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| {{drugbox |
| | #REDIRECT [[Warfarin#Pharmacology]] |
| | IUPAC_name = (RS)-4-hydroxy-3-(3-oxo-1-phenylbutyl)-<BR>2''H''-chromen-2-one
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| | image = Warfarin_svg.png
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| | CAS_number = 81-81-2
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| | ATC_prefix = B01
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| | ATC_suffix = AA03
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| | PubChem = 6691
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| | DrugBank = APRD00341
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| | smiles = CC(=O)CC(c1ccccc1)C2=C(O)c3ccccc3OC2=O <!-- Starts at bottom right -->
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| | C = 19 | H = 16 | O = 4
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| | molecular_weight = 308.33 g/mol
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| | bioavailability = 100%
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| | protein_bound = 99.5%
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| | metabolism = Hepatic: [[CYP2C9]], [[CYP2C19|2C19]], 2C8, 2C18, [[CYP1A2|1A2]] and [[CYP3A4|3A4]]
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| | elimination_half-life = 2.5 days
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| | excretion = [[Kidney|Renal]] (92%)
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| | pregnancy_AU = D
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| | pregnancy_US = X
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| | legal_AU = S4
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| | legal_UK = POM
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| | legal_US = Rx-only
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| | routes_of_administration = Oral or Intravenous
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| }}
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| {{SI}}
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| {{WikiDoc Cardiology Network Infobox}}
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| {{CMG}}
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| {{Editor Help}}
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| '''Warfarin''' (also known under the brand names of '''Coumadin''', '''Jantoven''', '''Marevan''', and '''Waran''') is an [[anticoagulant]] [[medication]] that is administered orally or, very rarely, by injection. It is used for the [[prophylaxis]] of [[thrombosis]] and [[embolism]] in many disorders. Its activity has to be monitored by frequent [[blood test]]ing for the [[prothrombin time|international normalized ratio]] (INR). It is named for the Wisconsin Alumni Research Foundation.
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| Warfarin is a synthetic derivative of [[coumarin]], a chemical found naturally in many plants, notably woodruff (''Galium odoratum'', Rubiaceae), and at lower levels in licorice, lavender and various other species. Warfarin was originally developed as a rat poison; however, more modern poisons are much more potent and toxic (e.g., [[brodifacoum]]). Warfarin and contemporary rodenticides belong to the same class of drugs (coumarins) and both decrease blood coagulation by interfering with [[vitamin K]] metabolism. For this reason, drugs in this class are also referred to as vitamin K antagonists. <ref>Ansell J, Hirsh J, Poller L, Bussey H, Jacobson A, Hylek E. The pharmacology and management of the vitamin K antagonists: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. ''Chest'' 2004;126(3 Suppl):204S-233S. PMID 15383473.</ref>
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| ==Mechanism of action==
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| Warfarin inhibits the synthesis of biologically active forms of the [[vitamin K]]-dependent [[clotting]] factors [[thrombin|II]], [[factor VII|VII]], [[factor IX|IX]] and [[factor X|X]], as well as the regulatory factors [[protein C]], [[protein S]] and [[protein Z]]. Other proteins not involved in blood clotting, such as [[osteocalcin]], or matrix Gla protein, may also be affected.
