Agents and Actions

, Volume 21, Issue 1–2, pp 195–202 | Cite as

Antagonists of PAF-acether do not suppress thrombin-induced aggregation of ADP-deprived and aspirin-treated human platelets

  • S. Adnot
  • D. Joseph
  • B. B. Vargaftig
Platelets and Thrombosis


Four chemically distinct PAF-acether antagonists were used to test the hypothesis that the cyclooxygenase and ADP-independent thrombin-induced aggregation of human platelets is due to PAF-acether. The compouds 48740 RP, CV-3988, BN 52021 and Ro 19-3704 inhibited aggregation by PAF-acether whereas 48740 RP also interfered with aggregation by arachidonic acid, U 46619, collagen and thrombin. Aspirin-treated platelets aggregated in response to PAF-acether and to 0.25 U/ml thrombin as much as control platelets in absence of detectable thromboxane A2, and were less responsive to 0.05–0.1 U/ml. Thrombin-induced aggregation of aspirin-treated platelets was unaffected by the PAF-acether antagnists BN 52021, CV-3988 and Ro 19-3704. In separate experiments, platelets were exposed for five min to convulxin, a glycoprotein extracted from a snake venom which depletes granular ADP and ATP. A combination of PGI2, aspirin and anticrotalid serum used to disaggregate allowed the recovery of approximately 80% free platelets, which failed to respond to PAF-acether but still aggregated in presence of thrombin. This residual ADP and cyclooxygenase-independent aggregation is not accountable for by the platelet formation of PAF-acether, since it was not modified by the latters' antagonists nor by platelet exposure to convulxin. Our results do not support the proposal that PAF-acether mediates a third pathway of human platelet aggregation.


