ORIGINAL ARTICLESMechanisms of action of recombinant activated factor VII in the context of tissue factor concentration and distributionOvanesov, Mikhail Va,b,1; Panteleev, Mikhail Aa; Sinauridze, Elena Ia; Kireev, Dmitry Aa; Plyushch, Olga Pa; Kopylov, Konstantin Ga; Lopatina, Elena Ga; Saenko, Evgueni Lb; Ataullakhanov, Fazoil Ia,c,dAuthor Information aNational Research Center for Hematology, Moscow, Russia bUniversity of Maryland School of Medicine, Rockville, Maryland, USA cMoscow State University, Russia dCenter for Theoretical Problems of Physical and Chemical Pharmacology, Moscow, Russia 1 Present address: Janelia Farm Research Campus, Howard Hughes Medical Institute, Ashburn, Virginia, USA. Received 27 July, 2007 Revised 25 September, 2007 Accepted 28 September, 2007 Correspondence to Mikhail V. Ovanesov, Janelia Farm Research Campus, Howard Hughes Medical Institute, 19700 Helix Drive, Ashburn, VA 20147, USA Tel: +1 240 731 0308; e-mail: firstname.lastname@example.org Correspondence to Mikhail A. Panteleev, National Research Center for Hematology, 4a Novyi Zykovskii pr., Moscow, 125167 Russia Tel: +7 495 612 3522; fax: +7 495 612 8870; e-mail: email@example.com Blood Coagulation & Fibrinolysis: December 2008 - Volume 19 - Issue 8 - p 743-755 doi: 10.1097/MBC.0b013e3283104093 Buy Metrics Abstract Supraphysiological concentrations of recombinant activated factor VII (rVIIa, NovoSeven) are used to control bleeding in hemophilia. Current experimental evidence suggests that rVIIa may increase thrombin generation via two pathways: one being tissue factor (TF)-dependent and another being activated platelet-dependent. Contribution of TF to the rVIIa action may justify different administration profiles of rVIIa. In the present study, thrombin and fibrin generation and spatial clot formation assays in platelet-free hemophilia A and normal plasma were used to investigate this contribution. By varying the concentration of TF and the way it becomes available to plasma, we obtained the following results. Activation of clotting with less than 5 pmol/l of TF facilitates thrombin and fibrin generation at low, but not at supraphysiological rVIIa concentrations. Activation with more than 13 pmol/l of TF saturates thrombin and fibrin generation kinetics, making it insensitive to rVIIa. rVIIa minimally modulates clot growth on the surface of TF-expressing fibroblasts. On the contrary, rVIIa produces spontaneous clot formation in nonflowing platelet-free plasma far away from fibroblasts via plasma lipid particles. Therefore, both the concentration and the distribution of TF determine relevance of a particular experimental system for the studies of rVIIa action. The results indicate that 300–1600 nmol/l (megadoses) of rVIIa may deliver coagulation outside of the TF-rich areas of blood vessel damage via the platelet-derived microparticles. Therefore, rate and extent of platelet-derived microparticles generation might be important with regard to rVIIa treatment safety. © 2008 Lippincott Williams & Wilkins, Inc.