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| The precursors of these factors require carboxylation of their [[glutamic acid]] residues to allow the coagulation factors to bind to [[phospholipid]] surfaces inside blood vessels, on the vascular [[endothelium]]. The enzyme that carries out the carboxylation of [[glutamic acid]] is [[gamma-glutamyl carboxylase]]. The carboxylation reaction will only proceed if the carboxylase enzyme is able to convert a [[reduction (chemistry)|reduced]] form of vitamin K (vitamin K hydroquinone) to vitamin K epoxide at the same time. The vitamin K epoxide is in turn recycled back to vitamin K and vitamin K hydroquinone by another enzyme, the [[vitamin K epoxide reductase]] (VKOR). Warfarin inhibits epoxide reductase<ref name=Whitlon>Whitlon DS, Sadowski JA, Suttie JW. Mechanisms of coumarin action: significance of vitamin K epoxide reductase inhibition. ''Biochemistry'' 1978;17:1371–7. PMID 646989.</ref> (specifically the VKORC1 subunit<ref>Li T, Chang CY, Jin DY, Lin PJ, Khvorova A, Stafford DW. Identification of the gene for vitamin K epoxide reductase. ''Nature'' 2004;427(6974):541-4. PMID 14765195.</ref><ref name="pmid14765194">{{cite journal |author=Rost S, Fregin A, Ivaskevicius V, ''et al'' |title=Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2 |journal=Nature |volume=427 |issue=6974 |pages=537-41 |year=2004 |pmid=14765194 |doi=10.1038/nature02214}}</ref>), thereby diminishing available vitamin K and vitamin K hydroquinone in the tissues, which inhibits the carboxylation activity of the glutamyl carboxylase. When this occurs, the coagulation factors are no longer carboxylated at certain [[glutamic acid]] residues, and are incapable of binding to the [[endothelial]] surface of blood vessels, and are thus biologically inactive. As the body stores of previously-produced active factors degrade (over several days) and are replaced by inactive factors, the anticoagulation effect becomes apparent. The coagulation factors are produced, but have decreased functionality due to undercarboxylation; they are collectively referred to as PIVKAs (proteins induced [by] vitamin K absence/antagonism). Hence, the effect of warfarin is to diminish blood clotting in the patient.
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| Paradoxically, the initial effect of warfarin administration is to promote clot formation. This is because the level of [[protein S]] is also dependent on vitamin K activity. Reduced levels of protein S lead to a reduction in activity of protein C (for which it is the co-factor) and therefore reduced inhibition of [[factor V|factor Va]] and [[factor VIII|factor VIIIa]]. This then causes the hemostasis system to be temporarily biased towards thrombus formation, leading to a prothrombotic state. This is one of the benefits of co-administering [[heparin]], an anticoagulant that acts upon [[antithrombin]] and helps reduce the risk of thrombosis, which is common practice in settings where warfarin is loaded rapidly.
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| ==Uses==
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| ===Medical use===
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| Warfarin is prescribed to people with an increased tendency for [[thrombosis]] or as prophylaxis in those individuals who have already formed a blood clot ([[thrombus]]) which required treatment. This can help prevent formation of future blood clots and help reduce the risk of [[embolism]] (migration of a thrombus to a spot where it blocks blood supply to a vital organ). Common clinical indications for warfarin use are [[atrial fibrillation]], [[artificial heart valve]]s, [[deep venous thrombosis]], [[pulmonary embolism]], [[antiphospholipid syndrome]] and occasionally after [[myocardial infarction]].<ref name=Hirsh>Hirsh J, Fuster V, Ansell J, Halperin JL. American Heart Association/American College of Cardiology Foundation guide to Warfarin therapy. ''J Am Coll Cardiol'' 2003;41:1633-52. PMID 12742309.</ref>
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| Dosing of warfarin is complicated by the fact that it is known to interact with many commonly used medications and other chemicals that may be present in appreciable quantities in food. These interactions may enhance or reduce warfarin's anticoagulation effect. Many commonly used antibiotics, such as [[metronidazole]] or the [[macrolide]]s, will greatly increase the effect of warfarin by reducing the metabolism of warfarin in the body. Other broad-spectrum antibiotics can reduce the amount of the normal bacterial flora in the bowel, which make significant quantities of Vitamin K, thus potentiating the effect of warfarin. In addition, food that contains large quantities of Vitamin K will reduce the warfarin effect; and medical conditions such as hypo- or hyperthyroidism will alter the rate of breakdown of the clotting factors.
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| Therefore, in order to optimise the therapeutic effect without risking dangerous side effects, such as bleeding, close monitoring of the degree of anticoagulation is required by blood testing ([[prothrombin time|INR]]). Initially, checking may be as often as twice a week; the intervals can be lengthened if the patient manages stable therapeutic INR levels on an unchanged warfarin dose.
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| When initiating warfarin therapy ("warfarinisation"), the doctor will decide how strong the anticoagulant therapy needs to be. The target INR level will vary from case to case dependent upon the clinical indicators, but tends to be 2-3 in most conditions. In particular, target INR will be 2.5-3.5 in patients with artificial (mechanical) heart valves.
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| The oral anticoagulant [[ximelagatran]] (Exanta®) was expected to replace warfarin to a large degree when introduced; however, reports of [[hepatotoxicity]] (liver damage) prompted its manufacturer to withdraw it from further development. Other drugs offering the efficacy of warfarin without a need for monitoring, such as [[dabigatran]], [[rivaroxaban]], and Idraparinux are under development.
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| === Pesticide use ===
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| Coumarins, a class of drugs of which warfarin is a member, are used as a rodenticide for controlling rats and mice in residential, industrial, and agricultural areas. The active ingredient in rat poison is [[brodifacoum]], which is sometimes referred to as a super-warfarin, because it is longer acting than the drug warfarin. It is both odorless and tasteless. It is effective when mixed with food bait, because the rodents will return to the bait and continue to feed over a period of days, until a lethal dose is accumulated (considered to be 1 mg/kg b.w./day over four to five days for warfarin; for brodifacoum, no reliable cumulative toxicity datas are available at this time, but it could be concluded, given the similarity with other 4-hydroxycoumarin derivatives, that these would be in order of tens of µg/kg b.w./day for periods of 2-10 days). It may also be mixed with talc and used as a ''tracking powder'', which accumulates on the animal's skin and fur, and is subsequently consumed during grooming. The use as rat poison is now declining because many rat populations have developed resistance to warfarin.
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| The [[LD50|LD<sub>50</sub>]] is 50–500 mg/kg. The [[IDLH]] value is 100mg/m³ (warfarin; various species). LD<sub>50</sub>(mouse, oral) = 0.40 mg/kg; (rat, oral) = 0.27 mg/kg (brodifacoum). The IDLH value for brodifacoum is not defined, but given the toxicity of brodifacoum, it would be substantially lower, perhaps less than 1/100 of the warfarin value, i.e. <1 mg/m³.
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| ==Side-effects==
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| ===Hemorrhage===
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| * Bleeding is the commonest side-effect of warfarin treatment.
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| * The risk of severe bleeding is small but definite (1-2% annually) and any benefit needs to outweigh this risk when warfarin is considered as a therapeutic measure.
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| * Risk of bleeding is augmented if the INR is out of range (due to accidental or deliberate overdose or due to interactions), and may cause [[hemoptysis]] (coughing up blood), excessive bruising, bleeding from nose or gums, or blood in [[urine]] or [[stool]].
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| * The risks of bleeding is increased when warfarin is combined with [[antiplatelet drug]]s such as [[clopidogrel]], [[aspirin]], or [[nonsteroidal anti-inflammatory drug]]s.<ref name="pmid17698822">{{cite journal |author=Delaney JA, Opatrny L, Brophy JM, Suissa S |title=Drug drug interactions between antithrombotic medications and the risk of gastrointestinal bleeding |journal=CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne |volume=177 |issue=4 |pages=347-51 |year=2007 |pmid=17698822 |doi=10.1503/cmaj.070186}}</ref> The risk may also be also increased elderly patients<ref name="pmid17515465">{{cite journal |author=Hylek EM, Evans-Molina C, Shea C, Henault LE, Regan S |title=Major hemorrhage and tolerability of warfarin in the first year of therapy among elderly patients with atrial fibrillation |journal=Circulation |volume=115 |issue=21 |pages=2689-96 |year=2007 |pmid=17515465 |doi=10.1161/CIRCULATIONAHA.106.653048}}</ref> and in patients on [[hemodialysis]].<ref name="pmid17720522">{{cite journal |author=Elliott MJ, Zimmerman D, Holden RM |title=Warfarin anticoagulation in hemodialysis patients: a systematic review of bleeding rates |journal=Am. J. Kidney Dis. |volume=50 |issue=3 |pages=433–40 |year=2007 |pmid=17720522 |doi=10.1053/j.ajkd.2007.06.017}}</ref>
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| *A warfarin treated patient should be given medical attention in case of one of these situations-
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| ** [[INR]] >3.0 in a non-bleeding patient (whose INR target range is 2.0 to 3.0)
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| ** Significant bleeding in warfarin treated patient, irrespective of elevation of the INR levels
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| ====Risk factors associated with increased bleeding with warfarin <ref name="pmid11522005">{{cite journal| author=Penning-van Beest FJ, van Meegen E, Rosendaal FR, Stricker BH| title=Characteristics of anticoagulant therapy and comorbidity related to overanticoagulation. | journal=Thromb Haemost | year= 2001 | volume= 86 | issue= 2 | pages= 569-74 | pmid=11522005 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11522005 }} </ref>====
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| * [[Warfarin]] interacts with many drugs that may increase the risks for bleeding. (For '''warfarin drug interaction''' click [[Warfarin drug interactions|here]])
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| * Incorrect dosages of warfarin
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| * [[Diarrhea]]
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| * [[Heart failure]]
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| * [[Fever]]
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| * Impaired [[liver function test]]
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| * Use of [[acenocoumarol]] over [[phenprocoumon]]
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| * [[Malabsorption]]
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| * [[Vitamin K]] deficiency due to
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| ** Poor dietary intake
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| ** Vitamin K malabsorption ([[celiac disease]], [[antibiotic]]s)
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| ====Pseudo elevated INR====
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| * Sometimes the INR can be falsely increased due to presence of heparin in the blood sample.
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| * Inadequate filling of pediatric collection tubes
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| ==== Treatment options for patients with elevated INR or bleeding with the use of warfarin====
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| The treatment plan for patients on [[warfarin]] are monitored and managed by the levels of [[INR]]. Though supportive large randomized trials are lacking for them, the below stated plan are used as broad guidelines in patient treatments.
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| <table>
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| {|class="wikitable" border="1" style="text-align:center; width:750px;"
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| |-style="background:#CDC9C9"
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| | INR levels
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| | Bleeding
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| | Treatment
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| |-
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| | > 5
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| | No
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| * Frequent [[INR]] monitoring
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| * Decrease [[warfarin]] dose or
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| * Skip one warfarin dose
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| * Start with lower doses of warfarin when INR comes under therapeutic range
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| |-
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| | 5-9
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| | No
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| * Frequent INR monitoring
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| * Stop warfarin temporarily or
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| * Stop warfarin temporarily + add a small dose of oral [[vitamin K]]
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| * Start with lower doses of warfarin when INR comes under therapeutic range
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| |-
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| | >9
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| | No
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| * Frequent INR monitoring
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| * Stop warfarin temporarily +
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| * Administer 2.5 to 5 mg oral vitamin K1
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| * Start with lower doses of warfarin when INR comes under therapeutic range.
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| |-
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| | Any INR value
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| |Serious or life threatening bleeding
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| * Frequent INR monitoring
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| * Stop warfarin temporarily
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| * Administer 10 mg vitamin K1 by slow IV infusion
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| * Add [[prothrombin]] complex concentrate, [[fresh frozen plasma]], or recombinant human [[factor VIIa]]
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| |-
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| |}
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| ====Vitamin K: route of administration in patients with warfarin overanticoagulation====
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| In patients with [[warfarin]] overanticoagulation, [[vitamin K]] administration can decrease the risks of [[bleeding]]. Oral and [[intravenous]] routes of [[vitamin K]] administration are found to be more effective than subcutaneous routes. Also, oral routes are preferred over intravenous routes, due to ease of administration and absence of [[anaphylaxsis]] seen with oral routes <ref name="pmid16505257">{{cite journal| author=Dezee KJ, Shimeall WT, Douglas KM, Shumway NM, O'malley PG| title=Treatment of excessive anticoagulation with phytonadione (vitamin K): a meta-analysis. | journal=Arch Intern Med | year= 2006 | volume= 166 | issue= 4 | pages= 391-7 | pmid=16505257 | doi=10.1001/.391 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16505257 }} </ref>.
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| ===Warfarin necrosis===
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| {{main|warfarin necrosis}}
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| A feared (but rare) complication of warfarin is [[warfarin necrosis]], which occurs more frequently shortly after commencing treatment in patients with a deficiency of [[protein C]]. Protein C is an innate anticoagulant that, like the procoagulant factors that warfarin inhibits, requires vitamin K-dependent carboxylation for its activity. Since warfarin initially decreases protein C levels faster than the coagulation factors, it can paradoxically increase the blood's tendency to coagulate when treatment is first begun (many patients when starting on warfarin are given [[heparin]] in parallel to combat this), leading to massive thrombosis with skin [[necrosis]] and [[gangrene]] of limbs. Its natural counterpart, [[purpura fulminans]], occurs in children who are [[homozygous]] for protein C mutations.
