Acquired C1 inhibitor deficiency: Management and prognosis

INTRODUCTION — Acquired angioedema due to deficiency of C1 esterase inhibitor (AAE-C1-INH), also called acquired C1-INH deficiency (ACID), is a rare syndrome of recurrent episodes of angioedema, without urticaria, which is associated with B cell lymphoproliferative disorders in some patients [1]. Angioedema typically affects the skin or mucosal tissues of the upper respiratory and gastrointestinal tracts. The swelling is self-limited, although laryngeal involvement may cause fatal asphyxiation. Clinically, this disorder is very similar to hereditary angioedema (HAE), although AAE-C1-INH develops in older patients and is frequently associated with underlying disease, whereas the hereditary disorder presents in younger patients who are otherwise healthy [2].

This topic review will discuss the management and prognosis of AAE-C1-INH. The clinical manifestations, epidemiology, pathogenesis, and diagnosis of this disorder are reviewed elsewhere. (See "Acquired C1 inhibitor deficiency: Clinical manifestations, epidemiology, pathogenesis, and diagnosis".)

HAE, which is caused by mutations in the gene for C1-INH, is discussed separately. (See "Hereditary angioedema (due to C1 inhibitor deficiency): Pathogenesis and diagnosis" and "Hereditary angioedema: Epidemiology, clinical manifestations, exacerbating factors, and prognosis" and "Hereditary angioedema: Acute treatment of angioedema attacks" and "Hereditary angioedema (due to C1 inhibitor deficiency): General care and long-term prophylaxis".)

OVERVIEW OF MANAGEMENT — The management of a patient with AAE-C1-INH involves several components [3]:

●Educating the patient about the potential triggers and early recognition of angioedema attacks and ensuring that the patient understands that there is a real risk of fatal asphyxiation with attacks involving the upper airway. (See 'Patient education about laryngeal edema' below and 'Avoidance of exacerbating factors' below.)

●Providing the patient with written instructions about treatment of acute attacks, which can be given to other providers in the emergency setting (form 1). (See 'Written treatment plan' below and 'Airway management in laryngeal edema' below.)

●Prescribing appropriate "on-demand" therapies for attacks of angioedema and ensuring that the patient is either trained to self-administer these treatments or has access to appropriate medications at the hospitals nearest to the patient's home. (See 'Pharmacologic treatment of acute attacks' below.)

●Managing associated diseases, if present, or, if none are initially found, monitoring for the development of an associated disease. (See 'Associated disorders' below.)

●Evaluating the need for prophylaxis to prevent angioedema attacks. (See 'Prophylaxis to prevent angioedema episodes' below.)

PREPARATION FOR ACUTE ANGIOEDEMA EPISODES — Laryngeal attacks are the most dangerous type of attack in AAE-C1-INH because edema can lead to fatal airway obstruction. Upper airway angioedema usually progresses over hours, although it can occur precipitously. Intubation may become very difficult due to distortion of the anatomy of the upper airway. Because of the dangers associated with laryngeal attacks, it is important to make sure that patients are prepared to respond effectively to the development of symptoms near or in the throat.

Angioedema may also affect the gastrointestinal tract, causing colicky abdominal pain, nausea, vomiting, and/or diarrhea. Episodes of abdominal angioedema are often debilitating but are not life threatening. Angioedema affecting the skin is temporarily disfiguring but rarely dangerous, unless it affects the mouth or lips since it can compromise the airway in these situations. The approach to treating abdominal and cutaneous attacks is similar to that used in patients with hereditary angioedema (HAE), which is reviewed in detail separately. (See "Hereditary angioedema: Acute treatment of angioedema attacks", section on 'Gastrointestinal attacks' and "Hereditary angioedema: Acute treatment of angioedema attacks", section on 'Cutaneous attacks'.)

