If a patient is bleeding, intravenous vitamin K may be dosed at 1 to 10 mg, depending on the severity. Intravenous vitamin K can often reverse coagulopathy within 4 to 6 hours.
Subcutaneous vitamin K should be reserved for select patients since vitamin K is a fat-soluble vitamin and subject to erratic absorption from the subcutaneous tissue.
If the clinician desires emergent reversal, four-factor prothrombin complex concentrates 4F-PCCs can be rapidly administered with a full reversal of coagulopathy within 15 to 30 minutes with less volume compared to plasma.
Management of drug-drug interactions related to warfarin and its sequelae should involve an interprofessional approach involving laboratory technicians, nurses, pharmacists, and physicians. The first step in managing these interactions often comes at the time of warfarin prescribing. Physicians should work closely with pharmacists to avoid prescribing medications that have interactions. If these medications are absolutely necessary, adjusting the patient's dose of warfarin may be necessary with close follow-up and monitoring early in the treatment regimen.
The patient should also receive education on the prevalence of these interactions, many of which exist with drugs or supplements that do not require a prescription. In the event of toxicity, physicians must rapidly assess bleeding risk or the degree of bleeding and identify less common complications of warfarin therapy. Coordination with a pharmacist, blood bank technician, and nursing staff are all often required to quickly obtain and administer appropriate reversal agents and appropriately monitor response to therapy.
Emergent bleeding can represent an "all hands on deck" situation, and coordinated care across professional lines is key for efficient therapeutic action. Only by working together can the interprofessional healthcare tea minimize drug-drug interactions with warfarin and rapidly treat those that were not preventable, leading to optimal patient care. Old and new oral anticoagulants: Food, herbal medicines and drug interactions. Rapidly progressive nonuremic calciphylaxis in the setting of warfarin.
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Due to variability in absorption and dietary vitamin K intake, dosing for warfarin is variable. A low therapeutic index exists and thus the INR level needs to be monitored regularly. For most conditions the INR is maintained between , however in certain instances i. Thromboembolic prophylaxis in atrial fibrillation and atrial flutter, deep venous thrombosis, pulmonary embolism, left ventricular thrombus, coronary aneurysms, pulmonary hypertension, stroke.
Warfarin overdose is quite common and can cause life-threatening bleeding. Since multiple factors alter vitamin K such as dietary intake and normal gut flora, the INR level can increase if vitamin K intake declines due to acute illness or antibiotics eliminate normal vitamin K producing flora.
Reversal of warfarin includes the administration of vitamin K, however this takes a few hours to have its effect since the vitamin K clotting factors require synthesis. Eur J Clin Invest ; 33 Suppl. Major bleeding caused by warfarin in a genetically susceptible patient. Pharmacotherapy ; 22 : 97 — Aging and the anticoagulant response to warfarin therapy. Ann Intern Med ; : — Mungall D, White R. Aging and warfarin therapy. Hereditary resistance to coumarin anticoagulant drugs in man and rat.
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Time response of cytochrome P 1A2 activity on cessation of heavy smoking. Clin Pharmacol Ther ; 76 : — Atrial fibrillation and antithrombotic treatment in Italian hospitalized patients: a prospective, observational study. J Thromb Thrombolysis ; 12 : — Recent national patterns of warfarin use in atrial fibrillation. Circulation ; 97 : — Factors influencing physicians' reported use of anticoagulation therapy in nonvalvular atrial fibrillation: a cross-sectional survey. Clin Ther ; 25 : — Warfarin use in atrial fibrillation: A random sample survey of family physician beliefs and preferences.
Can J Clin Pharmacol ; 9 : — Adverse drug reactions as cause of admission to hospital: prospective analysis of 18 patients. BMJ ; : 15 — Circulation ; : — Oxford University Press is a department of the University of Oxford. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide. Sign In or Create an Account. Sign In. Advanced Search.
Search Menu. Article Navigation. Close mobile search navigation Article Navigation. Volume 7. Article Contents Introduction.
A brief history of warfarin. The coagulation system and the site of action of warfarin. Mechanism of action of warfarin. Bleeding complications. Variability in response. Why we need to change. Thrombin inhibition: a promising new concept.
Reviewing the reality: why we need to change. Lin Peter J. E-mail address : peterlin1 rogers. Oxford Academic. Google Scholar. Cite Cite Peter J.
Select Format Select format. Permissions Icon Permissions. Introduction For nearly 60 years, vitamin K antagonists VKAs such as warfarin have been the mainstay of oral anticoagulation in a range of thromboembolic disorders, ranging from stroke prevention in atrial fibrillation AF to the treatment and secondary prevention of venous thromboembolism.
A brief history of warfarin More than 80 years ago, livestock farmers in North Dakota, United States, observed severe, unexplained bleeding in cattle, which was later linked to their diet of fermented hay or silage made from sweet clover, grown as a substitute for corn at this time.
Warfarin—drug interactions Warfarin is a racaemic mixture of two enantiomers, R - and S -warfarin, the S -form being three to five times more potent than the R -form. Genetic and environmental variability Warfarin therapy is further complicated by genetic and environmental factors. Need for safer and more practical agents Warfarin therapy has been invaluable as an oral anticoagulant over the past 60 years; however, its limitations have provided the stimulus for the development of new oral anticoagulants that will overcome the drawbacks of VKA therapy.
Thrombin inhibition: a promising new concept As described earlier, the coagulation cascade ultimately leads to thrombin generation, which in turn leads to platelet activation and fibrin formation. Biochemistry ; 11 : — Sadler JE. Medicine: K is for koagulation. Nature ; : — The pharmacology of oral anticoagulants: implications for therapy. J Heart Valve Dis ; 2 : 53— Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range.
Chest ; : S—S. Patients with unstable control have a poorer dietary intake of vitamin K compared to patients with stable control of anticoagulation. Thromb Haemost ; 93 : — Transport of vitamin K to bone in humans. J Nutr ; : S—S. The physiology of vitamin K nutriture and vitamin K-dependent protein function in atherosclerosis. J Thromb Haemost ; 2 : — Plasma lipoproteins as carriers of phylloquinone vitamin K1 in humans. Am J Clin Nutr ; 67 : — Phylloquinone transport and its influence on gamma-carboxyglutamate residues of osteocalcin in patients on maintenance hemodialysis.
Am J Clin Nutr ; 58 : — Warfarin-associated hemorrhage and cerebral amyloid angiopathy: a genetic and pathologic study. Neurology ; 55 : — Eur J Clin Pharmacol ; 61 : — Patients with an ApoE epsilon4 allele require lower doses of coumarin anticoagulants. Pharmacogenet Genomics ; 15 : 69— Identification of the gene for vitamin K epoxide reductase.
Pharmacodynamic resistance to warfarin associated with a Val66Met substitution in vitamin K epoxide reductase complex subunit 1. Thromb Haemost ; 93 : 23— A polymorphism in the VKORC1 gene is associated with an interindividual variability in the dose-anticoagulant effect of warfarin. Blood ; : — Pharmacogenomics J ; 5 : — N Engl J Med ; : — A novel functional VKORC1 promoter polymorphism is associated with inter-individual and inter-ethnic differences in warfarin sensitivity.
Hum Mol Genet ; 14 : — VKORC1 haplotypes and their impact on the inter-individual and inter-ethnical variability of oral anticoagulation. Thromb Haemost ; 94 : — Combined genetic profiles of components and regulators of the vitamin K-dependent gamma-carboxylation system affect individual sensitivity to warfarin.
Thromb Haemost ; 95 : — J Hum Genet ; 51 : — Pharmacogenet Genomics ; 16 : — Clin Pharmacol Ther ; 79 : — Influence of coagulation factor, vitamin K epoxide reductase complex subunit 1, and cytochrome P 2C9 gene polymorphisms on warfarin dose requirements. PLoS Med ; 2 : e Assembly of the warfarin-sensitive vitamin K 2,3-epoxide reductase enzyme complex in the endoplasmic reticulum membrane.
Morisseau C, Hammock BD. Epoxide hydrolases: mechanisms, inhibitor designs, and biological roles. Annu Rev Pharmacol Toxicol ; 45 : — Co-purification of microsomal epoxide hydrolase with the warfarin-sensitive vitamin K1 oxide reductase of the vitamin K cycle.
Biochem Pharmacol ; 55 : — Common genetic variants of microsomal epoxide hydrolase affect warfarin dose requirements beyond the effect of cytochrome P 2C9. Clin Pharmacol Ther ; 77 : — Ross D, Siegel D. Methods Enzymol ; : — Wallin R, Hutson S. Vitamin K-dependent carboxylation. Evidence that at least two microsomal dehydrogenases reduce vitamin K1 to support carboxylation.
Compound heterozygous mutations in the gamma-glutamyl carboxylase gene cause combined deficiency of all vitamin K-dependent blood coagulation factors. Br J Haematol ; : — Berkner KL.
The vitamin K-dependent carboxylase. J Nutr ; : — Genomic sequence and transcription start site for the human gamma-glutamyl carboxylase. Blood ; 89 : — A missense mutation in gamma-glutamyl carboxylase gene causes combined deficiency of all vitamin K-dependent blood coagulation factors. Blood ; 92 : — Gamma-glutamyl carboxylase GGCX microsatellite and warfarin dosing. A molecular mechanism for genetic warfarin resistance in the rat. The inhibitory effect of calumenin on the vitamin K-dependent gamma-carboxylation system.
Characterization of the system in normal and warfarin-resistant rats. Broze Jr GJ. Protein Z-dependent regulation of coagulation. Thromb Haemost ; 86 : 8— Haematologica ; 89 : — Kristensen SR. Warfarin treatment of a patient with coagulation factor IX propeptide mutation causing warfarin hypersensitivity.
Non-fatal major bleeding during treatment with vitamin K antagonists: influence of soluble thrombomodulin and mutations in the propeptide of coagulation factor IX.
Thromb Res ; 45 : — Decrease in protein C antigen and formation of an abnormal protein soon after starting oral anticoagulant therapy. Br J Haematol ; 57 : — Coumarin necrosis associated with hereditary protein C deficiency. Ann Intern Med ; : 59— Warfarin induced skin necrosis. Br J Surg ; 87 : — Dahlback B. Blood coagulation and its regulation by anticoagulant pathways: genetic pathogenesis of bleeding and thrombotic diseases.
J Intern Med ; : — Effect of anticoagulant therapy on the hypercoagulable state in patients carrying the factor V ArgGln mutation.
Thromb Res ; 92 : — Drug-metabolizing enzymes: evidence for clinical utility of pharmacogenomic tests. A prospective, randomized pilot trial of model-based warfarin dose initiation using CYP2C9 genotype and clinical data. Clin Med Res ; 3 : — A randomized trial of initial warfarin dosing based on simple clinical criteria.
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