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Revisión sistemática" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2371 "Ancho" => 2692 "Tamanyo" => 256970 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Search strategy. 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AAE, acquired angioedema; HAE, hereditary angioedema; U-HAE, hereditary angioedema of unknown origin; HAE-FXII, hereditary angioedema with <span class="elsevierStyleItalic">F12</span> gene mutation; FH, family history; NSAIDs, Non-Steroidal Anti-Inflammatory Drugs; C1q, component C1q of the complement; C4, fraction 4 of the complement; C1-INH, concentration of C1-esterase inhibitor; C1-INHf, functional activity of C1 esterase inhibitor; ACEI, angiotensin-converting enzyme inhibitors; N, normal; rel, related; U, urticaria.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Angioedema (AE) is the swelling (oedema) of the subcutaneous and/or submucosal tissue due to a transient increase in vascular permeability by the release of vasoactive mediators, which produces a swelling of the affected area.</p><p id="par0010" class="elsevierStylePara elsevierViewall">AE can be associated or not to urticaria. A consensus classification of AE without wheals has recently been published, which essentially divides Hereditary AE (HAE) and Acquired AE (AAE) (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">1</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0015" class="elsevierStylePara elsevierViewall">Hereditary forms are divided into those occurring with deficiency of the C1 esterase inhibitor (C1-INH) and <span class="elsevierStyleItalic">C1NH</span> gene mutation (C1-INH-HAE) and those without C1-INH deficiency (nC1-INH-HAE).</p><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Hereditary angioedema with C1 esterase inhibitor deficiency</span><p id="par0020" class="elsevierStylePara elsevierViewall">2 phenotypic variants have been described as antigenic concentrations of C1-INH.<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">2</span></a> Type I (85%) is characterized by a quantitative decrease of C1-INH and, therefore, a decrease in its functional activity; in type II (15%) normal or elevated concentrations of dysfunctional C1-INH, with a low functional activity.</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Hereditary angioedema without C1 esterase inhibitor deficiency</span><p id="par0025" class="elsevierStylePara elsevierViewall">In 2000 a variant of HAE was described in which both, concentrations and function of C1-INH were normal.<a class="elsevierStyleCrossRefs" href="#bib0315"><span class="elsevierStyleSup">3,4</span></a> It was proposed to call it type III HAE or HAE with normal C1 inhibitor (nC1-INH-HAE).<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">3</span></a> This HAE type has also been termed oestrogen dependent HAE<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">4</span></a> or HAE associated with oestrogen.<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">2</span></a> The molecular basis for some families with this type of HAE is a mutation in the gene <span class="elsevierStyleItalic">F12</span> encoding coagulation factor XII (FXII),<a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">5,6</span></a> so it was proposed to call it HAE-FXII.<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">7</span></a> To refer to cases of HAE without C1-INH deficiency and without mutation in the <span class="elsevierStyleItalic">F12</span> gene, the term HAE without C1-INH deficiency of unknown cause<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">7</span></a> was proposed. It is proposed to stop using the term HAE typeIII.<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">8</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">The prevalence of the various types of HAE is unknown. It is estimated that C1-INH-HAE affects 1:10,000 and 1:100,000<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">9</span></a> (about 1:50,000). In Spain the minimum prevalence is 1.09/100,000.<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">10</span></a> On the other hand, there are no prevalence studies of nC1-INH-HAE, although it seems very low.</p></span></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Pathophysiology</span><p id="par0035" class="elsevierStylePara elsevierViewall">Both C1-INH-HAE as well as nC1-INH-HAE are characterized by increased production of bradykinin (BK),<a class="elsevierStyleCrossRefs" href="#bib0305"><span class="elsevierStyleSup">1,2,6,9</span></a> that binds to type 2 BK receptor (BR2) and produces a localized increase in vascular permeability and AE<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">9</span></a> (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). The BK is rapidly metabolized by endogenous kininases<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">9</span></a> (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>).</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0040" class="elsevierStylePara elsevierViewall">High concentrations of endogenous or exogenous oestrogens may lead to a worsening of AE<a class="elsevierStyleCrossRefs" href="#bib0355"><span class="elsevierStyleSup">11,12</span></a> by several mechanisms.<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">9</span></a> Taking drugs that inhibit angiotensin converting enzyme (ACE) inhibitors can also cause a worsening of AE by inhibition of the primary BK inactivator.<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">9</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Genetics</span><p id="par0045" class="elsevierStylePara elsevierViewall">Both C1-INH-HAE as well as HAE-FXII are autosomal dominant hereditary diseases.<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">9</span></a></p><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Hereditary angioedema types I and II with C1 esterase inhibitor deficiency</span><p id="par0050" class="elsevierStylePara elsevierViewall">The C1-INH protein is encoded by the gene <span class="elsevierStyleItalic">C1NH</span> or <span class="elsevierStyleItalic">SERPING1</span>, located on chromosome 11, subregion q11–q13.1.<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">2</span></a> Patients suffering from C1-INH-HAE are mostly heterozygous, although homozygous cases have been described in patients with consanguineous parents.<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">9</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">Mutations in the <span class="elsevierStyleItalic">C1NH</span> gene are very heterogeneous. More than 300 different ones have been published.<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">9</span></a> Mutations in C1-INH-HAE type I are distributed throughout the gene and are very diverse.<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">9</span></a> By contrast, in the C1-INH-HAE type II mutations are of the single base modification type (point mutations), located in the exon 8, in the region encoding the active centre or hinge region of the protein, generating a non-functional C1-INH.<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">9</span></a> There is a high prevalence of de novo mutations (around 25% of C1-INH-HAE cases).<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">9</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Hereditary angioedema with normal C1 esterase inhibitor</span><p id="par0060" class="elsevierStylePara elsevierViewall">nC1-INH-HAE is very heterogeneous and includes HAE-FXII. The <span class="elsevierStyleItalic">F12</span> gene encoding the FXII is located on chromosome 5. The 2 mutations described initially consist of substitutions in the DNA of one base for another (<span class="elsevierStyleItalic">missense mutations</span>) (p.Thr 309Lys, p.Thr 309Arg) and are located in exon 9 of gene <span class="elsevierStyleItalic">F12</span>.<a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">5,6,11,13,14</span></a> Sporadic cases have been described of other mutations that affect the same region of gene <span class="elsevierStyleItalic">F12</span>.<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">11</span></a></p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Clinical signs and symptoms</span><p id="par0065" class="elsevierStylePara elsevierViewall">HAE is characterized by recurrent episodes of transient, limited, cold, white, hard and non-pruritic swelling of the dermis or subcutaneous or submucosal tissue, without accompanying urticaria.<a class="elsevierStyleCrossRefs" href="#bib0310"><span class="elsevierStyleSup">2,9</span></a> It can affect different areas of the subcutaneous tissue in the submucosa of the gastrointestinal tract and upper respiratory tract.<a class="elsevierStyleCrossRefs" href="#bib0310"><span class="elsevierStyleSup">2,7,9</span></a><a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> summarizes the typical symptoms depending on the affected area. The most frequent episodes in C1-INH-HAE are peripheral cutaneous and abdominal,<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">15</span></a> and peripheral in nC1-INH-HAE.<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">11</span></a> Combined and migratory attacks are frequent.<a class="elsevierStyleCrossRefs" href="#bib0310"><span class="elsevierStyleSup">2,15</span></a> In nC1-INH-HAE there is a higher incidence of facial involvement (labial and lingual) and a lower percentage of abdominal and laryngeal attacks.<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">11</span></a> Characteristically, haemorrhages have been observed in oedematous areas of the skin.<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">11</span></a></p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0070" class="elsevierStylePara elsevierViewall">The episodes are self-limited. Typically, the attack intensity increases during the first 12–24<span class="elsevierStyleHsp" style=""></span>h, and then begins to subside spontaneously during the following 48–72<span class="elsevierStyleHsp" style=""></span>h, although they can last up to 5 days.