title: Carbon monoxide releasing molecule-2 enhances α2-antiplasmin activity.
abstract: The objective of this study was to determine whether carbon monoxide releasing molecule (tricarbonyldichlororuthenium (II) dimer, CORM-2) directly affects α2-antiplasmin activity. For this purpose, purified α2-antiplasmin was exposed to 0 or 100 μmol/l CORM-2 for 5 min at 37°C and then placed in α2-antiplasmin-deficient plasma (25 μg/ml α2-antiplasmin and 3.3 μmol/l CORM-2 final concentrations). In a second series of experiments, α2-antiplasmin and deficient plasma were combined and then exposed to 0 or 100 μmol/l CORM-2. Coagulation was activated with tissue factor and fibrinolysis initiated with tissue-type plasminogen activator (n = 8 per condition). Thrombus growth/disintegration kinetics were monitored with thrombelastography until clot lysis time occurred. Samples containing α2-antiplasmin preexposed to 100 μmol/l CORM-2 demonstrated no changes in the velocity of clot growth, but had a significant prolongation of the time to maximum rate of lysis, clot lysis time, and a significant decrease in the maximum rate of clot lysis compared with samples preexposed to 0 μmol/l CORM-2. In sharp contrast, addition of 100 μmol/l CORM-2 to premixed α2-antiplasmin in its deficient plasma resulted in significant, marked increases in the velocity of clot growth and the strength with concurrent antifibrinolytic effects as in the first series. In conclusion, CORM-2 exerts its antifibrinolytic effects by direct enhancement of α2-antiplasmin activity. It appears that combined modification of both fibrinogen and α2-antiplasmin are responsible for the robust procoagulant/antifibrinolytic effects of CORM-2 in the fibrinolytic environment.
authors.affiliation: Department of Anesthesiology, Hahnemann University Hospital, Drexel University College of Medicine, Broad & Vine Streets, Philadelphia, PA 19102, USA.
authors.forename: Saninuj N
authors.initials: SN
authors.lastname: Malayaman
authors.forename: Jack B
authors.initials: JB
authors.lastname: Cohen
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Machovec
authors.forename: Brian E
authors.initials: BE
authors.lastname: Bernhardt
authors.forename: Matt R
authors.initials: MR
authors.lastname: Arkebauer
authors.forename: Vance G
authors.initials: VG
authors.lastname: Nielsen
mesh_terms: D000933:Antifibrinolytic Agents / Q000494:pharmacology*; D001780:Blood Coagulation Tests; D002248:Carbon Monoxide / Q000737:chemistry / Q000494:pharmacology*; D005340:Fibrinogen / Q000378:metabolism; D005341:Fibrinolysin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005342:Fibrinolysis / Q000187:drug effects; D006801:Humans; D009942:Organometallic Compounds / Q000737:chemistry / Q000494:pharmacology; D010949:Plasma / Q000737:chemistry; D013916:Thrombelastography; D013925:Thromboplastin / Q000494:pharmacology; D013927:Thrombosis / Q000097:blood*; D010959:Tissue Plasminogen Activator / Q000494:pharmacology; D000979:alpha-2-Antiplasmin / Q000494:pharmacology*
chemical_list: D000933:Antifibrinolytic Agents; D009942:Organometallic Compounds; D000979:alpha-2-Antiplasmin; C447082:tricarbonyldichlororuthenium (II) dimer; D002248:Carbon Monoxide; D005340:Fibrinogen; D013925:Thromboplastin; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin