Models of blood coagulation
ABSTRACT Our research aims to provide quantitatively transparent, biologically realistic descriptions of the processes involved in hemostasis which will permit predictions of the behavior of the coagulation system in normal and pathologic states. We use four models of coagulation: (1) numerical approximations of the tissue factor (Tf) pathway of thrombin generation based upon mechanism and dynamics; (2) Tf activation of the "blood coagulation proteome" from isolated cells and proteins; (3) Tf activated contact pathway inhibited whole blood in vitro; and (4) blood shed from standardized microvascular wounds in vivo. The results from these models are integrated in interactive assessments aimed at achieving convergence of biochemical rigor and biological authenticity. Microvascular injury is the most biologically secure but least accessible to mechanistic study. Numerical models while quantitatively transparent are biologically limited. By the integrated analyses of all four models, we establish observations which require inclusion or discovery of new parameters to achieve mechanistically interpretable biological reality. Discoveries made in this fashion have included thrombin's role in the initiation phase, TFPI/ATIII/APC synergy interactions, rfVIIa in fVII deficiency, the roles of fVIII and fIX in the Tf reaction, and the cleavage of fIX by fXa membrane. Ideally, our results will provide descriptions which predict the behavior of the biological blood coagulation system under normal and pathologic conditions.
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ABSTRACT: Blood coagulation occurs through a cascade of enzymes and cofactors that produces a fibrin clot, while otherwise maintaining haemostasis. The 11 human coagulation factors (FG, FII-FXIII) have been identified across all vertebrates, suggesting that they emerged with the first vertebrates around 500 Mya. Human FVIII, FIX and FXI are associated with thousands of disease-causing mutations. Here we evaluated the strength of selective pressures on the 14 genes coding for the 11 factors during vertebrate evolution, and compared these with human mutations in FVIII, FIX and FXI. Positive selection was identified for fibrinogen (FG), FIII, FVIII, FIX and FX in the mammalian Primates and Laurasiatheria and the Sauropsida (reptiles and birds). This showed that the coagulation system in vertebrates was under strong selective pressures, perhaps to adapt against blood-invading pathogens. The comparison of these results with disease-causing mutations reported in FVIII, FIX and FXI showed that the number of disease-causing mutations and the probability of positive selection were inversely related to each other. It was concluded that when a site was under positive selection, it was less likely to be associated with disease-causing mutations. In contrast, sites under negative selection were more likely to be associated with disease-causing mutations and be destabilizing. A residue-by-residue comparison of the FVIII, FIX and FXI sequence alignments confirmed this. This improved understanding of evolutionary changes in FVIII, FIX and FXI provided greater insight into disease-causing mutations, and better assessments of the codon sites that may be mutated in applications of gene therapy.Molecular Biology and Evolution 12/2014; 31(11). DOI:10.1093/molbev/msu248 · 14.31 Impact Factor
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ABSTRACT: In this work we review a number of results concerning the existence of stable steady states for systems of ordinary differential equations of the type usually termed as biochemical cascades. These are typically nonlinear sys-tems involving interconnected activation-inhibitory feedback loops, and are known to play a basic role in the regulation of key physiological human func-tions. In particular, conditions will be recalled that ensure the existence of at most one stable steady state as opposed to multistability, i.e. the existence of several stable steady states. The latter is considered to be a key feature in biological processes mediated by biochemical cascades.