<a class="elsevierStyleCrossRefs" href="#bib0310"><span class="elsevierStyleSup">2,11</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">Over 80% of patients with C1-INH-HAE perceive several hours before some attacks that AE is going to occur due to the presence of the so-called prodromal symptoms and this can be seen in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>.<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">16</span></a> Sometimes, prodromal symptoms may occur without the subsequent AE attack. Erythema marginatum has not described in nC1-INH-HAE as prodrome of the attacks.<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">11</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">The clinical expression or phenotype of both C1-INH-HAE and nC1-INH-HAE is highly variable in terms of episode frequency and severity depending on the patient. It is characterized by its unpredictability, even when they are of the same family and share the same genetic alteration; also in the same individual at different stages of his life.<a class="elsevierStyleCrossRefs" href="#bib0310"><span class="elsevierStyleSup">2,7,9,13,14</span></a> There are reports of asymptomatic mutation carriers in gene <span class="elsevierStyleItalic">C1NH</span>, being up to 13.7% on a Spanish record.<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">10</span></a> nC1-INH-HAE penetrance is lower than C1-INH-HAE and is much higher in females (>90% of asymptomatic male carriers versus 40% female in the HAE-FXII variant).<a class="elsevierStyleCrossRefs" href="#bib0305"><span class="elsevierStyleSup">1,11,13,14</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">There is a C1-INH-HAE classification according to severity<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">2</span></a> which has not been validated. A classification of AE's episodes by severity has also been proposed based on the impact of AE in the patient's daily activities,<a class="elsevierStyleCrossRefs" href="#bib0310"><span class="elsevierStyleSup">2,17</span></a> but it has neither been validated.</p><p id="par0090" class="elsevierStylePara elsevierViewall">Although symptoms in C1-INH-HAE can begin at any age, more than half of the patients start developing them during the first decade of life, with a third during the second decade. Only a minority presents symptoms in the first year of life.<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">2</span></a> The disease is usually worse during puberty, with female patients reporting more severe forms due to high concentrations of endogenous oestrogen.<a class="elsevierStyleCrossRefs" href="#bib0355"><span class="elsevierStyleSup">11,12</span></a> Age has been linked to early onset of symptoms with a greater severity of the clinical signs and symptoms.<a class="elsevierStyleCrossRefs" href="#bib0375"><span class="elsevierStyleSup">15,18</span></a> Recent data from Spain shows a delay of approximately 13 years between the onset of symptoms and diagnosis of C1-INH-HAE.<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">10</span></a> The age of symptom onset starts later in nC1-INH-HAE (about 60% between the second and third decades), relative to oestrogen hormone activity;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">11</span></a> women have more severe and frequent symptoms during hyper-estrogenic periods due to exogenous contribution of oestrogens (contraceptive or hormone replacement therapies) or endogenous elevation during pregnancy.<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">8</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">In patients with C1-INH-HAE, precipitating factors related to AE's attacks are identified in up to 50% of episodes (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>).<a class="elsevierStyleCrossRefs" href="#bib0310"><span class="elsevierStyleSup">2,9</span></a> Oestrogens are the most characteristic precipitating factors in nC1-INH-HAE. Some cases of exacerbations have been described after ACEI and ARA II were taken.<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">11</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Diagnosis</span><p id="par0100" class="elsevierStylePara elsevierViewall">HAE clinical suspicion based on episodes of cutaneous AE, abdominal pain or recurrent laryngeal oedema, should be confirmed by laboratory measurements, especially if a family history of similar symptoms is added. Summary in <a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>.</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0105" class="elsevierStylePara elsevierViewall">Screening C1-INH-HAE is performed by determining C4 concentrations, which are low between crises in most cases. However, cases with normal C4<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">9</span></a> have been reported, so if clinical suspicion is high, concentrations of quantitative and functional C1-INH should be requested simultaneously, and if they are normal, its determination can be performed during an AE attack.<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">9</span></a> To diagnose C1-INH deficiency, the results should be confirmed in two determinations between one and three months apart.<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">9</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">C1-INH deficiency can be diagnosed with 98–100% specificity and positive predictive value of 79% if C4 concentrations are low and there is a decreased functional activity of C1-INH.<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">9</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">C1q concentrations must be requested to differentiate between inherited and acquired forms of C1-INH deficiency because C1q is decreased in the latter.<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">9</span></a> Complement values are displayed in different types of bradykinergic AE in <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>.</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0120" class="elsevierStylePara elsevierViewall">Diagnosis of nC1-INH-HAE is by exclusion, based on clinical suspicion and family history.<a class="elsevierStyleCrossRefs" href="#bib0340"><span class="elsevierStyleSup">8,9,11</span></a> In some cases, the presence of mutation in gene <span class="elsevierStyleItalic">F12</span>(HAE-FXII) is confirmed, but many cases of nC1-INH-HAE are left without biological confirmation.<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">8</span></a> A recently published study showed that the determination of spontaneous amidase activity in plasma of subjects with BK-mediated AE is significantly high compared with that of controls and subjects with histaminergic AE (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.01).<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">19</span></a> Although this determination is not available for routine use, in the future it could be of great value in differentiating the pathogenesis of different types of AE.</p><p id="par0125" class="elsevierStylePara elsevierViewall">Diagnosis in the ER is a challenge, as the clinical presentation, in many cases, is indistinguishable from a histaminergic AE, or an acute abdomen in abdominal forms of presentation. This subject has been reviewed in depth.<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">20</span></a></p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Treatment</span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">General measures</span><p id="par0130" class="elsevierStylePara elsevierViewall">Patients with C1-INH-HAE and nC1-INH-HAE should avoid taking oestrogens or oestrogen action drugs and ACEI.<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">21</span></a></p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Treatment of acute episode</span><p id="par0135" class="elsevierStylePara elsevierViewall">Administration of a drug at the onset of the AE episode in order to stop the progression of oedema and shorten its life. It has been called “on demand treatment” of AE episodes. A patient with HAE should initially receive early on demand treatment for AE attacks,<a class="elsevierStyleCrossRefs" href="#bib0305"><span class="elsevierStyleSup">1,17,22</span></a> before considering initiating long-term prophylaxis (LTP).</p><p id="par0140" class="elsevierStylePara elsevierViewall">AE acute attacks of C1-INH-HAE and nC1-INH-HAE do not respond to conventional treatment with antihistamines, corticosteroids and adrenaline.<a class="elsevierStyleCrossRefs" href="#bib0305"><span class="elsevierStyleSup">1,2,21</span></a></p><p id="par0145" class="elsevierStylePara elsevierViewall">Indications to treat an AE attack in C1-INH-HAE have varied in recent years. Currently, the recommendation is to treat all attacks, regardless of location.<a class="elsevierStyleCrossRefs" href="#bib0385"><span class="elsevierStyleSup">17,22</span></a> Furthermore, it has been shown that early treatment of AE attacks shortens their duration.<a class="elsevierStyleCrossRefs" href="#bib0415"><span class="elsevierStyleSup">23,24</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">There are 4 specific drugs for treating AE attacks in C1-INH-HAE, whose efficacy and safety have been studied in double-blind placebo-controlled clinical trials,<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">17</span></a> with different availability<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">1</span></a> (<a class="elsevierStyleCrossRefs" href="#tbl0020">Tables 4 and 5</a>).<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">a.</span><p id="par0155" class="elsevierStylePara elsevierViewall">Purified and pasteurized human C1-INH plasma concentrate (phC1INH):<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">-</span><p id="par0160" class="elsevierStylePara elsevierViewall">Its action mechanism consists in the replacement of C1-INH. There are 2 products sold in Spain (Berinert<span class="elsevierStyleSup">®</span>, CSL-Behring GmbH, Marburg, Germany; Cinryze<span class="elsevierStyleSup">®</span>, Shire HGT, Zug, Switzerland).