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Journal of Thrombosis and Thrombolysis 20(1), 6568, 2005.C 2005 Springer Science + Business Media, Inc. Manufactured in The Netherlands.Cell-Based Models of Coagulation: A Paradigm in EvolutionRichard C. BeckerCardiovascular Thrombosis Center, Duke University Medical
Center, Duke Clinical Research Institute, Durham, NCKey Words. cell-based, coagulation, thrombosisThe complex system regulating hemostasis, as well
as an increasing number of inherited and acquired
conditions associated with their dysregulation, must
be understood fully before meaningful scientific studies to identify pharmacologic and/or cellular treatment strategies can take place. The importance of
an evolving paradigm for coagulation that can be applied directly to protective hemostasis and pathologic
thrombosis can not be overstated as a fundamental
starting point for these important endeavors.Cell-Based Model of CoagulationThe waterfall or cascade model of coagulation, proposed almost simultaneously by McFarlane,
Davie, and Ratnoff in the early 1960s, expanded earlier theories of Morawitz and provided a biochemical structure for understanding coagulation reactions (and the basis for several clinical disorders of
hemostasis). However, its separation into intrinsic
and extrinsic pathways, as well as the absence of
platelets and other cellular elements from the overall
framework, limited the models application to in vivo
hemostasis and thrombosis.A cell-based model of coagulation [1] establishes
a physiological, integrated, and functional view of
complex biochemical events occurring on cellular (or
other biological) surfaces, rather than distinct and
relatively independent cascades that may be operational in static fluid systems (Fig. 1). It also provides
a scientific foundation for understanding the importance of specific platelet binding sites for coagulation
proteases [2,3], the nonhemostatic roles of coagulation factors (which include vessel wall inflammation
and cellular proliferation), the dynamic nature of cellular interactions and the inter-individual variability of platelet procoagulant activity (and thrombotic
potential).According to the cell-based model of coagulation, initiation takes place on intact cells or cellular
fragments (monocytes, macrophages, neutrophils,
activated endothelial cells, smooth muscle cells,
apoptotic cells, platelet microparticles, circulating
vesicles) bearing the transmembrane glycoprotein
tissue factor [4]. Exposed tissue factor binds and
fully activates coagulation factor (f) VII, which subsequently activates fIX and fX (which then activates
fV), generating a small amount of thrombin from prothrombin (fII). In the priming or amplification phase,
surface-bound thrombin activates platelets (bioamplification), as well as fV, fXI, and fVIII (cleaving the
latter from von Willebrand factor). fXIa generates additional...