title: The effects of argatroban on thrombin generation and hemostatic activation in vitro.
abstract: We evaluated argatroban, a direct thrombin inhibitor, as a heparin adjunct for anticoagulation. Platelet-poor plasma (PPP) was isolated from blood collected from 12 volunteers. Thrombin generation measurements were performed in donor PPP that was mixed with antithrombin (AT)-poor plasma to yield AT levels of 0%, 20%, 60%, and 100%. Effects of argatroban (0-1.0 microg/mL), heparin (0.25 U/mL), or the combination of argatroban (0.5 microg/mL) and heparin were also studied. The addition of increasing concentrations of argatroban, heparin, or both to donor PPP (AT level approximately 100%) caused progressive decreases in the lag time and peak formation of thrombin generation. Heparin (0.25 U/mL) at small AT concentrations had a minimal effect on lag time or peak thrombin formation; its effectiveness of inhibiting thrombin was directly correlated with the concentration of AT. Argatroban at 0.5 microg/mL was effective in decreasing thrombin formation at both low and normal AT levels, but it was most effective when combined with heparin. Additionally, blood samples were obtained from 47 cardiac surgical patients, and the interaction of heparin (>1.5 U/mL) and AT or argatroban on clot formation was evaluated with kaolin activated clotting times (ACTs). Significant increases of ACTs at all heparin levels were observed with the addition of argatroban (0.125 and 0.25 microg/mL). The addition of AT (0.2 U/mL) to heparinized blood samples further prolonged ACTs. In summary, we showed that argatroban, unlike heparin, could effectively reduce thrombin generation regardless of AT levels and could prolong ACTs in vitro at clinically used concentrations.
authors.affiliation: Department of Anesthesiology and Surgery (Cardiothoracic), Division of Cardiothoracic Anesthesia and Critical Care, Emory University School of Medicine, The Emory Healthcare, Atlanta, Georgia.
authors.forename: Kenichi A
authors.initials: KA
authors.lastname: Tanaka
authors.forename: Fania
authors.initials: F
authors.lastname: Szlam
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Katori
authors.forename: Nobukazu
authors.initials: N
authors.lastname: Sato
authors.forename: J David
authors.initials: JD
authors.lastname: Vega
authors.forename: Jerrold H
authors.initials: JH
authors.lastname: Levy
mesh_terms: D000368:Aged; D000925:Anticoagulants / Q000494:pharmacology*; D000991:Antithrombins / Q000032:analysis / Q000378:metabolism; D001120:Arginine / Q000031:analogs & derivatives; D001792:Blood Platelets / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D006487:Hemostasis / Q000187:drug effects*; D006493:Heparin / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D019934:International Normalized Ratio; D008297:Male; D008875:Middle Aged; D010314:Partial Thromboplastin Time; D010875:Pipecolic Acids / Q000494:pharmacology*; D010976:Platelet Count; D015842:Serine Proteinase Inhibitors / Q000032:analysis / Q000378:metabolism; D013449:Sulfonamides; D013917:Thrombin / Q000096:biosynthesis* / Q000378:metabolism; D014914:Whole Blood Coagulation Time
chemical_list: D000925:Anticoagulants; D000991:Antithrombins; D010875:Pipecolic Acids; D015842:Serine Proteinase Inhibitors; D013449:Sulfonamides; D006493:Heparin; D001120:Arginine; D013917:Thrombin; C031942:argatroban