A Comprehensive Model for the Humoral Coagulation Network in Humans

Coagulation is an important process in hemostasis and comprises a complicated interaction of multiple enzymes and proteins. We have developed a mechanistic quantitative model of the coagulation network. The model accurately describes the time courses of coagulation factors following in vivo activation as well as in vitro blood coagulation tests of prothrombin time (PT, often reported as international normalized ratio (INR)) and activated partial thromboplastin time (aPTT). The model predicts the concentration–time and time–effect profiles of warfarin, heparins, and vitamin K in humans. The model can be applied to predict the time courses of coagulation kinetics in clinical situations (e.g., hemophilia) and for biomarker identification during drug development. The model developed in this study is the first quantitative description of the comprehensive coagulation network.

[1]  S. J. Uniat THEORIES OF BLOOD COAGULATION. , 1965, University of Toronto undergraduate dental journal.

[2]  K. Kurachi,et al.  The molecular-weight dependence of the rate-enhancing effect of heparin on the inhibition of thrombin, factor Xa, factor IXa, factor XIa, factor XIIa and kallikrein by antithrombin. , 1981, The Biochemical journal.

[3]  M. Rowland,et al.  Cyclic interconversion of vitamin K1 and vitamin K1 2,3-epoxide in man. , 1983, British journal of clinical pharmacology.

[4]  N. Holford Clinical Pharmacokinetics and Pharmacodynamics of Warfarin , 1986, Clinical pharmacokinetics.

[5]  N H Holford,et al.  Clinical pharmacokinetics and pharmacodynamics of warfarin. Understanding the dose-effect relationship. , 1986, Clinical pharmacokinetics.

[6]  C. H. Yang,et al.  Comprehensive clinical and statistical analysis of hemophilia in Korea. , 1988, Journal of Korean medical science.

[7]  A. Breckenridge,et al.  The relationship between inhibition of vitamin K1 2,3-epoxide reductase and reduction of clotting factor activity with warfarin. , 1988, British journal of clinical pharmacology.

[8]  M A Khanin,et al.  A mathematical model of the kinetics of blood coagulation. , 1989, Journal of theoretical biology.

[9]  R. Colman,et al.  Effect of Heparin on the Inhibition of the Contact System Enzymes , 1989, Annals of the New York Academy of Sciences.

[10]  F Keller,et al.  The quick machine--a mathematical model for the extrinsic activation of coagulation. , 1994, Haemostasis.

[11]  D. Lalloo,et al.  Coagulopathy following bites by the Papuan taipan (Oxyuranus scutellatus canni) , 1995, Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis.

[12]  A. Bach,et al.  Assessment of vitamin K status in human subjects administered "minidose" warfarin. , 1996, The American journal of clinical nutrition.

[13]  F I Ataullakhanov,et al.  A mathematical model for the spatio-temporal dynamics of intrinsic pathway of blood coagulation. I. The model description. , 1996, Thrombosis research.

[14]  S. Booth,et al.  Relationships between dietary intakes and fasting plasma concentrations of fat-soluble vitamins in humans. , 1997, The Journal of nutrition.

[15]  E. Ohman,et al.  Heparin and low-molecular-weight heparin: mechanisms of action, pharmacokinetics, dosing considerations, monitoring, efficacy, and safety. , 1998, Chest.

[16]  W J Jusko,et al.  Characteristics of indirect pharmacodynamic models and applications to clinical drug responses. , 1998, British journal of clinical pharmacology.

[17]  M A Khanin,et al.  Mathematical model for the blood coagulation prothrombin time test. , 1998, Thrombosis research.

[18]  B. Furie,et al.  Vitamin K-dependent biosynthesis of gamma-carboxyglutamic acid. , 1999, Blood.

[19]  B. Furie,et al.  Vitamin K-Dependent Biosynthesis of γ-Carboxyglutamic Acid , 1999 .

[20]  K. Mann,et al.  Biochemistry and Physiology of Blood Coagulation , 1999, Thrombosis and Haemostasis.

[21]  K. Mann,et al.  A model describing the inactivation of factor Va by APC: bond cleavage, fragment dissociation, and product inhibition. , 1999, Biochemistry.

[22]  K. Mann,et al.  Models of blood coagulation , 2000, Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis.

[23]  M A Khanin,et al.  Analysis of the activated partial thromboplastin time test using mathematical modeling. , 2001, Thrombosis research.

[24]  D. Monroe,et al.  Platelets and thrombin generation. , 2002, Arteriosclerosis, thrombosis, and vascular biology.

[25]  K. Mann,et al.  The dynamics of thrombin formation. , 2003, Arteriosclerosis, thrombosis, and vascular biology.

[26]  L. Aarons,et al.  A Bayesian Method Based on Clotting Factor Activity for the Prediction of Maintenance Warfarin Dosage Regimens , 2003, Therapeutic Drug Monitoring.

[27]  Stephen B Duffull,et al.  Development of a dosing strategy for enoxaparin in obese patients. , 2003, British journal of clinical pharmacology.

[28]  G. Guyatt,et al.  The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy , 2004 .

[29]  K. Stoeckel,et al.  Elimination half-life of vitamin K1 in neonates is longer than is generally assumed: implications for the prophylaxis of haemorrhaghic disease of the newborn , 2004, European Journal of Clinical Pharmacology.

[30]  J. Hirsh,et al.  Heparin and low-molecular-weight heparin: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. , 2004, Chest.

[31]  X. H. Xu,et al.  The kinetic model and simulation of blood coagulation--the kinetic influence of activated protein C. , 2004, Medical engineering & physics.

[32]  J. Hirsh,et al.  The pharmacology and management of the vitamin K antagonists: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. , 2004, Chest.

[33]  Mikhail A. Panteleev,et al.  Mathematical Modeling and Computer Simulation in Blood Coagulation , 2006, Pathophysiology of Haemostasis and Thrombosis.

[34]  Dougald M Monroe,et al.  Rethinking the coagulation cascade. , 2005, Current hematology reports.

[35]  YJ Zeng,et al.  A kinetic model for simulation of blood coagulation and inhibition in the intrinsic path , 2005, Journal of medical engineering & technology.

[36]  S. Booth,et al.  Plasma concentrations of dihydro-vitamin K1 following dietary intake of a hydrogenated vitamin K1-rich vegetable oil , 1996, Lipids.

[37]  P. Bass,et al.  Tissue factor pathway inhibitor: structure, biology and involvement in disease , 2006, The Journal of pathology.

[38]  M. Pirmohamed,et al.  Pharmacogenetics of warfarin: current status and future challenges , 2007, The Pharmacogenomics Journal.

[39]  Amin Rostami-Hodjegan,et al.  The use of mechanistic DM-PK-PD modelling to assess the power of pharmacogenetic studies -CYP2C9 and warfarin as an example. , 2007, British journal of clinical pharmacology.

[40]  E N Jonsson,et al.  A PK–PD Model for Predicting the Impact of Age, CYP2C9, and VKORC1 Genotype on Individualization of Warfarin Therapy , 2007, Clinical pharmacology and therapeutics.

[41]  D. Lalloo,et al.  A model for venom-induced consumptive coagulopathy in snake bite. , 2008, Toxicon : official journal of the International Society on Toxinology.

[42]  Elaine Gray,et al.  Heparin and low-molecular-weight heparin , 2008, Thrombosis and Haemostasis.