An Inhibitory Anti-factor IX Antibody Effectively Reduces Thrombus Formation in a Rat Model of Venous Thrombosis

Giora Z. Feuerstein; John R. Toomey; Richard Valocik; Paul Koster; Arun Patel; Michael N. Blackburn

doi:10.1055/s-0037-1614852

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 1999; 82(05): 1443-1445
DOI: 10.1055/s-0037-1614852

Rapid Communications

Schattauer GmbH

An Inhibitory Anti-factor IX Antibody Effectively Reduces Thrombus Formation in a Rat Model of Venous Thrombosis

Giora Z. Feuerstein

¹From SmithKline Beecham Pharmaceuticals, Departments of Cardiovascular Pharmacology, King of Prussia, PA, USA

,

John R. Toomey

¹From SmithKline Beecham Pharmaceuticals, Departments of Cardiovascular Pharmacology, King of Prussia, PA, USA

,

Richard Valocik

¹From SmithKline Beecham Pharmaceuticals, Departments of Cardiovascular Pharmacology, King of Prussia, PA, USA

,

Paul Koster

¹From SmithKline Beecham Pharmaceuticals, Departments of Cardiovascular Pharmacology, King of Prussia, PA, USA

,

Arun Patel

²Protein Biochemistry and Structural Biology, King of Prussia, PA, USA

,

Michael N. Blackburn

³Protein Biochemistry and Structural Biology, King of Prussia, PA, USA

› Institutsangaben

Abstract

Summary

An inhibitory anti-factor IX/IXa antibody (BC2) has been investigated as an anti-thrombotic agent in a rat venous thrombosis model. The treatment of rats post-injury with a single bolus dose of BC2 (3mg/kg, iv.) resulted in an ~4 fold reduction in venous thrombus mass (P = 0.043). This efficacy was matched by a minimal (<2.5 fold) prolongation of the aPTT and had no effect on the prothrombin time (PT). Heparin by comparison, given as a bolus followed by continuous infusion, at doses comparable in efficacy at reducing thrombus formation, prolonged the aPTT >50 fold. These results demonstrate that the anti-factor IX/IXa antibody (BC2), when compared to heparin, can effectively reduce venous thrombosis with less disruptive consequences on blood clotting.

Keywords

Antibodies - anticoagulants - thrombosis - factor IX

Volltext

Referenzen

References
1 Appleby RD, Olds RJ. The inherited basis of venous thrombosis. Pathology 1997; 29: 41-347.
2 Dunbabin DW. Prophylaxis against deep venous thrombosis and pulmonary embolism in patients with stroke. Vasc Med 1996; 1: 207-12.
3 Walenga JM, Bick RL. Heparin-induced thrombocytopenia, paradoxical thromboembolism, and other side effects of heparin therapy. Med Clinics North Amer 1998; 82: 635-58.
4 Holmer E, Kurachi K, Soderstrom G. The molecular weight dependence of the rate enhancing effect of heparin on the inhibition of thrombin, factor Xa, factor IXa, factor Xla, factor XIIa and kallikrein by anti-thrombin. Biochem J 1981; 193: 395-400.
5 Hoppensteadt DA, Walenga JM, Fasanella A, Jeske W, Fareed J. TFPI antigen levels in normal human volunteers after intravenous and subcutaneous administration of unfractionated heparin and a low molecular weight heparin. Thromb Res 1995; 77: 175-85.
6 Hamamoto T, Kisiel W. The effect of heparin on the regulation of factor VIIa-tissue factor activity by tissue factor pathway inhibitor. Blood Coagul Fibrinolysis 1996; 7: 470-6.
7 Hirsh J. Low-molecular-weight heparin. Circulation 1998; 98: 1575-1582.
8 Mast AE. Low-molecular-weight-heparin. In: Vascular Surgery: Theory and Practice. Stamford: Appleton and Lange; Callow A, Ernst C. eds: 1995: 847-56.
9 Kelley RF, Refino CJ, O’Connell MP, Modi N, Sehl P, Lowe D, Pater C, Bunting S. A soluble tissue factor mutant is a selective anti-coagulant and anti-thrombotic agent. Blood 1997; 89: 3219-27.
10 Holst J, Kristensen AT, Kristensen HI, Ezban M, Hedner U. Local application of recombinant active-site inhibited human clotting factor VIIa reduces thrombus weight and improves patency in a rabbit venous thrombosis model. Eur J Vasc Endovasc Surg 1998; 15: 515-20.
11 Feuerstein GZ, Patel A, Toomey JR, Bugelski P, Nichols AJ, Church WR, Valocik R, Koster P, Baker A, Blackburn MN. Anti-thrombotic efficacy of a novel murine anti-human factor IX antibody in rats. Arterioscler Thromb Vasc Biol. 1999 In press.
12 Schumacher WA, Heran CL. Effect of thromboxane receptor antagonists on venous thrombosis in rats. J Pharmacol Exp Therap 1989; 248: 1109-15.
13 Tollefsen DM, Blinder MA. Heparin. In: Hematology – Basic Principles and Practice. Hoffman R, Benz EJ, Shattil SJ, Furie B, Cohen HJ, Silberstein LE. eds: New York: Churchill Livingstone; 1995: 1802-13.
14 Lecompte T, Luo SK, Stieltjes N, Lecrubier C, Samama MM. Thrombocytopenia associated with low-molecular-weight heparin. Lancet 1991; 338: 1217.
15 Lollar P, Fass DN. Inhibition of activated porcine factor IX by dansyl-glutamyl-glycyl-anginyl-chloromethylketone. Arch Biochem Biophys 1984; 233: 438-46.
16 Benedict CR, Ryan J, Wolitzky B, Ramos R, Gerlach M, Tijburg P, Stern D. Active site blocked factor IXa prevents intravascular thrombus formation in the coronary vasculature without inhibiting extravascular coagulation in a canine thrombosis model. J Clin Invest 1991; 88: 1760-5.
17 Spanier TB, Oz MC, Madigan JD, Rose EA, Stern DM, Nowygrod R, Schmidt AM. Selective anti-coagulation with active site blocked factor IXa in synthetic patch vascular repair results in decreased blood loss and operative time. ASAIO 1997; 43: M526-M530.
18 Hoffman M, Monroe DM, Oliver JA, Roberts HR. Factors IXa and Xa play distinct roles in tissue factor-dependent initiation of coagulation. Blood 1995; 86: 1794-1801.
19 Mann KG, Kalafatis M. The coagulation explosion. Cerebrovasc Dis 1995; 5: 93-7.