Anticoagulation: the present and future.

Thrombin is a central bioregulator of coagulation and is therefore a key target in the therapeutic prevention and treatment of thromboembolic disorders, including deep vein thrombosis and pulmonary embolism. The current mainstays of anticoagulation treatment are heparins, which are indirect thrombin inhibitors, and coumarins, such as warfarin, which modulate the synthesis of vitamin K-dependent proteins. Although efficacious and widely used, heparins and coumarins have limitations because their pharmacokinetics and anticoagulant effects are unpredictable, with the risk of bleeding and other complications resulting in the need for close monitoring with their use. Low-molecular-weight heparins (LMWHs) provide a more predictable anticoagulant response, but their use is limited by the need for subcutaneous administration. In addition, discontinuation of heparin treatment can result in a thrombotic rebound due to the inability of these compounds to inhibit clot-bound thrombin. Direct thrombin inhibitors (DTI) are able to target both free and clot-bound thrombin. The first to be used was hirudin, but DTIs with lower molecular weights, such as DuP 714, PPACK, and efegatran, have subsequently been developed, and these agents are better able to inhibit clot-bound thrombin and the thrombotic processes that take place at sites of arterial damage. Such compounds inhibit thrombin by covalently binding to it, but this can result in toxicity and nonspecific binding. The development of reversible noncovalent DTIs, such as inogatran and melagatran, has resulted in safer, more specific and predictable anticoagulant treatment. Oral DTIs, such as ximelagatran, are set to provide a further breakthrough in the prophylaxis and treatment of thrombosis.

[1]  A Abrahamsson,et al.  The direct thrombin inhibitor melagatran and its oral prodrug H 376/95: intestinal absorption properties, biochemical and pharmacodynamic effects. , 2001, Thrombosis research.

[2]  G. Agnelli,et al.  The rationale for long-term prophylaxis of venous thromboembolism. , 2000, Orthopedics.

[3]  J. Hirsh,et al.  The emerging role of low-molecular-weight heparin in cardiovascular medicine. , 2000, Progress in cardiovascular diseases.

[4]  D. Hoppensteadt,et al.  Antithrombin Agents: The New Class of Anticoagulant and Antithrombotic Drugs , 1999, Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis.

[5]  S. Carlsson,et al.  Antithrombotic effects and bleeding time of thrombin inhibitors and warfarin in the rat. , 1999, Thrombosis research.

[6]  I. Pina,et al.  FDA panel votes against approval for bivalirudin. , 1999, Circulation.

[7]  J. Stürzebecher,et al.  Synthetic inhibitors of thrombin and factor Xa: from bench to bedside. , 1999, Thrombosis research.

[8]  P. Held,et al.  Pharmacokinetics and Pharmacodynamics of Melagatran, a Novel Synthetic LMW Thrombin Inhibitor, in Patients with Acute DVT , 1999, Thrombosis and Haemostasis.

[9]  K. Menear,et al.  Progress towards the discovery of orally active thrombin inhibitors. , 1998, Current medicinal chemistry.

[10]  M. Samama,et al.  Anticoagulation: The Old and the New , 1998 .

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

[12]  N. Goldsack,et al.  Molecules in focus Thrombin , 1998 .

[13]  J. Mehta,et al.  Melagatran, an oral active-site inhibitor of thrombin, prevents or delays formation of electrically induced occlusive thrombus in the canine coronary artery. , 1998, Journal of cardiovascular pharmacology.

[14]  H. Bounameaux.  Unfractionated versus low-molecular-weight heparin in the treatment of venous thromboembolism , 1998, Vascular medicine.

[15]  B. Eriksson,et al.  Antithrombotic Effect of Two Low Molecular Weight Thrombin Inhibitors and a Low-Molecular Weight Heparin in a Caval Vein Thrombosis Model in the Rat , 1997, Thrombosis and Haemostasis.

[16]  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.

[17]  W. Ripka.  New thrombin inhibitors in cardiovascular disease. , 1997, Current opinion in chemical biology.