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| ===Purple toe syndrome===
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| Another rare complication that may occur early during warfarin treatment (usually within 3 to 8 weeks) is purple toe syndrome. This condition is thought to result from small deposits of cholesterol breaking loose and flowing into the blood vessels in the skin of the feet, which causes a blueish purple color and may be painful. It is typically thought to affect the big toe, but it affects other parts of the feet as well, including the bottom of the foot (plantar surface). The occurrence of purple toe syndrome may require discontinuation of warfarin.<ref>Talmadge DB, Spyropoulos AC. Purple toes syndrome associated with warfarin therapy in a patient with antiphospholipid syndrome. ''Pharmacotherapy'' 2003;23:674-7. PMID 12741443.</ref>
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| ==Pharmacology==
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| [[Image:Warfarintablets5-3-1.jpg|thumb|3mg (blue), 5mg (pink) and 1mg (brown) warfarin tablets (UK colours)]]
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| ===Pharmacokinetics===
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| Warfarin consists of a racemic mixture of two active optical [[isomer]]s - R and S forms - each of which is cleared by different pathways. S-warfarin has five times the potency of the R-isomer with respect to vitamin K antagonism.<ref name=Hirsh/>
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| Warfarin is slower acting than the common anticoagulant [[heparin]], though it has a number of advantages. Heparin must be given by injection, while warfarin is available orally. Warfarin has a long half-life and need only be given once a day. Heparin can also cause a prothrombotic condition, [[heparin-induced thrombocytopenia]] (an antibody-mediated decrease in [[platelet]] levels), which paradoxically increases the risk for [[thrombosis]]. Warfarin's long half life, on the other hand, means it often takes several days to reach therapeutic effect. Furthermore, if given initially without additional anticoagulant cover, it can paradoxically increase thrombosis risk. For these main reasons, [[hospital]]ised patients are usually given heparin initially, and are then moved on to warfarin.
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| ===Antagonism===
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| Warfarin can be reversed with vitamin K, or for rapid reversal (e.g., in case of severe bleeding), with [[blood plasma|fresh frozen plasma]] but this treatment is being replaced by use of [[prothrombin complex concentrate]].
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| Details on reversing warfarin are provided in [[clinical practice guidelines]] from the [[American College of Chest Physicians]].<ref name="pmid15383473">{{cite journal |author=Ansell J, Hirsh J, Poller L, Bussey H, Jacobson A, Hylek E |title=The pharmacology and management of the vitamin K antagonists: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy |journal=Chest |volume=126 |issue=3 Suppl |pages=204S-233S |year=2004 |pmid=15383473 |doi=10.1378/chest.126.3_suppl.204S}} ([http://www.chestjournal.org/cgi/content/full/126/3_suppl/204S/T6 summary])</ref>
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| For patients with an [[international normalized ratio]] (INR) between 4.5 and 10.0, 1 mg of oral vitamin k is effective.<ref name="pmid12186515">{{cite journal |author=Crowther MA, Douketis JD, Schnurr T, ''et al'' |title=Oral vitamin K lowers the international normalized ratio more rapidly than subcutaneous vitamin K in the treatment of warfarin-associated coagulopathy. A randomized, controlled trial |journal=Ann. Intern. Med. |volume=137 |issue=4 |pages=251-4 |year=2002 |pmid=12186515 |doi=}}</ref>
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| ===Pharmacogenomics===
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| Warfarin activity is determined partially by genetic factors. The American [[Food and Drug Administration]] "highlights the opportunity for healthcare providers to use genetic tests to improve their initial estimate of what is a reasonable warfarin dose for individual patients" .<ref>{{cite web |url=http://www.fda.gov/bbs/topics/NEWS/2007/NEW01684.html |title=FDA Approves Updated Warfarin (Coumadin) Prescribing Information |format= |work=}}</ref>
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| ====VKORC1====
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| [[Polymorphism (biology)|Polymorphism]]s in the ''[[vitamin K epoxide reductase]] complex 1 (VKORC1)'' gene explain 30% of the dose variation between patients<ref name="pmid15883587">{{cite journal |author=Wadelius M, Chen LY, Downes K, ''et al'' |title=Common VKORC1 and GGCX polymorphisms associated with warfarin dose |journal=Pharmacogenomics J. |volume=5 |issue=4 |pages=262-70 |year=2005 |pmid=15883587 |doi=10.1038/sj.tpj.6500313}}</ref>: particular mutations make VKORC1 less susceptible to suppression by warfarin<ref name="pmid14765194"/> There are a main haplotypes that explain 25% of variation: low-dose haplotype group (A) and a high-dose haplotype group (B).<ref name="pmid15930419">{{cite journal |author=Rieder MJ, Reiner AP, Gage BF, ''et al'' |title=Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose |journal=N. Engl. J. Med. |volume=352 |issue=22 |pages=2285-93 |year=2005 |pmid=15930419 |doi=10.1056/NEJMoa044503}}</ref> For the three combinations of the haplotypes, the mean daily maintenance dose of warfarin was:
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| * A/A: 2.7+/-0.2 mg
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| * A/B: 4.9+/-0.2 mg
