title: Carbon monoxide releasing molecule-2 increases fibrinogen-dependent coagulation kinetics but does not enhance prothrombin activity.
abstract: We have previously determined that tricarbonyldichlororuthenium (II) dimer (CORM-2) increases plasma clot velocity of formation and strength by enhancing thrombin-fibrinogen interactions as determined by thrombelastography. The purpose of the present investigation was to further define the nature of CORM-2 interaction with prothrombin and fibrinogen by exposing purified proteins to CORM-2 or generating protein concentration-response curves in the absence or presence of CORM-2. Purified prothrombin was exposed to 0 or 100 micromol/l CORM-2 prior to being added to prothrombin-deficient plasma (n=7-8 per condition). Fibrinogen-deficient plasma had fibrinogen added for a final concentration of 100-800 mg/dl and was exposed to 0 or 100 micromol/l CORM-2 (n=4 per condition). Following tissue factor activation, thrombelastographic data were collected until clot strength stabilized. Exposure of prothrombin to CORM-2 did not significantly enhance coagulation kinetics. In sharp contrast, CORM-2 exposure enhanced fibrinogen coagulation kinetics in a concentration-dependent fashion, with peak effect seen at a fibrinogen concentration of 300 mg/dl that then progressively decreased throughout the range tested. Our data demonstrate that CORM-2 does not enhance plasma coagulation kinetics by modifying prothrombin; instead, the concept that CORM-2 modifies fibrinogen is the most likely explanation for the enhanced thrombin-fibrinogen interactions observed.
authors.affiliation: Department of Anesthesiology, The University of Alabama at Birmingham, USA. vance.nielsen@drexelmed.edu
authors.forename: Vance G
authors.initials: VG
authors.lastname: Nielsen
authors.forename: S Nini
authors.initials: SN
authors.lastname: Malayaman
authors.forename: Ejaz S
authors.initials: ES
authors.lastname: Khan
authors.forename: James K
authors.initials: JK
authors.lastname: Kirklin
authors.forename: James F
authors.initials: JF
authors.lastname: George
mesh_terms: D001777:Blood Coagulation / Q000187:drug effects*; D002248:Carbon Monoxide / Q000378:metabolism; D005340:Fibrinogen / Q000378:metabolism*; D006801:Humans; D009942:Organometallic Compounds / Q000494:pharmacology*; D011516:Prothrombin / Q000378:metabolism*; D013916:Thrombelastography / Q000187:drug effects
chemical_list: D009942:Organometallic Compounds; C447082:tricarbonyldichlororuthenium (II) dimer; D002248:Carbon Monoxide; D011516:Prothrombin; D005340:Fibrinogen