Skip to main content

Advertisement

SpringerLink
Log in

Effects of SolCD39, a Novel Inhibitor of Platelet Aggregation, on Platelet Deposition and Aggregation after PTCA in a Porcine Model

  • Published:
Journal of Thrombosis and Thrombolysis Aims and scope Submit manuscript

Abstract

Introduction: This study evaluated CD39 in a porcine model of balloon angioplasty and in plasma of patients undergoing percutaneous intervention. CD39 (E-NTPDase1), is the endothelial ecto-ADPase inhibiting platelet function via hydrolysis of released platelet ADP.

Methods and Results: A recombinant soluble form of CD39 (solCD39) given intravenously to pigs had an elimination half life of 5–7 days, increased the bleeding time to an extent similar to aspirin, and inhibits platelet aggregation by > 90%. Platelet counts and clot retraction remained normal following solCD39 administration. In a pig model of acute coronary balloon injury, solCD39 resulted in non-statistically significant decreases in platelet (7.7 ± 1.4 versus 11.7 ± 3.4) and fibrin (3.5 ± 0.4 versus 4.2 ± 0.7) deposition ratios. Adding ex vivo to human platelet rich plasma (PRP) solCD39 produced nearly 100% inhibition of ADP-induced platelet aggregation. A dose-response effect of solCD39 on platelet aggregation induced by collagen or a thrombin receptor activating peptide (TRAPSFLLRN) was noted in PRP obtained from volunteers and patients receiving aspirin, clopidogrel or ticlopidine. SolCD39 also provided additional and complete inhibition of TRAP-induced platelet aggregation in PRP from patients who had received abciximab, aspirin and clopidogrel.

Conclusions: SolCD39, a novel inhibitor of platelet activation and recruitment with a relatively long half-life appears to be well tolerated and is a potent inhibitor of ADP-, collagen-, or TRAP-induced platelet activation. Its potential use in percutaneous coronary intervention requires further study.

Abbreviated Abstract. E-NTPDase1/CD39 is the endothelial ecto-ADPase responsible for inhibition of platelet function. A recombinant soluble form (solCD39) had an elimination half life of 5–7 days in pigs, elevated bleeding times similar to aspirin, did not affect clot retraction, and inhibited platelet aggregation by > 90%. When combined with standard heparin therapy in a pig model of acute coronary balloon injury, solCD39 resulted in a trend toward a decrease in platelet and fibrin deposition. SolCD39 added ex vivo to human platelet rich plasma yielded nearly 100% inhibition of ADP-induced platelet aggregation and provided further inhibition when combined with standard therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Fitzgerald DJ, Roy L, Catella F, Fitzgerald GA. Platelet activation in unstable coronary disease. N Engl J Med 1986;315:983–989.

    PubMed  Google Scholar 

  2. Marcus AJ. Platelets: Their role in hemostasis, thrombosis, and inflammation. In: Gallin JI, Snyderman R, eds. Inflammation: Basic Principles and Clinical Correlates. Philadelphia, PA: Lippincott Williams and Wilkins, 1999:77–95.

    Google Scholar 

  3. Marcus AJ, Safier LB, Hajjar KA, et al. Inhibition of platelet function by an aspirin-insensitive endothelial cell ADPase. Thromboregulation by endothelial cells. J Clin Invest 1991;88:1690–1696.

    PubMed  Google Scholar 

  4. Marcus AJ, Broekman MJ, Drosopoulos JH, et al. The endothelial cell ecto-ADPase responsible for inhibition of platelet function is CD39. J Clin Invest 1997;99:1351–1360.

    PubMed  Google Scholar 

  5. Kansas GS, Wood GS, Tedder TF. Expression, distribution, and biochemistry of human CD39. Role in activation-associated homotypic adhesion of lymphocytes. J Immunol 1991;146:2235–2244.

    PubMed  Google Scholar 

  6. Ling NR, Hardie D, Lowe J, Johnson GD, Khan M, MacLennan IC. A phenotypic study of cells from Burkitt lymphoma and EBV-B- lymphoblastoid lines and their relationship to cells in normal lymphoid tissues. Int J Cancer 1989;43:112–118.

    PubMed  Google Scholar 

  7. Rowe M, Hildreth JE, Rickinson AB, Epstein MA. Monoclonal antibodies to Epstein-Barr virus-induced, transformation- associated cell surface antigens: Binding patterns and effect upon virus-specific T-cell cytotoxicity. Int J Cancer 1982;29:373–381.

    PubMed  Google Scholar 

  8. Gayle RB, Maliszewski CR, Gimpel SD, et al. Inhibition of platelet function by recombinant soluble ecto-ADPase/CD39. J Clin Invest 1998;101:1851–1859.

    PubMed  Google Scholar 

  9. Mertz ET. The anomaly of a normal Duke’s and a very prolonged saline bleeding time in swine suffering from an inherited bleeding disease. Am J Physiol 1942;136:360–362.

    Google Scholar 

  10. Doettl K, Ripke O. Medicine in its Chemical Aspects. Bayer, Leverkusen, Germany, 1938:252.

  11. Bowie EJ, Owen CA, Zollman PE, Zollman PE, Thompson JH, Fass DN. Tests of hemostasis in swine: Normal values and values in pigs affected with von Willebrand’s disease. Am J Vet Res 1973;34:1405–1407.

