P-Selectin Antagonism Causes Dose-dependent Venous Thrombosis Inhibition

Summary

Inhibition of P-selectin by antibody or selectin antagonist decreases inflammation and thrombosis. This study evaluates the dose-response relationship using a selectin receptor antagonist. Eight male baboons (Papio anubis) underwent inferior vena caval thrombosis using a 6 h balloon occlusion model. Three animals received 500 μg/kg P-selectin antagonist (rPSGL-Ig) and five 1 mg/kg rPSGL-Ig with or without a non-anticoagulant dose of Dalteparin. These animals were compared to our published results in this model with 4 saline controls and 8 animals that received 4 mg/kg rPSGL-Ig. A statistically significant dose-response relationship existed between rPSGL-Ig dose and thrombosis (p < 0.01), and between rPSGL-Ig dose and spontaneous recanalization (p < 0.05). Inflammatory assessment revealed decreased gadolinium enhancement in all rPSGL-Ig groups compared to previously reported control, despite no significant differences in inflammatory cell extra-vasation. No dose of rPSGL-Ig caused anticoagulation. Selectin antagonism results in a dose-dependent decrease in thrombosis and increase in spontaneous recanalization.

Keywords

Selectin - antagonism - thrombosis - inflammation - venous

• References

• 1 Ruckley CV. Socioeconomic impact of chronic venous insufficiency and leg ulcers. Angiology 1997; 48: 67-9.
• 2 Stewart G. Neutrophils and deep venous thrombosis. Haemostasis 1993; 23: 127-40.
• 3 Wakefield TW, Strieter RM, Wilke CA, Kadell AM, Wrobleski SK, Burdick MD, Schmidt R, Kunkel SL, Greenfield LJ. Venous thrombosis-associated inflammation and attenuation with neutralizing antibodies to cytokines and adhesion molecules. Arterioscler Thromb Vasc Biol 1995; 15: 258-68.
• 4 Wakefield TW, Greenfield LJ, Rolfe MW, DeLucia III A, Strieter RM, Abrams GD, Kunkel SL, Esmon CT, Wrobleski SK, Kadell AM, Burdick MD, Taylor FB. Inflammatory and procoagulant mediator interactions in an experimental baboon model of venous thrombosis. Thromb Haemost 1993; 69: 164-72.
• 5 Downing LJ, Wakefield TW, Strieter RM, Prince MR, Londy FJ, Fowlkes JB, Hulin MS, Kadell AM, Wilke CA, Brown SL, Wrobleski SK, Burdick MD, Anderson DC, Greenfield LJ. Anti-P-selectin antibody decreases inflammation and thrombus formation in venous thrombosis. J Vasc Surg 1997; 25: 816-28.
• 6 Wakefield TW, Strieter RM, Schaub R, Myers DD, Prince MR, Wrobleski SK, Londy FJ, Kadell AM, Brown SL, Henke PK, Greenfield LJ. Venous thrombosis prophylaxis by inflammatory inhibition without anticoagulation therapy. J Vasc Surg 2000; 31: 309-24.
• 7 Hayward R, Campbell B, Shin YK, Scalia R, Lefer AM. Recombinant soluble P-selectin glycoprotein ligand-1 protects against myocardial ischemic reperfusion injury in cats. Cardiovasc Res 1999; 41: 65-76.
• 8 Khor SP, McCarthy K, Dupont M, Murray K, Timony G. Pharmacokinetics, pharmacodynamics, allometry, and dose selection for rPSGL-Ig for phase I trial. J Pharm Exp Therapeutics 2000; 293: 618-24.
• 9 Froehlich JB, Prince MR, Greenfield LJ, Downing LJ, Shah NL, Wakefield TW. "Bulls-Eye" sign on gadolinium-enhanced magnetic resonance venography determines thrombus presence and age: A preliminary study. J Vasc Surg 1997; 26: 809-16.
• 10 Wrobleski S, Linn M, Myers Jr D, Farris D, Chapman A, Schaub R, Wakefield T. Coagulation reference values for wild caught juvenile baboons. American Association for Laboratory Animal Sciences (Mtg) 2000
