HAE type III is rare and has only been documented recently. Unlike types I and II, this form does not appear to be connected with C1-inhibitor deficiency. This type mainly affects females and appears to be influenced by contact with estrogens and also by hormone replacement therapy (e.g. oral contraceptives). Its pathogenesis is credited to increased activity of the enzyme kininogenase, which leads to rise in the levels of bradykinin. Other patients with type III HAE have alterations in gene F12, which encodes a protein which participates in blood coagulation. Some patients with type III HAE have a mutation in the F12 gene which produces a protein involved in blood clotting. Due to the results of a genetic test on 4 affected German families, it is believed that this type of the condition is caused by a disease-causing gene in chromosome 5q.35.2-q35.3.