Selective inhibition of factor Xa is more efficient than factor VIIa-tissue factor complex blockade at facilitating coronary thrombolysis in the canine model

Jeffrey Lefkovits, Janis L. Malycky, Jonnagadda S Rao, Charles E. Hart, Edward F. Plow, Eric J. Topol, Francesca A. Nicolini

Research output: Contribution to journalArticle

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Abstract

Objectives. 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 μg/kg body weight per min for 90 min, n = 10); TFPI (100 to 150 μg/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.

Original languageEnglish
Pages (from-to)1858-1865
Number of pages8
JournalJournal of the American College of Cardiology
Volume28
Issue number7
DOIs
StatePublished - Dec 1 1997
Externally publishedYes

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Factor VIIa
Factor Xa
Thromboplastin
Canidae
Thrombolytic Therapy
Thrombin
Reperfusion
Dogs
Coronary Thrombosis
Plasminogen Activators
Tissue Plasminogen Activator
Thrombosis
Theoretical Models
Body Weight
lipoprotein-associated coagulation inhibitor
tick anticoagulant peptide
Proteins

ASJC Scopus subject areas

  • Nursing(all)

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Selective inhibition of factor Xa is more efficient than factor VIIa-tissue factor complex blockade at facilitating coronary thrombolysis in the canine model. / Lefkovits, Jeffrey; Malycky, Janis L.; Rao, Jonnagadda S; Hart, Charles E.; Plow, Edward F.; Topol, Eric J.; Nicolini, Francesca A.

In: Journal of the American College of Cardiology, Vol. 28, No. 7, 01.12.1997, p. 1858-1865.

Research output: Contribution to journalArticle

Lefkovits, Jeffrey ; Malycky, Janis L. ; Rao, Jonnagadda S ; Hart, Charles E. ; Plow, Edward F. ; Topol, Eric J. ; Nicolini, Francesca A. / Selective inhibition of factor Xa is more efficient than factor VIIa-tissue factor complex blockade at facilitating coronary thrombolysis in the canine model. In: Journal of the American College of Cardiology. 1997 ; Vol. 28, No. 7. pp. 1858-1865.
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abstract = "Objectives. 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 μg/kg body weight per min for 90 min, n = 10); TFPI (100 to 150 μg/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.",
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T1 - Selective inhibition of factor Xa is more efficient than factor VIIa-tissue factor complex blockade at facilitating coronary thrombolysis in the canine model

AU - Lefkovits, Jeffrey

AU - Malycky, Janis L.

AU - Rao, Jonnagadda S

AU - Hart, Charles E.

AU - Plow, Edward F.

AU - Topol, Eric J.

AU - Nicolini, Francesca A.

PY - 1997/12/1

Y1 - 1997/12/1

N2 - Objectives. 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 μg/kg body weight per min for 90 min, n = 10); TFPI (100 to 150 μg/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.

AB - Objectives. 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 μg/kg body weight per min for 90 min, n = 10); TFPI (100 to 150 μg/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.

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