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Spatial Propagation and Localization of Blood Coagulation Are Regulated by Intrinsic and Protein C Pathways, Respectively

Mikhail A. Panteleev ^*, Mikhail V. Ovanesov , Dmitrii A. Kireev ^*, Aleksei M. Shibeko ^*, Elena I. Sinauridze ^*, Natalya M. Ananyeva , Andrey A. Butylin ^* , Evgueni L. Saenko  and Fazoil I. Ataullakhanov ^*  ¶

^* Laboratory of Physical Biochemistry of Blood, National Research Center for Hematology, Russian Academy of Medical Sciences, Moscow, Russia; Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland; Division of Neurobiology, Department of Psychiatry, The Johns Hopkins University, Baltimore, Maryland; Faculty of Physics, Moscow State University, Moscow, Russia; and ^¶ Laboratory of Metabolic Modeling and Bioinformatics, Institute of Theoretical and Experimental Biophysics, Pushchino, Moscow Region, Russia

Correspondence: Address reprint requests to Fazoil I. Ataullakhanov, National Research Center for Hematology, Russian Academy of Medical Sciences, 4a Novozykovskii proezd, Moscow 125167, Russia. Tel.: 7-095-212-55-31; Fax: 7-095-212-88-70; E-mail: fazly{at}hc.comcor.ru.

Blood coagulation in vivo is a spatially nonuniform, multistage process: coagulation factors from plasma bind to tissue factor (TF)-expressing cells, become activated, dissociate, and diffuse into plasma to form enzymatic complexes on the membranes of activated platelets. We studied spatial regulation of coagulation using two approaches: 1), an in vitro experimental model of clot formation in a thin layer of plasma activated by a monolayer of TF-expressing cells; and 2), a computer simulation model. Clotting in factor VIII- and factor XI-deficient plasmas was initiated normally, but further clot elongation was impaired in factor VIII- and, at later stages, in factor XI-deficient plasma. The data indicated that clot elongation was regulated by factor Xa formation by intrinsic tenase, whereas factor IXa was formed by extrinsic tenase on activating cells and diffused into plasma, thus sustaining clot growth. Far from the activating cells, additional factor IXa was produced by factor XIa. Exogenously added TF had no effect on the clot growth rate, suggesting that plasma TF does not contribute significantly to the clot propagation process in a reaction-diffusion system without flow. Addition of thrombomodulin at 3–100 nM caused dose-dependent termination of clot elongation with a final clot size of 2–0.2 mm. These results identify roles of specific coagulation pathways at different stages of spatial clot formation (initiation, elongation, and termination) and provide a possible basis for their therapeutic targeting.

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