</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">-</span><p id="par0165" class="elsevierStylePara elsevierViewall">Berinert<span class="elsevierStyleSup">®</span> is available in Europe since 1985 and has demonstrated its efficacy and safety in case series,<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">21</span></a> in a placebo-controlled trial (IMPACT1)<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">25</span></a> and in open clinical trials (IMPACT2).<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">26</span></a> The infection transmission risk with Berinert<span class="elsevierStyleSup">®</span> is very low.<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">27</span></a></p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">-</span><p id="par0170" class="elsevierStylePara elsevierViewall">In 2010 the <span class="elsevierStyleItalic">European Medicines Agency</span> (EMA) approved the marketing of Cinryze<span class="elsevierStyleSup">®</span>.<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">28</span></a> It has demonstrated its efficacy and safety in a controlled clinical trial<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">29</span></a> and its open-label extension.<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">30</span></a></p></li></ul></p></li><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">b.</span><p id="par0175" class="elsevierStylePara elsevierViewall">Icatibant Acetate (Firazyr<span class="elsevierStyleSup">®</span>, Shire HGT, Zug, Switzerland) is a synthetic decapeptide similar to BK, acting as selective, potent and competitive antagonist of BR2, approved by EMA in 2008.<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">31</span></a> It has shown an excellent safety and efficacy profile in controlled clinical trials. Only local reactions at the site of administration (in 95% cases) have been described.<a class="elsevierStyleCrossRefs" href="#bib0460"><span class="elsevierStyleSup">32,33</span></a> The subcutaneous route facilitates self-administration, with a high degree of satisfaction.<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">34</span></a></p></li><li class="elsevierStyleListItem" id="lsti0030"><span class="elsevierStyleLabel">c.</span><p id="par0180" class="elsevierStylePara elsevierViewall">The recombinant human C1-INH (rhC1INH) (Ruconest<span class="elsevierStyleSup">®</span>, Pharming Group NV, Leiden, the Netherlands; SOBI, Stockholm, Sweden) was approved by the EMA in October 2010 for the treatment of acute AE attacks in over 18 year-olds,<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">35</span></a> although it has yet to be marketed in Spain. It is produced in transgenic female rabbits in which the human <span class="elsevierStyleItalic">CINH</span> gene is inserted and is excreted in milk, from which it is obtained by purification. It has a similar inhibitory potency and high structural analogy with phC1INH, although with a lower half-life (3<span class="elsevierStyleHsp" style=""></span>h). The active substance has been termed conestat alfa. The doses that have proven effective in clinical studies vary between 50 and 100<span class="elsevierStyleHsp" style=""></span>U/kg,<a class="elsevierStyleCrossRefs" href="#bib0480"><span class="elsevierStyleSup">36,37</span></a> being the dose of 50<span class="elsevierStyleHsp" style=""></span>U/kg the one finally approved by EMA.<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">35</span></a> Due to being recombinant, it has the advantage of mass production and the reduction of the potential theoretical risk of transmission of infectious diseases inherent to plasma derivatives.<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">37</span></a> A disadvantage could be its immunogenic potential with high risk to produce neutralizing antibodies and/or allergic reactions; however, only one anaphylactic reaction in a patient with an allergy to rabbit has been reported in a phase I clinical trial.<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">21</span></a> Although the experience with the use of this drug is limited, it has demonstrated its good safety and efficacy profile in other clinical trials.<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">38</span></a></p></li><li class="elsevierStyleListItem" id="lsti0035"><span class="elsevierStyleLabel">d.</span><p id="par0185" class="elsevierStylePara elsevierViewall">Ecallantide (Kalbitor<span class="elsevierStyleSup">®</span>, Dyax Corp., Cambridge, MA, USA) is a reversible, powerful and high specificity inhibitor of human plasma kallikrein approved by the FDA only for use as acute treatment in over 12 year-olds.<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">39</span></a> Its efficacy has been demonstrated in several clinical trials.<a class="elsevierStyleCrossRefs" href="#bib0385"><span class="elsevierStyleSup">17,40</span></a> However, some allergic reactions, including anaphylaxis, have been reported.<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">21</span></a></p></li><li class="elsevierStyleListItem" id="lsti0040"><span class="elsevierStyleLabel">e.</span><p id="par0190" class="elsevierStylePara elsevierViewall">In countries where there is no availability of phC1INH, icatibant acetate, rhC1INH or ecallantide, fresh frozen plasma (FFP) can be used at doses similar to those used in coagulopathies.<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">21</span></a> Their use is controversial because its mechanism of action consists in the replacement of C1-INH, but also replenishes the substrates where this one operates (FXII, prekallikrein, etc.), which could pose a risk of worsening the secondary attack due to a BK increase (if the BK increases before C1-INH can act).<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">21</span></a> It is preferable to use it solvent-detergent treated, reducing the possibility of transmission of infectious diseases.</p></li></ul></p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia><elsevierMultimedia ident="tbl0025"></elsevierMultimedia><p id="par0195" class="elsevierStylePara elsevierViewall">The characteristics, dosage, side effects and contraindications of drugs used for treatment of acute attacks are summarized in <a class="elsevierStyleCrossRefs" href="#tbl0020">Tables 4 and 5</a>.</p><p id="par0200" class="elsevierStylePara elsevierViewall">There are no studies comparing the efficacy, safety and tolerance of phC1INH, icatibant acetate, ecallantide and rhC1INH. A paper comparing the characteristics and purity profile of the 3 products containing C1-INH (Berinert<span class="elsevierStyleSup">®</span>, Cinryze<span class="elsevierStyleSup">®</span> and Ruconest<span class="elsevierStyleSup">®</span>), was recently published, being Berinert<span class="elsevierStyleSup">®</span> the one showing higher purity of the 2 phC1INH.<a class="elsevierStyleCrossRef" href="#bib0505"><span class="elsevierStyleSup">41</span></a> Although rhC1INH (Ruconest<span class="elsevierStyleSup">®</span>) has a higher purity than the 2 phC1INH, it presents glycosylation differences with respect to human C1-INH.<a class="elsevierStyleCrossRef" href="#bib0505"><span class="elsevierStyleSup">41</span></a></p><p id="par0205" class="elsevierStylePara elsevierViewall">It is recommended that patients have the specific medication at home (e.g. phC1INH, icatibant acetate), so that, in case of attack, they can take it to the nearest medical centre for administration or for self-administration (after appropriate training).<a class="elsevierStyleCrossRef" href="#bib0510"><span class="elsevierStyleSup">42</span></a></p><p id="par0210" class="elsevierStylePara elsevierViewall">With respect to the treatment of nC1-INH-HAE, clinical experience is limited, there are no controlled studies and just some clinical cases. AE attacks do not respond to conventional treatment with corticosteroids, H1-antihistamines and adrenaline, and the analysis of published data indicates that the therapeutic approach is similar to C1-INH-HAE, with good response in some cases to intravenous tranexamic acid, icatibant acetate or phC1INH.<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">11</span></a></p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Long-term prophylaxis</span><p id="par0215" class="elsevierStylePara elsevierViewall">The purpose of LTP is to decrease the frequency, severity and duration of AE attacks.<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">2</span></a> The indications for initiating LTP is under debate. The Spanish study group of bradykinin-mediated angioedema established as indications having had one oedema of the glottis episode, more than one episode of AE per month plus a severe orofacial or abdominal attack or alterations in the quality of life.<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">9</span></a> However, an international consensus published in 2012 recommended its indication when, despite optimized treatment, the patient has more than 12 moderate-severe episodes a year or is affected by the disease over 24 days a year.<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">17</span></a></p><p id="par0220" class="elsevierStylePara elsevierViewall">A systematic review on the drugs used as LTP in C1-INH-HAE has been recently published.<a class="elsevierStyleCrossRef" href="#bib0515"><span class="elsevierStyleSup">43</span></a></p><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Antifibrinolytics</span><p id="par0225" class="elsevierStylePara elsevierViewall">Epsilon aminocaproic acid and tranexamic acid (cyclical derivative from the first) have been effective in preventing AE attacks.<a class="elsevierStyleCrossRefs" href="#bib0385"><span class="elsevierStyleSup">17,21,43</span></a> It is believed that the beneficial effect is due to plasmin inhibition and tissue plasminogen activator.<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">21</span></a> The dose and side effects are summarized in <a class="elsevierStyleCrossRefs" href="#tbl0020">Tables 4 and 5</a>, respectively.</p><p id="par0230" class="elsevierStylePara elsevierViewall">Changes in the retina of laboratory animals have been reported, therefore performing a periodic ophthalmoscopy is recommended.<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">21</span></a> Due to its thrombogenic potential, it should be stopped before surgery.