Skip to main content
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1975 Apr;72(4):1446–1450. doi: 10.1073/pnas.72.4.1446

Physiological role of an endoperoxide in human platelets: hemostatic defect due to platelet cyclo-oxygenase deficiency.

C Malmsten, M Hamberg, J Svensson, B Samuelsson
PMCID: PMC432552  PMID: 1055417

Abstract

The endoperoxide prostaglandin G2 (PGG2) induced platelet aggregation as well as the platelet release reaction (release of ADP and serotonin) when added to human platelet-rich plasma. Formation of a metabolite of PGG2 [8-(l-hydroxy-3-oxopropyl)-9,12L-dihydroxy-5,10-heptadecadienoic acid] and a lipoxygenase product [12L-hydroxy-5,8,10,14-eicosatetraenoic acid] accompanied the release reaction caused by aggregating agents such as collagen, ADP, epinephrine, and thrombin. Indomethacin inhibited the release reaction and PGG2 formation induced by these agents but had no effect on PGG2-induced release reaction. The aggregating effect of PGG2 was abolished by furosemide, which is a competitive inhibitor of ADP-induced primary aggregation. These data indicate that the aggregating effect of PGG2 is due to release of ADP and that PGG2 synthesis is required for induction of the release reaction by various aggregating agents. A subject with a hemostatic defect due to abnormal release mechanism [decreased aggregation with epinephrine (second wave) and collagen and normal platelet ADP] had a deficiency of the cyclo-oxygenase that catalyzes formation of PGG2. Normal aggregation and release reaction were obtained with added PGG2. Ii is concluded that the endoperoxide (PGG2) is essential in normal hemostasis because of its role in initiating the release reaction required for aggregation by collagen and the second wave of aggregation caused by, e.g., ADP.

Full text

PDF
1446

Images in this article

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bruno J. J., Taylor L. A., Droller M. J. Effects of prostaglandin E2 on human platelet adenyl cyclase and aggregation. Nature. 1974 Oct 25;251(5477):721–723. doi: 10.1038/251721a0. [DOI] [PubMed] [Google Scholar]
  2. Hamberg M., Samuelsson B. Detection and isolation of an endoperoxide intermediate in prostaglandin biosynthesis. Proc Natl Acad Sci U S A. 1973 Mar;70(3):899–903. doi: 10.1073/pnas.70.3.899. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Hamberg M., Samuelsson B. Prostaglandin endoperoxides. Novel transformations of arachidonic acid in human platelets. Proc Natl Acad Sci U S A. 1974 Sep;71(9):3400–3404. doi: 10.1073/pnas.71.9.3400. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Hamberg M., Samuelsson B. Prostaglandin endoperoxides. VII. Novel transformations of arachidonic acid in guinea pig lung. Biochem Biophys Res Commun. 1974 Dec 11;61(3):942–949. doi: 10.1016/0006-291x(74)90246-0. [DOI] [PubMed] [Google Scholar]
  5. Hamberg M., Svensson J., Samuelsson B. Prostaglandin endoperoxides. A new concept concerning the mode of action and release of prostaglandins. Proc Natl Acad Sci U S A. 1974 Oct;71(10):3824–3828. doi: 10.1073/pnas.71.10.3824. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Hamberg M., Svensson J., Wakabayashi T., Samuelsson B. Isolation and structure of two prostaglandin endoperoxides that cause platelet aggregation. Proc Natl Acad Sci U S A. 1974 Feb;71(2):345–349. doi: 10.1073/pnas.71.2.345. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Holmsen H., Weiss H. J. Further evidence for a deficient storage pool of adenine nucleotides in platelets from some patients with thrombocytopathia--"storage pool disease". Blood. 1972 Feb;39(2):197–209. [PubMed] [Google Scholar]
  8. Kloeze J. Relationship between chemical structure and platelet-aggregation activity of prostaglandins. Biochim Biophys Acta. 1969 Oct 28;187(3):285–292. doi: 10.1016/0005-2760(69)90001-0. [DOI] [PubMed] [Google Scholar]
  9. Rossi E. C., Levin N. W. Inhibition of ADP-induced platelet aggregation by furosemide. J Lab Clin Med. 1973 Jan;81(1):140–147. [PubMed] [Google Scholar]
  10. Salzman E. W., Kensler P. C., Levine L. Cyclic 3',5'-adenosine monophosphate in human blood platelets. IV. Regulatory role of cyclic amp in platelet function. Ann N Y Acad Sci. 1972 Oct 27;201:61–71. doi: 10.1111/j.1749-6632.1972.tb16287.x. [DOI] [PubMed] [Google Scholar]
  11. Shio H., Ramwell P. Effect of prostaglandin E 2 and aspirin on the secondary aggregation of human platelets. Nat New Biol. 1972 Mar 15;236(63):45–46. doi: 10.1038/newbio236045a0. [DOI] [PubMed] [Google Scholar]
  12. Silver M. J., Smith J. B., Ingerman C., Kocsis J. J. Arachidonic acid-induced human platelet aggregation and prostaglandin formation. Prostaglandins. 1973 Dec;4(6):863–875. doi: 10.1016/0090-6980(73)90121-4. [DOI] [PubMed] [Google Scholar]
  13. Smith J. B., Ingerman C., Kocsis J. J., Silver M. J. Formation of an intermediate in prostaglandin biosynthesis and its association with the platelet release reaction. J Clin Invest. 1974 May;53(5):1468–1472. doi: 10.1172/JCI107695. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Smith J. B., Ingerman C., Kocsis J. J., Silver M. J. Formation of prostaglandins during the aggregation of human blood platelets. J Clin Invest. 1973 Apr;52(4):965–969. doi: 10.1172/JCI107262. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Vargaftig B. B., Zirinis P. Platelet aggregation induced by arachidonic acid is accompanied by release of potential inflammatory mediators distinct from PGE2 and PGF2. Nat New Biol. 1973 Jul 25;244(134):114–116. doi: 10.1038/newbio244114a0. [DOI] [PubMed] [Google Scholar]
  16. Weiss H. J. Platelet aggregation, adhesion and adenosine diphosphate release in thrombopathia (platelet factor 3 deficiency). A comparison with Glanzmann's thrombasthenia and von Willebrand's disease. Am J Med. 1967 Oct;43(4):570–578. doi: 10.1016/0002-9343(67)90180-5. [DOI] [PubMed] [Google Scholar]
  17. Weiss H. J., Rogers J. Thrombocytopathia due to abnormalities in platelet release reaction--studies on six unrelated patients. Blood. 1972 Feb;39(2):187–196. [PubMed] [Google Scholar]
  18. Willis A. L. An enzymatic mechanism for the antithrombotic and antihemostatic actions of aspirin. Science. 1974 Jan 25;183(4122):325–327. doi: 10.1126/science.183.4122.325. [DOI] [PubMed] [Google Scholar]
  19. Willis A. L. Isolation of a chemical trigger for thrombosis. Prostaglandins. 1974 Jan 10;5(1):1–25. doi: 10.1016/s0090-6980(74)80126-7. [DOI] [PubMed] [Google Scholar]
  20. Willis A. L., Weiss H. J. A congenital defect in platelet prostaglandin production associated with impaired hemostasis in storage pool disease. Prostaglandins. 1973 Dec;4(6):783–794. doi: 10.1016/0090-6980(73)90114-7. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES