Blood coagulation inhibitors

Nar, H., Bauer, M., Schmid, A., et al (2001) Structural basis for inhibition promiscuity of dual specific thrombin and factor Xa blood coagulation inhibitors. 

B51. Broze, G. J., Warren, L. A., Novotny, W. F., Higuchi, D. A., Girard, J. J., and Miletich, J. P The lipoprotein-associated coagulation inhibitor which inhibits the factor Vll-tissue factor complex also inhibits factor Xa Insight into its possible mechanism of action. Blood 71,335-343 (1988). 

Novotny W. F Girard T. J., Miletich J. P., Broze G. J. Platelets secrete a coagulation inhibitor functionally and antigenically similar to the lipoprotein associated coagulation inhibitor. Blood 1988 72,2020-5. 

Volume 222. Proteolytic Enzymes in Coagulation, Fibrinolysis, and Complement Activation (Part A Mammalian Blood Coagulation Factors and Inhibitors)... 

Trifluoromethyl ketones are also powerful inhibitors of proteases of the trypsin family (trypsin, thrombin, enzymes of blood coagulation). " ... 

Interactions of heparinoids with the most diverse proteins such as enzymes and enzyme inhibitors, cytokines, and adhesion molecules have been described. To date, many more than a hundred heparin binding proteins are known. A number of heparin binding proteins are members of the serpin family of serine protease inhibitors. The best described example is antithrombin [4]. Antithrombin III (AT III) is able to inhibit various serine proteases involved in the blood coagulation process by formation of stable, equimolar complexes. Binding of heparin to AT III accelerates the kinetics of this complex formation by several orders of magnitude. This has been the basis for the successful clinical use of heparin as an anticoagulant for nearly sixty years. 

Mectianism of Action A factorXa inhibitor and pentasaccharide that selectively binds to antithrombin, and increases its affinity for factor Xa, thereby inhibiting factor Xa and stopping the blood coagulation cascade. Therapeutic Effect Indirectly prevents formation of thrombin and subsequently the fibrin clot. 

Tetrahydropyrazolo[3,4-f]pyridines have been prepared as cannabinoid modulators <2007W0112399>. The pyra-zolo[3,4-4pyridine, Apixaban (BMS-562247), has been found to be a highly potent, selective, efficacious, and orally bioavailable inhibitor of blood coagulation factor xa <2007JMC5339>. Several pyrazolo[3,4-f]pyridines have been found to be potent inhibitors of human eosinophil phosphodiesterase <2007JMC344>. 

Vlasuk GP. Structural and functional characterization of tick anticoagulant peptide (TAP) a potent and selective inhibitor of blood coagulation factor Xa. Thrombosis and Haemostasis 1993 70 212-216. 

Waxman L, Smith DE, Arcuri KE, Vlasuk GP. Tick anticoagulant peptide (TAP) is a novel inhibitor of blood coagulation factor Xa, Science 1990 248 593. 

Dunwiddie CT, Waxman L, Vlasuk GP, Friedman PA. Purification and characterization of inhibitors of blood coagulation factor Xa from hematophagous organisms. Methods in Enzymol 1993 233 291-312. 

Schreuder H, Arkema A, deBoer B, Kalk K, Dijkema R, Mulders J, Theunissen H, Hoi W. Crystallization and preliminary crystallographic analysis of antistasin, a leech-derived inhibitor of blood coagulation factor Xa. JMol Biol 1993 231 1137-1138. 

Considerably more is known about anticoagulants from the blood-feeding hookworm, Ancylostoma caninum. Several families of small, anti-clotting peptides have been described in A. caninum. AcAP, an 8.7 kDa peptide secreted by adult worms that does not exhibit homology to other anticoagulants, but is a potent inhibitor of Factor Xa, was described by Cappello et at. (1995). A family of related peptides, one of which uniquely inhibited a complex of blood coagulation factor VIIA and tissue factor, was also reported (Stanssens et al., 1996). 

Noveck, R. J., and Hubbard, R. C. Parecoxib sodium, an injectable COX-2-specific inhibitor, does not affect unfractionated heparin-regulated blood coagulation parameters. J. Clin. Pharmacol. 44 474—480, 2004. 

Protease nexin 2 is identical to the secreted form of the amyloid precursor protein containing the Kunitz-type serine protease inhibitor domain (128,129), Protease nexin 2 circulates in blood stored as a platelet a-granule protein, which is secreted upon platelet activation (127). Protease nexin 2 inhibits trypsin- and chymotrypsin-like serine proteases and is also a potent inhibitor of factor Xla (126,127,128). Its location in platelets and its ability to inhibit factor Xla suggests a role in regulating blood coagulation for protease nexin 2. 

I 10 Day KC, Hoffman LC, Palmier MO, et al, Recombinant lipoprotein-associated coagulation inhibitor inhibits tissue thromboplastin-induced intravascular coagulation in the rabbit. Blood 1990 76 1538-1545. 

Bostrom SL, Hansson GF Kjaer M, et al. Effects of melagatran, the active form of the oral direct thrombin inhibitor ximelagatran, and dalteparin on the endogenous thrombin potential in venous blood from healthy male subjects. Blood Coagul Fibrinolysis 2003 14 457-462. 

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