Hereditary Angioedema as a Clinical Picture of Excessive Activation of the Kinin Cascade – Case Report

Case Description

A 21-year-old woman presented to the emergency department with acute throat swelling. Her personal medical history included recurrent episodes of non-itchy limb swelling that usually resolved spontaneously within 3 days. These episodes began to appear during puberty, with a frequency of approximately once a month, and were never accompanied by hives. The patient tried to manage the swelling with high doses of antihistamines, but without effect.

The patient’s mother experienced similar swelling episodes, but with lower frequency. The patient’s grandfather died at the age of 30 from suffocation.

The patient had previously visited the emergency room twice with extreme abdominal pain accompanied by vomiting and diarrhea, but the cause of her symptoms was not determined. At the time, she was taking combined hormonal contraception containing estrogen and progestins.

Treatment Administered

Upon admission, the patient was immediately administered adrenaline, clemastine, and dexamethasone. The medication had no effect on the laryngeal swelling, so a laryngeal intubation was performed and the patient was transferred to the intensive care unit. An empirical dose of plasma C1 inhibitor (C1-INH) was administered, and the edema quickly subsided. The woman was discharged with rescue medication (subcutaneous bradykinin B₂ receptor antagonist) in case of further attacks.

Definitive Diagnosis and Further Therapy

Laboratory testing confirmed a deficiency of C1-INH, and the patient was diagnosed with type 1 hereditary angioedema (HAE). Long-term prophylaxis with subcutaneous plasma-derived C1-INH administered twice weekly was initiated. The patient switched to contraception without estrogen. In the following months, breakthrough attacks occasionally occurred, but they responded well to the rescue medication.

Discussion

When HAE is suspected, serum levels of C1-INH and complement component 4 are measured, and the function of C1-INH is assessed. In patients with type 1 HAE, C1-INH levels are found to be less than 50% of normal values combined with reduced C1-INH function.

Unlike mast cell-mediated angioedema, HAE attacks do not respond to adrenaline, antihistamines, or corticosteroids. The swelling is caused by deregulation of the kallikrein-kinin cascade leading to bradykinin production. Bradykinin binds to B₂ receptors on the surface of endothelial cells, triggering a complex signaling pathway that results in increased vascular permeability, fluid extravasation, and swelling.

Acute HAE attacks are treated with C1-INH (plasma-derived or recombinant), icatibant (a competitive selective bradykinin receptor antagonist), or ecallantide (a direct inhibitor of plasma kallikrein). For short-term prophylaxis before invasive procedures that often trigger attacks, intravenous plasma-derived C1-INH can be used. The regimen of long-term prophylaxis is individualized based on disease activity and patient burden, utilizing plasma-derived C1-INH concentrates or kallikrein inhibitors such as lanadelumab or berotralstat.

Conclusion

HAE patient symptoms are caused by insufficient inhibition of the kinin cascade, leading to unpredictable and potentially life-threatening angioedema attacks that significantly impact the quality of life. However, advancements in clinical research in recent years have provided new treatment modalities with the potential to dramatically reduce the number of attacks, allowing HAE patients to lead normal lives.

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Source: Petersen R. S., Fijen L. M., Levi M., Cohn D. M. Hereditary angioedema: the clinical picture of excessive contact activation. Semin Thromb Hemost 2022 Nov 23, doi: 10.1055/s-0042-1758820 [Epub ahead of print].