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, thrombosisMarino F, Pelc LA, Vogt A, Gandhi PS, Di Cera E. J Biol Chem. 2010 Jun 18;285(25):19145-52. Epub 2010 Apr 19. Thrombin elicits functional responses critical to blood homeostasis by interacting with diverse physiological substrates. Ala-scanning mutagenesis of 97 residues covering 53% of the solvent accessible surface area of the enzyme identifies Trp(215) as the single most important determinant of [...]
View Post autolysis loop, fibrinogen, Protein C, protein C activation, W215AKenichi A. Tanaka,a Andras Gruber,b Fania Szlam,a Leslie A. Bush,c Stephen 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 [...]
View Post Anticoagulant, E217A, Protein C, W215A, WE-thrombinDi Cera E. Mol Aspects Med. 2008 Aug;29(4):203-54. Epub 2008 Feb 1. Thrombin is a Na+-activated, allosteric serine protease that plays opposing functional roles in blood coagulation. Binding of Na+ is the major driving force behind the procoagulant, prothrombotic and signaling functions of the enzyme, but is dispensable for cleavage of the anticoagulant protein C. The [...]
View Post enzyme, Protein C, Thrombin, thrombodulinKenichi 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-thrombinBerny-Lang MA, Hurst S, Tucker EI, Pelc LA, Wang RK, Hurn PD, Di Cera E, McCarty OJ, Gruber A. Arterioscler Thromb Vasc Biol. 2008 Feb;28(2):329-34. Epub 2007 Oct 25. Treatment of ischemic stroke by activation of endogenous plasminogen using tissue plasminogen activator is limited by bleeding side effects. In mice, treatment of experimental ischemic stroke [...]
View Post E217A, endogenous plasminogen, endogenous protein C, ischemic stroke, plasminogen activator, Protein C, W215A, WE treatmentBerny MA, White TC, Tucker EI, Bush-Pelc LA, Di Cera E, Gruber A, McCarty OJ. Arterioscler Thromb Vasc Biol. 2008 Feb;28(2):329-34. Epub 2007 Oct 25. OBJECTIVE: Thrombin containing the mutations Trp215Ala and Glu217Ala (WE) selectively activates protein C and has potent antithrombotic effects in primates. The aim of this study was to delineate the molecular mechanism of direct WE-platelet interactions under static [...]
View Post Glu217Ala, Protein C, thrombin generation, Trp215Ala, von Willebrand factorGruber 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, Trp215AlaGruber A, Ferna ́ ndez JA, Bush L, Marzec U, Griffin JH, Hanson SR, Di Cera E. J Thromb Haemost 2006; 4: 392–7. Anticoagulation with activated protein C (APC) reduces the mortality of severe sepsis. We investigated whether the circulating protein C (PC) pool could be utilized for sustained anticoagulation by endogenous APC. To generate [...]
View Post Anticoagulant, Anticoagulation, APC, E217A, Protein C, sepsis, W215A