Di Cera E. Prog Mol Biol Transl Sci. 2011;99:145-84. Thrombosis is the most prevalent cause of fatal diseases in developed countries. An antithrombotic agent that can be administered to patients with severe acute thrombotic diseases without the risk of causing hemorrhage, as experienced with antithrombotic/thrombolytic therapy in the treatment of acute ischemic stroke or systemic anticoagulants [...]
View Post antithrombotic, ischemic stroke, protease-activated receptors, Protein C, protein C activation, thrombolytic therapy, thrombosisWong PC, Crain EJ, Watson CA, Schumacher WA. J Thromb Thrombolysis. 2011 Aug;32(2):129-37. BMS-262084 is a 4-carboxy-2-azetidinone-containing irreversible inhibitor of FXIa, which is selective over other coagulation proteases. We evaluated the in vitro and in vivo properties of BMS-262084 in rabbits. Studies were conducted in arteriovenous-shunt thrombosis (AVST), venous thrombosis (VT), electrolytic-mediated carotid arterial thrombosis (ECAT) and cuticle bleeding [...]
View Post antithrombotic, Factor XIaSchumacher WA, Luettgen JM, Quan ML, Seiffert DA. Arterioscler Thromb Vasc Biol. 2010 Mar;30(3):388-92. Epub 2010 Feb 5. The dose-limiting issue with available anticoagulant therapies is bleeding. Is there an approach that could provide antithrombotic protection with reduced bleeding? One hypothesis is that targeting proteases upstream from the common pathway provides a reduction in thrombin sufficient to impede occlusive [...]
View Post antithrombotic, coagulation, FXIa, hemostasis, thrombin generation, thromboembolic, thromboembolismTucker EI, Marzec UM, White TC, Hurst S, Rugonyi S, McCarty OJ, Gailani D, Gruber A, Hanson SR. Blood. 2009 Jan 22;113(4):936-44. Epub 2008 Oct 22. The protease thrombin is required for normal hemostasis and pathologic thrombogenesis. Since the mechanism of coagulation factor XI (FXI)-dependent thrombus growth remains unclear, we investigated the contribution of FXI to thrombus formation in a primate thrombosis model. Pretreatment [...]
View Post antithrombotic, aXIMab, factor XI, factor XII, fibrin formation, ThrombinKenichi A. Tanaka,a Andras Gruber,b Fania Szlam,a Leslie A. Bush,cStephen R. Hanson,b and Enrico Di Cerac Blood Coagul Fibrinolysis. 2008 July; 19(5): 465–468. Thrombin mutant W215A/E217A acts as an anticoagulant when administered intravenously by activating plasma protein C in concert with endothelial thrombomodulin [1,2]. The double mutation in the catalytic domain of the W215A/E217A molecule leads to compromised interactions with fibrinogen [...]
View Post antithrombotic, aPTT, clotting, DTIs, E217A, fibrinogen, Protein C, W215A, W215A/E217A, WE-thrombinSchumacher WA, Seiler SE, Steinbacher TE, Stewart AB, Bostwick JS, Hartl KS, Liu EC, Ogletree ML. Eur J Pharmacol. 2007 Sep 10;570(1-3):167-74. Epub 2007 Jun 5. The effect of inhibiting activated blood coagulation factor XIa was determined in rat models of thrombosis and hemostasis. BMS-262084 is an irreversible and selective small molecule inhibitor of factor XIa with an IC(50) of 2.8 nM against [...]
View Post antithrombotic, factor XI, Factor XIa, thrombosisGlueck CJ, Munjal J, Aregawi D, Agloria M, Winiarska M, Khalil Q, Wang P. Transl Res. 2007 Aug;150(2):93-100. Epub 2007 May 25. Thrombophilia-hypofibrinolysis may play an important role in rare premature (< or = age 45 years) arterial occlusive events in atherothrombotic cardiovascular (ATCVD) disease, particularly in normolipidemic patients. Whether thrombophilia-hypofibrinolysis contributed to ATCVD < or = age 45 years was assessed [...]
View Post antithrombotic, FXIGruber A, Cantwell AM, Di Cera E, Hanson SR. J Biol Chem. 2002 Aug 2;277(31):27581-4. Epub 2002 Jun 17. Administration of the thrombin mutant W215A/E217A (WE), rationally designed for selective activation of the anticoagulant protein C, elicits safe and potent anticoagulant and antithrombotic effects in a baboon model of platelet-dependent thrombosis. The lowest dose of WE tested (0.011 mg/kg [...]
View Post Anticoagulant, antithrombotic, E217A, procoagulant, Protein C, W215A, W215A/E217AGruber A, Marzec UM, Bush L, Di Cera E, Fernández JA, Berny MA, Tucker EI, McCarty OJ, Griffin JH, Hanson SR. Blood. 2007 May 1;109(9):3733-40. Epub 2007 Jan 16. The anticoagulant and anti-inflammatory enzyme, activated protein C (APC), naturally controls thrombosis without affecting hemostasis. We therefore evaluated whether the integrity of primary hemostasis was preserved during limited pharmacological antithrombotic protein C activator (PCA) treatment in [...]
View Post antithrombotic, double-mutant thrombin, enzyme, Glu217Ala, Protein C, protein C activation, Trp215AlaJin L, Pandey P, Babine RE, Weaver DT, Abdel-Meguid SS, Strickler JE. Acta Crystallogr D Biol Crystallogr. 2005 Oct;61(Pt 10):1418-25. Epub 2005 Sep 28. Activated factor XI (FXIa) is a key enzyme in the amplification phase of the blood-coagulation cascade. Thus, a selective FXIa inhibitor may have lesser bleeding liabilities and provide a safe alternative for antithrombosis therapy to available drugs [...]
View Post antithrombotic, factor XI, Factor XIa