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The kallikrein-kinin system: BK generation and catabolism. The kallikrein-kinin system consists of 3 plasma proteins that assemble when blood comes into contact with triggers, for example, negatively charged surfaces: FXII, plasma prekallikrein (PKK), and the nonenzymatic cofactor high-molecular-weight kininogen (HK); 80% of blood HK-PKK association is bound onto the endothelium. FXII and HK directly bind to polyanions; surface binding induces a conformational change in FXII, leading to limited proteolytic activity. Consecutively, activated FXII (FXIIa) cleaves PKK, generating plasma kallikrein (KK). In an amplified reaction, KK efficiently activates further FXII proenzyme molecules and cleaves its cofactor HK to yield BK, the B2 receptor ligand. This enzymatic activity is estimated in plasma by spontaneous kininogenase activity. The incubation on ice of plasma with dextran sulfate refers to full proenzyme activation, with subsequent measurement of the plasma PAA. Proenzyme activation and protease activities are under C1-INH control. The circulating CPN converts BK into des Arg 9 -BK, the B1 receptor ligand, and the membrane-bound (glycosyl-phosphatidylinositol anchor, GPI) APP and ACE inactivate the receptor-binding capacity of both peptides. Reprinted with permission from Defendi et al 6 (after modifications).
Contexts in source publication
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... BK level elevation produces an increase in endothelial permeability, vascular leakage, and angioedema. 2,5 A schematic representation of BK generation and catabolism is shown in Fig 1(reprinted with permission from Defendi et al 6 [after modifications]). ...
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... patients' clinical symptoms were classified into asymptomatic, mild, moderate, and severe according to an in-house score (see Table E1 in this article's Online Repository at www.jacionline.org). The missense p.Thr309Lys mutation was detected in all 5 female patients who had a phenotypic variant in which angioedema is exclusively precipitated by high estrogen levels (A10-II4, A9-II2, A11-II8, A12-II6, and A16-III1) and in 6 asymptomatic relatives (see Fig E1 in this article's Online Repository at www.jacionline.org for family pedigree). ...
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... angioedema (HAE) related to estrogens, nowadays identified as HAE with normal C1 inhibitor (C1-INH) function, 1 is a kind of bradykinin (BK)-induced angioedema. In some cases, a mutation has been detected in the F12 gene (HAE-factor XII [HAE-FXII]). 2-4 BK, the high-affinity ligand of type 2 BK receptor, is produced from high-molecular-weight kininogen upon cleav- age by proteases (kallikrein, FXIIa, and plasmin), 5 hereafter called kininogenases. BK is catabolized mainly by metallopeptidases (kininases): angiotensin-converting enzyme (ACE), aminopeptidase P (APP), and carboxypeptidase N (CPN). 2,4 BK level elevation produces an increase in endothe- lial permeability, vascular leakage, and angioedema. 2,5 A schematic representation of BK generation and catabolism is shown in Fig 1(reprinted with permission from Defendi et al 6 [after modifications]). We report data from studies performed on a large 3-generation Spanish family with a strictly estrogen-precipitating angioedema phenotype in an attempt to investigate factors that might affect the clinical expression of this disease. The study was approved by the Research Ethical Committee of the Hospital Universitario La Paz, Madrid, Spain, and all the participants provided informed consent. The propositus (patient A10-II4), a 33-year-old woman, had a history of severe episodes of hand and face edema with dysphonia and dysphagia related to fertility treatment with estradiol plus desogestrel-ethinylestradiol over the previous 6 years. Estrogen therapy was suspended indefinitely. The patient remained symptom-free until the onset of each of her pregnancies. The F12 gene was screened according to previously described methodology in 19 first-degree relatives. 7 Three sisters (A9-II.2, A11-II.8, and A12-II.6) and 1 niece (A16-III.1) described having angioedema episodes seemingly related to high estrogen levels (oral contraceptives and/or pregnancy). The patients’ clinical symptoms were classified into asymptomatic, mild, moderate, and severe according to an in-house score (see Table E1 in this article’s Online Repository at www.jacionline.org). The missense p.Thr309Lys mutation was detected in all 5 female patients who had a phenotypic variant in which angioedema is exclusively precipitated by high estrogen levels (A10-II4, A9-II2, A11-II8, A12-II6, and A16-III1) and in 6 asymptomatic relatives (see Fig E1 in this article’s Online Repository at www.jacionline.org for family pedigree). All the F12 gene mutation carriers were heterozygous for the mutation. Clinical characteristics of the mutation carriers are shown in Table E2 in this article’s Online Repository at www.jacionline.org. Penetrance of the disease was 45.5% for all the mutation carriers, 62.5% for female carriers, and 0% for male carriers. C4, antigenic, and functional C1-INH were measured as described. 7 The kinin-formation pathway was investigated by measuring spontaneous kininogenase activity (SKA), corresponding to kallikrein amidase activity by using the PFR p NA peptide as previously performed, 4,8 and prekallikrein activation ability (PAA) corresponding to the ability of plasma to develop the activatable proenzyme prekallikrein upon dextran sulfate incubation as described. 9 Kinin catabolism was studied by measuring plasma APP, CPN, and ACE activity as reported. 10 The presence of the SNP -2399A in the XPNPEP2 gene was screened in 4 patients according to previously reported methods. 11 Complement data are shown in Table E3 in this article’s Online Repository at www.jacionline.org. SKA, PAA, SKA/PAA ratio, and kinin catabolism enzymes activities are shown in Table E4 in this article’s Online Repository at www.jacionline.org. The association between C4, C1-INH, C1-INH function, SKA, PAA, SKA/PAA, APP, CPN, and ACE and the expression of clinical symptoms, sex, or the F12 gene mutation was studied by ANOVA by using mixed models. The models included the clinical symptoms, sex, or the F12 gene mutation as a main effect and the subject as a random effect (Table I). The estimated main effect for sex, clinical symptoms, or presence of F12 gene mutation was not statistically significant for the studied variables. Nevertheless, it is worth noting that the estimated C1-INH function mean was lower in symptomatic patients ( P 5 .082), and PAA was higher in patients with clinical symptoms and those with F12 gene mutation ( P 5 .088 and P 5 .083, respectively), which might indicate an activation of the contact system. Three out of 11 patients with F12 gene mutation had a decrease in at least 1 of the studied BK catabolic enzymes. All of them were women: 2 had moderate HAE-FXII disease severity, and 1 had severe HAE-FXII disease. APP activity was low in 2 of 5 (40%) symptomatic patients, but not in any of the 13 asymptomatic ones, which indicates some association ( P 5 .06). No association was observed between CPN activity and clinical expression. The SNP -2399A of XPNPEP2 gene was not detected in the index case (A10-II4) or in symptomatic (A9-II2 and A11-II8) and asymptomatic (A3-III4) individuals. Individuals who had not been treated for angioedema caused by C1-INH deficiency were shown to have a significant inverse relationship among APP and CPN activity and disease severity. 10 This association was also observed in an HAE-FXII family in which 3 female symptomatic patients carried the SNP -2399A in the XPNPEP2 gene, which had been associated with decreased APP. 11 In our study, plasma, APP, and CPN activities were found not to be significantly associated with the clinical manifestations in this family. However, decreased plasma APP was found only in symptomatic carriers and in none of the asymptomatic carriers. Moreover, none of the symptomatic F12 gene mutation carriers had the SNP -2399A in the XPNPEP2 gene. Based on the results of kininase activity and blind to disease clinical activity, the laboratory tried to predict the risk of developing severe angioedema for each patient, regardless of the presence of F12 gene mutation (Table E4). The laboratory prediction matched the presence of clinical symptoms in 8 of 11 patients with the F12 gene mutation (kappa index 5 0.42; P 5 .09), which indicates moderate agreement. As far as we know, mutations in the F12 gene have been described as causative for HAE-FXII 2,3 and the presence of the SNP -2399A in the XPNPEP2 gene has been identified as a possible aggravating factor. 11 This together with differences found in the clinical expression of the disease have led us to postulate that this disease is actually multifactorial and the mutation in the F12 gene is a prerequisite for the expression of disease symptoms. Other factors may have protective or aggravating effects on clinical features. While our data affirm the important role played by estrogens as precipitating clinical expression in HAE-FXII, they are by no means the only factors. A low level of kininase activity could be an aggravating factor. The low penetrance of the disease phenotype in this family suggests that there must be some unknown protective factor that prevents the development of angioedema. Based on the results of this study with a limited number of subjects, enzymatic activities (metallopeptidases, SKA or PAA) could not be recommended as the exclusive predictive parameters of clinical severity in HAE-FXII. Further studies are needed to identify additional factors that contribute to the variability in clinical ...
Citations
... A large 72-bp deletion (c.971_1018 + 24del72) at the edge of exon 9/intron 9 in the proline-rich region of FXII was reported for the first time in 2 non-related Turkish families. [55][56][57] ...
... It is also thought that mutant FXII, rather than prekallikrein, can be activated more quickly by plasmin and escape C1-INH inhibition, which helps explain the effectiveness of anti-fibrinolytic drugs in this disease. [57] Recent developments related to normal C1-INH level-HAE Aside from FXII, 2 new mutations have been reported in nC1-INH-HAE patients. Here also, the development of angioedema is mediated by bradykinin. ...
Hereditary angioedema (HAE) is a rare, inherited disease mostly associated with mutations in the SERPING1 gene (serpin family G member 1), which encodes the C1 inhibitor (C1-INH) protein. Regulation can lead to plasma deficiency and ensuing repeated attacks of severe angioedema. This disease was first described clinically and genetically in 1888 by William Osler, who named it 'hereditary angioneurotic edema (HANE).' It took 75 years until Donaldson and Evans identified the fundamental role of C1-INH in the pathophysiology of so-called HANE by Osler. Significant progress has been made in the research of this genetic disease when the role of neural factors was documented as being too small to lead to edema, the name was changed as HAE. Therefore, the name of more than 490 different mutations have been reported in the region of the C1-INH gene (SERPING1) until mid-2018. It is now known that C1-INH deficiency overstimulates the plasma contact (kallikrein-kinin) system, which eventually results in the overproduction of bradykinin. By binding to the bradykinin B2 receptor, bradykinin increases vascular permeability (vasodilation) and causes contraction of nonvascular smooth muscle, and acts as a main/major mediator in the pathophysiology of HAE. Reports since 2000 have described a new type of HAE with 'normal' CI-INH levels, primarily in Caucasians. A number of abnormalities in the genes encoding for factor XII, angiopoietin-1, and plasminogen have been identified in this novel disease entity. The establishment of treatment modalities for HAE with normal C1-INH is also expected.
... 5 So far, a number of studies showed that a proportion of patients initially diagnosed as InH-AAE was affected by FXII-HAE with lack of family history, with a prevalence varying from 12% to 100% across different centers (Table 1), whose data derive from different study designs and by patients' ancestry. [3][4][5][6] However, in several HAE patients presenting with normal C1-INH, no mutations in FXII gene are detectable and these patients have been previously classified as U-HAE. Within this latter subset of patients, we recently discovered a causal mutation in the Angiopoietin 1 (ANGPT1) gene. ...
... A chromogenic assay (Technochrom C1-Inhibitor, Technoclone, Vienna, Austria) was used to measure C1-INH activity. HAE severity scores were calculated according to published literature (Bygum et al., 2011;Gómez-Traseira et al., 2013). ...
Introduction: The presence of coronary endothelial dysfunction was previously shown in Hereditary Angioedema (HAE) patients. The aim of our study was to evaluate the effect of HAE on systemic endothelial function and whether there was a relationship among endothelial function, asymmetric dimethylarginine (ADMA) -which is a strong inhibitor of nitric oxide synthesis-, and disease severity scores.
Methods: Twenty-four HAE patients (18 females, aged 47.9 ± 2 years) without factors known to interfere with endothelial function were studied and compared with 24 healthy peers age- and gender-matched. Endothelial function was assessed by means of non-invasive finger plethysmography (reactive hyperaemia index: RHI) and ADMA levels by high-performance liquid chromatography. HAE severity scores have been calculated according to published literature.
Results: In HAE patients RHI was lower (2.03 ± 0.46 vs. 2.82 ± 0.34, p < 0.0001) and ADMA higher (0.636 ± 7 vs. 585 ± 5 micromol/L, p < 0.01) than in controls. A statistically significant inverse correlation was revealed between RHI and patients' ADMA levels (r = −0.516, p = 0.009) as well as between RHI and patients' chronological age (r = −0.49, p = 0.015). A statistically significant correlation between RHI and ADMA was confirmed even when excluding the possible influence of cholesterol (r = −0.408, p = 0.048). No other significant correlations were found with the examined laboratory and clinical parameters (chronological age, age at disease onset, disease duration, severity scores, and gender).
