Carbon monoxide-releasing molecule-2 decreases fibrinolysis in human plasma.
Carbon monoxide, derived from carbon monoxide-releasing molecules, has been recently demonstrated to enhance the velocity of formation and strength of plasma thrombi. We tested the hypothesis that carbon monoxide-releasing molecule-2 would modulate fibrinolysis of plasma thrombi. Normal plasma was exposed to 0, 25, 50, 100 or 200 micromol/l carbon monoxide-releasing molecule-2, with coagulation activated with tissue factor and fibrinolysis initiated with tissue-type plasminogen activator. Additional experiments utilized factor XIII, plasminogen activator inhibitor-1, thrombin activatable fibrinolysis inhibitor or alpha2-antiplasmin-deficient plasmas. Thrombus growth/disintegration kinetics was monitored with thrombelastography. Carbon monoxide-releasing molecule-2, in a concentration-dependent fashion, increased the velocity of thrombus formation and strength, and markedly attenuated fibrinolysis in normal plasma. In factor XIII-deficient plasma, carbon monoxide-releasing molecule-2 mediated effects on thrombus growth/disintegration kinetics were similar to that seen with normal plasma; however, carbon monoxide-releasing molecule-2 had a less marked effect on thrombus growth/disintegration in both plasminogen activator inhibitor-1 and thrombin activatable fibrinolysis inhibitor-deficient plasma, with even less carbon monoxide-releasing molecule-2-mediated effects noted in alpha2-antiplasmin-deficient plasma. Carbon monoxide-releasing molecule-2 attenuated fibrinolysis by enhancing the velocity of clot growth and strength while augmenting the effects of plasminogen activator inhibitor-1, thrombin activatable fibrinolysis inhibitor and alpha2-antiplasmin. These findings serve as the rationale for further investigations to determine if carbon monoxide-releasing molecules could be utilized as hemostatic agents.
Nielsen
Vance G
VG
Department of Anesthesiology, The University of Alabama at Birmingham, Birmingham, Alabama, USA. vgnielsen333@gmail.com
Kirklin
James K
JK
George
James F
JF
D001777:Blood Coagulation / Q000187:drug effects; D002248:Carbon Monoxide / Q000494:pharmacology*; D025901:Carboxypeptidase B2 / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005176:Factor XIII / Q000494:pharmacology; D005340:Fibrinogen / Q000032:analysis; D005342:Fibrinolysis / Q000187:drug effects*; D006490:Hemostatics / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D009942:Organometallic Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D010314:Partial Thromboplastin Time; D017395:Plasminogen Activator Inhibitor 1 / Q000494:pharmacology; D011517:Prothrombin Time; D013916:Thrombelastography; D013925:Thromboplastin / Q000494:pharmacology; D010959:Tissue Plasminogen Activator / Q000494:pharmacology; D000979:alpha-2-Antiplasmin / Q000494:pharmacology
D006490:Hemostatics; D009942:Organometallic Compounds; D017395:Plasminogen Activator Inhibitor 1; D000979:alpha-2-Antiplasmin; C447082:tricarbonyldichlororuthenium (II) dimer; D002248:Carbon Monoxide; D005340:Fibrinogen; D005176:Factor XIII; D013925:Thromboplastin; D025901:Carboxypeptidase B2; D010959:Tissue Plasminogen Activator