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Hereditary Angioedema Therapy

Hereditary angioedema is characterized by unpredictable recurrent attacks of subcutaneous or submucosal swellings. Patients present with well circumscribed, nonitching edema of upper airway, face, extremities, genitals and gastrointestinal system. Angioedema of the larynx can be life-threatening. Attacks have a slow onset and may last between 2 and 5 days.

Prevalence is estimated to be one in 10,000 individuals.  There are two forms of C1 esterase inhibitor deficiency.  The inherited form is usually detected in the first or second decade of life and has an autosomal dominant pattern of inheritance. The acquired form primarily affects adult or elderly patients with autoimmune or lymphoproliferative disorders. (See article on C1 esterase inhibitor).

Hereditary angioedema is caused by a deficiency or dysfunction of C1 esterase inhibitor that results in loss of inhibition of plasma kallikrein, leading to increased cleavage of high-molecular-weight kininogen and the release of bradykinin. Bradykinin increases local capillary permeability, resulting in angioedema.

Management of angioedema consists of treatment of acute attacks and longer term prophylaxis. In the past, acute attacks in adults were usually treated by transfusion of 2 units of fresh frozen plasma. If necessary, additional units were transfused until the patients' symptoms resolved. Some patients experienced a paradoxical worsening of symptoms.

In 2009, FDA approved Berinert (CSL Behring) for the treatment of acute abdominal, facial or laryngeal attacks of hereditary angioedema in children and adults. This is a plasma derived, nanofiltered, lyophilized concentrate of C1 esterase inhibitor. Recommended dose is 20 U/kg. Relief from symptoms occurs begins to occur in approximately 30 minutes. Complete resolution usually occurs within 5 hours.  Berinert is well tolerated in most patients.

Current prophylactic options for hereditary angioedema include attenuated androgens, fibrinolytic agents, and intravenous C1 esterase inhibitors. Anabolic steroids such as danazol, stanozolol, and oxandrolone probably work by increasing intrinsic C1 inhibitor production and promoting bradykinin degradation through an increase in aminopeptidase P. They show good efficacy at higher doses. However, adverse effects are common, and androgens are contraindicated in pregnancy and for prepubertal children. Tranexamic acid is a popular option for children but has poor efficacy. Cinryze is a C1 esterase inhibitor approved by FDA for routine prophylaxis against angioedema attacks in adolescent and adult patients. It is a highly purified, pasteurized and nanofiltered plasma-derived C1 esterase inhibitor. Recommended dose is 1000 units given IV over 10 minutes; dosing can be repeated every 3 to 4 days. Cinryze decreases the frequency, severity and duration of angioedema attacks, but requires intravenous access via an indwelling port. Ecallantide (Kalbitor, Dyax), is a potent inhibitor of kallikrein production that is administered subcutneously. Time to improvement of symptoms averages about 2 hours. Anaphylaxis has been reported in approximately 3% of patients. 

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