Thromb Haemost 1999; 82(03): 1182-1187
DOI: 10.1055/s-0037-1614350
Letters to the Editor
Schattauer GmbH

Thrombostatin Inhibits Induced Canine Coronary Thrombosis

Ahmed A. K. Hasan
1   From the Hematology/Oncology and University of Michigan, Ann Arbor, MI
6   Thromgen, Inc., Ann Arbor, MI, USA
,
Sam S. Rebello
3   Department of Pharmacology, and the University of Michigan, Ann Arbor, MI
,
Edward Smith
1   From the Hematology/Oncology and University of Michigan, Ann Arbor, MI
,
Sujata Srikanth
1   From the Hematology/Oncology and University of Michigan, Ann Arbor, MI
,
Steven Werns
2   Cardiology Division, Department of Internal Medicine, the University of Michigan, Ann Arbor, MI
,
Edward Driscoll
5   the Veterans Administration Hospital, Ann Arbor, MI, and USA
,
Jessica Faul
5   the Veterans Administration Hospital, Ann Arbor, MI, and USA
,
Dean Brenner
1   From the Hematology/Oncology and University of Michigan, Ann Arbor, MI
5   the Veterans Administration Hospital, Ann Arbor, MI, and USA
,
Daniel Normolle
4   Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI
,
Benedict R. Lucchesi
5   the Veterans Administration Hospital, Ann Arbor, MI, and USA
,
Alvin H. Schmaier
1   From the Hematology/Oncology and University of Michigan, Ann Arbor, MI
6   Thromgen, Inc., Ann Arbor, MI, USA
› Author Affiliations
Further Information

Publication History

Received 08 March 1999

Accepted after revision 11 May 1999

Publication Date:
09 December 2017 (online)

Preview

Summary

Thrombostatin (RPPGF), an angiotensin converting enzyme metabolite of bradykinin, is an inhibitor of α-thrombin’s ability to activate platelets. We examined the in vivo pharmacokinetics and pharmacodynamics of thrombostatin in rabbits and its ability to inhibit coronary thrombosis induced by electrolytic injury in dogs. Plasma half-life of thrombostatin had a t1/2α of 2.6 min and a t1/2β of 24 min in rabbits. Ligating the renal arteries did not prolong clearance (t1/2α = 2.4 min; t1/2β = 12 min). Thrombostatin produced a prolonged in vivo antiplatelet effect. At 30 min after a single intravenous administration in rabbits, thrombostatin’s plasma concentration was <8.7 μM (5 μg/ml). However, ex vivo 20 and 40 nM γ-thrombin-induced platelet aggregation of these rabbits’ platelets was inhibited 40% for 2.75 and 1 h, respectively. In vitro, flow cytometry studies revealed that thrombostatin specifically bound to human platelets and washed human platelets treated with thrombostatin were less responsive to γ-thrombin than control platelets. Using electrolytic injury to induce coronary artery thrombosis, dogs treated with thrombostatin, aspirin, or combined thrombostatin and aspirin occluded in 62 ± 25 (mean ± SD), 62 ± 36, or 89 ± 32 min versus untreated animals which occluded at 39 ± 27 min, (p <0.01, p <0.01 and p <0.001, respectively). These studies show that thrombostatin binds to platelets and can delay coronary occlusion in vivo.

Abbreviations: RPPGF: thrombostatin; PAR1: protease activated receptor 1, the first cloned thrombin receptor; PRP: platelet-rich plasma; PPP: plateletpoor plasma; LCX: left circumflex coronary artery; APTT: activated partial thromboplastin time; PT: prothrombin time