Analysis of cold activation of the contact system in hereditary angioedema with normal C1 inhibitor.

Hereditary angioedema (HAE) attacks are caused by excessive activation of the contact system. Understanding how the contact system is activated in HAE, especially in patients with normal C1 inhibitor (HAEnCI), is essential to effectively treat this disease. Contact system activation involves the cleavage of several proteins including Factor XII (FXII), high molecular weight kininogen (HK), prekallikrein, sgp120 (ITIH4) and C1 inhibitor (C1-INH) before the subsequent generation of bradykinin that mediates HAE. In this study, we evaluated the fragmentation and enzymatic activity of contact system proteins in HAEnCI plasma samples before and after contact system activation induced by incubation in the cold. Our results show that in contrast to normal plasma, cold activation induced contact system activation in the majority of the HAEnCI patient samples we tested, in which each contact system protein exhibited fragmentation, FXII and kallikrein enzymatic activity increased, and C1-INH functional activity decreased. HAEnCI samples with low FXII concentrations or functional activity were not affected by cold activation. One HAEnCI sample with a plasminogen gene mutation activated the fibrinolytic system, as shown by an increase in concentration of plasma D dimers. Our results suggest that cold activation seems to be initiated by the cleavage of prekallikrein, and that it needs FXII in order to occur. Reported to be susceptible to excessive contact system activation after incubation in the cold, we further applied this system of study to the evaluation of plasma from women undergoing estrogen treatment. Similar to plasma from HAEnCI patients, excessive contact system activation was demonstrated.

A mechanism for hereditary angioedema with normal C1 inhibitor: an inhibitory regulatory role for the factor XII heavy chain.

The plasma proteins factor XII (FXII) and prekallikrein (PK) undergo reciprocal activation to the proteases FXIIa and kallikrein by a process that is enhanced by surfaces (contact activation) and regulated by the serpin C1 inhibitor. Kallikrein cleaves high-molecular-weight kininogen (HK), releasing the vasoactive peptide bradykinin. Patients with hereditary angioedema (HAE) experience episodes of soft tissue swelling as a consequence of unregulated kallikrein activity or increased prekallikrein activation. Although most HAE cases are caused by reduced plasma C1-inhibitor activity, HAE has been linked to lysine/arginine substitutions for Thr309 in FXII (FXII-Lys/Arg309). Here, we show that FXII-Lys/Arg309 is susceptible to cleavage after residue 309 by coagulation proteases (thrombin and FXIa), resulting in generation of a truncated form of FXII (δFXII). The catalytic efficiency of δFXII activation by kallikrein is 15-fold greater than for full-length FXII. The enhanced rate of reciprocal activation of PK and δFXII in human plasma and in mice appears to overwhelm the normal inhibitory function of C1 inhibitor, leading to increased HK cleavage. In mice given human FXII-Lys/Arg309, induction of thrombin generation by infusion of tissue factor results in enhanced HK cleavage as a consequence of δFXII formation. The effects of δFXII in vitro and in vivo are reproduced when wild-type FXII is bound by an antibody to the FXII heavy chain (HC; 15H8). The results contribute to our understanding of the predisposition of patients carrying FXII-Lys/Arg309 to angioedema after trauma, and reveal a regulatory function for the FXII HC that normally limits PK activation in plasma.

Wolf in the sheep's clothing: intestinal angioedema mimicking infectious colitis.

Hereditary angioedema (HAE) is a relatively rare clinical entity that can potentially cause life-threatening airway or intestinal oedema, patients with the latter usually presents with symptoms of gastroenteritis like vomiting, diarrhoea and abdominal pain. Here, we present a unique case of a less recognised type of HAE that is type III in a patient who presented with signs and symptoms consistent with infectious colitis. She previously had similar episodes and was managed multiple times with antibiotics, with no satisfactory response. There, she underwent extensive diagnostic evaluation. On the basis of findings of further investigations on the current visit, she was eventually diagnosed with intestinal angioedema. To the best of our knowledge, the present paper represents the third reported case of type III HAE-induced intestinal angioedema. Additionally, we undertake a literature review of HAE.