Patient education about laryngeal edema — All patients with AAE-C1-INH must be counseled about the earliest signs of an attack affecting the upper airway, which typically includes the sensation of a lump or feeling of tightness in the throat or swallowing difficulties. Patients should also have a plan to get prompt and appropriate treatment. Any patient with throat symptoms should seek emergency care immediately. The patient should not attempt to manage early laryngeal attacks at home, although, if therapy for self-administration is available and can be given quickly, the patient can initiate therapy and then call for an ambulance to take them to the nearest emergency department. It is important to discuss that, even if the treatment has worked well in the past, the patient should always proceed immediately to an emergency care setting when the throat is involved because all of the first-line therapies take approximately 30 minutes or more to begin working. In rare circumstances, acute treatment, particularly with plasma-derived C1-INH (pdC1-INH), can be less effective than in hereditary C1-INH deficiency; thus, a second dose is occasionally required. In contrast, abdominal angioedema or cutaneous angioedema can often be managed by patients at home if they have access to acute treatments. The emergency treatments that are appropriate for administration at home are discussed elsewhere. (See "Hereditary angioedema: Acute treatment of angioedema attacks", section on 'Initiating acute treatment of HAE attacks at home'.)

Written treatment plan — AAE-C1-INH is a rare disorder, and few emergency department providers are familiar with the treatment. Patients can be equipped with a document that briefly explains their diagnosis, outlines the indicated treatment for acute attacks, and provides contact information for the supervising clinician (form 1).

Airway management in laryngeal edema — Assessment and protection of the upper airway is the first and most important management issue in the patient with an acute attack involving any part of the airway because none of the available therapies including C1-INH concentrate, icatibant, and ecallantide can be considered universally effective in all cases. In addition, these agents take time to work, and the patient's airway must be protected in the interim. Asphyxiation remains an important and preventable cause of death in patients with this disorder, even in settings with appropriate medications available. (See 'Prognosis' below.)

Intubation should be performed immediately if stridor or signs of respiratory arrest are present. A clinician trained in difficult airway management should be summoned if possible because failed attempts can lead to fatal obstruction. Emergent cricothyroidotomy may be required in rare cases. (See "Approach to the difficult airway in adults for emergency medicine and critical care" and "Emergency cricothyrotomy (cricothyroidotomy) in adults".)

Once the patient is assessed and either intubated or deemed stable, additional therapies can be considered. Transfer to the intensive care unit should be arranged. Frequent and meticulous monitoring of airway status should continue throughout the course of the attack until complete resolution, and patients should not be discharged until all airway symptoms have resolved.

Pharmacologic treatment of acute attacks — There are several medications available for acute treatment of episodes of angioedema due to genetic C1-INH deficiency that can be used for AAE-C1-INH. None of these drugs are registered/approved specifically for AAE-C1-INH, and availability varies around the world (table 1):

●C1INH concentrate, derived from human plasma (pdC1-INH) (see 'C1 inhibitor concentrate' below)

●Recombinant human C1-INH (rhC1-INH, conestat alfa) (see 'Recombinant C1 inhibitor' below)

●Icatibant, a synthetic bradykinin B₂-receptor antagonist (see 'Icatibant' below)

●Ecallantide, a recombinant plasma kallikrein inhibitor (see 'Ecallantide' below)

●Human plasma, either solvent/detergent-treated plasma (S/D plasma) or fresh frozen plasma (FFP) (see 'Plasma' below)

The therapy with which there is most experience is pdC1-INH, followed by icatibant. A clinical response should be evident within two hours with pdC1-INH, icatibant, or ecallantide. Each medication is discussed in detail below, including mechanism of action, dosing, availability, efficacy data, and adverse effects.

The treatment of AAE-C1-INH is extrapolated from that of HAE [2,4,5]. No controlled studies have been performed in patients with AAE-C1-INH, and no therapies are specifically registered/approved for treatment of this condition. Based on clinical experience, there appears to be some differences in the response of these two disorders to the available therapies, as discussed in this section.

C1 inhibitor concentrate — The most widely used therapy for acute laryngeal edema is pdC1-INH, which is available as Cinryze or Berinert (brand names). pdC1-INH became available in the United States in 2009 but has been available in Europe for decades. Observational studies indicate that pdC1-INH is effective in the majority of patients with AAE-C1-INH, reducing the average attack duration by 60 percent or more [6].

Based on the controlled studies performed in HAE-C1-INH, an initial dose of 20 units/kg is suggested. The dosing, administration, and adverse effects of pdC1-INH are reviewed elsewhere. (See "Hereditary angioedema: Acute treatment of angioedema attacks", section on 'First-line agents: Dosing, efficacy, and adverse reactions'.)

