Is there value in kinetic modeling of thrombin generation? Yes.

摘要: IntroductionTheultimateteacheronhumanphysiologyishumanpathologyand the clinical trials aimed at i ts amelioration. However, thepathway between disease and cure most frequently arises froma reductionist approach. Perhaps no better illustration of thisprocess is history diagnosis treatment ofhemophilia A, which involved identification ofthe defectinblood, in plasma, cryoprecipitate [1] ultimately by theabsenceorimpairmentofthefactor(F)VIIImolecule.Essentialto evolution development knowledge andtreatment were vitro tests experimental methods, theresults could be validated whilesimultaneously providing quantitative methods essential toidentify factor (F)VIII molecule.The activated partial thromboplastin time (APTT) test [2],still hemophilia management, isclearly biologically artificial, employing citrate plasma anon-physiologic activator with excess phospholipid. Nonethe-less, its utility not doubt. relevance somemolecular defects hemostasis identified using APTT areindoubtastheyarenotassociatedwithahemostaticpathology.Our laboratory, while predominately ap-proach uses a variety models including: numerical synthesisof clotting reaction solved on computer [3]; closed andopen (flow)systems utilizing reconstituted synthetic plasmaclotting proteome [4–6]; minimally altered, corn trypsin inhib-itor-treated whole blood without endothelial andinflammatory cells [7,8]; oozing from microvascularwoundsinvolunteers[9].Thenumericalmodelshavebeenusedin studies to discriminate potential mechanisticpathways[10–12],epidemiologicstudiesofhemorrhagecontroland thrombosis [13] support drug design andevaluation [14–16].Numerical systems their validationHuman biology fundamentally opaque numericalmodels are transparent (Fig. 1); gradientfrom through human physiol-ogybecomeslessandlesstransparent.Whentheresultsofthesemodels converge we believe understand process; whenthey diverge it becomes basis discovery newpathways. The fundamental role long-term project understanding coagulationhas continues recognized number investiga-tors all levels empirical model complexity. Mathematicalconstructs coagulation network have beendeveloped ensembles differential equations [3,17–22]or more elaborate constructs for both flow-basedmodel [19,23–32]. All these developwithin gradient usedto investigate chemistry coagulation. coincidence ofnumerical suggests modelsare correct this level.Numerical present distillation insights fromempirical offer promise predicting outcomeswhen networks perturbed. Like empiricalmodelsfrom whichthey derivetheircontent,numericalmodelsare incomplete imperfect representations livingsystems they attempt describe. totallytransparent physiology 1)requires constant validation increasingly com-plex studies. Any discontinuity observedin proceeding results identificationof new discoveries. At each step progression 1), thecosts execution increases an exponentialfashion. Numerical hypotheses tested takeseconds cost little. Clinical take years areexorbitantly expensive.Clot SpeedBiochemistry science. Mylaboratorys initial foray into dealt theisolation characterization multiple forms ofthrombin [33] activation prothrombin [34]. Thesestudies subsequently proceeded isolation FV[35], FVa [36], participation FVa,FXa phospholipid prothrombinase complex [37].The greater than 300 000-fold increase activa-tion rates FXa, FVa, phospholipid, Ca