Circulation, Vol 85, 805-815, Copyright © 1992 by American Heart Association
GR Sitko, DR Ramjit, II Stabilito, D Lehman, JJ Lynch and GP Vlasuk
BACKGROUND. Effective thrombolytic recanalization of an occluded coronary
vessel is often limited by acute thrombotic reocclusion, which has
galvanized the search for effective adjunctive or conjunctive
antithrombotic agents. METHODS AND RESULTS. Recombinant versions of tick
anticoagulant peptide (rTAP) and hirudin (rHIR) are highly selective and
potent polypeptide inhibitors of factor Xa and thrombin, respectively. The
comparative antithrombotic efficacies of rTAP, rHIR, and heparin,
administered conjunctively with recombinant tissue-type plasminogen
activator (rt-PA), on thrombolytic reperfusion and reocclusion, were
determined in a canine model of occlusive coronary artery thrombosis with a
superimposed critical stenosis. In this model, a platelet-rich occlusive
thrombus was formed after damage to the intimal surface of the left
circumflex coronary artery induced by electrolytic injury. Fifteen minutes
after occlusion, the dogs received a systemic intravenous administration of
either saline (control), heparin (200 units/kg bolus + 2 units/kg/min,
heparin (HEP) 200 or 100 units/kg bolus + 1 unit/kg/min, HEP 100), rHIR (50
or 100 micrograms/kg/min, rHIR 50 or 100, respectively), or rTAP (100
micrograms/kg/min, rTAP 100) followed 15 minutes later by rt-PA (100
micrograms/kg bolus + 10 micrograms/kg/min over 90 minutes). Infusions of
the conjunctive agents were discontinued 60 minutes after termination of
rt-PA. The incidence and time (mean +/- SEM) to thrombolytic reperfusion
were determined for control (five of 12; 68.0 +/- 7.8 minutes), HEP 100
(six of eight; 40.1 +/- 8.3 minutes), HEP 200 (six of eight; 39.8 +/- 9.5
minutes), rHIR 50 (six of eight; 51.7 +/- 14.6 minutes), rHIR 100 (eight of
eight; 19.5 +/- 4.2 minutes), and rTAP 100 (eight of eight; 22.8 +/- 10.0
minutes). The incidence and time to reocclusion after rt-PA were determined
for control (four of five; 45.7 +/- 12.5 minutes), HEP 100 (four of six;
18.2 +/- 10.7 minutes), HEP 200 (five of six; 26.2 +/- 20.7 minutes), rHIR
50 (four of six; 47.3 +/- 21.6 minutes), rHIR 100 (six of eight; 89.8 +/-
5.9 minutes), and rTAP 100 (three of eight; 54.0 +/- 16.3 minutes). All of
the dogs that reoccluded in the rHIR 100 group did so after termination of
the inhibitor infusion, whereas two of the three dogs in the rTAP 100 group
that reoccluded did so during the inhibitor infusion. Coronary artery blood
flow was characterized by intermittent periods of reocclusion and
recanalization in all groups except rTAP 100. CONCLUSIONS. The potent
antithrombotic effects of rTAP in this model directly implicate de novo
thrombin formation as a major source of thrombin activity within the highly
thrombogenic residual thrombus. These findings suggest that direct
inhibition of prothrombinase activity may be an effective strategy in the
development of a new class of conjunctive agents.
ARTICLES
Conjunctive enhancement of enzymatic thrombolysis and prevention of thrombotic reocclusion with the selective factor Xa inhibitor, tick anticoagulant peptide. Comparison to hirudin and heparin in a canine model of acute coronary artery thrombosis
Department of Pharmacology, Merck Sharp and Dohme Research Laboratories, West Point, Pa.
This article has been cited by other articles:
 |
|
 |
|
  P. Stoll, N. Bassler, C. E. Hagemeyer, S. U. Eisenhardt, Y. C. Chen, R. Schmidt, M. Schwarz, I. Ahrens, Y. Katagiri, B. Pannen, et al. Targeting Ligand-Induced Binding Sites on GPIIb/IIIa via Single-Chain Antibody Allows Effective Anticoagulation Without Bleeding Time Prolongation Arterioscler. Thromb. Vasc. Biol., May 1, 2007; 27(5): 1206 - 1212. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. R. Abendschein, P. K. Baum, P. Verhallen, P. R. Eisenberg, M. E. Sullivan, and D. R. Light A Novel Synthetic Inhibitor of Factor Xa Decreases Early Reocclusion and Improves 24-h Patency after Coronary Fibrinolysis in Dogs J. Pharmacol. Exp. Ther., April 13, 2001; 296(2): 567 - 572. [Abstract] [Full Text]
|
|
|
|
 |
|
