defining the boundaries of normal thrombin generation investigations into hemostasis定义的边界正常止血凝血酶生成调查.pdfVIP

Defining the Boundaries of Normal Thrombin Generation: Investigations into Hemostasis 1 2 2 2 Christopher M. Danforth , Thomas Orfeo , Stephen J. Everse , Kenneth G. Mann , Kathleen E. Brummel- Ziedins2* 1 Department of Mathematics and Statistics, Center for Complex Systems, Vermont Advanced Computing Center, University of Vermont, Burlington, Vermont, United States of America, 2 Department of Biochemistry, College of Medicine, University of Vermont, Burlington, Vermont, United States of America Abstract In terms of its soluble precursors, the coagulation proteome varies quantitatively among apparently healthy individuals. The significance of this variability remains obscure, in part because it is the backdrop against which the hemostatic consequences of more dramatic composition differences are studied. In this study we have defined the consequences of normal range variation of components of the coagulation proteome by using a mechanism-based computational approach that translates coagulation factor concentration data into a representation of an individual’s thrombin generation potential. A novel graphical method is used to integrate standard measures that characterize thrombin generation in both empirical and computational models (e.g max rate, max level, total thrombin, time to 2 nM thrombin (‘‘clot time’’)) to visualize how normal range variation in coagulation factors results in unique thrombin generation phenotypes. Unique ensembles of the 8 coagulation factors encompassing the limits of normal range variation were used as initial conditions for the computational modeling, each ensemble representing ‘‘an individual’’ in a theoretical healthy population. These ‘‘individuals’’ with unremarkabl