Conclusion: The dysfunction previously shown in HAE patients at the coronary arteries seems to involve the peripheral vessels as well, without a correlation with disease severity.
... In the present study, we described the clinical features of Brazilian patients with FXII-HAE from 42 families, who were evaluated at 9 HAE reference centers coordinated by the Brazilian Study Group on Hereditary Angioedema (GEBRAEH). Since the first report of this disease in Germany, several families presenting FXII-HAE have been identified in France, Spain, Italy, the United Kingdom, Luxemburg, Turkey, Australia, and Morocco, [27][28][29][30][31][32][33][34][35][36][37][38] with T328K as the most commonly associated mutation. In South America, few Brazilian families presenting FXII-HAE have been reported previously. ...
Background:
Hereditary angioedema (HAE) with normal C1 inhibitor (C1-INH) is a rare condition with clinical features similar to those of HAE with C1-INH deficiency. Mutations in the F12 gene have been identified in subsets of patients with HAE with normal C1-INH, mostly within families of European descent.
Objectives:
Our aim was to describe clinical characteristics observed in Brazilians from 42 families with HAE and F12 gene mutations (FXII-HAE), and to compare these findings with those from other populations.
Methods:
We evaluated a group of 195 individuals, which included 102 patients clinically diagnosed with FXII-HAE and their 93 asymptomatic relatives.
Results:
Genetic analysis revealed that of the 195 subjects, 134 individuals (77.6% females) carried a pathogenic mutation in F12. The T328K substitution was found in 132 individuals, and the c.971_1018+24del72 deletion was found in 2 patients. The mean age at onset of symptoms in patients with FXII-HAE was 21.1 years. The most common symptoms were subcutaneous edema (85.8% of patients), abdominal pain attacks (69.7%), and upper airway edema (32.3%). Of male individuals carrying F12 mutations, 53.3% (16 of 30) were symptomatic. Compared with reports from Europe, fewer female patients (68.6%) reported an influence of estrogen on symptoms.
Conclusions:
Our study included a large number of patients with FXII-HAE, and, as the first such study conducted in a South American population, it highlighted significant differences between this and other study populations. The high number of symptomatic males and patients with estrogen-independent FXII-HAE found here suggests that male sex and the absence of a hormonal influence should not discourage clinicians from searching for F12 mutations in cases of HAE with normal C1-INH.
... Based on the clinical history, the patients were previously evaluated as appropriate on the basis of known causes of angioedema, including the sequence of SERPING1 and F12 genes [18][19][20]. C1-INH-HAE and HAE-FXII severity scores were calculated respectively according to Gomez-Traseira et al. and Bygum et al. [21,22]. ...
Introduction: Hereditary angioedema due to C1-INH deficiency (C1-INH-HAE) or with normal C1-INH is characterized by recurrent swellings due to uncontrolled production of vasoactive mediators, among which bradykinin (BK) is crucial. Through the binding and activation of the two human BK-receptors, kinins may have dual beneficial and deleterious effects in vascular and inflammation physiopathology by inducing oxidative stress. We aimed to assess the serum concentrations of advanced glycation end products (AGEs) and advanced oxidation protein products (AOPPs) in patients affected by HAE.
Material and methods: Blood samples were collected to measure the serum concentrations of AGEs and AOPPs by spectrofluorimetric and spectrophotometric methods in patients affected by C1-INH-HAE and FXII-HAE during the remission state.
Results: We showed that the circulating levels of AOPPs observed on control group (0.94 (0.36) nmol/ mg) were significantly lower than those observed on the C1-INH-HAE group (1.68 (0.47) nmol/mg; p = 0.002) and FXII-HAE (1.50 (0.27) nmol/mg; p = 0.001). Moreover, the circulating levels of AGEs were significantly higher in C1-INH-HAE group (211.58 (151.05) AU/g; p = 0.02) than the FXII group (141.48 (89.59) AU/g), thus demonstrating a state of heightened oxidative stress.
Conclusions: Our observations show additional underlying events involved in HAE and are of central importance for further investigations of differences in bradykinin receptors signaling among the two disease subgroups.
