Summary
The biochemistry of vitamin K metabolism and the role of vitamin K-dependent γ-carboxylation of the vitamin K-dependent coagulation factors are now well understood. Likewise, there is a clear understanding of the role of oral anticoagulants in the inhibition of these coagulation factors. However, the effect of oral anticoagulants on extrahepatic γ-carboxylated proteins such as osteocalcin and matrix γ-carboxyglutamate (Gla)-protein (MOP), and the effects of long term anticoagulants on bone mineral metabolism are just now being recognised. The relevance of these observations on mineral metabolism for elderly individuals, and in particular postmenopausal women who are on long term anticoagulants, is still unknown but worthy of continued close observation.
The most significant hazard of oral anticoagulants is haemorrhage. Clinical trials continue to demonstrate that less intense (lower dosage) warfarin therapy can significantly decrease this risk of haemorrhage while at the same time providing equal efficacy when compared to more intense warfarin therapy. The more widespread use of the International Normalised Ratio (INR) for the control of anticoagulants will undoubtedly further decrease the risk of haemorrhage, but new innovations such as the use of ultra low-dose warfarin or newer techniques for the continued monitoring of oral anticoagulants are still required, particularly as the indications for oral anticoagulants continue to expand.
Similar content being viewed by others
References
Altman R, Rouvier J, Gurfinkel E, D’Ortencio O, Manzanel R, et al. Comparison of two levels of anticoagulant therapy in patients with substitute heart valves. Journal of Thoracic and Cardiovascular Surgery 101: 427–431, 1991
Becker CO. Oral anticoagulant therapy and skin necrosis: speculation on pathogenesis. Advances in Experimental Medicine and Biology 214: 217–222, 1987
Bern MM, Lokich JJ, Wallach SR, Bothe Jr A, Benotti PN, et al. Very low doses of warfarin can prevent thrombosis in central venous catheters. Annals of Internal Medicine 112: 423–428, 1990
Boston Area Anticoagulation Trial for Atrial Fibrillation Investigators. The effect of low-dose warfarin on the risk of stroke in patients with nonrheumatic atrial fibrillation. New England Journal of Medicine 323: 1505–1511, 1990
Broekmans AW, Bertina RM, Loeliger EA, Hoffmann V, Klingemann HG. Protein C and development of skin necrosis during anticoagulant therapy. Thrombosis and Haemostasis 49: 251, 1983
Comp PC. Deficiency of naturally occurring anticoagulants: antithrombin III, protein C and protein S. In Brain & Carbone (Eds) Current therapy in hematology-oncology 3, pp. 120–122, B.C. Decker Inc., Toronto, 1988
Connolly SJ, Laupacis A, Gent M, Roberts RS, Cairns JA, et al. Canadian Atrial Fibrillation Anticoagulation (SAFA) Study. Journal of the American College of Cardiology 18: 349–355, 1991
Conte RR, Kehoe WA, Nielson N, Lodhia H. Nine-year experience with a pharmacist-managed anticoagulation clinic. American Journal of Hospital Pharmacy 43: 2460–2464, 1986
Deykin D. Warfarin therapy. New England Journal of Medicine 283: 801–803, 1970
Duroux P. A randomized trial of subcutaneous low molecular weight heparin (CY 216) compared with intravenous unfractionated heparin in the treatment of deep vein thrombosis: a collaborative European multicentre study. Thrombosis and Haemostasis 65: 251–256, 1991
Exner DV, Brien WF, Murphy MJ. Superwarfarin ingestion. Canadian Medical Association Journal 146: 34–35, 1992
Ezekowitz MD, Bridgers SL, James KE, Carliner NH, Colling CL, et al. Warfarin in the prevention of stroke associated with non-rheumatic atrial fibrillation. New England Journal of Medicine 327: 1406–1412, 1992