Resistance — A small percentage of patients with AAE-C1-INH become less responsive to pdC1-INH over time, requiring higher doses to control symptoms [7,8]. One patient required multiple infusions totaling 12,000 units of pdC1-INH (the usual initial dose is 1500 units) over a period of two hours to control laryngeal edema. The newer therapies for bradykinin-mediated angioedema, ecallantide and icatibant, offer alternatives for the treatment of patients who become resistant to pdC1-INH, and we would suggest trying these if resistance is suspected. (See 'Ecallantide' below and 'Icatibant' below.)

The mechanism by which resistance to pdC1-INH develops appears to involve extremely rapid catabolism of the inhibitor protein, although this has not been formally demonstrated. In blood samples collected from the patient described above, no significant increase of C1-INH function could be detected at any point during the multiple infusions, while C1-INH antigen normalized due to the increase in cleaved C1-INH. These data suggest that the infused C1-INH was rapidly bound by the autoantibodies and converted in its cleaved inactive form upon interaction with target proteases. The patient described above had high levels of anti-C1-INH antibodies in serum.

Recombinant C1 inhibitor — There are limited data regarding the efficacy of recombinant human C1-INH (rhC1-INH; Ruconest [brand name]) in AAE-C1-INH. rhC1-INH has a shorter half-life than pdC1-INH. This is a theoretical disadvantage in treating AAE-C1-INH, which is characterized by increased C1-INH consumption, although no published data are available to confirm. The dosing and adverse effects of this agent are discussed elsewhere. (See "Hereditary angioedema: Acute treatment of angioedema attacks", section on 'Recombinant C1 inhibitor'.)

Icatibant — Icatibant is an antagonist of the bradykinin B₂-receptor, which has also been successful in treating a small number of patients not responsive to C1-INH concentrate [9,10]. Because icatibant does not depend on C1-INH catabolic rate, the authors prefer it to C1-INH concentrate in their own practice.

The dosing, administration, and adverse effects of icatibant are reviewed elsewhere. (See "Hereditary angioedema: Acute treatment of angioedema attacks", section on 'Bradykinin B2-receptor antagonist'.)

Plasma — Plasma has been used in the treatment of acute laryngeal attacks and severe abdominal attacks in both AAE-C1-INH and HAE, although the efficacy has not been formally investigated. Where available, S/D plasma is preferred because the risk of disease transmission is theoretically lower. If not available, FFP may be given. Plasma contains an array of complement components, including C1-INH.

Two units is the usual initial dose for treatment of angioedema. This dose can be repeated every two to four hours until there is clinical improvement. Once the attack begins to subside, further plasma is not usually required. If a patient has comorbid conditions that increase the risk for volume overload, then dosing of 10 to 15 mL per kg body weight is recommended instead, with monitoring of volume status and cardiopulmonary function.

The administration, infection risks, and adverse effects of plasma are reviewed elsewhere. (See "Hereditary angioedema: Acute treatment of angioedema attacks", section on 'Plasma'.)

Ecallantide — Ecallantide (Kalbitor [brand name]) is an inhibitor of plasma kallikrein that has been effective in a small number of case reports of patients with AAE-C1-INH [11,12]. Kallikrein is the enzyme that releases bradykinin, the mediator of angioedema, from high-molecular-weight kininogen. Ecallantide is approved by the US Food and Drug Administration (FDA) for acute angioedema attacks in patients with HAE [13]. It is only available in the United States.

Ecallantide was used successfully to treat angioedema attacks in two patients with AAE-C1-INH, one of them resistant to pdC1-INH, with prompt resolution of symptoms [11]. Both patients developed a relapse of angioedema within 12 hours, but the symptoms were mild and resolved spontaneously without need for further treatment.

The dosing, administration, and adverse effects of ecallantide are reviewed elsewhere. (See "Hereditary angioedema: Acute treatment of angioedema attacks", section on 'Kallikrein inhibitor (United States only)'.)

Ineffective therapies — Our and others' experience support the view that antihistamines, glucocorticoids, and epinephrine are not effective in acute treatment of AAE-C1-INH [14]. There are no trials that directly evaluate the use of these therapies in AAE-C1-INH or HAE. We strongly recommend not relying on these drugs to treat angioedema in patients with C1-INH deficiency. In one review of 22 patients, investigators concluded that "in the acute setting, high-dose glucocorticoids with or without subcutaneous epinephrine seem to be effective, depending on the severity of symptoms" [15]. However, they did not provide the data to support the statement, and this conclusion is not consistent with our clinical experience. On the other hand, these therapies should be considered if there is any uncertainty about the patient's diagnosis because allergic forms of angioedema do respond to these therapies.

