Defective blood protein cause of hereditary swellings

Scientists have shown that hereditary angioedema (HAE) type III — a rare and serious disorder, characterised by painful swellings in the skin and other organs — is caused by a defective blood protein, coagulation factor XII. The results from their study, published in The Journal of Clinical Investigation, may contribute to future treatment strategies.

Oedema, or tissues becoming swollen because of fluid retention, is a common symptom in a number of pathologies such as allergies or kidney and heart diseases. The swelling is caused by blood vessels leaking fluid into the surrounding tissue. In hereditary angioedema (HAE), the leakage, and hence the swelling, is primarily caused by the hormone bradykinin.

People with HAE suffer painful episodes of swelling typically involving the skin and gastrointestinal tract. The attacks can be life-threatening since the airways may become obstructed. The most common variants of the disease are called HAE type I and II, and the causes of these are well known. 

“HAE type III was discovered just recently. If we want to treat the disease, we must first understand the underlying mechanism,” said Dr. Jenny Björkqvist at the Department of Molecular Medicine and Surgery, Karolinska Institutet, one of the researchers behind the study.

The researchers already knew that patients with HAE type III have a mutation in the blood protein factor XII, but they did not know why this would cause swellings. In the current study, the researchers discovered that a single sugar was missing in the mutated factor XII in HAE type III patients. The mutated factor XII was found to be overactive. This caused an excess of bradykinin production, resulting in vessel leakage and swelling.

There are natural inhibitors in blood that normally prevent factor XII from becoming activated. These inhibitors can also bind to and inhibit the mutated factor XII, but this is not enough to completely stop the overactivation.

The researchers hope that the study results can be used to establish the first treatment for patients with HAE type III.

Participating in the study were researchers from Karolinska Institutet, Karolinska University Hospital, University Medical Center Hamburg-Eppendorf, University Medical Center Utrecht, Leibniz-Institut für Analytische Wissenschaften, Heidelberg University, University of Bonn, Univerisity Joseph Fourier, CSL Limited and CSL Behring.