Predicting the pharmacology of thrombin inhibitors

Summary.  Thrombotic disorders can lead to uncontrolled thrombin generation and clot formation within the circulatory system leading to vascular thrombosis. Direct inhibitors of thrombin have been developed and tested in clinical trials for the treatment of a variety of these thrombotic disorders. The bleeding complications observed during these trials have raised questions about their clinical use. The development of a computer‐based model of coagulation using the kinetic rates of individual reactions and concentrations of the constituents involved in each reaction within blood has made it possible to study coagulation pathologies in silico. We present an extension of our initial model of coagulation to include several specific thrombin inhibitors. Using this model we have studied the effect of a variety of inhibitors on thrombin generation and compared these results with the clinically observed data. The data suggest that numerical models will be useful in predicting the effectiveness of inhibitors of coagulation.

[1]  K Fujikawa,et al.  Activation of human blood coagulation factor XI independent of factor XII. Factor XI is activated by thrombin and factor XIa in the presence of negatively charged surfaces. , 1991, The Journal of biological chemistry.

[2]  H. Krumholz.  Organization to Assess Strategies for Ischemic Syndromes (OASIS). , 1997 .

[3]  K. C. Jones,et al.  A Model for the Stoichiometric Regulation of Blood Coagulation* , 2002, The Journal of Biological Chemistry.

[4]  A. A. van den Bos,et al.  Angiographic dose-finding study with r-hirudin (HBW 023) for the improvement of thrombolytic therapy with streptokinase (HIT-SK). Interim results. , 1995, European heart journal.

[5]  D D Monkovic,et al.  Activation of human factor V by factor Xa and thrombin. , 1990, Biochemistry.

[6]  A. Greinacher,et al.  Recombinant Hirudin in Clinical Practice: Focus on Lepirudin , 2001, Circulation.

[7]  M. Simoons.  A comparison of recombinant hirudin with heparin for the treatment of acute coronary syndromes. , 1996, The New England journal of medicine.

[8]  E. Antman.  Hirudin in acute myocardial infarction. Thrombolysis and Thrombin Inhibition in Myocardial Infarction (TIMI) 9B trial. , 1996, Circulation.

[9]  C. Esmon,et al.  The roles of protein C and thrombomodulin in the regulation of blood coagulation. , 1984, The Journal of biological chemistry.

[10]  U. Tebbe,et al.  Safety observations from the pilot phase of the randomized r-Hirudin for Improvement of Thrombolysis (HIT-III) study. A study of the Arbeitsgemeinschaft Leitender Kardiologischer Krankenhausärzte (ALKK) , 1994, Circulation.

[11]  S. Rapaport,et al.  Formation of Intrinsic Factor‐X‐Activator Activity, with Special Reference to the Role of Thrombin , 1971, British journal of haematology.

[12]  L. Wilkins.  Randomized trial of intravenous heparin versus recombinant hirudin for acute coronary syndromes. The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIa Investigators. , 1994, Circulation.

[13]  E. Antman.  Hirudin in acute myocardial infarction. Safety report from the Thrombolysis and Thrombin Inhibition in Myocardial Infarction (TIMI) 9A Trial. , 1994, Circulation.

[14]  J. Hirsh,et al.  Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. , 1995, The New England journal of medicine.

[15]  S. Pizzo,et al.  Human Factor XIII from plasma and platelets. Molecular weights, subunit structures, proteolytic activation, and cross-linking of fibrinogen and fibrin. , 1973, The Journal of biological chemistry.

[16]  U. Tebbe,et al.  Recombinant hirudin and front-loaded alteplase in acute myocardial infarction: final results of a pilot study. HIT-I (hirudin for the improvement of thrombolysis). , 1995, European heart journal.

[17]  K. Mann,et al.  A model for the tissue factor pathway to thrombin. II. A mathematical simulation. , 1994, The Journal of biological chemistry.

[18]  W. Weeks,et al.  Complications of warfarin therapy: causes, costs, and the role of the anticoagulation clinic. , 2000, Effective clinical practice : ECP.

[19]  G. Broze,et al.  Factor XI activation in a revised model of blood coagulation , 1991, Science.

[20]  E. Ohman,et al.  Heparin and low-molecular-weight heparin: mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy, and safety. , 2001, Chest.

[21]  K. Mann,et al.  Blood clotting in minimally altered whole blood. , 1996, Blood.

[22]  S. Yusuf.  Design, baseline characteristics, and preliminary clinical results of the Organization to Assess Strategies for Ischemic Syndromes-2 (OASIS-2) trial. , 1999, The American journal of cardiology.

[23]  U. Tebbe,et al.  HBW 023 (recombinant hirudin) for the acceleration of thrombolysis and prevention of coronary reocclusion in acute myocardial infarction: results of a dose‐finding study (HIT‐II) by the Arbeitsgemeinschaft Leitender Kardiologischer Krankenhausärzte , 1998, Coronary artery disease.

[24]  J. Deinum,et al.  The Importance of Enzyme Inhibition Kinetics for the Effect of Thrombin Inhibitors in a Rat Model of Arterial Thrombosis , 1997, Thrombosis and Haemostasis.

[25]  K. Wegscheider,et al.  Recombinant hirudin (lepirudin) for the improvement of thrombolysis with streptokinase in patients with acute myocardial infarction: results of the HIT-4 trial. , 1999, Journal of the American College of Cardiology.

[26]  J. Bartholomew,et al.  Argatroban Anticoagulant Therapy in Patients With Heparin-Induced Thrombocytopenia , 2001, Circulation.