... H ereditary angioedema caused by the p.Thr309Lys mutation in the F12 gene (HAE-FXII) is a rare life-threatening multifactorial disease in which the pathophysiology is not completely known. 1,2 Given the similarities with hereditary angioedema due to C1-inhibitor deficiency, bradykinin could also be the final mediator causing oedema. 2 In this sense, when an acute attack happens, there is a lack of response to high doses of antihistamines, corticosteroids and epinephrine. 2,3,4 In addition, there have been reports of good response to off-label treatment with tranexamic acid, plasma-derived human C1-inhibitor concentrate (pdhC1INH), icatibant acetate and ecallantide; although there have also been cases of poor response. ...
A 27-year-old pregnant female patient with a non-pruritic, non-erythematous facial angioedema episode unresponsive to a high dose of parenteral corticosteroids and antihistamines was referred to our clinic. She had previously had six episodes of facial and upper airway oedema while she was under treatment with ethinylestradiol-drospirenone. Her mother referred only a facial angioedema after dental extraction and her maternal grandmother had had angioedema attacks in two out of the three pregnancies. The p.Thr309Lys mutation in the F12 gene occurred in all of them. She received short-term prophylaxis with pdhC1INH 1 500U before caesarean delivery and no oedema occurred. However, 21 hours after caesarean delivery she developed oedema of the lips, tongue and eyelids, along with dysphagia and dysphonia. Treatment with pdhC1INH 1 500U and icatibant acetate ten minutes later was unsuccessful. Thirty minutes later dexchlorpheniramine, corticosteroids and epinephrine were administered and the patient improved within 15 minutes. The anamnesis revealed that she had eaten a peeled peach in syrup 15 minutes prior to the reaction. Commercial skin-prick tests (SPTs) were positive to peach, apple, cherry, plum, several nuts and pollens. Her sIgE was positive to peach, apple, rPru p 3 and other lipid transfer proteins.
... Gómez-Traseira et al. [107] describes 20 cases (11 females and 9 males on a large 3-generation Spanish family). The p.Thr309Lys mutation was detected in five female patients who had a phenotypic variant in which AE was exclusively precipitated by high estrogen levels and in six asymptomatic relatives. ...
[1] Department of Allergology, Nuestra Señora del Prado University General Hospital, Talavera de la Reina, Spain
[2] Spanish Study Group on Bradykinin-Induced Angioedema (SGBA), Spanish Society of Allergology and Clinical Immunology (SEAIC), Madrid, Spain
[3] Department of Allergology, Hospital Doce de Octubre Institute for Health Research (i+12), Madrid, Spain
[4] Highly-specialized Severe Asthma Unit, Hospital Doce de Octubre Institute for Health Research (i+12), Madrid, Spain
[5] Department of Immunology, Central Laboratory of Madrid Community—BRSalud, San Sebastián de los Reyes, Madrid, Spain
[6] Department of Allergology, Hospital La Paz Institute for Health Research (IdiPAZ), Madrid, Spain
[7] Biomedical Research Network on Rare Diseases, CIBERER (U754), Madrid, Spain
The origins of the discovery of the “Complement System” date from the second half of the nineteenth century. The official paternity of the Complement System is attributed to Jules Bordet. The complement system can be activated through three major pathways. The classical pathway, the alternative pathway, and the lectin pathway converge in a common final lytic pathway. Hereditary angioedema (HAE) due to C1-inhibitor (C1-INH) deficiency (C1-INH-HAE) was first described by Robert Graves in his clinical lectures. The autosomal dominant pattern of HAE was recognized by Sir William Osler. The pathophysiologic basis of C1-INH-HAE as a deficiency of a plasma inhibitor was discovered in the early 1960s. In 1986, the C1NH gene was identified, which encodes the C1-INH protein. Although the possible relationship between angioedema and estrogens in women was described as early as 1986, it was not until the first decade of the twenty-first century when several series of patients with HAE were described with normal levels of the fractions of the complement system. In the last decade, several drugs have been approved and marketed in Europe, in the United States, and in other countries, contributing to the improved management of C1-INH-HAE and patient’s quality of life.
... In Factor XII-related AE (FXII-AE), causative mutations have been identified in the Factor XII encoding gene (OMIM 610618) [1,[9][10][11], leading to pathological BK production [12]. Yet the mutation alone cannot explain the diversity of the disease among the same family and FXII-AE is multifactorial [13,14]. The nC1Inh-AE can also occur without FXII mutation, triggered by oral oestrogen/progestin combination (OP) intake [15][16][17] through possible transcriptional regulations which remain to be formally explicated [5]. ...
... Diagnosis of nC1Inh-AE is still controversial: detection of F12 gene mutation is pertinent only to FXII-AE but cannot explain why many carriers are asymptomatic [13,14]. Enzymatic tests have been performed to investigate increased kinin-forming conditions [26], C1Inh-protease complexes [27] or defective kinin catabolism [13,28]. ...
Background
Angioedema without wheals (AE) is a symptom characterised by localised episodes of oedema presumably caused by kinin release from kininogen cleavage. It can result from a hereditary deficiency in C1 Inhibitor (C1Inh), but it can present with normal level of C1Inh. These forms are typically difficult to diagnose although enhanced kinin production is suspected or demonstrated in some cases.
Objectives
We wanted to investigate bradykinin overproduction in all AE condition with normal C1Inh, excluding cases with enhanced kinin catabolism, and to propose this parameter as a disease biomarker.
Methods
We retrospectively investigated high molecular weight kininogen (HK) cleavage pattern, using gel electrophoresis and immunorevelation. Plasma samples were drawn using the same standardised procedure from blood donors or AE patients with normal C1Inh conditions, normal kinin catabolism, and without prophylaxis.
Results
Circulating native HK plasma concentrations were similar in the healthy men (interquartile range: 98–175μg/mL, n = 51) and in healthy women (90–176μg/mL, n = 74), while HK cleavage was lower (p<0.001) in men (0–5%) than women (3–9%). Patients exhibited lower native HK concentration (p<10⁻⁴; 21–117μg/mL, n = 31 for men; 0–84μg/mL, n = 41 for women) and higher HK cleavage (p<10⁻⁴; 10–30% and 14–89%, respectively) than healthy donors. Pathological thresholds were set at: <72μg/mL native HK, >14.4% HK cleavage for men; <38μg/mL; native HK, >33.0% HK cleavage for women, with >98% specificity achieved for all parameters. In plasma from patients undergoing recovery two months after oestrogen/progestin combination withdrawal (n = 13) or two weeks after AE attack (n = 2), HK cleavage was not fully restored, suggesting its use as a post-attack assay.
Conclusion
As a diagnostic tool, HK cleavage can offer physicians supportive arguments for kinin production in suspected AE cases and improve patient follow-up in clinical trials or prophylactic management.
... El AEH-nC1-INH es muy heterogé neo e incluye el AEH-FXII. El gen F12 que codifica al FXII se encuentra en el cromosoma 5. Las 2 mutaciones inicialmente descritas consisten en sustituciones en el ADN de una base por otra (missense mutations) (p.Thr309Lys, p.Thr309Arg) y está n localizadas en el exó n 9 del gen F12 5,6,11,13,14 . Se han descrito casos esporá dicos de otras mutaciones que afectan a la misma regió n del gen F12 11 . ...
... La expresió n clínica o fenotipo tanto del AEH-C1-INH como del AEH-nC1-INH es muy variable en cuanto a la frecuencia y gravedad de los episodios en distintos pacientes, incluso cuando son de la misma familia y comparten la misma alteració n gené tica, y tambié n en un mismo individuo durante las diferentes etapas de su vida, y se caracteriza por su imprevisibilidad 2,7,9,13,14 . Se han descrito casos de pacientes asintomá ticos portadores de mutació n en el gen C1NH, siendo de hasta un 13,7% en un registro españ ol 10 . ...
... Se han descrito casos de pacientes asintomá ticos portadores de mutació n en el gen C1NH, siendo de hasta un 13,7% en un registro españ ol 10 . En el AEH-nC1-INH la penetrancia es menor que en el AEH-C1-INH, y es mucho mayor en el sexo femenino (> 90% de portadores asintomá ticos varones frente a un 40% de mujeres en la variante AEH-FXII) 1,11,13,14 . ...
... Compared to that of normal control, plasma of HAE III patients showed higher FXII activity, but the FXII pro-coagulant activity remains normal, as indicated by APTT assay, and such activity is not subject to regulation by C 1 INH and agents that inhibit conformational activation FXII [19], suggesting a closer link between HAE III and FXII mutation. Actually, a third of HAE III patients harbored mutations in Thr309Lys, Thr328Lys or Thr309Arg [3,20]. Currently, the reason why HAE III only occurs in females is not clear, but it has been proved that FXII is clearly regulated by estrogen, which makes an explanation. ...