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| * B/B: 6.2+/-0.3 mg
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| ''VKORC1'' polymorphisms also explain why African Americans are relatively resistant to warfarin (higher proportion of group B haplotypes), while Asian Americans are more sensitive (higher proportion of group A haplotypes).<ref name="pmid15930419"/>
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| ====CYP2C9====
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| ''CYP2C9'' is an [[isozyme]] of [[cytochrome P450]]. Polymorphisms of CYP2C9 explain another 10% of variation in warfarin dosing<ref name="pmid15883587"/>, mainly among Caucasian patients as these variants are rare in African American and most Asian populations.<ref name="pmid15714076">{{cite journal |author=Sanderson S, Emery J, Higgins J |title=CYP2C9 gene variants, drug dose, and bleeding risk in warfarin-treated patients: a HuGEnet systematic review and meta-analysis |journal=Genet. Med. |volume=7 |issue=2 |pages=97-104 |year=2005 |pmid=15714076 |doi=}}</ref> A [[meta-analysis]] of mainly Caucasian patients found<ref name="pmid15714076"/>:
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| * CYP2C9*2 allele:
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| ** present in 12.2% of patients
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| ** mean reduction was in warfarin dose was 0.85 mg (17% reduction)
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| ** relative bleeding risk was 1.91
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| * CYP2C9*3 allele:
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| ** present in 7.9% of patients
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| ** mean reduction was in warfarin dose was 1.92 mg (37% reduction)
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| ** relative bleeding risk was 1.77
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| ===Loading regimens===
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| Because of warfarin's poorly predictable [[pharmacokinetics]], several researchers have proposed algorithms for commencing warfarin treatment:
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| * The Kovacs 10 mg algorithm was better than a 5 mg algorithm.<ref name="pmid12729425">{{cite journal |author=Kovacs MJ, Rodger M, Anderson DR, ''et al'' |title=Comparison of 10-mg and 5-mg warfarin initiation nomograms together with low-molecular-weight heparin for outpatient treatment of acute venous thromboembolism. A randomized, double-blind, controlled trial |journal=Ann. Intern. Med. |volume=138 |issue=9 |pages=714-9 |year=2003 |pmid=12729425 |doi=|url=http://annals.org/cgi/content/full/138/9/714}} ([http://annals.org/cgi/content/full/138/9/714/F1 summary of 10 mg algorithm])</ref>
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| * The Fennerty 10 mg regimen is for urgent anticoagulation<ref name="pmid3144365">{{cite journal |author=Fennerty A, Campbell IA, Routledge PA |title=Anticoagulants in venous thromboembolism |journal=BMJ |volume=297 |issue=6659 |pages=1285-8 |year=1988 |pmid=3144365 |doi= | url=http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=3144365}}</ref>
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| * The Tait 5 mg regimen is for "routine" (low-risk) anticoagulation ([http://www.blackwell-synergy.com/action/showPopup?citid=citart1&id=f1&doi=10.1046%2Fj.1365-2141.1998.00716.x summary])<ref name="pmid9633885">{{cite journal |author=Tait RC, Sefcick A |title=A warfarin induction regimen for out-patient anticoagulation in patients with atrial fibrillation |journal=Br. J. Haematol. |volume=101 |issue=3 |pages=450-4 |year=1998 |pmid=9633885 |doi=10.1046/j.1365-2141.1998.00716.x }}</ref>
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| * From a cohort of orthopedic patients, Millican ''et al'' derived an 8-value model, including CYP29C and VKORC1 genotype results, that could predict 80% of the variation in warfarin doses. It is awaiting validation in larger populations and has not been reproduced in those who require warfarin for other indications.<ref>{{cite journal |author=Millican E, Jacobsen-Lenzini PA, Milligan PE, ''et al'' |title=Genetic-based dosing in orthopaedic patients beginning warfarin therapy |journal= |volume=110 |issue=5 |pages=1511-5 |year=2007 |pmid=17387222 |doi=10.1182/blood-2007-01-069609}} [http://www.warfarindosing.org Online tool based on the study].</ref>
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| ===Adjusting the maintenance dose===
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| Recommendations by the [[American College of Chest Physicians]]<ref name="pmid15383473"/> have been distilled to help manage dose adjustments.<ref>{{cite web |url=http://www.aafp.org/afp/20050515/pocform.html |title=Point-of-Care Guides - May 15, 2005 - American Family Physician |format= |work=}}</ref>
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| ===Interactions and contraindications===
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| There are many drug-drug interactions with warfarin, and its metabolism varies greatly between patients. Some foodstuffs have also been reported to interact with warfarin<ref>Holbrook AM, Pereira JA, Labiris R, McDonald H, Douketis JD, Crowther M, Wells PS. Systematic overview of warfarin and its drug and food interactions. ''Arch Intern Med'' 2005;165:1095-106. PMID 15911722.</ref> This makes finding the correct dosage difficult, and accentuates the need of monitoring; when initiating a medication that is known to interact with warfarin (e.g. [[simvastatin]]), INR checks are increased or dosages adjusted until a new ideal dosage is found.
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| Warfarin cannot be given to [[pregnant]] women, especially in the first trimester, as it is a [[teratogen]] causing deformations of the face and bones. During the third trimester, antepartum hemorrhage can occur. Instead of warfarin, [[low molecular weight heparin]] is generally used. (See [[anticoagulation in pregnancy]].)
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| Excessive use of alcohol is also known to affect the metabolism of warfarin and can elevate the INR. Patients should be cautioned against the excessive use of alcohol while taking warfarin. A common recommendation is limiting the maximum daily intake to no more than a few drinks. Patients suffering from liver damage or alcoholism are usually treated with heparin injections instead.
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| Warfarin also interacts with the many herbs, including - but not limited to - the following: <ref>Austin, Steve, and Forrest Batz. The A-Z Guide to Drug-Herb-Vitamin Interactions: How to Improve Your Health and Avoid Problems When Using Common Medications and Natural Supplements Together. Ed. Schulyer M. Lininger. 1st ed. New York: Three Rivers P, 1999. p.224.</ref>
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| * [[Ginkgo]] (a.k.a. Ginkgo Biloba), which is commonly used to increase brain blood flow, prevent dementia, and improve memory. However, ginkgo may increase blood pressure, and may increase bleeding, especially in people already taking certain anti-clotting medications such as warfarin.
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| * [[St. John's Wort]] is commonly used to help with mild to moderate depression. However, it may prolong the effects of certain anesthetic drugs and reduce the effects oral contraceptives and anti-organ transplant rejection medications, and interfere with warfarin.
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| * [[Ginseng]] is commonly used to help with fatigue and weakness. However, ginseng may increase blood pressure and heart rate and may increase bleeding, especially in people already taking certain anti-clotting medications such as warfarin.
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| * [[Garlic]] (as a supplement, not in the diet) is commonly used to help lower high cholesterol levels, high triglycerides, and high blood pressure. However, may increase bleeding especially in people already taking certain anti-clotting medications such as warfarin.
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| * [[Ginger]] is commonly used to help nausea and poor digestion. However, it may increase bleeding, especially in patients already taking certain anti-clotting medications such as warfarin.
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| ===Superwarfarin toxicity===
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| * Superwarfarins are long-acting rat poisons that are 100 times more potent than [[warfarin]]
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| * Market name: [[Brodifacoum]], [[bromadiolone]], [[coumafuryl]], [[difenacoum]]
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| * Increased risks of superwarfarin poisoning can be seen in:
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| ** Occupational hazard
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| ** Drug addicts
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| ** Accidental exposure
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| ** Suicide cases
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| * Presentation
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| ** [[Bleeding]]
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| * Diagnosis
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| ** Superwarfarin assays
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| ** Abnormal coagulation profile (↑ [[PT]], [[aPTT]], [[INR]])
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| * Treatment - High doses of [[vitamin K]] for longer durations (may be weeks to months)
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| ==History==
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| The early 1920s saw the outbreak of a previously unrecognized disease of cattle in the northern United States and Canada. Cattle would die of uncontrollable [[bleeding]] from very minor injuries, or sometimes drop dead of internal hemorrhage with no external signs of injury. In 1921, Frank Schofield, a Canadian [[veterinarian]], determined that the cattle were ingesting moldy silage made from sweet clover that functioned as a potent anticoagulant.<ref>Schofield FW. Damaged sweet clover; the cause of a new disease in cattle simulating haemorrhagic septicemia and blackleg. ''J Am Vet Med Ass'' 1924;64:553-6.</ref> In 1929, North Dakota veterinarian Dr L.M. Roderick demonstrated that the condition was due to a lack of functioning [[prothrombin]].<ref>Roderick LM. A problem in the coagulation of the blood; "sweet clover disease of the cattle". ''Am J Physiol'' 1931;96:413-6. [http://ajplegacy.physiology.org/cgi/reprint/96/2/413 PDF].</ref>
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| The identity of the anticoagulant substance in moldy sweet clover remained a mystery until 1940 when [[Karl Paul Link]] and his student Harold Campbell, chemists working at the University of Wisconsin, determined that it was the [[coumarin]] derivative 4-hydroxycoumarin.<ref>Stahmann MA, Huebner CF, Link KP. Studies on the hemorrhagic sweet clover disease. V. Identification and synthesis of the hemorrhagic agent. ''J Biol Chem'' 1941;138:513-27 [http://www.jbc.org/cgi/reprint/138/2/513 PDF].</ref> Over the next few years, numerous similar chemicals were found to have the same anticoagulant properties. The first of these to be widely commercialized was dicoumarol, patented in 1941. Link continued working on developing more potent coumarin-based anticoagulants for use as rodent poisons, resulting in warfarin in 1948. (The name warfarin stems from the acronym ''WARF'', for ''Wisconsin Alumni Research Foundation'' + the ending ''-arin'' indicating its link with coumarin.) Warfarin was first registered for use as a rodenticide in the US in 1952; although it was developed by Link, the WARF financially supported the research and was granted the patent.
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| The exact mechanism of action remained unknown until it was demonstrated, in 1978, that warfarin inhibited epoxide reductase and hence interfered with vitamin K metabolism.<ref name=Whitlon />
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| After an incident in 1951, where a naval enlisted man unsuccessfully attempted suicide with warfarin and recovered fully, studies began in the use of warfarin as a therapeutic anticoagulant. It was found to be generally superior to dicoumarol, and in 1954 was approved for medical use in humans. A famous early patient prescribed warfarin was Dwight Eisenhower, president of the USA, subsequent to his [[myocardial infarction|heart attack]] in 1955.
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| A 2003 theory posits that warfarin was used by a conspiracy of Lavrenty Beria, Nikita Khrushchev and others to poison Soviet leader Joseph Stalin. Warfarin is tasteless and colorless, and produces symptoms similar to those that Stalin exhibited.<ref>Jonathan Brent, Vladimir Naumov. ''Stalin's Last Crime : The Plot Against the Jewish Doctors, 1948-1953''. HarperCollins, 2003. ISBN 0-06-019524-X.</ref>
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| ==Other coumarins==
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| In some countries, other coumarins are used instead of warfarin, such as [[acenocoumarol]] and [[phenprocoumon]]. These have a shorter (acenocoumarol) or longer (phenprocoumon) half-life, and are not completely interchangeable with warfarin.
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| ==References==
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| {{reflist|2}}
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| ==External links==
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| *[http://ace.orst.edu/cgi-bin/mfs/01/pips/warfarin.htm Warfarin pesticide profile] from US Department of Agriculture
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| *[http://www.warf.org/about/index.jsp?cid=26&scid=34 Historical information on Warfarin]
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| *[http://www.chemsoc.org/exemplarchem/entries/2002/hook/warfarin.htm Warfarin factsheet] from the Royal Society of Chemistry
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| *[http://www.clotcare.com/clotcare/postings.aspx?by=med&medid=1&word=Warfarin Warfarin information for patients and healthcare providers]
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| *[http://dietary-supplements.info.nih.gov/factsheets/cc/coumadin1.pdf Important information to know when you are taking: Coumadin and Vitamin K]from the [[National Institutes of Health]]
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| *[http://www.pace-med-apps.com/CoumCalc.aspx Free Online Coumadin Dosing Calculator] - Dosing Algorithm from the University of Michigan CVS
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