title: Anticoagulation: the present and future.
abstract: 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.
authors.affiliation: Klinik und Poliklinik für Anästhesiologie. Westf. Wilhelms-Universität, Münster, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Van Aken
authors.forename: C
authors.initials: C
authors.lastname: Bode
authors.forename: H
authors.initials: H
authors.lastname: Darius
authors.forename: C
authors.initials: C
authors.lastname: Diehm
authors.forename: A
authors.initials: A
authors.lastname: Encke
authors.forename: D C
authors.initials: DC
authors.lastname: Gulba
authors.forename: S
authors.initials: S
authors.lastname: Haas
authors.forename: W
authors.initials: W
authors.lastname: Hacke
authors.forename: W
authors.initials: W
authors.lastname: Puhl
authors.forename: M
authors.initials: M
authors.lastname: Quante
authors.forename: H
authors.initials: H
authors.lastname: Riess
authors.forename: R
authors.initials: R
authors.lastname: Scharf
authors.forename: S
authors.initials: S
authors.lastname: Schellong
authors.forename: T
authors.initials: T
authors.lastname: Schrör
authors.forename: K L
authors.initials: KL
authors.lastname: Schulte
authors.forename: U
authors.initials: U
authors.lastname: Tebbe
mesh_terms: D000284:Administration, Oral; D000590:Amino Acid Chloromethyl Ketones / Q000627:therapeutic use; D000925:Anticoagulants / Q000008:administration & dosage / Q000009:adverse effects / Q000145:classification / Q000494:pharmacology / Q000627:therapeutic use; D001120:Arginine / Q000031:analogs & derivatives; D001384:Azetidines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D001596:Benzylamines; D001665:Binding Sites / Q000187:drug effects; D001682:Biological Availability; D001777:Blood Coagulation / Q000187:drug effects; D015897:Comorbidity; D003374:Coumarins / Q000009:adverse effects / Q000627:therapeutic use; D015195:Drug Design; D004617:Embolism / Q000188:drug therapy*; D005260:Female; D005544:Forecasting; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology; D006331:Heart Diseases / Q000150:complications; D006470:Hemorrhage / Q000139:chemically induced; D006493:Heparin / Q000009:adverse effects / Q000627:therapeutic use; D006495:Heparin, Low-Molecular-Weight / Q000009:adverse effects / Q000627:therapeutic use; D024764:Hirudin Therapy; D006801:Humans; D009369:Neoplasms / Q000150:complications; D010875:Pipecolic Acids / Q000494:pharmacology; D011247:Pregnancy; D011250:Pregnancy Complications, Hematologic / Q000188:drug therapy; D011355:Prodrugs / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D012449:Safety; D012694:Serine / Q000031:analogs & derivatives* / Q000494:pharmacology; D020521:Stroke / Q000517:prevention & control; D013449:Sulfonamides; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000737:chemistry; D019851:Thrombophilia / Q000188:drug therapy*; D013927:Thrombosis / Q000188:drug therapy*
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D000925:Anticoagulants; D001384:Azetidines; C101287:BMS 186282; D001596:Benzylamines; D003374:Coumarins; D006146:Guanidines; D006495:Heparin, Low-Molecular-Weight; D010875:Pipecolic Acids; D011355:Prodrugs; D013449:Sulfonamides; C109573:melagatran; D012694:Serine; C426686:ximelagatran; D006493:Heparin; D001120:Arginine; D013917:Thrombin; C031942:argatroban; C040308:phenylalanyl-prolyl-arginine-chloromethyl ketone; D005998:Glycine