AVOIDANCE OF EXACERBATING FACTORS — Factors that exacerbate or precipitate attacks include physical or psychological stress and certain medications.

Medications that can increase the frequency and/or severity of attacks in acquired angioedema (AAE-C1-INH) include the following:

●Estrogen-containing medications, such as hormone replacement therapy and contraceptives [16].

●Tamoxifen, a selective estrogen receptor modulator (SERM) that has mixed agonist/antagonist actions on the estrogen receptor. In one reported case, a patient with hereditary angioedema (HAE) who developed increased episodes on tamoxifen was successfully treated with the aromatase inhibitor letrozole [17]. If tamoxifen or another SERM is essential to the patient's therapy, then worsening symptoms of AAE-C1-INH may need to be managed by increasing therapy to prevent angioedema episodes, rather than discontinuing the SERM.

●Angiotensin-converting enzyme (ACE) inhibitors [18]. In contrast, the experience of the authors is that angiotensin II receptor blockers (ARBs) are well tolerated.

ASSOCIATED DISORDERS

Monitoring for development — If no associated condition is identified initially, we monitor patients by performing all age-appropriate cancer screening and repeating studies for B cell malignancies annually. Specifically, we obtain a complete physical examination, a complete blood count (CBC) with differential, a serum protein electrophoresis and immunofixation, a chest radiograph, and an abdominal ultrasound. Although there are limited published data regarding the rate at which disorders are detected over time, one patient has been followed with no apparent associated disease for over a decade.

Management of identified disorders — Successful treatment of lymphoproliferative disorders that are identified in a patient with AAE-C1-INH usually results in reduction of attacks of angioedema. Two independent case series provide evidence that partial or complete clinical and/or biochemical remission of AAE-C1-INH occurs upon treatment of associated lymphoproliferative diseases [19,20]. The effect of treating other associated disorders is informed by single case reports [21-23].

In patients with lymphoma, a variety of therapies, including surgery, chemotherapy, and biologic agents, such as rituximab, have been reported to be helpful in reducing episodes of angioedema [19,20]. Responses to treatment range from partial to complete (and apparently stable) remission. However, treatment of the underlying disorder is not indicated in every case, and the risk-benefit balance should be considered in each patient. It would not be prudent to risk potential adverse effects to treat a lymphoproliferative disorder that had a very mild course for the sole purpose of controlling angioedema attacks, since the latter can often be managed with the therapies discussed in this review.

Alterations in complement abnormalities are variable following treatment for lymphoma in patients with AAE-C1-INH. C1-INH levels, C1q, and C4 levels may normalize in concert or independently. Disappearance of autoantibodies can also occur. We have observed a wide range of changes in complement studies and autoantibody levels in the patients we manage following treatment for lymphoma, although we have not detected a consistent pattern [19]. Patients can have complete reversal of clinical and complement abnormalities but persistence of anti-C1-INH autoantibodies. Such findings highlight the uncertainties regarding the pathogenesis of AAE-C1-INH. (See "Acquired C1 inhibitor deficiency: Clinical manifestations, epidemiology, pathogenesis, and diagnosis", section on 'Pathogenesis'.)

Monitoring MGUS — Patients with AAE-C1-INH who are found to have monoclonal gammopathy of undetermined significance (MGUS) must be followed and evaluated regularly as MGUS can transform to a more serious disorder at a rate of approximately 1 percent per year. It is not known if treatment of MGUS prior to transformation would impact the patient's outcome. The recommendations for monitoring are reviewed separately. (See "Clinical course and management of monoclonal gammopathy of undetermined significance".)

PROPHYLAXIS TO PREVENT ANGIOEDEMA EPISODES — Short-term prophylaxis should always be administered if intubation, oral surgery, or general surgery is planned. It is often administered prior to lesser dental procedures. Other minimally traumatic procedures not involving the oral cavity, such as a colonoscopy, may not require prophylaxis, although it is best to provide prophylaxis if the patient's tolerance to a procedure is unknown. The approach is identical to that for patients with hereditary angioedema (HAE). Only a few case reports describe short-term prophylaxis in patients with AAE-C1-INH specifically, and these have used either plasma-derived (pdC1-INH) or recombinant human C1-INH (rhC1-INH) concentrates [24,25].