• 11 McEver RP, Cummings RD. Role of PSGL-1 binding to selectins in leukocyte recruitment. J Clin Invest 1997; 100: 485-92.
• 12 Theoret JF, Kumar A, Latour J-G, Merhi Y. Mechanisms of platelet binding to neutrophils in contact with damaged arterial surfaces under flow conditions. Circulation 1998; 98 (Suppl. 17) I-241 #1251.
• 13 Scalia R, Hayward R, Armstead VE, Minchenko AG, Lefer AM. Effect of recombinant soluble P-selectin glycoprotein ligand-1 on leukocyte-endothelium interaction in vivo. Role in rat traumatic shock. Circulation Res 1999; 84: 93-102.
• 14 Dulkanchainun TS, Goss JA, Imagawa DK, Shaw GD, Anselmo DM, Kaldas F, Wang T, Zhao D, Busuttil AA, Kato H, Murray NG, KupiecWeglinski JW, Busuttil RW. Reduction of hepatic ischemia/reperfusion injury by a soluble P-selectin glycoprotein ligand-1. Ann Surg 1998; 227: 832-40.
• 15 Takada M, Nadeau KC, Shaw GD, Marquette KA, Tilney NL. The cytokine-adhesion molecule cascade in ischemia/reperfusion injury of the rat kidney. Inhibition by a soluble P-selectin ligand. J Clin Invest 1997; 99: 2682-90.
• 16 Lefer AM, Campbell B, Scalia R, Lefer DJ. Synergism between platelets and neutrophils in provoking cardiac dysfunction after ischemia and reper-fusion: role of selectins. Circulation 1998; 98: 1322-8.
• 17 Zhang H, Schaub RG, Khor SP, Keith Jr JC, Kumar A. Anti-thrombotic effect of a recombinant soluble P-selectin glycoprotein ligand-1 chimera in a rat model of thrombosis (Abstract). Circulation 1999; 100 (Suppl. 01) 1471.
• 18 Eppihimer MJ, Schaub RG. Effect of recombinant PSGL-I (rPSGL-Ig) on vascular injury and thrombosis following venous stasis (Abstract). Circulation 1999; 100: 1812.
• 19 Zhang H, Schaub RG, Keith Jr JC, Kumar A. A recombinant soluble P-selectin glycoprotein ligand-1 chimera has a thrombolytic effect in a rat model of thrombosis. American College of Cardiology 2000
• 20 Rauch U, Bonderman D, Bohrmann B, Badimon JJ, Himber J, Riederer MA, Nemerson Y. Transfer of tissue factor from leukocytes to platelets is mediated by CD15 and tissue factor. Blood 2000; 96: 170-5.
• 21 Frenette PS, Denis CV, Weiss L, Jurk K, Subbarao S, Kehrel B, Hartwig JH, Vestweber D, Wagner DD. P-selectin glycoprotein ligand 1 (PSGL-1) is expressed on platelets and can mediate platelet-endothelial interactions in vivo. J Exp Med 2000; 191: 1413-22.
• 22 Kumar A, Villani MP, Patel UK, Keith JC, Schaub RG. Recombinant soluble form of PSGL-1 accelerates thrombolysis and prevents reocclusion in a porcine model. Circulation 1999; 99: 1363-9.
• 23 Toombs CF, DeGraaf GL, Martin JP, Geng JG, Anderson DC, Shebuski RJ. Pretreatment with a blocking monoclonal antibody to P-selectin accelerates pharmacological thrombolysis in a primate model of arterial thrombosis. J Pharm & Exp Ther 1995; 275: 941-9.
• 24 Palabrica T, Lobb R, Furie BC, Aronovitz M, Benjamin C, Hsu YM, Sager SA, Furie B. Leukocyte accumulation promoting fibrin deposition is mediated in vivo by P-selectin on adherent platelets. Nature 1992; 359: 848-51.
• 25 Downing LJ, Strieter RM, Kadell AM, Wilke CA, Greenfield LJ, Wakefield TW. Low-dose low-molecular-weight heparin is anti-inflammatory during venous thrombosis. J Vasc Surg 1998; 28: 848-54.
• 26 Darien BJ, Fareed J, Centgraf KS, Hart AP, MacWilliams PS, Clayton MK, Wolf H, Kruse-Elliott KT. Low molecular weight heparin prevents the pulmonary hemodynamic and pathomorphologic effects of endotoxin in a porcine acute lung injury model. Shock 1998; 9: 274-81.