physiologic buffers, activates C1s, which in turn depletes C4. This occurs when C1 inhibitor is deficient. The complex of prekallikrein-HK acquires an inducible active site not present in prekallikrein which in Tris-type buffers cleaves HK stoichiometrically to release bradykinin, or in phosphate buffer auto-activates to generate kallikrein and bradykinin. Thus immunologic depletion of C1 inhibitor from factor XII-deficient plasma (phosphate is the natural buffer) auto-activates on incubation to release bradykinin. Normal C1 inhibitor prevents this from occurring. During attacks of angioedema, if factor XII auto-activates on surfaces, the initial factor XIIa formed converts prekallikrein to kallikrein, and kallikrein cleaves HK to release bradykinin. Kallikrein also rapidly activates most remaining factor XII to factor XIIa. Additional cleavages convert factor XIIa to factor XIIf and factor XIIf activates C1r enzymatically so that C4 levels approach zero, and C2 is depleted. There is also a possibility that kallikrein is generated first as a result of activation of the prekallikrein-HK complex by heat shock protein 90 released from endothelial cells, followed by kallikrein activation of factor XII.

Clinical Pattern and Acute and Long-term Management of Hereditary Angioedema Due to C1-Esterase Inhibitor Deficiency.

BACKGROUND: Hereditary angioedema due to C1-esterase inhibitor deficiency (HAE-C1-INH) is a life-threatening disease. OBJECTIVES: To describe the clinical characteristics and management of patients with HAE-C1-INH during routine clinical practice. METHODS: An observational, retrospective study was performed in patients with HAE-C1-INH. Demographic, clinical, and analytical data were collected from 2 periods: period A (October 2009-September 2010) and period B (October 2007-September 2009). RESULTS: We studied 112 patients with HAE-C1-INH (57.1% females). Age at onset of symptoms was 14.4 years (lower in patients who had experienced attacks in the previous year). In period B (n=87), 62.1% of patients presented at least 1 edema attack (median, 3.5 attacks/patient/2 years), and 19.1% of attacks were treated. In period A (n=77), 58.4% of patients were on maintenance therapy. Stanozolol was the most widely used drug (48.9%), with a mean weekly dose of 6.7 mg. At least 1 attack was recorded in 72.7% of patients (median, 3.0 attacks/patient/year), and 31.5% of the attacks were treated. Treatment of acute attacks increased by 12.4%. CONCLUSION: Age at onset of symptoms is associated with clinical expression of disease. The higher age at onset of symptoms, the fewer number of attacks per patient and year, and the lower dose of attenuated androgens necessary to control the disease than in other series lead us to hypothesize that HAE-C1-INH could have a less severe expression in Spain. Acute attacks seem to be treated increasingly often.

Risk of angioedema following invasive or surgical procedures in HAE type I and II--the natural history.

BACKGROUND: Hereditary angioedema (HAE), caused by deficiency in C1-inhibitor (C1-INH), leads to unpredictable edema of subcutaneous tissues with potentially fatal complications. As surgery can be a trigger for edema episodes, current guidelines recommend preoperative prophylaxis with C1-INH or attenuated androgens in patients with HAE undergoing surgery. However, the risk of an HAE attack in patients without prophylaxis has not been quantified. OBJECTIVES: This analysis examined rates of perioperative edema in patients with HAE not receiving prophylaxis. METHODS: This was a retrospective analysis of records of randomly selected patients with HAE type I or II treated at the Frankfurt Comprehensive Care Centre. These were examined for information about surgical procedures and the presence of perioperative angioedema. RESULTS: A total of 331 patients were included; 247 underwent 700 invasive procedures. Of these procedures, 335 were conducted in 144 patients who had not received prophylaxis at the time of surgery. Categories representing significant numbers of procedures were abdominal (n = 113), ENT (n = 71), and gynecological (n = 58) procedures. The rate of documented angioedema without prophylaxis across all procedures was 5.7%; in 24.8% of procedures, the presence of perioperative angioedema could not be excluded, leading to a maximum potential risk of 30.5%. Predictors of perioperative angioedema could not be identified. CONCLUSION: The risk of perioperative angioedema in patients with HAE type I or II without prophylaxis undergoing surgical procedures ranged from 5.7% to 30.5% (CI 3.5-35.7%). The unpredictability of HAE episodes supports current international treatment recommendations to consider short-term prophylaxis for all HAE patients undergoing surgery.

A focused parameter update: hereditary angioedema, acquired C1 inhibitor deficiency, and angiotensin-converting enzyme inhibitor-associated angioedema.