The indications for long-term prophylaxis in patients with AAE-C1-INH are not well defined, and guidelines remain vague. The author's approach is to initiate prophylactic therapy in patients who cannot control symptoms by "on-demand therapy" and experience several days of disability each month. The author also administers prophylaxis to patients in whom "on-demand therapy" is not entirely or consistently effective.

The options for prophylactic therapy in patients with AAE-C1-INH are the same as those used in HAE [7,21,26-28]:

●Tranexamic acid

●Attenuated androgens

●Regular infusions of C1-INH concentrate

●Lanadelumab

●Berotralstat

It is the author's approach to start with tranexamic acid [2].

Tranexamic acid — Tranexamic acid is well tolerated by most patients with AAE-C1-INH and is available in many countries [29]. We begin with 3 grams daily, divided into two doses. If the patient's episodes of angioedema stop occurring, the dose of tranexamic acid may be gradually lowered, although some patients have recurrent symptoms when this is attempted and need to remain on the full dose indefinitely. If the attacks do not decrease in number and severity on full-dose tranexamic acid, the author then stops tranexamic acid and changes to another agent.

Tranexamic acid reduces the frequency and severity of attacks in the majority of patients [2]. As an example, of 13 patients treated with Tranexamic acid in one series, 8 responded very well, and 4 responded partially [7]. Use of tranexamic acid for the prevention of angioedema, including dosing and monitoring, is discussed in more detail separately. (See "Hereditary angioedema (due to C1 inhibitor deficiency): General care and long-term prophylaxis", section on 'Antifibrinolytics'.)

It is debated whether or not antifibrinolytics carry an increased risk of thrombosis, particularly in patients with associated malignancies. Until this question is conclusively answered, antithrombotic therapy may be coadministered to patients with other reasons for increased risk of thromboembolism (eg, those with malignancies, coronary heart disease, or history of thromboembolic stroke) who also need long-term tranexamic acid for AAE-C1-INH [30]. Thrombotic events were observed in four patients on antifibrinolytic agents, and the treatment was discontinued. In three of these patients, the frequency and severity of angioedema recurrences increased substantially after withdrawal of tranexamic acid and could not be controlled by on-demand treatment alone or with danazol. Therefore, after complete recovery from the acute thrombotic events, antifibrinolytic treatment was resumed with concomitant oral anticoagulants. No further thrombotic events have occurred in these three patients using this approach for over 10 years [10].

Lanadelumab — Lanadelumab is a fully human monoclonal antibody that inhibits plasma kallikrein. Lanadelumab has been approved for the long-term prophylactic treatment of HAE, and anecdotal reports of its efficacy in AAE-C1-INH have been published [31,32]. One case report of the efficacy of lanadelumab in an AAE-C1-INH patient with a 90 percent reduction in attack frequency found evidence of ongoing complement activation (absent C4 and C1q) but decreased kallikrein-kinin system activation manifest by somewhat reduced cleaved high-molecular-weight kininogen levels [33]. Lanadelumab is administered by subcutaneous injection every two to four weeks.

Rituximab — Rituximab is an anti-CD20 monoclonal antibody that is commonly used to treat non-Hodgkin lymphoma but is sometimes used to prevent angioedema in AAE-C1-INH patients [34]. In a review of 121 AAE-C1-INH patients, 59 were treated with rituximab with indications of lymphoproliferative disorders (n = 16), frequent angioedema attacks (n = 31), or both (n = 12) [35].

Androgens — Anabolic androgens, such as danazol, stanozolol, and others, control symptoms in approximately one-half of patients in our clinical experience [7,21,27,28]. Those who respond well to this therapy sometimes achieve control of symptoms with very low doses and remain on this agent for years. However, in the remaining patients, androgens either do not work from the outset or become ineffective after a period of time [7]. Use of androgens for the prevention of angioedema is discussed in more detail separately. (See "Hereditary angioedema (due to C1 inhibitor deficiency): General care and long-term prophylaxis", section on 'Attenuated androgens'.)

C1-INH concentrate — We have concerns about the use of C1-INH concentrate for prophylaxis because AAE-C1-INH patients sometimes become resistant to it (possibly due to anti-C1-INH antibodies), and we prefer to reserve it for treating acute attacks. Whether regular C1-INH infusion increase the levels of anti-C1-INH autoantibody worsening disease course has not been proven, but such possibility should be considered [36]. (See 'Resistance' above.)

