Thrombin generation assay and viscoelastic coagulation monitors demonstrate differences in the mode of thrombin inhibition between unfractionated heparin and bivalirudin.
BACKGROUND
Coagulation tests, such as activated partial thromboplastin time and activated clotting time, are used to monitor the effects of unfractionated heparin and the direct thrombin inhibitor, bivalirudin. These tests reflect only the initial phase of blood clotting, when <5% of thrombin has been formed. In this study, we sought to determine if similar increases in activated partial thromboplastin time or activated clotting time due to heparin or bivalirudin would reflect the same degree of inhibition of thrombin formation.


METHODS
Thrombin formation was evaluated in platelet-poor plasma activated in the presence of heparin (0-5 U/mL) or bivalirudin (0-30 microg/mL) using a thrombin generation assay (Thrombinoscope). Prothrombin activation was measured by prothrombin fragment 1.2 (F1.2) formation. Thrombus formation was further evaluated in kaolin-activated whole blood samples containing heparin (1.5 or 2.5 U/mL) or bivalirudin (12.5 or 25 microg/mL) using Sonoclot and thromboelastography.


RESULTS
Based on the Thrombinoscope results, increasing concentrations of bivalirudin and heparin progressively delayed the onset of thrombin formation, but only heparin dose-dependently decreased the amount of thrombin generated. Heparin and bivalirudin delayed the onset of F1.2 formation, but there was no difference in peak F1.2 levels between bivalirudin and non-anticoagulated samples (206 +/- 28.2 vs 182 +/- 23.9 nmol/L, P = 0.09). In heparinized samples, F1.2 levels were significantly lower (75.7 +/- 29.8 nmol/L, P < 0.05) than controls. Heparin and bivalirudin prolonged the onset of clotting on viscoelastic monitors, but only heparin decreased the rate of thrombus formation.


CONCLUSIONS
Thrombus formation kinetics differs between heparin and bivalirudin despite similar prolongation of clotting test values.
Tanaka
Kenichi A
KA
Department of Anesthesiology, Emory University School of Medicine, Atlanta, Georgia. USA. kenichi.tanaka@emoryhealthcare.org
Szlam
Fania
F
Sun
He Ying
HY
Taketomi
Taro
T
Levy
Jerrold H
JH
D000925:Anticoagulants / Q000494:pharmacology*; D000991:Antithrombins / Q000494:pharmacology*; D001809:Blood Viscosity / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006493:Heparin / Q000494:pharmacology*; D006629:Hirudins / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D010446:Peptide Fragments / Q000096:biosynthesis / Q000494:pharmacology*; D011516:Prothrombin / Q000096:biosynthesis; D011994:Recombinant Proteins / Q000494:pharmacology; D013916:Thrombelastography; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000096:biosynthesis*
D000925:Anticoagulants; D000991:Antithrombins; D006629:Hirudins; D010446:Peptide Fragments; D011994:Recombinant Proteins; C045879:prothrombin fragment 1.2; D011516:Prothrombin; D006493:Heparin; D013917:Thrombin; C074619:bivalirudin