<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">21</span></a></p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Attenuated androgens</span><p id="par0235" class="elsevierStylePara elsevierViewall">The efficacy of androgens has been demonstrated in double blind placebo controlled trials.<a class="elsevierStyleCrossRefs" href="#bib0310"><span class="elsevierStyleSup">2,17,21,43</span></a> Although the mechanism of action is unknown, increased plasma concentrations of C1-INH with high doses of attenuated androgens (AA) have been reported, together with an increase in mRNA-C1-INH expression in mononuclear cells and APP concentrations, an enzyme involved in the catabolism of kinins.<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">21</span></a></p><p id="par0240" class="elsevierStylePara elsevierViewall">The main ones used are danazol and stanozolol, 17-α-alkylated synthetic derivatives, more effective and have fewer side effects.<a class="elsevierStyleCrossRefs" href="#bib0310"><span class="elsevierStyleSup">2,21,44</span></a> Stanozolol has proved more effective and with a better safety profile,<a class="elsevierStyleCrossRef" href="#bib0520"><span class="elsevierStyleSup">44</span></a> but its use is off-label. The treatment objective is to control symptoms with the lowest effective dose, and there is no need to normalize C1-INH and C4 concentrations.<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">21</span></a></p><p id="par0245" class="elsevierStylePara elsevierViewall">AA are the treatment of choice because they are more effective than antifibrinolytic agents (AF) (97% versus 28%),<a class="elsevierStyleCrossRefs" href="#bib0310"><span class="elsevierStyleSup">2,21</span></a> unless there is a contraindication<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">21</span></a> (<a class="elsevierStyleCrossRef" href="#tbl0025">Table 5</a>).</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">C1-INH plasma concentrate (phC1INH)</span><p id="par0250" class="elsevierStylePara elsevierViewall">The regular administration of intravenous (IV) PhC1INH prevents the onset of AE attacks and has been used as LTP for 2 decades.<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">21</span></a> A crossover controlled with placebo phC1INH (Cinryze<span class="elsevierStyleSup">®</span>) study was conducted in which 22 patients with ≥2 attacks per month received 1000<span class="elsevierStyleHsp" style=""></span>U IV every 3–4 days for 12 weeks, followed by a similar period of placebo, or vice versa.<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">29</span></a> The results showed that the drug decreased by 50.8% the frequency (4.24–2.09 attacks/month, <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.001), the duration (from >4<span class="elsevierStyleHsp" style=""></span>h to 2<span class="elsevierStyleHsp" style=""></span>h, <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.02) and severity of attacks and the number of acute rescue treatments.<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">29</span></a> These results were confirmed in an open-label study where doses and intervals between these were individualized.<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">30</span></a></p><p id="par0255" class="elsevierStylePara elsevierViewall">Currently, the only phC1INH authorized by EMA for LTP is Cinryze<span class="elsevierStyleSup">®</span> at doses of 1000<span class="elsevierStyleHsp" style=""></span>U IV 2 times per week.<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">28</span></a> However, doses and intervals between these should be individualized.<a class="elsevierStyleCrossRefs" href="#bib0385"><span class="elsevierStyleSup">17,45</span></a></p><p id="par0260" class="elsevierStylePara elsevierViewall">The LTP with phC1INH should be limited to patients with a more severe clinical course, not responding to AA or AF, or where these are contraindicated.</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Others</span><p id="par0265" class="elsevierStylePara elsevierViewall">Subsequently, an open-label study was published. This used rhC1INH (Ruconest<span class="elsevierStyleSup">®</span>) for LTP in 25 patients with ≥2 attacks per month, administering 50<span class="elsevierStyleHsp" style=""></span>U/kg once a week for 8 weeks, obtaining a reduction in the number of attacks (mean 0.9 attacks/week versus 0.4 attacks/week, CI 95%: 0.28–0.56).<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">46</span></a> Although it was discussed that the shorter half-life of rhC1INH could have a negative influence on LTP suitability (1.6<span class="elsevierStyleHsp" style=""></span>h rhC1INH versus >30<span class="elsevierStyleHsp" style=""></span>phC1INH h), it has not been observed to have a clinical impact<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">37</span></a> and it seems that clinical efficacy has more to do with the peak concentration of C1-INH than with its half-life.<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">47</span></a></p><p id="par0270" class="elsevierStylePara elsevierViewall">All clinical trials have shown that both phC1INH as well as rhC1INH are well tolerated, with a very low rate of side effects, which are usually mild (anxiety, dizziness, dry mouth, hypotension, etc.).<a class="elsevierStyleCrossRefs" href="#bib0445"><span class="elsevierStyleSup">29,30,46</span></a></p><p id="par0275" class="elsevierStylePara elsevierViewall">However, there are 3 important points regarding the safety of these drugs. Being a plasma derivative, phC1INH can potentially be a virus transmission source.<a class="elsevierStyleCrossRefs" href="#bib0310"><span class="elsevierStyleSup">2,21</span></a> However, it has been shown that virus and prions removal processes are effective,<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">27</span></a> and seroconversion to HBV, HCV, HIV or parvovirus B19 has not been detected.<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">29</span></a> Another important point is immunogenicity. Studies with Cinryze<span class="elsevierStyleSup">®</span> did not detect the presence of anti-C1INH antibodies during the study period.<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">30</span></a> However, with rhC1INH, the presence of anti-rhC1INH antibodies was detected in 2 patients, although with no clinical significance,<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">46</span></a> as they lacked neutralizing or sensitizing activity.<a class="elsevierStyleCrossRef" href="#bib0540"><span class="elsevierStyleSup">48</span></a></p><p id="par0280" class="elsevierStylePara elsevierViewall">Finally, an FDA alert on the occurrence of thrombotic events in patients with C1-INH-HAE who were receiving phC1INH (Cinryze<span class="elsevierStyleSup">®</span>)<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">49</span></a> has been published. This has been attributed to the use of central catheters to facilitate self-administration of phC1INH,<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">50</span></a> but more studies are needed. A procoagulant effect with Berinert<span class="elsevierStyleSup">®</span> had been previously published, used at doses higher than 200<span class="elsevierStyleHsp" style=""></span>U/kg, which are much higher than those used for C1-INH-HAE.<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">21</span></a> However, this effect was not observed when using Berinert<span class="elsevierStyleSup">®</span> at recommended doses in patients with -C1-INH-HAE or C1-INH-AAE, or in children operated of transposition of the great arteries, administered in 100<span class="elsevierStyleHsp" style=""></span>U/kg<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">21</span></a> doses.</p><p id="par0285" class="elsevierStylePara elsevierViewall">Progesterone, danazol and tranexamic acid have been used off-label in the case of nC1-INH-HAE.<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">11</span></a></p></span></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Short term preprocedural treatment or prophylaxis</span><p id="par0290" class="elsevierStylePara elsevierViewall">It is the treatment administered before medical or surgical procedures to prevent them from triggering an AE attack. Short term prophylaxis (STP) must be carried out in all patients with C1-INH-HAE in situations that can precipitate an attack of AE, in all trauma-related medical procedures, and especially in those involving the cervicofacial region (odontostomatological manipulation, tonsillectomy, maxillofacial surgery, gastroscopy, bronchoscopy, endotracheal intubation, etc.), due to the possibility of developing oedema of the upper airway.<a class="elsevierStyleCrossRefs" href="#bib0405"><span class="elsevierStyleSup">21,22,51</span></a> In small operations where STP has not been carried out, a specific effective treatment for acute AE attacks should be available.<a class="elsevierStyleCrossRef" href="#bib0555"><span class="elsevierStyleSup">51</span></a> During surgery, it is advisable to avoid endotracheal intubation using techniques other than general anaesthetic, and if necessary, use a narrow tube.<a class="elsevierStyleCrossRefs" href="#bib0405"><span class="elsevierStyleSup">21,51</span></a></p><p id="par0295" class="elsevierStylePara elsevierViewall">There are no controlled studies on the efficacy of using STP versus not using it. The available data are mainly from observational studies, and in these, the risk of perioperative AE (excluding dental procedures) without the use of STP is 6–31%,<a class="elsevierStyleCrossRef" href="#bib0560"><span class="elsevierStyleSup">52</span></a> and ranges from 5 to 37% of all dental manipulations performed without STP.<a class="elsevierStyleCrossRefs" href="#bib0565"><span class="elsevierStyleSup">53–55</span></a> In one series, 40% of patients who underwent some type of surgery (excluding dental manipulations) without STP reported having presented some post-procedure AE.<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">54</span></a></p><p id="par0300" class="elsevierStylePara elsevierViewall">phC1INH, AA (estanazolol or danazol), tranexamic acid or FFP have been used.