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Thromb Haemost 1977; 38(03): 0612-0619
DOI: 10.1055/s-0038-1651876
Original Article
Schattauer GmbH

The Effect of Halofenate – Free Acid on Aggregation – the Release Reaction, Coagulant Activity, and Lipid Metabolism of Human Platelets

Huzoor- Akbar
1   Department of Clinical Science, The John Curtin School of Medical Research, The Australian National University, Canberra, A. C. T. 2601, Australia
,
N. G Ardlie
1   Department of Clinical Science, The John Curtin School of Medical Research, The Australian National University, Canberra, A. C. T. 2601, Australia
› Author Affiliations
Further Information

Publication History

Received 06 December 1976

Accepted 01 June 1977

Publication Date:
04 July 2018 (online)

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Summary

Halofenate – free acid (HFA), the major metabolite of the hypolipidemic drug, halofenate, inhibited platelet aggregation induced by collagen and sodium arachidonate and blocked the second phase of aggregation caused by ADP, thrombin and epinephrine in human platelet-rich plasma. The aggregation of washed platelets by thrombin and collagen was also blocked. HFA also inhibited the release by thrombin and collagen of 5-hydroxytryptamine from dense granules of platelets and the release by thrombin of β-glucuronidase from platelet α-granules. These inhibitory effects were concentration and time-dependent. HFA decreased platelet factor 3 activity by 31 % and also inhibited the incorporation of 14C-acetate and U-14C-glucose into platelet lipids by 89 % and 56 % respectively. Thrombin-induced lipid peroxidation and prostaglandin formation was investigated by measuring the by-product malonyldialdehyde, and this was found to be inhibited by HFA. It is suggested that the effect of HFA on aggregation is attributable to inhibition of the release reaction which may in turn be a consequence of the effects of the drug on platelet lipid synthesis.

 

  • References

  • 1 Ardlie N. G, Han P. 1974; Enzymatic basis for platelet aggregation and release: the significance of the platelet ‘atmosphere’ and the relationship between platelet function and blood coagulation. British Journal of Haematology 26: 331.
    CrossrefPubMedGoogle Scholar
  • 2 Aster R. H, Jandl J. H. 1964; Platelet sequestration in man. I. Methods. Journal of Clinical Investigation 43: 843.
    CrossrefPubMedGoogle Scholar
  • 3 Carvalho C. A, Colman R. W, Lees R. S. 1974; Clofibrate reversal of platelet hypersensitivity in hyperlipoproteinemia. Circulation 50: 570.
    CrossrefPubMedGoogle Scholar
  • 4 Colman R. W, Bennett J. S, Sheridan J. F, Cooper R. A, Shattil S. J. 1976; Halofenate: A potent inhibitor of normal and hypersensitive platelets. Journal of Laboratory and Clinical Medicine 88: 282.
    PubMedGoogle Scholar
  • 5 Hamberg M, Svensson J, Samuelsson B. (1974a): Prostaglandin endoperoxides. A new concept concerning the mode of action and release of prostaglandins. Proceedings of National Academy of Sciences 71: 3824.
    PubMedGoogle Scholar
  • 6 Hamberg M, Svensson J, Wakabaysht T, Samuelsson B. (1974b): Isolation and structure of two prostaglandin endoperoxides that cause platelet aggregation. Proceedings of National Academy of Sciences 71: 345.
    PubMedGoogle Scholar
  • 7 Havel R. J, Kane J. P. 1973; Drugs and lipid metabolism. Annual Reviews of Pharmacology 13: 287.
    PubMedGoogle Scholar
  • 8 Huzoor-Akbar. Ardlie N. G. 1976; Evidence that collagen releases human platelet constituents by two different mechanisms. British Journal of Haematology 34: 137.
    CrossrefPubMedGoogle Scholar
  • 9 Huzoor-Akbar. Ardlie N. G. (1977a): Effects of clofibrate on platelets and evidence of the involvement of platelet lipids in platelet function. Thrombosis Research 10: 95.
    PubMedGoogle Scholar
  • 10 Huzoor-Akbar. Ardlie N. G. (1977b): Platelet activation in haemostasis: Role of thrombin and other clotting factors in platelet-collagen interaction. Haemostasis 6: 59.
    PubMedGoogle Scholar
  • 11 Lin C. Y, Smith S. 1976; The effect of halofenate and clofibrate on aggregation and release of serotonin by human platelets. Life Sciences 18: 563.
    CrossrefPubMedGoogle Scholar
  • 12 Minsker D. H, Jordan P. T, Kling P, MacMillan A, Hucker H. B, Tocco D. J. 1976; The effect of halofenate or halofenate free acid on human, rat and guinea pig platelet aggregation. Thrombosis and Haemostasis 35: 358.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 13 Okuma M, Steiner M, Baldini M. 1970; Studies of lipid peroxides in platelets. I. Methods of assay and effect of storage. Journal of Laboratory and Clinical Medicine 75: 283.
    PubMedGoogle Scholar
  • 14 Rodbell M. 1964; Metabolism of isolated fat cells: effect of hormones on glucose metabolism and lipolysis. Journal of Biological Chemistry 239: 375.
    PubMedGoogle Scholar
  • 15 Silver M. J, Smith J. B, Ingerman C, Kocsis J. J. 1973; Arachidonic acid-induced human platelet aggregation and prostaglandin formation. Prostaglandins 4: 863.
    CrossrefPubMedGoogle Scholar
  • 16 Sirtori C, Hurwitz A, Sabih K, Azarnoff D. L. 1972; Clinical evaluation of Mk-185: a new hypolipidemic drug. Lipids 7: 96.
    CrossrefPubMedGoogle Scholar
  • 17 Smith J. B, Ingerman C, Kocsis J. J, Silver M. J. 1974; Formation of an intermediate in prostaglandin biosynthesis and its association with the platelet release reaction. Journal of Clinical Investigation 53: 1468.
    CrossrefPubMedGoogle Scholar
  • 18 Walsh P. N. 1972; Platelet coagulant activities in thrombasthenia. British Journal of Haematology 23: 553.
    CrossrefPubMedGoogle Scholar
  • 19 Weiss H. J. 1975; Platelet physiology and abnormalities of platelet function. New England Journal of Medicine 531: 580.
    PubMedGoogle Scholar
  • 20 Willis A. L, Vane F. M, Kuhn D. C, Scott C. G, Petrin M. 1974; An endoperoxide aggregator (LASS), formed in platelets in response to thrombotic stimuli: purification, identification and unique biological significance. Prostaglandins 8: 453.
    CrossrefPubMedGoogle Scholar
  • 21 Yeshurin D, Gorro A. M. 1976; Drug treatment of hyperlipidemia. The American Journal of Medicine 60: 379.
    CrossrefPubMedGoogle Scholar