Fennerty A, Dolben J, Thomas P, Backhouse G, Bentley DP, et al. Flexible induction dose regimen for warfarin and prediction of maintenance dose. British Medical Journal 288: 1268–1270, 1984
Fiore CE, Tamburino C, Foti R, Grimaldi D. Reduced bone mineral content in patients taking an oral anticoagulant. Southern Medical Journal 83: 538–542, 1990
Furie B, Furie BC. Molecular basis of vitamin K-dependent gamma-carboxylation. Blood 75: 1753–1762, 1990
Ginsberg JS, Hirsh J. Use of antithrombotic drugs during pregnancy. Chest 102 (Suppl.): 385S–390S, 1992
Grimaudo V, Gueissaz F, Hauert J, Sarrj A, Kruithof EKO, et al. Necrosis of skin induced by coumarin in a patient deficient in protein S. British Medical Journal 298: 233–234, 1989
Gurwitz JH, Avorn J, Ross-Degnan D, Choodnovskiy I, Ansell J. Aging and the anticoagulant response to warfarin therapy. Annals of Internal Medicine 116: 901–904, 1992
Hall JG, Pauli RM, Wilson KM. Maternal and fetal sequelae of anticoagulation during pregnancy. American Journal of Medicine 68: 122–140, 1980
Hart JP, Catterall A, Dodds RA, Klenerman L, Shearer MJ, et al. Circulating vitamin K1 levels in fractured neck of femur. Lancet 2: 283, 1984
Hauschka PV, Lian JB, Cole DEC, Gundberg CM. Osteocalcin and matrix Gla protein: vitamin K-dependent proteins in bone. Physiology Review 69: 990–1047, 1989
Hirsh J. Oral anticoagulant drugs. New England Journal of Medicine 324: 1865–1875, 1991
Hull RD, Delmore T, Carter C, Hirsh J, Genton E, et al. Adjusted subcutaneous heparin versus warfarin sodium in the long-term treatment of venous thrombosis. New England Journal of Medicine 306: 189–194, 1982a
Hull RD, Hirsh J, Jay R, England C, Gent M, et al. Different intensities of oral anticoagulant therapy in the treatment of proximal-vein thrombosis. New England Journal of Medicine 307: 1676–1681, 1982b
Hull RD, Raskob GE, Pineo GF, Green D, Trowbridge A, et al. Subcutaneous low-molecular-weight heparin compared with continuous intravenous heparin in the treatment of proximal vein thrombosis. New England Journal of Medicine 326: 975–982, 1992
Hull RD, Raskob GE, Rosenbloom D, Panju AA, Brill-Edwards P, et al. Heparin for 5 days as compared with 10 days in the initial treatment of proximal venous thrombosis. New England Journal of Medicine 322: 1260–1264, 1990
Iturbe-Alessio I, del Carmen Fonseca M, Mutchinik O, Santos MA, Zajarías A, et al. Risks of anticoagulant therapy in pregnant women with artificial heart valves. New England Journal of Medicine 315: 1390–1393, 1986
Knapen MHJ, Hamulyák K, Vermeer C. The effect of vitamin K supplementation on circulating osteocalcin (bone Gla-protein) and urinary calcium excretion. Annals of Internal Medicine 111: 1001–1005, 1989
Lancaster TR, Singer DE, Sheehan MA, Oertel LB, Maraventano SW, et al. The impact of long-term warfarin therapy on quality of life. Evidence from a randomized trial. Archives of Internal Medicine 151: 1944–1949, 1991
Levine MN, Raskob G, Hirsh J. Hemorrhagic complications of long-term anticoagulant therapy. Chest 95(Suppl. 2): 26S–36S, 1989
Lipsky JJ. Antibiotic-associated hypoprothrombinaemia. Journal of Antimicrobial Chemotherapy 21: 281–300, 1988
Lipton RA, Klass EM. Human ingestion of a ‘superwarfarin’ rodenticide resulting in a prolonged anticoagulant effect. Journal of the American Medical Association 252: 3004–3005, 1984
McInnes Gt, Helenglass G. The performance of clinics for outpatient control of anticoagulation. Journal of the Royal College of Physicians of London 21: 42–45, 1987
