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

被引:106
作者
Kumar, A
Villani, MP
Patel, UK
Keith, JC
Schaub, RG
机构
[1] Genet Inst Inc, Preclin R&D, Andover, MA 01810 USA
[2] Charles River PharmServ, Southbridge, MA USA
关键词
thrombolysis; fibrinolysis; thrombosis; cell adhesion molecules; platelets; leukocytes;
D O I
10.1161/01.CIR.99.10.1363
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Background-We investigated whether administration of a soluble recombinant P-selectin glycoprotein ligand-l 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 mu g/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 mu g/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.
引用
收藏
页码:1363 / 1369
页数:7
相关论文
共 42 条
  • [1] ANTMAN EM, 1998, J AM COLL CARDIOL, V31, P842
  • [2] BAZZONI G, 1991, HAEMATOLOGICA, V76, P491
  • [3] NEUTROPHIL DEPLETION SUPPRESSES IN-111-LABELED PLATELET ACCUMULATION IN INFARCTED MYOCARDIUM
    BEDNAR, M
    SMITH, B
    PINTO, A
    MULLANE, KM
    [J]. JOURNAL OF CARDIOVASCULAR PHARMACOLOGY, 1985, 7 (05) : 906 - 912
  • [4] A PLATELET ALPHA GRANULE MEMBRANE-PROTEIN THAT IS ASSOCIATED WITH THE PLASMA-MEMBRANE AFTER ACTIVATION - CHARACTERIZATION AND SUBCELLULAR-LOCALIZATION OF PLATELET ACTIVATION-DEPENDENT GRANULE-EXTERNAL MEMBRANE-PROTEIN
    BERMAN, CL
    YEO, EL
    WENCELDRAKE, JD
    FURIE, BC
    GINSBERG, MH
    FURIE, B
    [J]. JOURNAL OF CLINICAL INVESTIGATION, 1986, 78 (01) : 130 - 137
  • [5] BONFANTI R, 1989, BLOOD, V73, P1109
  • [6] THE BINDING-AFFINITY OF HUMAN-IGG FOR ITS HIGH-AFFINITY FC RECEPTOR IS DETERMINED BY MULTIPLE AMINO-ACIDS IN THE CH2 DOMAIN AND IS MODULATED BY THE HINGE REGION
    CANFIELD, SM
    MORRISON, SL
    [J]. JOURNAL OF EXPERIMENTAL MEDICINE, 1991, 173 (06) : 1483 - 1491
  • [7] CANNON CP, 1994, J THROMB THROMBOLYS, V1, P27
  • [8] P-SELECTIN INDUCES THE EXPRESSION OF TISSUE FACTOR ON MONOCYTES
    CELI, A
    PELLEGRINI, G
    LORENZET, R
    DEBLASI, A
    READY, N
    FURIE, BC
    FURIE, B
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1994, 91 (19) : 8767 - 8771
  • [9] THROMBOLYSIS IN MYOCARDIAL-INFARCTION (TIMI) TRIAL, PHASE-I - A COMPARISON BETWEEN INTRAVENOUS TISSUE PLASMINOGEN-ACTIVATOR AND INTRAVENOUS STREPTOKINASE - CLINICAL FINDINGS THROUGH HOSPITAL DISCHARGE
    CHESEBRO, JH
    KNATTERUD, G
    ROBERTS, R
    BORER, J
    COHEN, LS
    DALEN, J
    DODGE, HT
    FRANCIS, CK
    HILLIS, D
    LUDBROOK, P
    MARKIS, JE
    MUELLER, H
    PASSAMANI, ER
    POWERS, ER
    RAO, AK
    ROBERTSON, T
    ROSS, A
    RYAN, TJ
    SOBEL, BE
    WILLERSON, J
    WILLIAMS, DO
    ZARET, BL
    BRAUNWALD, E
    [J]. CIRCULATION, 1987, 76 (01) : 142 - 154
  • [10] Coller BS, 1997, THROMB HAEMOSTASIS, V78, P730