S-Nitrosoderivative of a Recombinant Fragment of von Willebrand Factor (S-Nitroso-AR545C) Inhibits Thrombus Formation in Guinea Pig Carotid Artery Thrombosis Model

Osnat Gurevitz; Michael Eldar; Ehud Skutelsky; Ilia Tamarin; Boris Shenkman; Regina Eskaraev; David Castel; Joseph Loscalzo; Aida Inbal

doi:10.1055/s-0037-1614136

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2000; 84(05): 912-917
DOI: 10.1055/s-0037-1614136

Review Article

Schattauer GmbH

S-Nitrosoderivative of a Recombinant Fragment of von Willebrand Factor (S-Nitroso-AR545C) Inhibits Thrombus Formation in Guinea Pig Carotid Artery Thrombosis Model

Osnat Gurevitz

¹From the Neufeld Cardiac Research and Thrombosis and Hemostasis Institutes, Sheba Medical Center, Tel Hashomer and Pathology Department, the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel; and the Whitaker Cardiovascular Institute and Evans Department of Medicine, Boston University School of Medicine, Boston, MA, USA

,

Michael Eldar

¹From the Neufeld Cardiac Research and Thrombosis and Hemostasis Institutes, Sheba Medical Center, Tel Hashomer and Pathology Department, the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel; and the Whitaker Cardiovascular Institute and Evans Department of Medicine, Boston University School of Medicine, Boston, MA, USA

,

Ehud Skutelsky

¹From the Neufeld Cardiac Research and Thrombosis and Hemostasis Institutes, Sheba Medical Center, Tel Hashomer and Pathology Department, the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel; and the Whitaker Cardiovascular Institute and Evans Department of Medicine, Boston University School of Medicine, Boston, MA, USA

,

Ilia Tamarin

¹From the Neufeld Cardiac Research and Thrombosis and Hemostasis Institutes, Sheba Medical Center, Tel Hashomer and Pathology Department, the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel; and the Whitaker Cardiovascular Institute and Evans Department of Medicine, Boston University School of Medicine, Boston, MA, USA

,

Boris Shenkman

¹From the Neufeld Cardiac Research and Thrombosis and Hemostasis Institutes, Sheba Medical Center, Tel Hashomer and Pathology Department, the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel; and the Whitaker Cardiovascular Institute and Evans Department of Medicine, Boston University School of Medicine, Boston, MA, USA

,

Regina Eskaraev

¹From the Neufeld Cardiac Research and Thrombosis and Hemostasis Institutes, Sheba Medical Center, Tel Hashomer and Pathology Department, the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel; and the Whitaker Cardiovascular Institute and Evans Department of Medicine, Boston University School of Medicine, Boston, MA, USA

,

David Castel

¹From the Neufeld Cardiac Research and Thrombosis and Hemostasis Institutes, Sheba Medical Center, Tel Hashomer and Pathology Department, the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel; and the Whitaker Cardiovascular Institute and Evans Department of Medicine, Boston University School of Medicine, Boston, MA, USA

,

Joseph Loscalzo

¹From the Neufeld Cardiac Research and Thrombosis and Hemostasis Institutes, Sheba Medical Center, Tel Hashomer and Pathology Department, the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel; and the Whitaker Cardiovascular Institute and Evans Department of Medicine, Boston University School of Medicine, Boston, MA, USA

,

Aida Inbal

¹From the Neufeld Cardiac Research and Thrombosis and Hemostasis Institutes, Sheba Medical Center, Tel Hashomer and Pathology Department, the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel; and the Whitaker Cardiovascular Institute and Evans Department of Medicine, Boston University School of Medicine, Boston, MA, USA

› Institutsangaben

Abstract

Summary

Antiplatelet drugs are the mainstays of therapy for acute and chronic cardiovascular diseases. S-nitroso-AR545C – an S-nitrosoderivative of a recombinant von Willebrand factor fragment AR545C spanning Ala 444 to Asp 730 and containing an Arg 545 Cys mutation, was previously found to inhibit ristocetin-and ADP-induced platelet aggregation and the interaction of platelets with extracellular matrix (ECM). In the current study we tested the antithrombotic properties of S-nitroso-AR545C on guinea pig platelets and in a platelet-rich thrombosis model in the guinea pig. Preincubation of guinea pig platelets with 0.1 µM of S-nitroso-AR545C decreased ristocetin-induced agglutination by 40% (p = 0.009) and completely abolished ADP-induced aggregation (p <0.0001). At concentration of 1.0 µM, S-nitroso-AR545C completely inhibited platelet adhesion (represented by surface coverage – SC) and decreased aggregate formation (represented by average aggregate size – AS) by more than 50%. Treatment of guinea pigs with 1.0 mg/kg S-nitroso-AR545C resulted in a significantly delayed time to arterial occlusion (31.7 ± 6.0 min vs. 13.9 ± 3.2 min, p <0.02). Similarly, total patency time was longer in the group injected with S-nitroso-AR545C compared to the control group. However, the difference was not statistically significant (33.8 ± 6.3 min vs. 20.2 ± 3.3 min, p = 0.07). No change in platelet count, hematocrit and bleeding time was observed 60 min after injection compared to baseline. In contrast, a significant decrease in SC (p <0.0001) and AS (p <0.01) were observed 60 min after the injection of S-nitroso-AR545C, whereas no change in these parameters was observed in the control group. These observations indicate that S-nitroso-AR545C exhibits significant antiadhesive and antiaggregating effects in-vitro and inhibits clot formation in-vivo suggesting that this compound may have potential therapeutic advantages.

Key words

von Willebrand factor - platelet inhibitors - nitric oxide

Volltext

Referenzen

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