Recombinant soluble form of PSGL-1 accelerates thrombolysis and prevents reocclusion in a porcine model.

ABSTRACT

BACKGROUND: We investigated whether administration of a soluble recombinant P-selectin glycoprotein ligand-1 chimera (rPSGL-Ig) in conjunction with thrombolytic therapy would enhance thrombolysis by preventing ongoing interactions of leukocytes with platelets and the injured arterial wall. METHODS AND RESULTS: An occlusive thrombus was formed in an internal iliac artery of Yorkshire pigs by placement of a copper coil in the artery under fluoroscopic guidance. Pigs then received heparin and, 15 minutes later, either vehicle or rPSGL-Ig followed by infusion with 25 mg tissue plasminogen activator according to the 90-minute regimen. Blood flow through the artery was monitored by angiography and scored on a scale of 0 to 3. Lysis of the thrombus was accelerated by 70% in pigs treated with rPSGL-Ig 250 microg/kg compared with control (13.3+/-5.0 versus 44. 4+/-13.3 minutes; n=9 each). Eight of 9 control pigs reoccluded in 13.8+/-16.9 minutes after the end of tissue plasminogen activator infusion, whereas no reocclusion was observed in 8 of 9 pigs in the rPSGL-Ig group. When the dose of rPSGL-Ig was increased to 500 microg/kg, time to lysis was shortened by 61% from control (18.0+/-8. 4 versus 46.0+/-8.9 minutes). Reocclusion occurred in 6.0+/-15.2 minutes in control but not in any rPSGL-Ig-treated pig (n=5 each). In addition, near-normal flow (score 2 or 3) after thrombolysis was achieved 59% and 58% faster in the 2 rPSGL-Ig groups than in their respective controls. CONCLUSIONS: Inhibition of leukocyte accumulation at the site of thrombosis with rPSGL-Ig may represent a safe therapeutic intervention that could be important in accelerating thrombolysis, achieving optimal reperfusion, and reducing incidence of acute reocclusion.