(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
This article has been cited by other articles:
 |
|
 |
|
  Y. Furukawa, E. Umemoto, M. H. Jang, K. Tohya, M. Miyasaka, and T. Hirata Identification of Novel Isoforms of Mouse L-selectin with Different Carboxyl-terminal Tails J. Biol. Chem., May 2, 2008; 283(18): 12112 - 12119. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. W. Bedard, V. Clerin, N. Sushkova, B. Tchernychev, T. Antrilli, C. Resmini, J. C. Keith Jr., J. K. Hennan, N. Kaila, S. DeBernardo, et al. Characterization of the Novel P-Selectin Inhibitor PSI-697 [2-(4-Chlorobenzyl)-3-hydroxy-7,8,9,10-tetrahydrobenzo[h] Quinoline-4-carboxylic acid] in Vitro and in Rodent Models of Vascular Inflammation and Thrombosis J. Pharmacol. Exp. Ther., February 1, 2008; 324(2): 497 - 506. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Pendu, V. Terraube, O. D. Christophe, C. G. Gahmberg, P. G. de Groot, P. J. Lenting, and C. V. Denis P-selectin glycoprotein ligand 1 and beta2-integrins cooperate in the adhesion of leukocytes to von Willebrand factor Blood, December 1, 2006; 108(12): 3746 - 3752. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Xiao, H. L. Goldsmith, F. A. McIntosh, H. Shankaran, and S. Neelamegham Biomechanics of P-Selectin PSGL-1 Bonds: Shear Threshold and Integrin-Independent Cell Adhesion Biophys. J., March 15, 2006; 90(6): 2221 - 2234. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. del Conde, C. N. Shrimpton, P. Thiagarajan, and J. A. Lopez Tissue-factor-bearing microvesicles arise from lipid rafts and fuse with activated platelets to initiate coagulation Blood, September 1, 2005; 106(5): 1604 - 1611. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Wang, X. Zhou, Z. Zhou, N. Mal, L. Fan, M. Zhang, A. M. Lincoff, E. F. Plow, E. J. Topol, and M. S. Penn Platelet, Not Endothelial, P-Selectin Is Required for Neointimal Formation After Vascular Injury Arterioscler. Thromb. Vasc. Biol., August 1, 2005; 25(8): 1584 - 1589. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Martinez, M. Joffraud, S. Giraud, B. Baisse, M. P. Bernimoulin, M. Schapira, and O. Spertini Regulation of PSGL-1 Interactions with L-selectin, P-selectin, and E-selectin: ROLE OF HUMAN FUCOSYLTRANSFERASE-IV AND -VII J. Biol. Chem., February 18, 2005; 280(7): 5378 - 5390. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Hirata, Y. Furukawa, B.-G. Yang, K. Hieshima, M. Fukuda, R. Kannagi, O. Yoshie, and M. Miyasaka Human P-selectin Glycoprotein Ligand-1 (PSGL-1) Interacts with the Skin-associated Chemokine CCL27 via Sulfated Tyrosines at the PSGL-1 Amino Terminus J. Biol. Chem., December 10, 2004; 279(50): 51775 - 51782. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Hansen, A. Kumar, D. Wolf, K. Frankenbergerova, A. Filusch, M.-L. Gross, S. Mueller, H. Katus, and H. Kuecherer Evaluation of cardioprotective effects of recombinant soluble P-selectin glycoprotein ligand-immunoglobulin in myocardial ischemia-reperfusion injury by real-time myocardial contrast echocardiography J. Am. Coll. Cardiol., August 18, 2004; 44(4): 887 - 891. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Yanaba, K. Komura, M. Horikawa, Y. Matsushita, K. Takehara, and S. Sato P-selectin glycoprotein ligand-1 is required for the development of cutaneous vasculitis induced by immune complex deposition J. Leukoc. Biol., August 1, 2004; 76(2): 374 - 382. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K Yanaba, K Takehara, and S Sato Serum concentrations of soluble P-selectin glycoprotein ligand-1 are increased in patients with systemic sclerosis: association with lower frequency of pulmonary fibrosis Ann Rheum Dis, May 1, 2004; 63(5): 583 - 587. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. A. Lopez, C. Kearon, and A. Y.Y. Lee Deep Venous Thrombosis Hematology, January 1, 2004; 2004(1): 439 - 456. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. D. Wagner and P. C. Burger Platelets in Inflammation and Thrombosis Arterioscler. Thromb. Vasc. Biol., December 1, 2003; 23(12): 2131 - 2137. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. E. R. Hicks, S. L. Nolan, V. C. Ridger, P. G. Hellewell, and K. E. Norman Recombinant P-selectin glycoprotein ligand-1 directly inhibits leukocyte rolling by all 3 selectins in vivo: complete inhibition of rolling is not required for anti-inflammatory effect Blood, April 15, 2003; 101(8): 3249 - 3256. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. S. Sabatine, D. A. Morrow, C. P. Cannon, S. A. Murphy, L. A. Demopoulos, P. M. DiBattiste, C. H. McCabe, E. Braunwald, and C. M. Gibson Relationship between baseline white blood cell count and degree of coronary artery disease and mortality in patients with acute coronary syndromes: A TACTICS-TIMI 18 substudy J. Am. Coll. Cardiol., November 20, 2002; 40(10): 1761 - 1768. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. J. M. Molenaar, C. C. M. Appeldoorn, S. A. M. de Haas, I. N. Michon, A. Bonnefoy, M. F. Hoylaerts, H. Pannekoek, T. J. C. van Berkel, J. Kuiper, and E. A. L. Biessen Specific inhibition of P-selectin-mediated cell adhesion by phage display-derived peptide antagonists Blood, November 15, 2002; 100(10): 3570 - 3577. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Gasser, A. Maria Waaga, J. E. Kist-Van Holthe, S. M. Lenhard, I. Laskowski, G. D. Shaw, W. W. Hancock, and N. L. Tilney Normalization of Brain Death--Induced Injury to Rat Renal Allografts by Recombinant Soluble P-Selectin Glycoprotein Ligand J. Am. Soc. Nephrol., July 1, 2002; 13(7): 1937 - 1945. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. J. Shebuski and K. S. Kilgore Role of Inflammatory Mediators in Thrombogenesis J. Pharmacol. Exp. Ther., March 1, 2002; 300(3): 729 - 735. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Piccio, B. Rossi, E. Scarpini, C. Laudanna, C. Giagulli, A. C. Issekutz, D. Vestweber, E. C. Butcher, and G. Constantin Molecular Mechanisms Involved in Lymphocyte Recruitment in Inflamed Brain Microvessels: Critical Roles for P-Selectin Glycoprotein Ligand-1 and Heterotrimeric Gi-Linked Receptors J. Immunol., February 15, 2002; 168(4): 1940 - 1949. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Wang, Z. Zhou, X. Zhou, K. Tarakji, E. J. Topol, and A. M. Lincoff Prevention of intimal hyperplasia with recombinant soluble P-selectin glycoprotein ligand-immunoglobulin in the porcine coronary artery balloon injury model J. Am. Coll. Cardiol., August 1, 2001; 38(2): 577 - 582. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-F. Theoret, J.-G. Bienvenu, A. Kumar, and Y. Merhi P-Selectin Antagonism with Recombinant P-Selectin Glycoprotein Ligand-1 (rPSGL-Ig) Inhibits Circulating Activated Platelet Binding to Neutrophils Induced by Damaged Arterial Surfaces J. Pharmacol. Exp. Ther., August 1, 2001; 298(2): 658 - 664. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Van de Werf New aspects of pharmacological reperfusion: from macro- to microlysis Eur. Heart J. Suppl., June 1, 2001; 3(suppl_C): C62 - C68. [Abstract] [PDF]
|
|
|
|
 |
|
 J.-G. Bienvenu, J.-F. Tanguay, J.-F. Theoret, A. Kumar, R. G. Schaub, and Y. Merhi Recombinant Soluble P-Selectin Glycoprotein Ligand-1-Ig Reduces Restenosis Through Inhibition of Platelet-Neutrophil Adhesion After Double Angioplasty in Swine Circulation, February 27, 2001; 103(8): 1128 - 1134. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. André, D. Hartwell, I. Hrachovinová, S. Saffaripour, and D. D. Wagner Pro-coagulant state resulting from high levels of soluble P-selectin in blood PNAS, November 22, 2000; (2000) 250475997. [Abstract] [Full Text]
|
|
|
|
|
|
S. P. Khor, K. McCarthy, M. DuPont, K. Murray, and G. Timony Pharmacokinetics, Pharmacodynamics, Allometry, and Dose Selection of rPSGL-Ig for Phase I Trial J. Pharmacol. Exp. Ther., May 1, 2000; 293(2): 618 - 624. [Abstract] [Full Text]
|
|
|
|
 |
|
 P. S. Frenette, C. V. Denis, L. Weiss, K. Jurk, S. Subbarao, B. Kehrel, J. H. Hartwig, D. Vestweber, and D. D. Wagner P-Selectin Glycoprotein Ligand 1 (PSGL-1) Is Expressed on Platelets and Can Mediate Platelet-Endothelial Interactions In Vivo J. Exp. Med., April 18, 2000; 191(8): 1413 - 1422. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Leppanen, P. Mehta, Y.-B. Ouyang, T. Ju, J. Helin, K. L. Moore, I. van Die, W. M. Canfield, R. P. McEver, and R. D. Cummings A Novel Glycosulfopeptide Binds to P-selectin and Inhibits Leukocyte Adhesion to P-selectin J. Biol. Chem., August 27, 1999; 274(35): 24838 - 24848. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Xie, A.-S. Rivier, A. Zakrzewicz, M. Bernimoulin, X.-L. Zeng, H. P. Wessel, M. Schapira, and O. Spertini Inhibition of Selectin-mediated Cell Adhesion and Prevention of Acute Inflammation by Nonanticoagulant Sulfated Saccharides. STUDIES WITH CARBOXYL-REDUCED AND SULFATED HEPARIN AND WITH TRESTATIN A SULFATE J. Biol. Chem., October 27, 2000; 275(44): 34818 - 34825. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Andre, D. Hartwell, I. Hrachovinova, S. Saffaripour, and D. D. Wagner Pro-coagulant state resulting from high levels of soluble P-selectin in blood PNAS, December 5, 2000; 97(25): 13835 - 13840. [Abstract] [Full Text] [PDF]
|
|