Direct thrombin inhibitors are not equally effective in vivo against arterial thrombosis: In vivo evaluation of DuP714 and Argatroban in a porcine angioplasty model and comparison to r-hirudin

Robert D. McBane, Nancy L. Hassinger, Jozef S. Mruk, Diane E. Grill, James H. Chesebro

Research output: Contribution to journalArticle

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Abstract

Background: Qualitative differences in antithrombotic efficacy between thrombin inhibitors may be explained by the affinity for which they bind thrombin. This affinity is inversely proportional to the inhibitory constant for the agent (Ki). Thrombin inhibitors, DuP714 (Ki = 10-11) and argatroban (Ki = 10-8), were compared to our previous studies with r-hirudin (Ki = 10-13). Methods and results: Prior to balloon angioplasty, thirty pigs randomly received DuP714 (0.1 mg/kg bolus and 0.6 mg/kg/h infusion; n = 8), argatroban (0.2 mg/kg/min. continuous infusion; n = 9), or saline (n = 17). Injured arterial segments were measured for 111In-platelet and 125I-fibrin(ogen) deposition and the incidence of macroscopic thrombus. In DuP714-treated animals, platelet and fibrin(ogen) deposition were significantly lower than controls in both carotid (10 ± 2 vs. 62 ± 18 and 20 ± 4 vs. 74 ± 6) and coronary (10 ± 4 vs. 160 ± 63 and 17 ± 3 vs. 86 ± 22) arteries (p < 0.005). In contrast, platelet and fibrin(ogen) deposition were similar when comparing argatroban to saline in carotid (41 ± 20 vs. 40 ± 9 and 71 ± 5 vs. 49 ± 7) and coronary (92 ± 33 vs. 151 ± 45 and 114 ± 37 vs. 89 ± 38) arteries (p = 0.82 and 0.38, respectively). Compared to argatroban, fibrin(ogen) (p < 0.001) and coronary platelet deposition (p < 0.05) were significantly reduced in animals treated with DuP714 with no significant difference in carotid platelet deposition (p = 0.10). Neither inhibitor prevented macroscopic thrombosis. In previous studies with r-hirudin in this model, platelet deposition was limited to a monolayer with complete inhibition of macroscopic thrombus. Conclusions: Direct thrombin inhibitors do not equally prevent arterial thrombosis. Qualitative differences may be explained in part by the affinity for which they bind thrombin.

Original languageEnglish (US)
Pages (from-to)525-532
Number of pages8
JournalThrombosis Research
Volume116
Issue number6
DOIs
StatePublished - 2005

Fingerprint

Hirudins
Antithrombins
Angioplasty
Thrombosis
Swine
Blood Platelets
Fibrin
Thrombin
Arteries
Balloon Angioplasty
argatroban
acetylphenylalanyl-prolyl-boroarginine
estropipate
Incidence

Keywords

  • Coronary disease
  • Inhibitors
  • Platelets
  • Thrombin
  • Thrombosis

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Hematology

Cite this

Direct thrombin inhibitors are not equally effective in vivo against arterial thrombosis : In vivo evaluation of DuP714 and Argatroban in a porcine angioplasty model and comparison to r-hirudin. / McBane, Robert D.; Hassinger, Nancy L.; Mruk, Jozef S.; Grill, Diane E.; Chesebro, James H.

In: Thrombosis Research, Vol. 116, No. 6, 2005, p. 525-532.

Research output: Contribution to journalArticle

McBane, Robert D. ; Hassinger, Nancy L. ; Mruk, Jozef S. ; Grill, Diane E. ; Chesebro, James H. / Direct thrombin inhibitors are not equally effective in vivo against arterial thrombosis : In vivo evaluation of DuP714 and Argatroban in a porcine angioplasty model and comparison to r-hirudin. In: Thrombosis Research. 2005 ; Vol. 116, No. 6. pp. 525-532.
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abstract = "Background: Qualitative differences in antithrombotic efficacy between thrombin inhibitors may be explained by the affinity for which they bind thrombin. This affinity is inversely proportional to the inhibitory constant for the agent (Ki). Thrombin inhibitors, DuP714 (Ki = 10-11) and argatroban (Ki = 10-8), were compared to our previous studies with r-hirudin (Ki = 10-13). Methods and results: Prior to balloon angioplasty, thirty pigs randomly received DuP714 (0.1 mg/kg bolus and 0.6 mg/kg/h infusion; n = 8), argatroban (0.2 mg/kg/min. continuous infusion; n = 9), or saline (n = 17). Injured arterial segments were measured for 111In-platelet and 125I-fibrin(ogen) deposition and the incidence of macroscopic thrombus. In DuP714-treated animals, platelet and fibrin(ogen) deposition were significantly lower than controls in both carotid (10 ± 2 vs. 62 ± 18 and 20 ± 4 vs. 74 ± 6) and coronary (10 ± 4 vs. 160 ± 63 and 17 ± 3 vs. 86 ± 22) arteries (p < 0.005). In contrast, platelet and fibrin(ogen) deposition were similar when comparing argatroban to saline in carotid (41 ± 20 vs. 40 ± 9 and 71 ± 5 vs. 49 ± 7) and coronary (92 ± 33 vs. 151 ± 45 and 114 ± 37 vs. 89 ± 38) arteries (p = 0.82 and 0.38, respectively). Compared to argatroban, fibrin(ogen) (p < 0.001) and coronary platelet deposition (p < 0.05) were significantly reduced in animals treated with DuP714 with no significant difference in carotid platelet deposition (p = 0.10). Neither inhibitor prevented macroscopic thrombosis. In previous studies with r-hirudin in this model, platelet deposition was limited to a monolayer with complete inhibition of macroscopic thrombus. Conclusions: Direct thrombin inhibitors do not equally prevent arterial thrombosis. Qualitative differences may be explained in part by the affinity for which they bind thrombin.",
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T1 - Direct thrombin inhibitors are not equally effective in vivo against arterial thrombosis