Berotralstat — Berotralstat is an orally available small molecule inhibitor of plasma kallikrein. Berotralstat is approved for the long-term prophylactic treatment of HAE. There have been no reports yet of its efficacy in AAE-C1-INH.

PROGNOSIS — There are no published studies that provide information about the long-term prognosis of patients with AAE-C1-INH. Among the 77 patients followed in Milan since 1975, 16 patients have died since diagnosis [10]. Eleven deaths were not related to AAE-C1-INH, and one patient died of laryngeal edema. Three patients died from complications of the associated lymphoproliferative disease, and one died due to hemorrhagic complication of hepatitis C virus cirrhosis, possibly acquired during treatment with plasma-derived C1-INH (pdC1-INH) in the 1970s (when viral controls for plasma products were not available).

The risk of asphyxiation due to upper airway closure remains a real and immediate risk for patients with AAE-C1-INH because of the limited knowledge of this condition on the part of clinicians. In the patient who died due to laryngeal edema, an infusion of 1000 units of C1-INH concentrate was started but too late to prevent progression of the swelling to airway closure. Attempts at endotracheal intubation failed because of massive laryngeal edema, and permanent anoxic brain damage was already established by the time a tracheotomy was performed. Our overall experience with 983 patients diagnosed in Italy since 1974 with HAE-C1-INH indicates that 63 died, 5 of them for laryngeal edema.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Urticaria and angioedema (excluding hereditary angioedema)".)

SUMMARY AND RECOMMENDATIONS

●Definition – Acquired angioedema due to deficiency of C1 inhibitor (AAE-C1-INH) is a rare syndrome of recurrent episodes of angioedema, without urticaria, which is associated with B cell lymphoproliferative disorders in some patients.

●Patient education and preparation for acute angioedema episodes – Patients should be educated about the risk of fatal laryngeal attacks and instructed on how to proceed should swelling in the throat develop. Because so few clinicians are familiar with this disorder, equipping the patient with information about proper treatment is critical. A printable form is provided (form 1). (See 'Patient education about laryngeal edema' above and 'Written treatment plan' above.)

●Airway protection during laryngeal angioedema – Patients with laryngeal attacks require immediate assessment of the airway. If respiratory distress or stridor is present, preparations to intubate should be made because even the first-line therapies take approximately 30 minutes or more to begin working. An expert should manage the airway, if possible. (See 'Airway management in laryngeal edema' above.)

●Pharmacotherapy for acute angioedema – For treatment of severe angioedema in patients with AAE-C1-INH, we suggest either icatibant (a bradykinin B₂-receptor antagonist (available in the United States, Europe, and other countries) or plasma-derived C1-INH (pdC1-INH) concentrate, in preference to other agents (Grade 2C). There is more experience with these therapies than with others. Other agents that may be effective based on case reports include the following (table 1):

•Ecallantide, a kallikrein inhibitor (available in the United States)

•Recombinant human C1-INH (rhC1-INH; available in most of Europe and the United States)

•Plasma (fresh frozen or solvent-detergent treated)

Patients should either be trained to self-administer one of these treatments or have access to appropriate treatments at the hospitals nearest to the patients' homes. (See 'Pharmacologic treatment of acute attacks' above.)

●Resistance to C1-INH can develop – Patients with AAE-C1-INH can become resistant to C1-INH concentrate over time. For patients with acute angioedema who do not improve in response to an initial dose of C1-INH concentrate, we suggest administering ecallantide or icatibant instead (Grade 2C).

●Treatment of underlying disorders – If an underlying disorder is identified, treatment of that disorder usually reduces the frequency of angioedema episodes. (See 'Associated disorders' above.)

●Prophylactic therapies – We suggest prophylactic therapy for patients with recurrent episodes of laryngeal edema or angioedema symptoms affecting the gastrointestinal tract or skin who, despite the availability of on-demand therapies, experience several days of disability per month (Grade 2C). Available agents for prevention of attacks include:

•Tranexamic acid

•Anabolic androgens

•Lanadelumab

•Berotralstat

We suggest tranexamic acid in preference to other agents in most patients (Grade 2C). Dosing and administration are discussed separately. (See 'Prophylaxis to prevent angioedema episodes' above and "Hereditary angioedema (due to C1 inhibitor deficiency): General care and long-term prophylaxis", section on 'Specific agents'.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Marco Cicardi, MD, who contributed to earlier versions of this topic review.