    PubMed  Google Scholar 

  12. Dewanjee MK, Rao SA, Didisheim P. Indium-111 tropolone, a new high-affinity platelet label: Preparation and evaluation of labeling parameters. J Nucl Med 1981;22:981–987.

    PubMed  Google Scholar 

  13. Dewanjee MK, Tago M, Josa M, Fuster V, Kaye MP. Quantification of platelet retention in aortocoronary femoral vein bypass graft in dogs treated with dipyridamole and aspirin. Circulation 1984;69:350–356.

    PubMed  Google Scholar 

  14. Pinsky DJ, Broekman MJ, Peschon JJ, et al. Elucidation of the thromboregulatory role of CD39/ectoapyrase in the ischemic brain. J Clin Invest 2002;109:1031–1040.

    Article  PubMed  Google Scholar 

  15. Drosopoulos JH, Broekman MJ, Islam N, Maliszewski CR, Gayle RB 3rd, Marcus AJ. Site-directed mutagenesis of human endothelial cell ecto-ADPase/soluble CD39: Requirement of glutamate 174 and serine 218 for enzyme activity and inhibition of platelet recruitment. Biochemistry 2000;39:6936–6943.

    Article  PubMed  Google Scholar 

  16. Gangadharan SP, Imai M, Rhynhart KK, Sevigny J, Robson SC, Conte MS. Targeting platelet aggregation: CD39 gene transfer augments nucleoside triphosphate diphosphohydrolase activity in injured rabbit arteries. Surgery 2001;130:296–303.

    Article  PubMed  Google Scholar 

  17. Bertrand ME, Rupprecht HJ, Urban P, Gershlick AH, Investigators FT, Double-blind study of the safety of clopidogrel with and without a loading dose in combination with aspirin compared with ticlopidine in combination with aspirin after coronary stenting: The clopidogrel aspirin stent international cooperative study (CLASSICS). Circulation 2000;102:624–629.

    PubMed  Google Scholar 

  18. Mehta SR, Yusuf S, Peters RJ, et al. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: The PCI-CURE study. Lancet 2001;358:527–533.

    Article  PubMed  Google Scholar 

  19. Gachet C. ADP receptors of platelets and their inhibition. Thromb Haemost 2001;86:222–232.

    PubMed  Google Scholar 

  20. Turner NA, Moake JL, McIntire LV. Blockade of adenosine diphosphate receptors P2Y(12) and P2Y(1) is required to inhibit platelet aggregation in whole blood under flow. Blood 2001;98:3340–3345.

    Article  PubMed  Google Scholar 

  21. Imai M, Takigami K, Guckelberger O, et al. Recombinant adenoviral mediated CD39 gene transfer prolongs cardiac xenograft survival. Transplantation 2000;70:864–870.

    Article  PubMed  Google Scholar 

  22. Goepfert C, Imai M, Brouard S, Csizmadia E, Kaczmarek E, Robson SC. CD39 modulates endothelial cell activation and apoptosis. Mol Med 2000;6:591–603.

    PubMed  Google Scholar 

  23. Sesti C, Broekman MJ, Drosopoulos JH, Islam N, Marcus AJ, Levi R. EctoNucleotidase in cardiac sympathetic nerve endings modulates ATP-mediated feedback of norepinephrine release. J Pharmacol Exp Ther 2002;300:605–611.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Section of Cardiology, Department of Medicine, Baylor College of Medicine, The Methodist DeBakey Heart Center, Houston, TX

    John M. Buergler MD, Grzegorz L. Kaluza MD, Daryl G. Schulz RTR, Albert E. Raizner MD, Neal S. Kleiman MD & Nadir M. Ali MD

  2. Immunex Corporation, Seattle, WA

    Charles R. Maliszewski PhD

  3. Divisions of Hematology and Medical Oncology, Departments of Medicine, VA New York Harbor Healthcare System and Weill Cornell Medical College, New York, NY

    M. Johan Broekman PhD & Aaron J. Marcus

  4. Department of Pathology, Weill Cornell Medical College, New York, NY

    Aaron J. Marcus

  5. The Methodist DeBakey Heart Center, Baylor College of Medicine, 6535 Fannin, Rm. F1034, Houston, TX, 77030

    John M. Buergler MD

Authors
  1. John M. Buergler MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Charles R. Maliszewski PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M. Johan Broekman PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Grzegorz L. Kaluza MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Daryl G. Schulz RTR
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Aaron J. Marcus
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Albert E. Raizner MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Neal S. Kleiman MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Nadir M. Ali MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to John M. Buergler MD.

Additional information

Supported in part by a Merit Review grant from the Department of Veterans Affairs (A.J.M., M.J.B.), and by National Institutes of Health grants HL 47073, HL 46403, and NS 41462 (A.J.M., M.J.B.) and by Immunex Corp., Seattle, WA.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Buergler, J.M., Maliszewski, C.R., Broekman, M.J. et al. Effects of SolCD39, a Novel Inhibitor of Platelet Aggregation, on Platelet Deposition and Aggregation after PTCA in a Porcine Model. J Thromb Thrombolysis 19, 115–122 (2005). https://doi.org/10.1007/s11239-005-1381-y

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11239-005-1381-y

Key Words

Search

Navigation