T2 - In vivo evaluation of DuP714 and Argatroban in a porcine angioplasty model and comparison to r-hirudin

AU - McBane, Robert D.

AU - Hassinger, Nancy L.

AU - Mruk, Jozef S.

AU - Grill, Diane E.

AU - Chesebro, James H.

PY - 2005

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N2 - Background: Qualitative differences in antithrombotic efficacy between thrombin inhibitors may be explained by the affinity for which they bind thrombin. This affinity is inversely proportional to the inhibitory constant for the agent (Ki). Thrombin inhibitors, DuP714 (Ki = 10-11) and argatroban (Ki = 10-8), were compared to our previous studies with r-hirudin (Ki = 10-13). Methods and results: Prior to balloon angioplasty, thirty pigs randomly received DuP714 (0.1 mg/kg bolus and 0.6 mg/kg/h infusion; n = 8), argatroban (0.2 mg/kg/min. continuous infusion; n = 9), or saline (n = 17). Injured arterial segments were measured for 111In-platelet and 125I-fibrin(ogen) deposition and the incidence of macroscopic thrombus. In DuP714-treated animals, platelet and fibrin(ogen) deposition were significantly lower than controls in both carotid (10 ± 2 vs. 62 ± 18 and 20 ± 4 vs. 74 ± 6) and coronary (10 ± 4 vs. 160 ± 63 and 17 ± 3 vs. 86 ± 22) arteries (p < 0.005). In contrast, platelet and fibrin(ogen) deposition were similar when comparing argatroban to saline in carotid (41 ± 20 vs. 40 ± 9 and 71 ± 5 vs. 49 ± 7) and coronary (92 ± 33 vs. 151 ± 45 and 114 ± 37 vs. 89 ± 38) arteries (p = 0.82 and 0.38, respectively). Compared to argatroban, fibrin(ogen) (p < 0.001) and coronary platelet deposition (p < 0.05) were significantly reduced in animals treated with DuP714 with no significant difference in carotid platelet deposition (p = 0.10). Neither inhibitor prevented macroscopic thrombosis. In previous studies with r-hirudin in this model, platelet deposition was limited to a monolayer with complete inhibition of macroscopic thrombus. Conclusions: Direct thrombin inhibitors do not equally prevent arterial thrombosis. Qualitative differences may be explained in part by the affinity for which they bind thrombin.

AB - Background: Qualitative differences in antithrombotic efficacy between thrombin inhibitors may be explained by the affinity for which they bind thrombin. This affinity is inversely proportional to the inhibitory constant for the agent (Ki). Thrombin inhibitors, DuP714 (Ki = 10-11) and argatroban (Ki = 10-8), were compared to our previous studies with r-hirudin (Ki = 10-13). Methods and results: Prior to balloon angioplasty, thirty pigs randomly received DuP714 (0.1 mg/kg bolus and 0.6 mg/kg/h infusion; n = 8), argatroban (0.2 mg/kg/min. continuous infusion; n = 9), or saline (n = 17). Injured arterial segments were measured for 111In-platelet and 125I-fibrin(ogen) deposition and the incidence of macroscopic thrombus. In DuP714-treated animals, platelet and fibrin(ogen) deposition were significantly lower than controls in both carotid (10 ± 2 vs. 62 ± 18 and 20 ± 4 vs. 74 ± 6) and coronary (10 ± 4 vs. 160 ± 63 and 17 ± 3 vs. 86 ± 22) arteries (p < 0.005). In contrast, platelet and fibrin(ogen) deposition were similar when comparing argatroban to saline in carotid (41 ± 20 vs. 40 ± 9 and 71 ± 5 vs. 49 ± 7) and coronary (92 ± 33 vs. 151 ± 45 and 114 ± 37 vs. 89 ± 38) arteries (p = 0.82 and 0.38, respectively). Compared to argatroban, fibrin(ogen) (p < 0.001) and coronary platelet deposition (p < 0.05) were significantly reduced in animals treated with DuP714 with no significant difference in carotid platelet deposition (p = 0.10). Neither inhibitor prevented macroscopic thrombosis. In previous studies with r-hirudin in this model, platelet deposition was limited to a monolayer with complete inhibition of macroscopic thrombus. Conclusions: Direct thrombin inhibitors do not equally prevent arterial thrombosis. Qualitative differences may be explained in part by the affinity for which they bind thrombin.

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