(Circulation. 1999;99:1363-1369.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Recombinant Soluble Form of PSGL-1 Accelerates Thrombolysis and Prevents Reocclusion in a Porcine Model
From Preclinical R&D, Genetics Institute, Inc., Andover, Mass, and Charles River PharmServices, Southbridge, Mass (M.P.V.).
Correspondence to Anjali Kumar, PhD, Preclinical R&D, Genetics Institute, Inc., One Burtt Rd, Andover, MA 01810. E-mail akumar{at}genetics.com
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 µg/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 µg/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.
Key Words: thrombolysis • fibrinolysis • thrombosis • cell adhesion molecules • platelets • leukocytes
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