<a class="elsevierStyleCrossRefs" href="#bib0310"><span class="elsevierStyleSup">2,21,22,51</span></a> There are no controlled studies to analyze its efficacy. It has been published that, in large series of patients, the use of STP with phC1INH, AA or tranexamic acid reduces the number of episodes of post-procedure AE,<a class="elsevierStyleCrossRefs" href="#bib0565"><span class="elsevierStyleSup">53–55</span></a> phC1INH being more effective than AA, and these, in turn, more effective than tranexamic acid.<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">54</span></a> An open-label study on the use of phC1INH (Cinryze<span class="elsevierStyleSup">®</span>) as STP<a class="elsevierStyleCrossRef" href="#bib0580"><span class="elsevierStyleSup">56</span></a> has been published.</p><p id="par0305" class="elsevierStylePara elsevierViewall">The risk of developing AE attacks after the procedure is not completely prevented by STP,<a class="elsevierStyleCrossRefs" href="#bib0565"><span class="elsevierStyleSup">53,54</span></a> so it is recommended to have another dose available of a specific drug to treat a possible severe acute attack,<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">21</span></a> and to establish an action plan together with the patient.</p><p id="par0310" class="elsevierStylePara elsevierViewall">The method of administration and dosage schedule of the different drugs is shown in <a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>.<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">21</span></a></p><p id="par0315" class="elsevierStylePara elsevierViewall">Regarding nC1-INH-HAE, there are few published data on whether or not to implement STP before procedures that could act as triggers.<a class="elsevierStyleCrossRefs" href="#bib0340"><span class="elsevierStyleSup">8,21</span></a></p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Peculiarities in children</span><p id="par0320" class="elsevierStylePara elsevierViewall">Clinical signs, symptoms and treatment of C1-INH-HAE in children have been recently reviewed.<a class="elsevierStyleCrossRef" href="#bib0585"><span class="elsevierStyleSup">57</span></a> The doses used are summarized in <a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>.</p></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Peculiarities during pregnancy</span><p id="par0325" class="elsevierStylePara elsevierViewall">The peculiarities of C1-INH-HAE treatment during pregnancy and childbirth have been revised in an international consensus document.<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">11</span></a> The treatment of nC1-INH-HAE is similar.<a class="elsevierStyleCrossRef" href="#bib0590"><span class="elsevierStyleSup">58</span></a></p></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">New treatments</span><p id="par0330" class="elsevierStylePara elsevierViewall">Different drugs are currently under research for use as LTP in C1-INH-HAE.<a class="elsevierStyleCrossRef" href="#bib0595"><span class="elsevierStyleSup">59</span></a> On the one hand, two phC1INH subcutaneous formulations (Berinert<span class="elsevierStyleSup">®</span>, Cinryze<span class="elsevierStyleSup">®</span>), one of them, Cinryze<span class="elsevierStyleSup">®</span> in combination with recombinant hyaluronic acid (rHuPH20), and on the other hand, an oral kallikrein inhibitor (BCX4161) (BioCryst Pharmaceuticals Ltd., Durham, NC, USA).<a class="elsevierStyleCrossRef" href="#bib0595"><span class="elsevierStyleSup">59</span></a> Other newly designed drugs are a recombinant human antikallikrein monoclonal antibody (DX-2930, Dyax Corp., Cambridge, MA, USA) and an anti-FXII monoclonal antibody (CSL-Behring, Marburg, Germany).<a class="elsevierStyleCrossRef" href="#bib0595"><span class="elsevierStyleSup">59</span></a></p></span></span><span id="sec0110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Financing</span><p id="par0335" class="elsevierStylePara elsevierViewall">The authors have not received funding for the preparation of this manuscript.</p></span><span id="sec0115" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Conflict of interests</span><p id="par0340" class="elsevierStylePara elsevierViewall">Dr. Caballero has participated in clinical trials sponsored by CSL Behring, Dyax Corp., Pharming Group NV and Shire HGT, has received honoraria for acting as speaker for educational and informational purposes sponsored by CSL Behring, Shire HGT and Viropharma (now owned by Shire HGT), has received funding for conference attendance by CSL Behring and Shire HGT, has received honoraria for acting as a consultant by CSL Behring, Shire HGT, SOBI and Viropharma (now owned by Shire HGT).</p><p id="par0345" class="elsevierStylePara elsevierViewall">Dr. Pedrosa has participated in clinical trials sponsored by CSL Behring and Shire HGT, has received honoraria for acting as speaker for educational and informational purposes sponsored by Shire HGT, has received funding for conference attendance by CSL Behring and Shire HGT.</p><p id="par0350" class="elsevierStylePara elsevierViewall">Dr. Gomez-Traseira has participated in clinical trials sponsored by CSL Behring and Shire HGT, has received honoraria for acting as speaker for educational and informational purposes sponsored by Shire HGT, has received funding for conference attendance by CSL Behring and Shire HGT.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:9 [ 0 => array:3 [ "identificador" => "sec0005" "titulo" => "Introduction" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0010" "titulo" => "Hereditary angioedema with C1 esterase inhibitor deficiency" ] 1 => array:2 [ "identificador" => "sec0015" "titulo" => "Hereditary angioedema without C1 esterase inhibitor deficiency" ] ] ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Pathophysiology" ] 2 => array:3 [ "identificador" => "sec0025" "titulo" => "Genetics" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0030" "titulo" => "Hereditary angioedema types I and II with C1 esterase inhibitor deficiency" ] 1 => array:2 [ "identificador" => "sec0035" "titulo" => "Hereditary angioedema with normal C1 esterase inhibitor" ] ] ] 3 => array:2 [ "identificador" => "sec0040" "titulo" => "Clinical signs and symptoms" ] 4 => array:2 [ "identificador" => "sec0045" "titulo" => "Diagnosis" ] 5 => array:3 [ "identificador" => "sec0050" "titulo" => "Treatment" "secciones" => array:7 [ 0 => array:2 [ "identificador" => "sec0055" "titulo" => "General measures" ] 1 => array:2 [ "identificador" => "sec0060" "titulo" => "Treatment of acute episode" ] 2 => array:3 [ "identificador" => "sec0065" "titulo" => "Long-term prophylaxis" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0070" "titulo" => "Antifibrinolytics" ] 1 => array:2 [ "identificador" => "sec0075" "titulo" => "Attenuated androgens" ] 2 => array:2 [ "identificador" => "sec0080" "titulo" => "C1-INH plasma concentrate (phC1INH)" ] 3 => array:2 [ "identificador" => "sec0085" "titulo" => "Others" ] ] ] 3 => array:2 [ "identificador" => "sec0090" "titulo" => "Short term preprocedural treatment or prophylaxis" ] 4 => array:2 [ "identificador" => "sec0095" "titulo" => "Peculiarities in children" ] 5 => array:2 [ "identificador" => "sec0100" "titulo" => "Peculiarities during pregnancy" ] 6 => array:2 [ "identificador" => "sec0105" "titulo" => "New treatments" ] ] ] 6 => array:2 [ "identificador" => "sec0110" "titulo" => "Financing" ] 7 => array:2 [ "identificador" => "sec0115" "titulo" => "Conflict of interests" ] 8 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2014-09-15" "fechaAceptado" => "2014-12-11" "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0040">Please cite this article as: Caballero Molina T, Pedrosa Delgado M, Gómez Traseira C. Angioedema hereditario. Med Clin (Barc). 2015;145:356–365.</p>" ] ] "multimedia" => array:8 [ 0 => array:8 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "fuente" => "Modified from Guilarte.<a class="elsevierStyleCrossRef" href="#bib0600"><span class="elsevierStyleSup">60</span></a>" "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1670 "Ancho" => 2499 "Tamanyo" => 231793 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Pathophysiology of hereditary angioedema.</p> <p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">TPA, tissue plasminogen activator; BK, bradykinin; B1R, bradykinin B1 receptor; B2R, bradykinin B2 receptor; C1, fraction 1 of complement; C1rs, components C1r and C1s of the complement; C1-INH, C1 esterase inhibitor; C2, fraction 2 of complement; C4, fraction 4 of complement; C4b2a, C3 convertase; FXI, coagulation factor XI; FXIa, activated coagulation factor XI; FXII, coagulation factor XII; FXIIa, activated coagulation factor <span class="elsevierStyleSmallCaps">xii</span>; HK, high molecular weight kininogen; K, kallikrein; PK, prekallikrein; UK, urokinase.</p>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1716 "Ancho" => 2795 "Tamanyo" => 296657 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Catabolism of bradykinin.</p> <p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">APP, Aminopeptidase P; BK, bradykinin; CPN, carboxypeptidase N; DPPIV, dipeptidyl peptidase IV; ACE, angiotensin-converting enzyme; NEP, neutral endopeptidase; BR1, bradykinin receptor type 1; BR2, bradykinin receptor type 2.</p>" ] ] 2 => array:8 [ "identificador" => "fig0015" "etiqueta" => "Fig. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "fuente" => "Modified from Caballero et al.<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">9</span></a>" "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 2582 "Ancho" => 2826 "Tamanyo" => 384591 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Diagnostic algorithm of angioedema.</p> <p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">AE, angioedema; AAE, acquired angioedema; HAE, hereditary angioedema; U-HAE, hereditary angioedema of unknown origin; HAE-FXII, hereditary angioedema with <span class="elsevierStyleItalic">F12</span> gene mutation; FH, family history; NSAIDs, Non-Steroidal Anti-Inflammatory Drugs; C1q, component C1q of the complement; C4, fraction 4 of the complement; C1-INH, concentration of C1-esterase inhibitor; C1-INHf, functional activity of C1 esterase inhibitor; ACEI, angiotensin-converting enzyme inhibitors; N, normal; rel, related; U, urticaria.