[18]  J. Björkman,et al.  Melagatran, hirudin and heparin as adjuncts to tissue-type plasminogen activator in a canine model of coronary artery thrombolysis , 1997 .

[19]  M. Moia,et al.  Subcutaneous Recombinant Hirudin (HBW 023) Versus Intravenous Sodium Heparin in Treatment of Established Acute Deep Vein Thrombosis of the Legs: a Multicentre Prospective Dose-ranging Randomized Trial , 1997, Thrombosis and Haemostasis.

[20]  E. Minar,et al.  The Risk of Recurrent Venous Thromboembolism in Patients with and without Factor V Leiden , 1997, Thrombosis and Haemostasis.

[21]  U. Eriksson,et al.  In vitro effects of inogatran, a selective low molecular weight thrombin inhibitor. , 1997, Thrombosis research.

[22]  B. Eriksson,et al.  Prevention of deep-vein thrombosis after total hip replacement: direct thrombin inhibition with recombinant hirudin, CGP 39393 , 1996, The Lancet.

[23]  Lydia Tabernero,et al.  Crystallographic determination of the structures of human α‐thrombin complexed with BMS‐186282 and BMS‐189090 , 1996 .

[24]  M. Samama,et al.  [New antithrombotic agents]. , 1995, Presse medicale.

[25]  E. Hylek,et al.  Risk Factors for Intracranial Hemorrhage in Outpatients Taking Warfarin , 1994, Annals of Internal Medicine.

[26]  Jeffrey S. Ginsberg,et al.  Use of antithrombotic agents during pregnancy. , 1992, Chest.

[27]  D. Waters,et al.  Reactivation of unstable angina after the discontinuation of heparin. , 1992, The New England journal of medicine.

[28]  D. Collen,et al.  Plasma Fibrinopeptide A Levels in Patients With Acute Myocardial Infarction Treated With Alteplase: Correlation With Concomitant Heparin, Coronary Artery Patency, and Recurrent Ischemia , 1992, Circulation.

[29]  P. Wolf,et al.  Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. , 1991, Stroke.

[30]  D. Massel,et al.  Clot-bound thrombin is protected from inhibition by heparin-antithrombin III but is susceptible to inactivation by antithrombin III-independent inhibitors. , 1990, The Journal of clinical investigation.

[31]  J. Kelton,et al.  Heparin and platelets. , 1990, Hematology/oncology clinics of North America.

[32]  M Gent,et al.  Warfarin sodium versus low-dose heparin in the long-term treatment of venous thrombosis. , 1979, The New England journal of medicine.

[33]  A. Belanger,et al.  The Framingham study. , 1976, British medical journal.

[34]  E. Ohman,et al.  Antithrombotic therapy in patients undergoing percutaneous coronary intervention. , 2001, Chest.

[35]  Eter,et al.  A COMPARISON OF RECOMBINANT HIRUDIN WITH A LOW-MOLECULAR-WEIGHT HEPARIN TO PREVENT THROMBOEMBOLIC COMPLICATIONS AFTER TOTAL HIP REPLACEMENT , 2000 .

[36]  J. Shafer.  Cardiovascular chemotherapy: anticoagulants. , 1998, Current opinion in chemical biology.

[37]  S. Pehrsson,et al.  Effects of Melagatran, a New Low-molecular-weight Thrombin Inhibitor, on Thrombin and Fibrinolytic Enzymes , 1998, Thrombosis and Haemostasis.

[38]  Kenneth J. Alford,et al.  Novastan® (Brand of Argatroban): A Small-Molecule, Direct Thrombin Inhibitor , 1997, Seminars in thrombosis and hemostasis.

[39]  S. D. Kimball.  Challenges in the development of orally bioavailable thrombin active site inhibitors. , 1995, Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis.

[40]  S. Pauker,et al.  Antithrombotic therapy in valvular heart disease. , 1992, Chest.

[41]  J. Maffrand.  Direct thrombin inhibitors. , 1992, Nouvelle revue francaise d'hematologie.

[42]  R. Gagnon.  [Intravenous thrombolysis in acute myocardial infarction]. , 1988, L'union medicale du Canada.