These parameters were developed by the Joint Task Force on Practice Parameters (JTFPP), representing the American Academy of Allergy, Asthma & Immunology (AAAAI); the American College of Allergy, Asthma & Immunology (ACAAI); and the Joint Council of Allergy, Asthma and Immunology. The AAAAI and the ACAAI have jointly accepted responsibility for establishing "A focused parameter update: Hereditary angioedema, acquired C1 inhibitor deficiency, and angiotensin-converting enzyme inhibitor-associated angioedema." This is a complete and comprehensive document at the current time. The medical environment is a changing environment, and not all recommendations will be appropriate for all patients. Because this document incorporated the efforts of many participants, no single individual, including those who served on the JTFPP, is authorized to provide an official AAAAI or ACAAI interpretation of these practice parameters. Any request for information about or an interpretation of these practice parameters by the AAAAI or ACAAI should be directed to the Executive Offices of the AAAAI, the ACAAI, and the Joint Council of Allergy, Asthma and Immunology. The Joint Task Force on Practice Parameters understands that the cost of diagnostic tests and therapeutic agents is an important concern that might appropriately influence the work-up and treatment chosen for a given patient. The JTFPP recognizes that the emphasis of our primary recommendations regarding a medication might vary, for example, depending on third-party payer issues and product patent expiration dates. However, because the cost of a given test or agent is so widely variable and there is a paucity of pharmacoeconomic data, the JTFPP generally does not consider cost when formulating practice parameter recommendations. In some instances the cost benefit of an intervention is considered relevant, and commentary might be provided. These parameters are not designed for use by pharmaceutical companies in drug promotion. The Joint Task Force is committed to ensuring that the practice parameters are based on the best scientific evidence that is free of commercial bias. To this end, the parameter development process includes multiple layers of rigorous review. These layers include the Workgroup convened to draft the parameter, the Task Force Reviewers, and peer review by members of each sponsoring society. Although the Task Force has the final responsibility for the content of the documents submitted for publication, each reviewer comment will be discussed, and reviewers will receive written responses to comments when appropriate. To preserve the greatest transparency regarding potential conflicts of interest, all members of the Joint Task Force and the Practice Parameters Workgroups will complete a standard potential conflict of interest disclosure form, which will be available for external review by the sponsoring organization and any other interested individual. In addition, before confirming the selection of a Workgroup chairperson, the Joint Task Force will discuss and resolve all relevant potential conflicts of interest associated with this selection. Finally, all members of parameter workgroups will be provided a written statement regarding the importance of ensuring that the parameter development process is free of commercial bias.

Management of dental-oral procedures in patients with hereditary angioedema due to C1 inhibitor deficiency.

BACKGROUND: Hereditary angioedema due to C1 inhibitor deficiency (HAE-C1-INH) has considerable implications for dental health care providers, since dental procedures may trigger severe and even life-threatening episodes. The aim of the present study was to analyze the efficacy and safety of premedication with attenuated androgens (AAs), plasma-derived human C1 esterase inhibitor concentrate (pdhC1INH), or both to prevent the development of upper airway angioedema after dental-oral procedures in patients with HAE-C1-INH. MATERIAL AND METHODS: All dental-oral procedures performed on patients with HAE-C1-INH who were followed up at La Paz University Hospital, Madrid, Spain were reviewed. Demographic data, maintenance treatment, preprocedure prophylaxis, disease severity, and occurrence of upper airway angioedema were recorded. RESULTS: Twenty-four patients (14 male/10 female; mean age, 42.6 years) underwent 66 procedures. Most procedures were performed on patients with severe HAE-C1-INH (20 procedures) or moderate HAE-C1-INH (26 procedures). Only 9 procedures were performed without short-term prophylaxis. Mild upper airway angioedema developed after 3 procedures performed without short-term prophylaxis in patients with minimal or asymptomatic HAE-C1-INH. A statistically significant association was found between development of mild postprocedure upper airway angioedema and lack of maintenance treatment with AA, lack of increased dose of preprocedure AA, and failure to administer preprocedure pdhC1INH (P = .002, Fisher exact test). CONCLUSIONS: Increased doses of prophylactic AA, administration of pdhC1INH, or both were good options for ambulatory management of dental-oral procedures in patients with HAE-C1-INH. Prophylaxis with pdC1INH or increased doses of AA is advisable before dental-oral procedures, even in patients with low disease severity.

Therapeutic management of hereditary angioedema due to C1 inhibitor deficiency.

Hereditary angioedema (HAE) due to C1 inhibitor (C1-INH) deficiency is a rare genetic disease characterized by recurrent swellings of the subcutaneous and submucosal tissues that can manifest as cutaneous edema, abdominal pain and laryngeal edema with airway obstruction. These symptoms have a significant impact on patients' quality of life. The reduction in C1-INH function leads to uncontrolled activation of the contact system and generation of bradykinin, the mediator of increased vascular permeability and edema formation. In the past, few treatment options were available; however, several new therapies with proven efficacy have recently become available to treat and prevent HAE attacks, such as plasma-derived and recombinant C1-INHs that replace the deficient protein, bradykinin receptor antagonist (icatibant) that blocks bradykinin activity and kallikrein inhibitor (ecallantide) that prevents bradykinin release. Such therapies can improve disease outcome. This article reviews the therapeutic management of HAE, which involves the treatment of acute attacks and prophylaxis.

Hereditary and acquired complement component 1 esterase inhibitor deficiency: a review for the hematologist.

