BIOPHYSICAL THEORY AND MODELING |
Spatial propagation and localization of blood coagulation are respectively regulated by intrinsic and protein C pathways
Mikhail A Panteleev 1, Mikhail V Ovanesov 2, Dmitrii A Kireev 1, Aleksei M Shibeko 3, Elena I Sinauridze 1, Natalya M Ananyeva 2, Evgueni L Saenko 2 and Fazoil I Ataullakhanov 1*
1 National Research Center for Hematology, Moscow, Russia
2 University of Maryland School of Medicine, Rockville, MD
3 Moscow State University, Moscow, Russia
* To whom correspondence should be addressed. E-mail: fazly{at}hc.comcor.ru.
Submitted on June 19, 2005
Revised on August 16, 2005
Accepted on 2 November 2005
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Abstract |
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Blood coagulation in vivo is a spatially non-uniform, 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) in vitro experimental model of clot formation in a thin layer of plasma activated by a monolayer of TF-expressing cells; 2) 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, while factor IXa was formed by extrinsic tenase on activating cells and was delivered to platelets by diffusion, sustaining clot growth. Far from the activating cells, additional factor IXa was provided by factor XIa. Exogenously added TF had no effect on clot growth rate suggesting that plasma TF does not contribute significantly to 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 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 possible basis for their therapeutic targeting.
Key Words:
blood coagulation, intrinsic pathway, mathematical modeling, thrombomodulin, time-lapse videomicroscopy