Repeated attacks of type III hereditary angioedema with factor XII mutation during pregnancy.

In type III hereditary angioedema (HAE type III), the phenotype is the same as type I and type II disease, but the level and function of C1-esterase inhibitor (C1-INH) is normal. Hereditary angioedema type III has been described as an oestrogen-sensitive form because it can be triggered or aggravated by exposure to high oestrogen levels as seen during pregnancy, especially when associated with Factor XII mutation. This case report describes the evolution and management of repeated angioedema attacks during pregnancy in a woman with HAE, with normal levels and function of C1-INH (type III); and a mis-sense mutation of factor XII. The physiopathology and genetic features, the unpredictability of clinical manifestations and the management during pregnancy and delivery are discussed.

[Review of a new subtype of hereditary angio-oedema with normal complement C1-inhibitor].

Hereditary angio-oedema (HAE) is a rare, potentially fatal disease characterized by recurrent swelling of skin and mucosa. Besides HAE with quantitative (type I) or qualitative (type II) deficiency of complement C1-inhibitor (C1-INH), a new subtype of HAE is now described with normal levels of C1-INH. This subtype is possibly underdiagnosed, and a treatment regimen and general knowledge about the condition is still in its infancy. The purpose of this article is to inform Danish doctors about the disease to identify more Danish patients.

Factor XII Contact Activation.

Contact activation is the surface-induced conversion of factor XII (FXII) zymogen to the serine protease FXIIa. Blood-circulating FXII binds to negatively charged surfaces and this contact to surfaces triggers a conformational change in the zymogen inducing autoactivation. Several surfaces that have the capacity for initiating FXII contact activation have been identified, including misfolded protein aggregates, collagen, nucleic acids, and platelet and microbial polyphosphate. Activated FXII initiates the proinflammatory kallikrein-kinin system and the intrinsic coagulation pathway, leading to formation of bradykinin and thrombin, respectively. FXII contact activation is well characterized in vitro and provides the mechanistic basis for the diagnostic clotting assay, activated partial thromboplastin time. However, only in the past decade has the critical role of FXII contact activation in pathological thrombosis been appreciated. While defective FXII contact activation provides thromboprotection, excess activation underlies the swelling disorder hereditary angioedema type III. This review provides an overview of the molecular basis of FXII contact activation and FXII contact activation-associated disease states.

Treatment for hereditary angioedema with normal C1-INH and specific mutations in the F12 gene (HAE-FXII).

Hereditary angioedema with normal C1 esterase inhibitor and mutations in the F12 gene (HAE-FXII) is associated with skin swellings, abdominal pain attacks, and the risk of asphyxiation due to upper airway obstruction. It occurs nearly exclusively in women. We report our experience treating HAE-FXII with discontinuation of potential trigger factors and drug therapies. The study included 72 patients with HAE-FXII. Potential triggers included estrogen-containing oral contraceptives (eOC), hormonal replacement therapy, or angiotensin-converting enzyme inhibitors. Drug treatment comprised plasma-derived C1 inhibitor (pdC1-INH) for acute swelling attacks and progestins, tranexamic acid, and danazol for the prevention of attacks. Discontinuation of eOC was effective in 25 (89.3%) of 28 women and led to a reduction in the number of attacks (about 90%). After ending hormonal replacement therapy, three of eight women became symptom-free. Three women with exacerbation of HAE-FXII during intake of quinapril or enalapril had no further HAE-FXII attacks after discontinuation of those drugs. Eleven women were treated with pdC1-INH for 143 facial attacks. The duration of the treated facial attacks (mean: 26.6 h; SD: 10.1 h) was significantly shorter than that of the previous 88 untreated facial attacks in the same women (mean: 64.1 h; SD: 28.0 h; P < 0.01). The mean reduction in attack frequency was 99.8% under progestins after discontinuing eOC (16 women), 93.8% under tranexamic acid (four women), and 100% under danazol (three women). For patients with HAE-FXII, various treatment options are available which completely or at least partially reduce the number or duration of attacks.

Defective glycosylation of coagulation factor XII underlies hereditary angioedema type III.