 R. M. Camire, M. Kalafatis, P. Simioni, A. Girolami, and P. B. Tracy Platelet-Derived Factor Va/VaLeiden Cofactor Activities Are Sustained on the Surface of Activated Platelets Despite the Presence of Activated Protein C Blood, April 15, 1998; 91(8): 2818 - 2829. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. P. Hérault, A. Bernat, A. M. Pflieger, J. C. Lormeau, and J. M. Herbert Comparative Effects of Two Direct and Indirect Factor Xa Inhibitors on Free and Clot-Bound Prothrombinase J. Pharmacol. Exp. Ther., October 1, 1997; 283(1): 16 - 22. [Abstract] [Full Text]
|
|
|
|
|
|
S. S. Rebello, H. S. Blank, W. E. Rote, G. P. Vlasuk, and B. R. Lucchesi Antithrombotic Efficacy of a Recombinant Nematode Anticoagulant Peptide (rNAP5) in Canine Models of Thrombosis after Single Subcutaneous Administration J. Pharmacol. Exp. Ther., October 1, 1997; 283(1): 91 - 99. [Abstract] [Full Text]
|
|
|
|
|
|
D. Pratico, N. P. Murphy, and D. J. Fitzgerald J. Pharmacol. Exp. Ther., June 1, 1997; 281(3): 1178 - 1185. [Abstract] [Full Text]
|
|
|
|
 |
|
 B. Kaiser State-of-the-Art Review: Factor Xa Versus Factor IIa Inhibitors Clinical and Applied Thrombosis/Hemostasis, January 1, 1997; 3(1): 16 - 24. [Abstract] [PDF]
|
|
|
|
|
|
C. V. Jackson, J. Satterwhite, and E. Roberts Preclinical and Clinical Pharmacology of Efegatran (LY294468) : A Novel Antithrombin for the Treatment of Acute Coronary Syndromes Clinical and Applied Thrombosis/Hemostasis, October 1, 1996; 2(4): 258 - 267. [Abstract] [PDF]
|
|
|
|
|
|
C. R. McKenzie, D. R. Abendschein, and P. R. Eisenberg Sustained Inhibition of Whole-Blood Clot Procoagulant Activity by Inhibition of Thrombus-Associated Factor Xa Arterioscler. Thromb. Vasc. Biol., October 1, 1996; 16(10): 1285 - 1291. [Abstract] [Full Text]
|
|
|
|
 |
|
 E. M. Antman Hirudin in Acute Myocardial Infarction: Thrombolysis and Thrombin Inhibition in Myocardial Infarction (TIMI) 9B Trial Circulation, September 1, 1996; 94(5): 911 - 921. [Abstract] [Full Text]
|
|
|
|
|
|
R. S. Schwartz, D. J. Holder, D. R. Holmes Jr, J. P. Veinot, A. R. Camrud, M. A. Jorgenson, and R. G. Johnson Jr Neointimal Thickening After Severe Coronary Artery Injury Is Limited by Short-term Administration of a Factor Xa Inhibitor : Results in a Porcine Model Circulation, April 15, 1996; 93(8): 1542 - 1548. [Abstract] [Full Text]
|
|
|
|
|
|
B. J. Biemond, P. W. Friederich, M. Levi, G. P. Vlasuk, H. R. Buller, and J. W. ten Cate Comparison of Sustained Antithrombotic Effects of Inhibitors of Thrombin and Factor Xa in Experimental Thrombosis Circulation, January 1, 1996; 93(1): 153 - 160. [Abstract] [Full Text]
|
|
|
|
|
|
U. Orvim, R. M. Barstad, G. P. Vlasuk, and K. S. Sakariassen Effect of Selective Factor Xa Inhibition on Arterial Thrombus Formation Triggered by Tissue Factor/Factor VIIa or Collagen in an Ex Vivo Model of Shear-Dependent Human Thrombogenesis Arterioscler. Thromb. Vasc. Biol., December 1, 1995; 15(12): 2188 - 2194. [Abstract] [Full Text]
|
|
|
|
|
|
Y. Jang, L. A. Guzman, A. M. Lincoff, M. Gottsauner-Wolf, F. Forudi, C. E. Hart, D. W. Courtman, M. Ezban, S. G. Ellis, and E. J. Topol Influence of Blockade at Specific Levels of the Coagulation Cascade on Restenosis in a Rabbit Atherosclerotic Femoral Artery Injury Model Circulation, November 15, 1995; 92(10): 3041 - 3050. [Abstract] [Full Text]
|
|
|
|
|
|
D. R. Abendschein, Y. Y. Meng, S. Torr-Brown, and B. E. Sobel Maintenance of Coronary Patency After Fibrinolysis With Tissue Factor Pathway Inhibitor Circulation, August 15, 1995; 92(4): 944 - 949. [Abstract] [Full Text]
|
|
|
|
|
|
N. A. Prager, D. R. Abendschein, C. R. McKenzie, and P. R. Eisenberg Role of Thrombin Compared With Factor Xa in the Procoagulant Activity of Whole Blood Clots Circulation, August 15, 1995; 92(4): 962 - 967. [Abstract] [Full Text]
|
|
|
|
|
|
T. Yokoyama, A. B. Kelly, U. M. Marzec, S. R. Hanson, S. Kunitada, and L. A. Harker Antithrombotic Effects of Orally Active Synthetic Antagonist of Activated Factor X in Nonhuman Primates Circulation, August 1, 1995; 92(3): 485 - 491. [Abstract] [Full Text]
|
|
|
|
|
|
D. D. Callas, O. Iqbal, D. Hoppensteadt, and J. Fareed Fibrinolytic Compromise by Synthetic and Recombinant Thrombin Inhibitors: Implications in the Treatment of Thrombotic Disorders Clinical and Applied Thrombosis/Hemostasis, March 1, 1995; 1(2): 114 - 124. [Abstract] [PDF]
|
|