Molecular Mechanisms of Thrombosis.
Fundamental and Applied Aspects of the Contact Activation

V. N. Kolyadko, V. A. Korneeva, F. I. Ataullakhanov, and M. A. Panteleev

Center for Theoretical Problems of Physicochemical Pharmacology, Russian Academy of Sciences,
ul. Kosygina, 4a, Moscow, 119991 Russia

e-mail: vera.korneeva@gmail.com

Received April 2, 2014

Abstract—The human hemostatic system stops bleeding when vascular lesions occur. This is one of the most
vulnerable physiological systems. Hemostatic disorders, which are encountered in patients with various dis-
eases (i.e., atherosclerosis, trauma, sepsis, and cancer), may lead to both hemorrhage and thrombosis. Patho-
logical clot formation is dangerous, and thrombosis is the most common cause of death in developed countries.
Activated factor XII (fXIIa), a key enzyme of the contact pathway of coagulation, does not play a significant
role in maintaining hemostasis but is involved in the pathological blood clotting. Therefore, this enzyme is a
promising target for the development of antithrombotic drugs. Inhibition of the contact pathway is essential for
any ex vivo manipulation involving blood (i.e., transfusion, cardiopulmonary bypass, and blood sampling) and
when blood is exposed to foreign surfaces. In this review we consider modern views on the contact activation
and the pathophysiological role of this process in the blood coagulation and other systems of the organism.
Existing inhibitors of the contact pathway exhibit two mechanisms of action: a competitive binding to the active
site of fXIIa and an allosteric inhibition via the N-terminal regulatory domain, which blocks activation by
anionic surfaces and binding to physiological substrates. These two mechanisms are discussed. A comparison
of existing inhibitors, with special emphasis on the most promising ones, and the criteria for new fXIIa inhibi-
tors are also provided.

Keywords: hemostasis, coagulation factor XII (Hageman factor) inhibitors, contact activation, thrombosis, clin-
ical diagnostics

DOI: 10.1134/S1990747814040059

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