Hereditary angioedema type III (HAEIII) is a rare inherited swelling disorder that is associated with point mutations in the gene encoding the plasma protease factor XII (FXII). Here, we demonstrate that HAEIII-associated mutant FXII, derived either from HAEIII patients or recombinantly produced, is defective in mucin-type Thr309-linked glycosylation. Loss of glycosylation led to increased contact-mediated autoactivation of zymogen FXII, resulting in excessive activation of the bradykinin-forming kallikrein-kinin pathway. In contrast, both FXII-driven coagulation and the ability of C1-esterase inhibitor to bind and inhibit activated FXII were not affected by the mutation. Intravital laser-scanning microscopy revealed that, compared with control animals, both F12-/- mice reconstituted with recombinant mutant forms of FXII and humanized HAEIII mouse models with inducible liver-specific expression of Thr309Lys-mutated FXII exhibited increased contact-driven microvascular leakage. An FXII-neutralizing antibody abolished bradykinin generation in HAEIII patient plasma and blunted edema in HAEIII mice. Together, the results of this study characterize the mechanism of HAEIII and establish FXII inhibition as a potential therapeutic strategy to interfere with excessive vascular leakage in HAEIII and potentially alleviate edema due to other causes.

In vivo activation and functions of the protease factor XII.

Combinations of proinflammatory and procoagulant reactions are the unifying principle for a variety of disorders affecting the cardiovascular system. Factor XII (FXII, Hageman factor) is a plasma protease that initiates the contact system. The biochemistry of the contact system in vitro is well understood; however, its in vivo functions are just beginning to emerge. The current review concentrates on activators and functions of the FXII-driven contact system in vivo. Elucidating its physiologic activities offers the exciting opportunity to develop strategies for the safe interference with both thrombotic and inflammatory diseases.

[Prophylactic use of icatibant before tracheal intubation of a patient with hereditary angioedema type III. (A literature review of perioperative management of patients with hereditary angioedema type III)]. / Uso profiláctico de icatibant en un caso de angioedema hereditario tipo III. (Revisión de la literatura sobre manejo perioperatorio en pacientes con angioedema hereditario tipo III).

Type III hereditary angioedema is a rare familial disorder that has recently been described as a separate condition. Triggers for episodes of angioedema include surgery, dental procedures, and tracheal intubation maneuvers. Since episodes affecting the upper airway are potentially life-threatening, prophylactic treatment is recommended in these situations. The use of icatibant (Firazyr(®)), for prevention of angioedema prior to tracheal intubation, is reported in a patient with type iii hereditary angioedema. A literature review on the anesthetic management of this condition was conducted.

Hereditary angioedema with an estrogen trigger in a 12-year-old.

BACKGROUND: Hereditary angioedema (HAE) is rare autosomal dominant genetic disorder, commonly affecting girls around the menarche, which manifests clinically as recurrent episodes of angioedema. Laryngeal edema can lead to asphyxiation and death. Traditionally hormones have been avoided in the management due a reported association with flares in the literature. This case describes an alternative management with a progestin. CASE: A 12 year old HAE sufferer failed to receive relief from her symptoms of angioedema with standard treatment. A trial of depot medroxyprogesterone acetate has resulted in resolution of her symptoms for the last 14 months. CONCLUSION: Although estrogens and progestins have been avoided in the management of HAE in the past, the reasons for this are based only on a small number of case reports. In this case, successful treatment with depot medroxyprogesterone acetate indicates that progestins, as an alternative management for estrogen-triggered HAE, certainly warrants further research.

Hereditary angioedema type III (estrogen-dependent) report of three cases and literature review.

In this article, three cases of hereditary angioedema (HAE) type III (estrogen-dependent or with normal C1 inhibitor) are reported. The HAE was initially described in women of the same family in association with high-leveled estrogenic conditions such as the use of oral contraceptives and pregnancy. There is no change in the C1 inhibitor as happens in other types of hereditary angioedema, and mutations are observed in the encoding gene of the XII factor of coagulation in several patients. The current diagnosis is mainly clinical and treatment consists in the suspension of the triggering factors and control of acute symptoms. A brief review of physiopathology, clinical features, genetic alterations and treatment are also presented.