Hereditary angioedema (HAE), a rare autosomal dominant disorder, was first described in the late 19th century. The disease remained poorly understood and without therapeutic options until the latter half of the 20th century. Advances in the understanding of immunologic and hematologic pathways have shed light on HAE, a disease characterized by painful and unpredictable recurrent attacks of nonpitting edema without urticaria. Recognition that a deficiency of complement component 1 (C1) esterase inhibitor leads to overproduction of vasoactive kinins that cause angioedema paved the way for the development of early treatments. Increased understanding of the role of bradykinin in hereditary and acquired forms of C1 esterase inhibitor deficiency has led to the development of more targeted treatments for this painful, debilitating and potentially life-threatening disease.

The autoreactivity of B cells in hereditary angioedema due to C1 inhibitor deficiency.

Patients with hereditary angioedema (HAE) tend to produce autoantibodies and have a propensity to develop immunoregulatory disorders. We characterize the profile of autoantibodies in a group of HAE patients and investigate their memory B cells' phenotype and activation status. We studied the activity status phenotype, Toll-like receptor (TLR)-9 expression and total phosphotyrosine in B cells isolated from HAE patients. Additionally, the following autoantibodies were assessed in the serum of 61 HAE patients: anti-nuclear, rheumatoid factor, anti-cardiolipin, anti-tissue transglutaminase, anti-endomysial, anti-Saccharomyces cerevisiae, anti-thyroid and anti-neutrophil cytoplasmic antibodies. In 47·5% of HAE patients we detected at least one of the tested autoantibodies. Expression of CD69, CD5 and CD21 was found to be significantly higher on memory B cells from HAE patients compared to healthy controls (4·59 ± 4·41 versus 2·06 ± 1·81, P = 0·04, 8·22 ± 7·17 versus 3·65 ± 3·78, P = 0·05, 2·43 ± 0·54 versus 1·92 ± 0·41, P = 0·01, respectively). Total phosphotyrosine in B cells from HAE patients was significantly higher compared to healthy controls (4·8 ± 1·1 versus 2·7 ± 1·3, P = 0·0003). Memory B cells isolated from the HAE group contained higher amounts of TLR-9 compared to healthy controls (8·17 ± 4·1 versus 4·56 ± 1·6, P = 0·0027). Furthermore, the expression of TLR-9 in memory B cells from HAE patients with autoantibodies was significantly higher than the control group (10 ± 4·7 versus 4·56 ± 1·6, P = 0·0002) and from that in HAE patients without autoantibodies (10 ± 4·7 versus 5·8 ± 0·9, P = 0·036). HAE patients have enhanced production of autoantibodies due most probably to the increased activation of B cells, which was found to be in association with a high expression of TLR-9.

Alterations of coagulation and fibrinolysis in patients with angioedema due to C1-inhibitor deficiency.

Patients with functional deficiency of C1-inhibitor (C1-INH) suffer from recurrent acute attacks (AA) of localized oedema associated with activation of the contact system, complement and fibrinolysis. To unravel further the role of coagulation and fibrinolysis in the pathophysiology of C1-INH deficiency, we performed simultaneous thrombin and plasmin generation measurements in plasma from patients with hereditary angioedema (HAE) due to C1-INH deficiency during AA (n = 23), in remission (R) (n = 20) and in controls (n = 20). During AA thrombin generation after in-vitro activation of plasma was higher than in controls, as demonstrated by shorter thrombin peak-time (P < 0·05), higher thrombin peak-height (P < 0·001) and increased area under the curve (AUC) (P < 0·05). Additionally, elevated levels of prothrombin fragment 1+2 (P < 0·0001) were observed in non-activated plasma from the same patients. In contrast, in activated plasma from patients during AA plasmin generation estimated as plasmin peak-height (P < 0·05) and plasmin potential (P < 0·05) was reduced, but non-activated plasma of the same patients showed elevated plasmin-anti-plasmin (PAP) complexes (P < 0·001). This apparent discrepancy can be reconciled by elevated soluble thrombomodulin (sTM) (P < 0·01) and thrombin activatable fibrinolysis inhibitor (TAFI) in patients during AA providing possible evidence for a regulatory effect on fibrinolysis. Plasminogen activator inhibitor-1 (PAI-1) was reduced in patients during AA indicating, together with the observed reduction of plasmin generation, the consumption of fibrinolytic factors. In conclusion, our results support the involvement of coagulation and fibrinolysis in the pathophysiology of HAE and show the possible application of simultaneous measurement of thrombin and plasmin generation to evaluate different clinical conditions in HAE patients.

Angioedema triggered by pulp extirpation--a case report.

BACKGROUND: C1-esterase inhibitor deficiency results in episodes of non-allergic edema of parts of the body. Edema of the face may be triggered by dental therapy. CASE REPORT: We report a case of C1-esterase inhibitor deficiency which was detected in a 42-year-old woman. The patient was completely unaware that she had this disorder or of any related family history, and the patient developed an intense facial angioedema after pulp extirpation of lower premolar tooth. DISCUSSION: In this case, the diagnosis of angioedema due to C1-esterase inhibitor deficiency was established at a later stage. The differing causes of C1-esterase inhibitor deficiency are briefly discussed and the treatment modalities outlined.