Factor xii

Factor XII is an enzyme and the trigger factor of the intrinsic system. It establishes the connection from connective tissue or from the site of the lesion to the intrinsic system.

The synthesis of factor XII occurs in the liver. Unactivated factor XII consists of a single chain of a ß-globulin with a molecular weight of 80,000-90,000 D. It can be activated by a variety of substances. The physiological activators are endothelium and kallikrein.
The plasma level is 23-47 ug/ml, and the half-life is 50-60 hours.

Factor XIIa has a molecular weight of 28,000 D and consists of two polypeptide chains linked by disulfide bridges. It activates the F-IX to F-IXa. In addition, F-XIIa interferes with fibrinolysis and cleaves plasminogen.
In analyzing the gradually found clotting factors, it was observed that contact with glass surfaces activated clotting in some and not in others.
Ratnoff demonstrated that Hageman factor activity was activated by direct contact with glass surfaces. This led to a series of experiments that demonstrated that many substances such as fat, certain types of collagen, tannins, and proteins in connective tissue also activate factor XII. It was observed that all materials that activate the Hageman factor by contact have a negative surface charge.

Differential analyses of Hageman factor activation showed that, as part of these activation events, the permeability of small blood vessels is altered, resulting in leakage of plasma into extravascular tissues, often associated with pain and dilatation of small blood vessels and a local drop in blood pressure, inducing smooth muscle contraction. This observation led to the discovery of kinins, which are released from their precursors, kininogens. Margolis then discovered that the Hageman factor activates plasma kallikrein; this releases kikins from kininogens. Kininogen was converted to bradykinin by kallikrein.

Kallikrein cleaves the F-XII, thus activating it. This F-XIIa activates the F-XI, releases kallikrein from prekallikrein. Furthermore, the F-XI activates plasminogen to plasmin. Plasminogen activation in turn leads to activation of F-XII via a feedback mechanism. Through this feedback loop, large amounts of F-XII are produced very rapidly.

Factor XII was discovered by Ratnoff and Colopy in a patient named John Hageman who presented for surgery in Cleveland because of a bleeding ulcer. They did not observe the classic symptoms of an increased tendency to bleed, but found that his blood coagulated unusually slowly. It was soon discovered that the defect could be localized in the intrinsic pathway and the coagulation could be normalized by administration of normal plasma from which the previously known plasma factors had been removed. Further analyses showed that this factor had properties as had been postulated in earlier investigations. Hageman disease is a familial disease that occurs in both sexes.

1. HA Neumann (2014) The coagulation system. ABW-Wissenschaftsverlag GmbH Berlin S. 65f.