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Thromb Haemost 1972; 27(02): 309-318
DOI: 10.1055/s-0038-1649370
Originalarbeiten — Original Articles — Travaux Originaux
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Studies on the Interaction of Warfarin and Clofibrate in Man

R. A O’Reilly
1   Department of Medicine, Santa Clara Valley Medical Center and the Institute for Medical Research of Santa Clara County, San Jose 95128; the Paul M. Aggeler Memorial Hematology Research Laboratory, Children’s Hospital and Adult Medical Center, the Departments of Medicine and Surgery, University of California, San Francisco, and the Medical and Surgical Services, Francisco General Hospital, Francisco, California 94110
,
M. A Sahud
1   Department of Medicine, Santa Clara Valley Medical Center and the Institute for Medical Research of Santa Clara County, San Jose 95128; the Paul M. Aggeler Memorial Hematology Research Laboratory, Children’s Hospital and Adult Medical Center, the Departments of Medicine and Surgery, University of California, San Francisco, and the Medical and Surgical Services, Francisco General Hospital, Francisco, California 94110
,
A. J Robinson
1   Department of Medicine, Santa Clara Valley Medical Center and the Institute for Medical Research of Santa Clara County, San Jose 95128; the Paul M. Aggeler Memorial Hematology Research Laboratory, Children’s Hospital and Adult Medical Center, the Departments of Medicine and Surgery, University of California, San Francisco, and the Medical and Surgical Services, Francisco General Hospital, Francisco, California 94110
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Publication History

Publication Date:
29 June 2018 (online)

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Summary

To evaluate the basis for the hemorrhagic diathesis associated with oral anticoagulant therapy plus the hypolipidemic agent clofibrate, this interaction was studied in 8 normal subjects. Administration of clofibrate 2.0 g/day alone for 14 days had no effect on the platelet count, bleeding time, platelet aggregation, plasma adenosine diphosphatase, platelet release of adenosine diphosphate and adenosine triphosphate, platelet-collagen adhesion, one-stage prothrombin time, or vitamin K-dependent clotting factors (II, VII, IX and X) but significantly reduced platelet adhesiveness and epinephrine-induced platelet aggregation. After addition of large single doses of sodium warfarin, 1.5 mg/kg body weight, to the clofibrate regimen, all values remained within the normal range, including platelet adhesiveness, except epinephrine-induced platelet aggregation. The one-stage prothrombin activity and clotting factors II and X were significantly lower with warfarin plus clofibrate than with warfarin alone, but the plasma level of warfarin was unchanged. Co-administration of sodium warfarin and clofibrate for 21 days augmented the hypoprothrombinemia observed in long-term therapy with warfarin alone but caused no significant change in the plasma warfarin level. It is concluded that the hemorrhagic complications of therapy with warfarin plus clofibrate result primarily from the more rapid decline in the activities of clotting factors II and X and perhaps also from the reduced platelet aggregation.

 