Nalbandian RM, Mader IJ, Barrett JL, Pearce JF, Rupp EC. Petechiae, ecchymoses and necrosis of the skin induced by coumarin congeners: rare, occasionally lethal complications of anticoagulant therapy. Journal of the American Medical Association 192: 107–112, 1965
O’Reilly RA, Aggeler PM. Determinants of the response to oral anticoagulant drugs in man. Pharmacology Reviews 22: 35–96, 1970
Ovesen L, Lyduch S, Ott P. A simple technique for predicting maintenance dosage of warfarin — is it better than empirical dosing? European Journal of Clinical Pharmacology 37: 573–576, 1989
Pauli RM, Lian JB, Mosher DF, Suttie JW. Association of congenital deficiency of multiple vitamin k-dependent coagulation factors and the phenotype of the warfarin embryopathy: clues to the mechanism of teratogenicity of the coumarin derivatives. American Journal of Human Genetics 41: 566–583, 1987
Petersen P, Boysen G, Godtfredsen J, Andersen ED, Andersen B. Placebo-controlled, randomised trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrillation: the Copenhagen AFASAK study. Lancet 1: 175–179, 1989
Pineo GF, Gallus AS, Hirsh J. Unexpected vitamin K deficiency in hospitalized patients. Canadian Medical Association Journal 109: 880–883, 1973
Poller L, MacCallum PK, Thomson JM, Kerns W. Reduction of factor VII coagulant activity (VII C), a risk factor for ischemic heart disease, by fixed dose warfarin, a double blind crossover study. British Heart Journal 63: 231–233, 1990
Poller L, McKernan A, Thomson JM, Elstein M, Hirsch PJ, et al. Fixed minidose warfarin: a new approach to prophylaxis against venous thrombosis after major surgery. British Medical Journal 285: 1309–1312, 1987
Poller L, Tabener DA. Dosage and control of oral anticoagulants: an international study. British Journal of Haematology 51: 479–485, 1982
Prandoni P, Lensing AW, Buller HR, Carta M, Cogo A, et al. Comparison of subcutaneous low-molecular-weight heparin with intravenous standard heparin in proximal deep-vein thrombosis. Lancet 339: 441–445, 1992
Salzman EW. Treatment of venous thrombosis with subcutaneous heparin. New England Journal of Medicine 306: 232–233, 1982
Saour JN, Sieck JO, Mamo LAR, Gallus AS. Trial of different intensities of anticoagulation in patients with prosthetic heart valves. New England Journal of Medicine 322: 428–432, 1990
Smith P, Arnesen H, Holme I. The effect of warfarin on mortality and reinfarction after myocardial infarction. New England Journal of Medicine 323: 147–152, 1990
Stroke Prevention in Atrial Fibrillation Study Group Investigators. Preliminary report of the Stroke Prevention in Atrial Fibrillation study. New England Journal of Medicine 322: 863–868, 1990
Teitel JM, Bauer KA, Lau HK, Rosenberg RD. Studies of the prothrombin activation pathway utilizing radioimmunoassays for the F2/F1+2 fragment and thrombin-antithrombin complex. Blood 59: 1086–1097, 1982
Turpie AGG, Gunstensen J, Hirsh J, Nelson H, Gent M. Randomized comparison of two intensities of oral anticoagulant therapy after tissue heart valve replacement. Lancet 1: 1245–1245, 1988
Vermeer C. Gamma-carboxyglutamate-containing proteins and the vitamin K-dependent carboxylase. Biochemistry Journal 266: 625–636, 1990
White RH, Mccurdy SA, von Marensdorff H, Woodruff DE, Leftgoff L. Home prothrombin time monitoring after the initiation of warfarin therapy. Annals of Internal Medicine 111: 730–737, 1989
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Pineo, G.F., Hull, R.D. Adverse Effects of Coumarin Anticoagulants. Drug-Safety 9, 263–271 (1993). https://doi.org/10.2165/00002018-199309040-00004
Published:
Issue Date:
DOI: https://doi.org/10.2165/00002018-199309040-00004