</p>" ] ] 3 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">nC1-INH-HAE, hereditary angioedema with normal C1 esterase inhibitor; C1-INH, C1 esterase inhibitor; FXII, coagulation factor XII; H1, histamine receptor type 1; ACEI, angiotensin-converting enzyme inhibitors.</p><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Modified from Cicardi et al.<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">1</span></a></p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Acquired \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No identified cause \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Response to H1 antihistamines \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Idiopathic histaminergic acquired angioedema (IH-AAE) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Non-response to H1 antihistamines \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Idiopathic non-histaminergic acquired angioedema (InH-AAE) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ACEI treatment (enalapril, etc.) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No other cause of AE \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Acquired angioedema associated with ACEI (ACEI-AAE) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">C1-INH deficiency \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No family history. Start<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>40 years \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Acquired angioedema with C1-INH deficiency (C1-INH-AAE) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="4" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Hereditary \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">C1-INH deficiency \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">C1-INH genetic deficiency \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Hereditary angioedema with C1-INH deficiency (C1-INH-HAE) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " rowspan="2" align="left" valign="top">Normal C1-INH (nC1-INH-HAE)</td><td class="td" title="table-entry " align="left" valign="top">Gene mutation <span class="elsevierStyleItalic">F12</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Hereditary angioedema with FXII mutation (HAE-FXII) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Unknown cause \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Unknown cause hereditary angioedema (U-HAE) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1026525.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Classification of angioedema without wheals.</p>" ] ] 4 => array:7 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">ACEI, angiotensin-converting enzyme inhibitors.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " rowspan="5" align="left" valign="top">Precipitating factors or triggers</td><td class="td" title="table-entry " align="left" valign="top">Psychological factors \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Anxiety, emotional stress \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Hormonal factors \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Pregnancy, lactation, menstruation, puberty \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Infections \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Catarrh in the upper airways, <span class="elsevierStyleItalic">Helicobacter pylori</span> infection \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Injuries \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Especially important are those affecting the airway (endotracheal intubation, dental manipulations, upper endoscopy, bronchoscopy, cervicofacial surgery) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Drugs \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Oestrogens (contraceptives, hormone replacement therapy), ACEI \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Prodromes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Fatigue, mood swings, headache, abdominal pain, muscle and joint pain, erythema marginatum, paraesthesia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Symptoms of angioedema according to location \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Skin (limbs, face, cervical region, genitals, trunk, buttocks, etc.) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Recurring, non-pruritic, non-erythematous swelling, without an increase in local temperature, with poorly defined edges and not associated with urticaria. Generally, not painful, except under pressure \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Gastrointestinal tract \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Recurrent episodes of abdominal cramping, bloating, nausea, vomiting, constipation or diarrhoea. In severe cases it is associated with orthostatic hypotension, dehydration and hypovolemic shock. A differential diagnosis with an “acute abdomen” should be performed \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Upper airway \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Pharyngolaryngeal oedema, which may progress to airway obstruction, suffocation and death. Tongue oedema \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Other \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Bladder (voiding syndrome). Brain (headache) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1026526.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Precipitating factors, typical prodromes and symptoms of hereditary angioedema.</p>" ] ] 5 => array:7 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">C1-INH-AAE, acquired angioedema with C1 esterase inhibitor deficiency; ACEI-AAE, angiotensin-converting enzyme inhibitor-induced acquired angioedema; C1-INH-HAE, hereditary angioedema with C1 esterase inhibitor deficiency; nC1-INH-HAE, hereditary angioedema with normal C1 esterase inhibitor; C1-INH, C1-esterase inhibitor concentration; C1-INHf, C1 esterase inhibitor functional activity; C1q, component C1q of complement; C4, fraction 4 of complement; N, normal.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Type \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">C1-INH \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">C1-INHf \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">C4 \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">C1q \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">C1-INH-HAE type I \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Low \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><50% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Low/N \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">C \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">C1-INH-HAE type II \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">N/high \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><50% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Low \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">C \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">C1-INH-AAE \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Low/N \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Low \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Low \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Low \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">nC1-INH-HAE \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">C \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">N/low \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">C \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">C \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">ACEI-AAE \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">C \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">C \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">C \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">C \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1026522.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Complement values in the different types of bradykinergic angioedema.</p>" ] ] 6 => array:7 [ "identificador" => "tbl0020" "etiqueta" => "Table 4" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:3 [ "leyenda" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">AA, attenuated androgen; AF, antifibrinolytics; B2R, bradykinin B2 receptor; C1-INH, C1 esterase inhibitor; ID, initial dose (induction period); MD, maintenance dose (maintenance period); EACA, epsilon aminocaproic acid; EMA, <span class="elsevierStyleItalic">European Medicines Agency</span>; FDA, <span class="elsevierStyleItalic">Food and Drug Administration</span>; IV, intravenous; STP, short-term prophylaxis; FFP, fresh frozen plasma; phC1INH, purified human plasma concentrate of C1 esterase inhibitor; LTP, long-term prophylaxis; rhC1INH, recombinant human C1 esterase inhibitor; SC, subcutaneous.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Drug \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Tradename \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Company \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Mechanism of action \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Administration route \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Indications \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Adult dose \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Regulatory status \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " rowspan="2" align="left" valign="top">phC1INH</td><td class="td" title="table-entry " rowspan="2" align="left" valign="top">Berinert<span class="elsevierStyleSup">®</span></td><td class="td" title="table-entry " rowspan="2" align="left" valign="top">CSL-Behring (Marburg, Germany)</td><td class="td" title="table-entry " rowspan="2" align="left" valign="top">Replacement of C1-INH</td><td class="td" title="table-entry " rowspan="2" align="left" valign="top">IV</td><td class="td" title="table-entry " align="left" valign="top">Acute Tr. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">20<span class="elsevierStyleHsp" style=""></span>U/kg \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " rowspan="2" align="left" valign="top">Approved in Spain for acute treatment at any age. Approved by EMA for short-term prophylaxis. Approved by EMA for self-administration. Marketed in Spain</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">STP \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1000<span class="elsevierStyleHsp" style=""></span>U 1–6<span class="elsevierStyleHsp" style=""></span>h before \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="8" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">phC1INH \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Cinryze<span class="elsevierStyleSup">®</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Shire HGT (Zug, Switzerland) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">C1-INH replacement \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">IV \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Acute Tr. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1000<span class="elsevierStyleHsp" style=""></span>U (repeat after 1<span class="elsevierStyleHsp" style=""></span>h if no improvement)<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">EMA approved for acute treatment, short-term prophylaxis and long-term prophylaxis in adolescents (≥12 year-olds) and adults and for self-administration. Marketed in Spain \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">LTP \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1000<span class="elsevierStyleHsp" style=""></span>U every 3–4 days<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">STP \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1000<span class="elsevierStyleHsp" style=""></span>U 1–24<span class="elsevierStyleHsp" style=""></span>h before<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="8" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">rhC1INH \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Ruconest<span class="elsevierStyleSup">®</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Pharming Group NV (Leiden, Netherlands); SOBI (Stockholm, Sweden) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">C1-INH replacement \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">IV \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Acute Tr. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">≤84<span class="elsevierStyleHsp" style=""></span>kg: 50<span class="elsevierStyleHsp" style=""></span>U/kg; >84<span class="elsevierStyleHsp" style=""></span>kg: 4200<span class="elsevierStyleHsp" style=""></span>U \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">EMA approved for acute treatment in adult patients \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="8" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Icatibant acetate \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Firazyr<span class="elsevierStyleSup">®</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Shire HGT (Zug, Switzerland) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">BR2 blockage \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Acute Tr. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">30<span class="elsevierStyleHsp" style=""></span>mg<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">d</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">EMA approved for acute treatment in adult patients (≥18 year-olds). Approved by the EMA for self-administration \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="8" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Ecallantide \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Kalbitor<span class="elsevierStyleSup">®</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Dyax Corp. (Cambridge, MA, USA) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Kallikrein inhibition \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Acute Tr. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">30<span class="elsevierStyleHsp" style=""></span>mg \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">FDA approved for acute treatment of patients<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>12 years. Not approved by EMA. No possibility of self-administration \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="8" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">FFP \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Several \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">C1-INH replacement \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">IV \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Acute Tr. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2<span class="elsevierStyleHsp" style=""></span>U of 200<span class="elsevierStyleHsp" style=""></span>ml \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Available \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">STP \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2<span class="elsevierStyleHsp" style=""></span>U 1<span class="elsevierStyleHsp" style=""></span>h before \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="8" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Danazol \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Danatrol<span class="elsevierStyleSup">®</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Sanofi-Aventis (Paris, France) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Increased hepatic synthesis of C1-INH \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Oral \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">LTP \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ID: 400<span class="elsevierStyleHsp" style=""></span>mg/d; MD: maximum 200<span class="elsevierStyleHsp" style=""></span>mg/d<a class="elsevierStyleCrossRef" href="#tblfn0025"><span class="elsevierStyleSup">e</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Approved in Spain for long-term prophylaxis. Marketed in Spain \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">STP \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">400–600<span class="elsevierStyleHsp" style=""></span>mg/d during 5 days before and up to 2 days afterwards (spread over 2 or 3 takes) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="8" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Stanozolol \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Winstrol<span class="elsevierStyleSup">®</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Winthrop (Barcelona, Spain) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Increased hepatic synthesis of C1-INH \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Oral \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">LTP \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ID: 6–12<span class="elsevierStyleHsp" style=""></span>mg/d; MD: maximum 2<span class="elsevierStyleHsp" style=""></span>mg/d<a class="elsevierStyleCrossRef" href="#tblfn0030"><span class="elsevierStyleSup">f</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Available. Marketed in Spain. Off-label use \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">STP \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4–6<span class="elsevierStyleHsp" style=""></span>mg/d for 5 days before and up to 3 days afterwards (spread over 2 or 3 takes) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="8" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">EACA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Caproamín<span class="elsevierStyleSup">®</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Rottapharm (Barcelona, Spain) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Antiplasmin and anti-plasminogen activity \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Oral, IV \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1<span class="elsevierStyleHsp" style=""></span>g/6–8<span class="elsevierStyleHsp" style=""></span>h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Available. Marketed in Spain \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="8" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Tranexamic acid \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Amchafibrin<span class="elsevierStyleSup">®</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Rottapharm (Barcelona, Spain) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Antiplasmin and anti-plasminogen activity \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Oral, IV \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">LTP \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1000–3000<span class="elsevierStyleHsp" style=""></span>mg/d \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Available. Marketed in Spain \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">STP \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">75<span class="elsevierStyleHsp" style=""></span>mg/kg/d for 5 days before and up to 2 days afterwards (2 or 3 takes) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1026523.png" ] ] ] "notaPie" => array:6 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">The dose of Cinryze<span class="elsevierStyleSup">®</span> in acute treatment can be repeated after one hour; in a controlled clinical trial, 66% of patients required to repeat the dose.<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">29</span></a></p>" ] 1 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "b" "nota" => "<p class="elsevierStyleNotepara" id="npar0010">The interval between doses of Cinryze<span class="elsevierStyleSup">®</span> can be shortened or lengthened depending on the frequency of angioedema attacks.</p>" ] 2 => array:3 [ "identificador" => "tblfn0015" "etiqueta" => "c" "nota" => "<p class="elsevierStyleNotepara" id="npar0015">Although the label of Cinryze<span class="elsevierStyleSup">®</span> indicates that it can be administered between 1 and 24<span class="elsevierStyleHsp" style=""></span>h before the procedure, it should not be administered more than 6<span class="elsevierStyleHsp" style=""></span>h before.</p>" ] 3 => array:3 [ "identificador" => "tblfn0020" "etiqueta" => "d" "nota" => "<p class="elsevierStyleNotepara" id="npar0020">The dose can be repeated at 6<span class="elsevierStyleHsp" style=""></span>h if the response is incomplete (up to 85–92% of cases, a single dose is sufficient)<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">32</span></a> and up to 3 doses in 24<span class="elsevierStyleHsp" style=""></span>h or 8 doses over 4 weeks.