  • References

  • 1 Rogen A. S, Ferguson J. G. Clinical observations on patients treated with Atromid and anticoagulants. J. Atheroscler. Res 03: 671 1963;
    CrossrefPubMedGoogle Scholar
  • 2 O’Reilly R. A, Aggeler P. M. Determinants of the response to oral anticoagulant drugs in man. Pharmacol. Rev 22: 35 1970;
    PubMedGoogle Scholar
  • 3 Aggeler P. M, O’Reilly R. A. Effect of heptabarbital on the response to bishydroxycouma- rin in man. J. Lab. clin. Med 74: 229 1969;
    PubMedGoogle Scholar
  • 4 O’Reilly R. A, Aggeler P. M, Hoag M. S, Leong L. Studies on the coumarin anticoagulant drugs: assay of warfarin and its biologic application. Thrombos. Diathes. haemorrh. (Stuttg) 08: 82 1962;
    PubMedGoogle Scholar
  • 5 O’Reilly R. A, Aggeler P. M. Studies on coumarin anticoagulant drugs. Initiation of warfarin therapy without a loading dose. Circulation 38: 169 1968;
    PubMedGoogle Scholar
  • 6 Ivy A. G, Shajpiro P. F, Melnick P. Bleeding tendency in jaundice. Surg. Gynec. Obstet 60: 781 1935;
    PubMedGoogle Scholar
  • 7 Owen Jr. C. A, Bowie E. J. W, Didisheim P, Thompson Jr. J. H. Bleeding Disorders. 77 Little, Brown, and Co; Boston: 1969
    Google Scholar
  • 8 Brecher G, Schneiderman M, Gronkite E. P. Reproducibility and constancy of the platelet count. Amer. J. clin. Path 23: 15 1953;
    PubMedGoogle Scholar
  • 9 Salzman E. W. Measurement of platelet adhesiveness. A simple in vitro technique demonstrating an abnormality in von Willebrand’s disease. J. Lab. clin. Med 62: 724 1963;
    PubMedGoogle Scholar
  • 10 Bygdeman S, Wells R. Studies of platelet adhesiveness, blood viscosity and the microcirculation in patients with thrombotic disease. J. Atheroscler. Res 10: 33 1969;
    CrossrefPubMedGoogle Scholar
  • 11 Sahud M. A, Aggeler P. M. Platelet dysfunction - differentiation of a newly recognized primary type from that produced by aspirin. New Engl. J. Med 280: 453 1969;
    CrossrefPubMedGoogle Scholar
  • 12 Zucker M. B, Borrelli J. Platelet clumping produced by connective tissue suspensions and by collagen. Proc. Soc. Exp. Biol. (N. Y) 109: 779 1962;
    CrossrefPubMedGoogle Scholar
  • 13 Holmsen H, Holmsen I, Bernhardsen A. Microdetermination of adenosine diphosphate and adenosine triphosphate in plasma with the firefly luciferase system. Anal. Biochem 17: 456 1966;
    CrossrefPubMedGoogle Scholar
  • 14 Spaet T. H, Lejnieks I. A technique for estimation of platelet-collagen adhesion. Proc. Soc. Exp. Biol. (N. Y) 132: 1038 1961;
    PubMedGoogle Scholar
  • 15 Carson P, McDonald L, Pickard S, Pilkington T, Davies B, Love F. Effect of atromid on platelet stickiness. J. Atheroscler. Res 03: 619 1963;
    CrossrefPubMedGoogle Scholar
  • 16 O’Brien J. R, Heywood J. B. A comparison of platelet stickiness tests during an Atromid-S trial. Thrombos. Diathes. haemorrh. (Stuttg) 16: 768 1966;
    PubMedGoogle Scholar
  • 17 Robinson R. W, LeBeau R. J. Platelet adhesiveness and aggregation with chlorophenoxyiso- butyric ester. Amer. J. med. Sei 253: 106 1967;
    PubMedGoogle Scholar
  • 18 Symons D, DeToszeghi A, Cook I. J. Y. Effect of ethyl chlorophenoxyisobutyrate with or without androsterone on platelet stickiness. Lancet 02: 233 1964;
    PubMedGoogle Scholar
  • 19 Marquis N. R, Becker J. A, Vigdahl R. L. Platelet aggregation. III. An epinephrine induced decrease in cyclic AMP synthesis. Biochim. Biophys. Res. Comm 39: 783 1970;
    PubMedGoogle Scholar
