Selective inhibition of factor Xa is more efficient than factor VIIa-tissue factor complex blockade at facilitating coronary thrombolysis in the canine model.
OBJECTIVE
We determined the effect of adjunctive inhibition of the extrinsic coagulation pathway by factor VIIa-tissue factor complex inhibitors, DEGR VIIa and tissue factor pathway inhibitor (TFPI), and the selective factor Xa inhibitor, tick anticoagulant peptide (TAP), after thrombolytic therapy with tissue-type plasminogen activator (t-PA) in a canine model of electrically induced coronary thrombosis.


BACKGROUND
Ongoing thrombin generation is considered an important component of the heightened thrombin activity associated with thrombolytic therapy and may be responsible for reperfusion failure and reocclusion.


METHODS
Forty-two dogs with electrically induced coronary thrombus undergoing thrombolysis with t-PA (1 mg/kg over 20 min) were randomly assigned to one of the following adjunctive regimens: TAP (30 micrograms/kg body weight per min for 90 min, n = 10); TFPI (100 to 150 micrograms/kg per min for 90 min, n = 10); DEGR VIIa (1- to 2-mg/kg bolus, n = 10) and saline control (n = 12). The dogs were observed for 120 min after thrombolysis for reocclusion.


RESULTS
All three active study agents accelerated the time to reperfusion by an average of 12 min (all p < 0.05). Duration of reflow was greatest with TAP (117 +/- 8 min, p < 0.05 compared with saline control), whereas DEGR VIIa and TFPI did not prolong the duration of reflow. Reocclusion rates were similar among control, DEGR VIIa and TFPI groups (70%, 78% and 67%, respectively). Tick anticoagulant peptide reduced the occurrence of reocclusion (0%, p < 0.05 compared with saline control).


CONCLUSIONS
In this experimental model, during systematic blockade of various extrinsic coagulation pathway proteins, we demonstrated that whereas acceleration of thrombolysis occurs with factor VIIa-tissue factor complex inhibition, optimal enhancement of thrombolysis was achieved through specific factor Xa blockade.
Lefkovits
J
J
Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Department of Cardiology, Cleveland Clinic Foundation, Ohio 44195, USA.
Malycky
J L
JL
Rao
J S
JS
Hart
C E
CE
Plow
E F
EF
Topol
E J
EJ
Nicolini
F A
FA
D000818:Animals; D060829:Arthropod Proteins; D001777:Blood Coagulation / Q000187:drug effects; D003328:Coronary Thrombosis / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D004285:Dogs; D015942:Factor VIIa / Q000037:antagonists & inhibitors; D015951:Factor Xa / Q000502:physiology; D065427:Factor Xa Inhibitors; D006487:Hemostasis / Q000187:drug effects; D036341:Intercellular Signaling Peptides and Proteins; D008074:Lipoproteins / Q000097:blood / Q000627:therapeutic use*; D010455:Peptides / Q000627:therapeutic use*; D015912:Thrombolytic Therapy; D013925:Thromboplastin / Q000037:antagonists & inhibitors; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use
D060829:Arthropod Proteins; D065427:Factor Xa Inhibitors; D036341:Intercellular Signaling Peptides and Proteins; D008074:Lipoproteins; D010455:Peptides; C051928:lipoprotein-associated coagulation inhibitor; C063967:tick anticoagulant peptide; D013925:Thromboplastin; D015942:Factor VIIa; D015951:Factor Xa; D010959:Tissue Plasminogen Activator