Collagen Aspirin Arachidonic Acid Thrombin Platelet Aggregation 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. [1]
    J. Benveniste, P. M. Henson and C. G. Cochrane,Leukocyte-dependent histamine release from rabbit platelets: the role of IgE, basophils and platelet-activating factor. J. exp. Med.136, 1356–1376 (1972).Google Scholar
  2. [2]
    B. B. Vargaftig,Carrageenan and thrombin trigger prostaglandin synthetase-independent aggregation of rabbit platelets: inhibition by phospholipase A2 inhibitors. J. Pharm. Pharmacol.29, 222–228 (1977).Google Scholar
  3. [3]
    E. G. Lapetina, K. A. Chandrabose and P. Cuatreacasas,Ionophore A23187 and thrombin-induced platelet aggregation: independence from cyclooxygenase products. Proc. Natl. Acad. Sci. USA75, 818–822 (1978).Google Scholar
  4. [4]
    R. M. L. Kinlough-Rathbone, P. A. Packham, H. J. Reimers, J. P. Cazenave and J. F. Mustard,Mechanisms of platelet shape change, aggregation and release induced by collagen, thrombin, or A23187. J. Lab. Clin. Med.90, 707–719 (1977).Google Scholar
  5. [5]
    M. Chignard, J. P. Le Couedic, M. Tence, B. B. Vargaftig and J. Benveniste,The role of platelet-activating factor in platelet aggregation. Nature279, 788–800 (1979).Google Scholar
  6. [6]
    M. Chignard, J. P. Le Couedic, M. Tence, B. B. Vargaftig and J. Benveniste,Platelet-activating factor (PAF-acether) secretion from platelets: effects of aggregating agents. Brit. J. Haematol.46, 455–464 (1980).Google Scholar
  7. [7]
    L. Touqui, M. Hatmi and B. B. Vargaftig,Human platelets stimulated by thrombin produce PAF-acether (1-0-alkyl-2-acetyl-sn-glycero-3-phosphocholine) when the degradating enzyme acetyl hydrolase is blocked. Biochem. J.230, 811–816 (1985).Google Scholar
  8. [8]
    Z. I. Terashita, S. Tsushima, Y. Yoshioka, H. Nomura, Y. Inada and K. Nishikawa,CV-3988, a specific antagonist of platelet-activating factor. Life Sci.32, 1957–1982 (1983).Google Scholar
  9. [9]
    K. Burri, B. Barner, J. M. Cassal, P. Hadvary, G. Hirth and K. Muller,PAF: from agonists to antagonists by synthesis. Prostaglandins30, 691 (1985).Google Scholar
  10. [10]
    P. Sédivy, C. G. Caillard, A. Floch, F. Folliard, S. Mondot, C. Robaut and B. Terlain,48740 RP: a specific PAF-acether antagonist. Prostaglandins30, 688 (1985).Google Scholar
  11. [11]
    P. Braquet, GB Patent 8, 418, 424, July 19 (1984).Google Scholar
  12. [12]
    G. Marlas,Purification and preliminary structure of a potent platelet aggregating glycoprotein isolated from the venom of Crotalus durissus cascavella. Toxicon20, n° 1, 289–290 (1982).Google Scholar
  13. [13]
    B. B. Vargaftig, D. Joseph, F. Wal, G. Marlas, M. Chignard and L. G. Chevance,Convulxin-induced activation of intact and of thrombin-degranulated rabbit platelets: specific crossed desensitization with collagen. Eur. J. Pharmac.92, 57–68 (1983).Google Scholar
  14. [14]
    H. J. Reimers, R. L. Kinlough-Rathbone, J. P. Cazenave, A. F. Senyi, J. Hirsh, A. Packham and J. F. Mustard,In vitro and in vivo functions, of thrombin-treated platelets.Thromb. Haemostas. 35, 151–165 (1976).Google Scholar
  15. [15]
    F. Fouque and B. B. Vargaftig,Triggering by platelet-activating factor and adrenaline of cyclooxygenase-independent platelet aggregation. Br J. Pharmac.83, 625–633 (1984).Google Scholar
  16. [16]
    C. Lalau-Keraly and J. Benveniste,Specific desensitization of rabbit platelets by platelet-activating factor (PAF-acether) and derivatives. Br. H. Haematol.,51, 313–322 (1982).Google Scholar
  17. [17]
    F. Wal, D. Joseph, L. Touqui and B. B. Vargaftig,PAF-acether may not mediate the third pathway of platelet aggregation since self-desensitization reduces the effects of low thrombin but enhances those of convulxin. Thromb. Haemost.53, 99–104 (1985).Google Scholar
  18. [18]
    L. Touqui, M. Chignard, C. Jacquemin, F. Wal and B. B. Vargaftig,Dissociation between inhibition of phospholipid methylation and production of PAF-acether by rabbit platelets. Experientia,40, 374–377 (1984).Google Scholar
  19. [19]
    J. Westwick, G. Mark and V. V. Kakkar,The role of platelet-activating factor (PAF) in cyclo-oxygenase independent thrombin and collagen-induced platelet activation. J. Pharmacol. (Paris)14, 61 Abst (1985).Google Scholar
  20. [20]
    T. J. Hallam, M. C. Scrutton and R. B. Wallis,The role of 1-alkyl-2-acetyl-sn-glyceryl-3-phosphorylcholine (AcGEPC) and palmitoyl-lysophosphatidate in the responses of human blood platelets to collagen and thrombi. FEBS Letters162, 142–146 (1983).Google Scholar
  21. [21]
    E. Kloprogge, G. H. de Hass, G. Gorter and J. W. N. Akkerman,Stimulus-response coupling in human platelets. Evidence against a role of PAF-Acether in the “Third Pathway”. Thromb. Res.30, 107–112 (1983).Google Scholar
  22. [22]
    B. B. Vargaftig, M. Chignard, J. Benveniste, J. Lefort and F. Wal,Background and present status of research on platelet-activating factor (PAF-acether). Ann. N.Y. Acad. Sci.370, 119–137 (1981).Google Scholar
  23. [23]
    J. Benveniste and B. B. Vargaftig,Platelet activating factor: an, ether lipid with biological activity. In:Ether Lipids: biochemical and biomedical aspects. (Eds. H. K. Mangold and F. Pantolf), Amsterdam, Elsevier 1983, pp. 355–373.Google Scholar

Copyright information

© Birkhäuser Verlag 1987

Authors and Affiliations

  • S. Adnot
    • 1
  • D. Joseph
    • 1
  • B. B. Vargaftig
    • 1
  1. 1.Untté des Venins-Unité Associée Institut Pasteur/INSERM n° 285 Department de Physiopathologie expérimentale Institut PasteurParisFrance

Personalised recommendations