  • 20 Greene H. L, Herman R. H, Zakim D. The effect of clofibrate on rat tissue adenyl cyclase. Proc. Soc. Exp. Biol. (N. Y) 134: 1035 1970;
    CrossrefPubMedGoogle Scholar
  • 21 Oliver M. F, Roberts S. D, Hayes D, Pantridge J. F, Suzmann M. M, Bersohn I. Effect of Atromid and ethyl chlorophenoxyisobutyrate on anticoagulant requirements. Lancet 01: 143 1963;
    PubMedGoogle Scholar
  • 22 Thorp J. M. Experimental evaluation of an orally active combination of androsterone with ethyl chlorophenoxyisobutyrate. Lancet 01: 1323 1962;
    PubMedGoogle Scholar
  • 23 Solomon H. M, Schrogie J. J, Williams D. Displacement of phenylbutazone-14C and war- farin-14C from human albumin by various drugs and fatty acids. Biochem. Pharmacol 17: 143 1968;
    PubMedGoogle Scholar
  • 24 Schrogie J. J, Solomon H. M. Anticoagulant response to bishy dr oxycoumarin. II. Effect of D-thyroxine, clofibrate, and norethandrolone. Clin. Pharmacol. Ther 08: 70 1967;
    PubMedGoogle Scholar
  • 25 O’Reilly R. A. Interaction of several coumarin compounds with human and canine plasma albumin. Molec. Pharmacol 07: 209 1971;
    PubMedGoogle Scholar
  • 26 Aggeler P. M, O’Reilly R. A, Leong L, Kowitz P. E. Potentiation of anticoagulant effect of warfarin by phenylbutazone. New Engl. J. Med 276: 496 1967;
    CrossrefPubMedGoogle Scholar
  • 27 O’Reilly R. A, Aggeler P. M. Phenylbutazone potentiation of anticoagulant effect: fluoro- metric assay of warfarin. Proc. Soc. Exp. Biol. (N. Y) 128: 1080 1968;
    CrossrefPubMedGoogle Scholar
  • 28 Dybkaer R, Geill T. Effect of clofibrate on thrombocyte adhesivity and some coagulation parameters. Geront. Clin. (Basel) 09: 157 1967;
    CrossrefPubMedGoogle Scholar
  • 29 Nikkila E. A, Pelkonon R. Letters to the editor. Serum-lipid reducing agents and anticoagulant requirements. Lancet 01: 332 1963;
    PubMedGoogle Scholar
  • 30 Woods J. W, Penick G. D. Warfarin and diet-induced lipidosis in rats. Arch. Path 78: 234 1964;
    PubMedGoogle Scholar
  • 31 Wriqht H. P, Hayden M. Effect of diet upon the response to oral anticoagulants. J. clin. Path. 65. 1905
    PubMedGoogle Scholar
  • 32 Kupfer H. G, Fischer L. M. Effect of direct and indirect acting anticoagulants on coagulation factors in rats fed Purina or high fat diet. Fed. Proc 23: 511 1964;
    PubMedGoogle Scholar
  • 33 Furman R. H, Howard R. P, Alaupovic P. Letters to the editor. Serum-lipid reducing agents and anticoagulant requirements. Lancet 01: 893 1963;
    PubMedGoogle Scholar
  • 34 Furman R. G, Howard R. P, Alaupovic P. Reduction in serum lipid levels during oral administration of C-17 alkylated steroids, methyltestosterone and methylandrostanopyrazole, to hyperlipemic subjects. J. Lab. clin. Med 60: 876 1962;
    PubMedGoogle Scholar
  • 35 Hemker H. G, Veitkamp J. J, Loeliger E. A. Kinetic aspects of the interaction of blood clotting enzymes. III. Demonstration of an inhibitor of prothrombin conversion in vitamin K deficiency. Thrombos. Diathes. haemorrh. (Stuttg) 19: 346 1968;
    PubMedGoogle Scholar
  • 36 Anonymous. Today’s drugs. Clofibrate. Brit. med. J 03: 632 1970;
    PubMedGoogle Scholar
  • 37 Marquardt G. H, Fisher C. I, Levy P, Dowben R. M. Effect of anabolic steroids on liver function tests and creatine excretion. J. Amer. med. Ass 175: 851 1961;
    CrossrefPubMedGoogle Scholar
  • 38 Wynn V, Landon J, Kawerau E. Studies of hepatic function during methandienone therapy. Lancet 01: 69 1961;
    PubMedGoogle Scholar