</p>" ] 4 => array:3 [ "identificador" => "tblfn0025" "etiqueta" => "e" "nota" => "<p class="elsevierStyleNotepara" id="npar0025">The maximum maintenance dose of danazol is 200<span class="elsevierStyleHsp" style=""></span>mg/d; must be lowered to the lowest effective dose, which can be as low as 100<span class="elsevierStyleHsp" style=""></span>mg, 2 days a week.</p>" ] 5 => array:3 [ "identificador" => "tblfn0030" "etiqueta" => "f" "nota" => "<p class="elsevierStyleNotepara" id="npar0030">The maximum maintenance dose of stanozolol is 2<span class="elsevierStyleHsp" style=""></span>mg/d; it should be lowered gradually to the minimum effective dose, which can be as low as 2<span class="elsevierStyleHsp" style=""></span>mg, 2 days a week.</p> <p class="elsevierStyleNotepara" id="npar0035"><span class="elsevierStyleSup">Ω</span> The measurements were performed in patients with hereditary angioedema with asymptomatic C1 esterase inhibitor deficiency.</p>" ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Drugs for the treatment of hereditary angioedema and their availability in Spain.</p>" ] ] 7 => array:7 [ "identificador" => "tbl0025" "etiqueta" => "Table 5" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "<p id="spar0090" class="elsevierStyleSimplePara elsevierViewall">ACVA, acute cerebrovascular accident; HAE, hereditary angioedema; CPK, creatine phosphokinase; FFP, fresh frozen plasma; phC1INH, purified human plasma concentrate of C1 esterase inhibitor; rhC1INH, recombinant human C1 esterase inhibitor.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Drug \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " colspan="2" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Side effects</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Contraindications/precautions \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Attenuated androgens \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Residual hormonal activity derivatives \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Seborrhoea, acne, hirsutism, voice changes, decreased breast size, vasomotor symptoms, menstrual irregularities, decreased libido, virilization \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Children (Tanner I–IV), pregnancy, breast cancer, prostate cancer, nephrotic syndrome, impaired hepatic function, precautions in women \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Alkylation derivatives at position 17-α \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Hepatotoxicity:↑transaminases, necrosis, cholestasis, purpura, adenoma and hepatocellular carcinoma \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Other \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Lipoprotein profile disorders (atherogenesis), rhabdomyolysis (↑CPK), high blood pressure, premature closure of the epiphysis, increased haematocrit, weight gain \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="4" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Antifibrinolytics \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Muscle necrosis: asthenia, myalgia, CPK elevation, increased aldolase; dizziness, postural hypotension; nausea, diarrhoea and abdominal pain; dysmenorrhea; pruritus; thrombotic events \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Underlying prothrombotic disease \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="4" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">FFP \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Risk of transmission of infectious agents, risk of hypervolemia; potentially allergenic; alloimmunization \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Precautions: Potential worsening of the acute attack by simultaneous supply of substrates \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="4" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">phC1INH \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Theoretical risk of transmission of infectious agents, thrombosis (at very high doses), anaphylaxis (very rare) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="4" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Icatibant acetate \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Local reactions (itching, pain, oedema and erythema in administration area) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Precautions: patients with active coronary heart disease and patients with acute ischaemic stroke in the previous 2 weeks \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="4" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">rhC1INH \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Allergic reactions \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Rabbit allergy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="4" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Ecallantide \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Allergic reactions \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Prolongation of partial thromboplastin time. Allergic reactions (anaphylaxis, others) (self-administration not approved) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1026524.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0085" class="elsevierStyleSimplePara elsevierViewall">Side effects and contraindications of drugs used in hereditary angioedema.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:60 [ 0 => array:3 [ "identificador" => "bib0305" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Classification, diagnosis, and approach to treatment for angioedema: consensus report from the Hereditary Angioedema International Working Group" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M. Cicardi" 1 => "W. Aberer" 2 => "A. Banerji" 3 => "M. Bas" 4 => "J.A. Bernstein" 5 => "K. Bork" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/all.12380" "Revista" => array:6 [ "tituloSerie" => "Allergy" "fecha" => "2014" "volumen" => "69" "paginaInicial" => "602" "paginaFinal" => "616" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24673465" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0310" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hereditary and acquired angioedema: problems and progress: proceedings of the third C1 esterase inhibitor deficiency workshop and beyond" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "A. Agostoni" 1 => "E. Aygören-Pürsün" 2 => "K.E. Binkley" 3 => "A. Blanch" 4 => "K. Bork" 5 => "L. Bouillet" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jaci.2004.06.047" "Revista" => array:7 [ "tituloSerie" => "J Allergy Clin Immunol" "fecha" => "2004" "volumen" => "114" "numero" => "3 Suppl." "paginaInicial" => "S51" "paginaFinal" => "S131" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15356535" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0315" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hereditary angioedema with normal C1 inhibitor activity in women" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "K. Bork" 1 => "S.E. Barnstedt" 2 => "P. Koch" 3 => "H. Traupe" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/S0140-6736(00)02483-1" "Revista" => array:6 [ "tituloSerie" => "Lancet" "fecha" => "2000" "volumen" => "356" "paginaInicial" => "213" "paginaFinal" => "217" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10963200" "web" => "Medline" ] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0320" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Clinical, biochemical and genetic characterization of a novel estrogen-dependent inherited form of angioedema" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "K. Binkley" 1 => "A. Davis 3rd." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1067/mai.2000.108106" "Revista" => array:6 [ "tituloSerie" => "J Allergy Clin Immunol" "fecha" => "2000" "volumen" => "106" "paginaInicial" => "546" "paginaFinal" => "550" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10984376" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0325" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Missense mutations in the coagulation factor XII (Hageman factor) gene in hereditary angioedema with normal C1 inhibitor" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "G. Dewald" 1 => "K. Bork" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.bbrc.2006.03.092" "Revista" => array:6 [ "tituloSerie" => "Biochem Biophys Res Commun" "fecha" => "2006" "volumen" => "343" "paginaInicial" => "1286" "paginaFinal" => "1289" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16638441" "web" => "Medline" ] ] ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib0330" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Increased activity of coagulation factor XII (Hageman factor) causes hereditary angioedema type III" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "S. Cichon" 1 => "L. Martin" 2 => "H.C. Hennies" 3 => "F. Müller" 4 => "K. van Driessche" 5 => "A. 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Bork" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1517/13543784.2014.916275" "Revista" => array:6 [ "tituloSerie" => "Expert Opin Investig Drugs" "fecha" => "2014" "volumen" => "23" "paginaInicial" => "887" "paginaFinal" => "891" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24797354" "web" => "Medline" ] ] ] ] ] ] ] ] 59 => array:3 [ "identificador" => "bib0600" "etiqueta" => "60" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Actualización en angioedema hereditario por déficit del inhibidor de C1" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "M. 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Journal Information
Vol. 145. Issue 8.
Pages 356-365 (October 2015)
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Tables (5)
Table 2. Precipitating factors, typical prodromes and symptoms of hereditary angioedema.
Table 3. Complement values in the different types of bradykinergic angioedema.
Table 4. Drugs for the treatment of hereditary angioedema and their availability in Spain.
Table 5. Side effects and contraindications of drugs used in hereditary angioedema.
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