Kinetic model facilitates analysis of fibrin generation and its modulation by clotting factors: implications for hemostasis-enhancing therapies.
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2014-07-30
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Abstract
Current mechanistic knowledge of protein interactions driving blood coagulation has come largely from experiments with simple synthetic systems which only partially represent the molecular composition of human blood plasma Here we investigate the ability of the suggested molecular mechanisms to account for fibrin generation and degradation kinetics in diverse physiologically relevant in vitro systems We represented the protein interaction network responsible for thrombin generation fibrin formation and fibrinolysis as a computational kinetic model and benchmarked it against published and newly generated data reflecting diverse experimental conditions We then applied the model to investigate the ability of fibrinogen and a recently proposed prothrombin complex concentrate composition PCC AT a combination of the clotting factors II IX X and antithrombin to restore normal thrombin and fibrin generation in diluted plasma The kinetic model captured essential features of empirically detected effects of prothrombin fibrinogen and thrombin activatable fibrinolysis inhibitor titrations on fibrin formation and degradation kinetics Moreover the model qualitatively predicted the impact of tissue factor and tPA tenecteplase level variations on the fibrin output In the majority of considered cases PCC AT combined with fibrinogen accurately approximated both normal thrombin and fibrin generation in diluted plasma which could not be accomplished by fibrinogen or PCC AT acting alone We conclude that a common network of protein interactions can account for key kinetic features characterizing fibrin accumulation and degradation in human blood plasma under diverse experimental conditions Combined PCC AT fibrinogen supplementation is a promising strategy to reverse the deleterious effects of dilution induced coagulopathy associated with traumatic bleeding