Skip to main content
SpringerLink
Log in

Disaggregation and reaggregation of ‘irreversibly’ aggregated platelets: A method for more complete evaluation of anti-platelet drugs

  • Platelets and Thrombosis
  • Published:
Agents and Actions Aims and scope Submit manuscript

Abstract

Anti-platelet drugs are generally screened by evaluating their ability to influence initiation and development of irreversible aggregation of platelets. However, to fully characterize the inhibitory effects of an agent, it is essential to determine if it can also disperse irreversibly aggregated cells, whether drug-treated, dispersed platelets are refractory, sensitive to some but not all aggregating agents, as sensitive to all agents as before initial exposure, hypersensitive or whether they can be restored to a sensitive state by modulation of the platelet membrane. We have developed anvitro system for evaluating the influence of a variety of agents on disaggregation and reaggregation of aggregated blood platelets. Results demonstrate that some agents which inhibit aggregation can also cause disaggregation, while others cannot. The ability to disaggregate is often selective, revealing a dependence on the nature of the agent causing aggregation, and the time after irreversible aggregation that the inhibitor is added. Agents that elevate intracellular cyclic adenosine monophosphate levels were potent inducers of platelet dissociation in aggregates caused by adenosine diphosphate. On the other hand, antimalarials, calmodulin complexing agents and phospholipase inhibitors caused dissociation of platelet aggregates, irrespective of the agonist used. By and large, the dissociated cells were refractory to the action of agonists. Restoration of the sensitivity of disaggregated platelets by treatment with epinephrine demonstrate an ability of inhibitor treated, refractory platelets to recover full functional capacity almost immediately. Thus, careful study of the effects of inhibitors on disaggregation, recovery and reaggregation may reveal features critical to the selection of anti-platelet drugs for clinical utilization.

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. J. Hirsh, Role of platelets in thrombosis: rationale for use of anti-platelet drugs. InMechanisms of Hemostasis and Thrombosis (EdsC.H. Mielke andR. Rodvien). Symposia Specialists, Miami 1978.

    Google Scholar 

  2. L.A. Harker, R. Ross andJ. Glomset,Role of platelet in atherogenesis, Ann. N.Y. Acad. Sci.275, 321–329 (1976).

    PubMed  Google Scholar 

  3. L.A. Harker andJ.L. Richie,The role of platelets in acute vascular events, Circulation62 (Suppl. V), V13-V18 (1980).

    PubMed  Google Scholar 

  4. M.A. Packham andJ.F. Mustard,Clinical pharmacology of platelets, Blood50, 555–573 (1977).

    PubMed  Google Scholar 

  5. J. Hirsh,Platelet inhibitors in the treatment of thrombosis, Clin. Invest. Med.1, 191–206 (1979).

    Google Scholar 

  6. A.S. Gallus andJ. Hirsh,Anti-thrombotic drugs, Part II, Drugs12, 132–146 (1976).

    PubMed  Google Scholar 

  7. H.J. Weiss,Platelet-active drugs in the secondary prevention of cardiovascular events: an overview, Circulation62 (Suppl. V), V41-V43 (1980).

    PubMed  Google Scholar 

  8. E. Genton,A perspective on platelet-suppressant drug treatment in coronary artery and cerebrovascular disease, Circulation62 (Suppl. V), V111-V121 (1980).

    PubMed  Google Scholar 

  9. E. Braunwald,Treatment of the patient after myocardial infarction: the past decade and the next, New Engl. J. Med.302, 290–293 (1980).

    PubMed  Google Scholar 

  10. G.V.R. Born,Quantitative investigations into the aggregation of blood platelets, J. Physiol., Lond.162, 67P-68P (1962).

    Google Scholar 

  11. R.D. Feinman, J. Lubowsky, I.F. Charo andM.P. Zabinski,The lumiaggregometer: a new instrument for simultaneous measurements of secretion and aggregation, J. Lab. clin. Med.90, 125–129 (1977).

    PubMed  Google Scholar 

  12. G.H.R. Rao, K.R. Reddy andJ.G. White,The influence of epinephrine on prostacyclin (PGI 2)induced dissociation of ADP aggregated platelets, Prost. and Med.4, 385–397 (1980).

    Article  Google Scholar 

  13. G.H.R. Rao, K.R. Reddy andJ.G. White,Influence of trifluoperazine on platelet aggregation and disaggregation, Prost. and Med.5, 221–234 (1980).

    Google Scholar 

  14. G.H.R. Rao andJ.G. White,Disaggregation and reaggregation of irreversibly aggregated platelets, Circulation62, 1053A (1980).

    Google Scholar 

  15. G.H.R. Rao andJ.G. White,Arachidonate metabolism and platelet disaggregation-reaggregation, Thromb. Haemostas.46, 856A (1981).

    Google Scholar 

  16. G.H.R. Rao, G.J. Johnson, K.R. Reddy andJ.G. White,Rapid return of cyclooxygenase active platelets in dogs after a single oral dose of aspirin, Prostaglandins22, 761–772 (1981).

    Article  PubMed  Google Scholar 

  17. J.G. White,The sub-membrane filaments of blood platelets, Amer. J. Path.56, 267–271 (1969).

    PubMed  Google Scholar 

  18. G.H.R. Rao, A.C. Cox, J.M. Gerrard andJ.G. White,Effects of 2,2′-dipyrydil and related compounds on platelet prostaglandin synthesis and platelet function, Biochim. biophys. Acta628, 468–479 (1980).

    PubMed  Google Scholar 

  19. M. Cattaneo, R.L. Kinlough-Rathbone, D.W. Perry, A. Chahil, J.D. Vickers, S.C.T. Lam, M.A. Packham andJ.F. Mustard,The inhibitory effects of exogenous arachidonic acid on rabbit platelet aggregation and the release reaction, Blood60, 1179–1187 (1984).

    Google Scholar 

  20. G.C. LeBreton andD.L. Venton,Thromboxane A 2 receptor antagonist selectively reverses platelet aggregation, Adv. Prost. and Thrombox. Res.6, 497–503 (1980).

    Google Scholar 

  21. E.J. Harfenist, M.A. Packham andJ.F. Mustard,Reversibility of the association of fibrinogen with rabbit platelets exposed to ADP, Blood56, 189–198 (1980).

    PubMed  Google Scholar 

  22. A. Morita, M. Mori, K. Hasegawa, K. Kojima andS. Koyabashi,Anti-platelet aggregating and disaggregating activities of 6,9-methano-PGI 2, Life Sci.27, 695–701 (1980).

    Article  PubMed  Google Scholar 

  23. J.F. Martin, A.J. Suggett, E. Leach andS. Moncada,The effect of prostacyclin on platelet aggregation and disaggregation in vivo, Thromb. Res.18, 749–751 (1980).

    Article  PubMed  Google Scholar 

  24. M. Rodomski, J. Swies andR.J. Gryglewski,Disaggregatory action of phosphodiesterase inhibitors, Pharmacol. Res. Comm.13, 41–47 (1981).

    Google Scholar 

  25. I. Aursnes,Preactivation and deactivation of blood platelets, Thromb. Haemostas.47, 3–4 (1982).

    Google Scholar 

  26. R.L. Kinlough-Rathbone, J.F. Mustard, D.W. Perry, E. Dejana, J.P. Cazenave, M.A. Packham andE.J. Harfenist,Factors influencing the deaggregation of human and rabbit platelets, Thromb. Haemostas.49, 162–167 (1983).

    Google Scholar 

  27. J.B. Smith,The prostanoids in hemostasis and thrombosis: a review, Am. J. Path.99, 743–766 (1980).

    PubMed  Google Scholar 

  28. Coronary Drug Project Research Group,Aspirin in coronary heart disease, J. Chron. Dis.29, 625–642 (1976).

    Google Scholar 

  29. Aspirin Myocardial Infarction Study Research Group,A randomized controlled trial of aspirin in persons recovered from myocardial infarction, J. Am. med. Ass.243, 661–669 (1980).

    Google Scholar 

  30. J. Hirsh,Platelet inhibitors in the treatment of thrombosis, Clin. Invest. Med.1, 191–206 (1979).

    Google Scholar 

  31. G.H.R. Rao, G.J. Johnson andJ.G. White,Influence of epinphrine on the aggregation response of aspirintreated platelets, Prost. and Med.5, 45–58 (1980).

    Article  Google Scholar 

  32. G.H.R. Rao, J.M. Gerrard, C.J. Witkop andJ.G. White,Platelet aggregation independent of ADP release or prostaglandin synthesis in patients with the Hermansky-Pudlak syndrome, Prost. and Med.6, 459–472 (1981).

    Article  Google Scholar 

  33. B.B. Vargaftig, F. Fouque, J. Benveniste andJ. Odiot,Adrenaline and PAF-acether synergize to trigger cyclooxygenase independent activation of plasma-free human platelets, Thromb. Res.28, 557–573 (1982).

    Article  PubMed  Google Scholar 

  34. A.C. Cox, R.C. Carroll, J.G. White andG.H.R. Rao,Recycling of platelet phosphorylation and cytoskeletal assembly, J. Cell Biol.98, 8–15 (1984).

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Departments of Laboratory Medicine & Pathology, University of Minnesota Health Sciences Center, Mayo Memorial Building, Box 198, 55455, Minneapolis, Minnesota, USA

    Gundu H. R. Rao & James G. White

  2. Department of Pediatrics, University of Minnesota Health Sciences Center, Mayo Memorial Building, Box 198, 55455, Minneapolis, Minnesota, USA

    Gundu H. R. Rao & James G. White

Authors
  1. Gundu H. R. Rao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. James G. White
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rao, G.H.R., White, J.G. Disaggregation and reaggregation of ‘irreversibly’ aggregated platelets: A method for more complete evaluation of anti-platelet drugs. Agents and Actions 16, 425–434 (1985). https://doi.org/10.1007/BF01982884

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01982884

Keywords

Search

Navigation