Studies on the Interaction of Warfarin and Clofibrate in Man

R. A O’Reilly; M. A Sahud; A. J Robinson

doi:10.1055/s-0038-1649370

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 1972; 27(02): 309-318
DOI: 10.1055/s-0038-1649370

Originalarbeiten — Original Articles — Travaux Originaux

Schattauer GmbH

Studies on the Interaction of Warfarin and Clofibrate in Man

Authors

R. A O’Reilly

¹Department 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

¹Department 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

¹Department 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

Abstract

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.

Full Text

References

References
1 Rogen A. S, Ferguson J. G. Clinical observations on patients treated with Atromid and anticoagulants. J. Atheroscler. Res 03: 671 1963;
2 O’Reilly R. A, Aggeler P. M. Determinants of the response to oral anticoagulant drugs in man. Pharmacol. Rev 22: 35 1970;
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;
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;
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;
6 Ivy A. G, Shajpiro P. F, Melnick P. Bleeding tendency in jaundice. Surg. Gynec. Obstet 60: 781 1935;
7 Owen Jr. C. A, Bowie E. J. W, Didisheim P, Thompson Jr. J. H. Bleeding Disorders. 77 Little, Brown, and Co; Boston: 1969
8 Brecher G, Schneiderman M, Gronkite E. P. Reproducibility and constancy of the platelet count. Amer. J. clin. Path 23: 15 1953;
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;
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;
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;
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;
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;
14 Spaet T. H, Lejnieks I. A technique for estimation of platelet-collagen adhesion. Proc. Soc. Exp. Biol. (N. Y) 132: 1038 1961;
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;
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;
17 Robinson R. W, LeBeau R. J. Platelet adhesiveness and aggregation with chlorophenoxyiso- butyric ester. Amer. J. med. Sei 253: 106 1967;
18 Symons D, DeToszeghi A, Cook I. J. Y. Effect of ethyl chlorophenoxyisobutyrate with or without androsterone on platelet stickiness. Lancet 02: 233 1964;
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;
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;
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;
22 Thorp J. M. Experimental evaluation of an orally active combination of androsterone with ethyl chlorophenoxyisobutyrate. Lancet 01: 1323 1962;
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;
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;
25 O’Reilly R. A. Interaction of several coumarin compounds with human and canine plasma albumin. Molec. Pharmacol 07: 209 1971;
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;
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;
28 Dybkaer R, Geill T. Effect of clofibrate on thrombocyte adhesivity and some coagulation parameters. Geront. Clin. (Basel) 09: 157 1967;
29 Nikkila E. A, Pelkonon R. Letters to the editor. Serum-lipid reducing agents and anticoagulant requirements. Lancet 01: 332 1963;
30 Woods J. W, Penick G. D. Warfarin and diet-induced lipidosis in rats. Arch. Path 78: 234 1964;
31 Wriqht H. P, Hayden M. Effect of diet upon the response to oral anticoagulants. J. clin. Path. 65. 1905
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;
33 Furman R. H, Howard R. P, Alaupovic P. Letters to the editor. Serum-lipid reducing agents and anticoagulant requirements. Lancet 01: 893 1963;
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;
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;
36 Anonymous. Today’s drugs. Clofibrate. Brit. med. J 03: 632 1970;
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;
38 Wynn V, Landon J, Kawerau E. Studies of hepatic function during methandienone therapy. Lancet 01: 69 1961;