Warfarin

Warfarin.svg
Warfarin
Systematic (IUPAC) name
(RS)-4-hydroxy-3-(3-oxo-1-phenylbutyl)-
2H-chromen-2-one
Identifiers
CAS number 81-81-2
ATC code B01AA03
PubChem 6691
DrugBank APRD00341
ChemSpider 10442445
Chemical data
Formula C19H16O4 
Mol. mass 308.33 g/mol
SMILES eMolecules & PubChem
Pharmacokinetic data
Bioavailability 100%
Protein binding 99.5%
Metabolism Hepatic: CYP2C9, 2C19, 2C8, 2C18, 1A2 and 3A4
Half life 2.5 days
Excretion Renal (92%)
Therapeutic considerations
Pregnancy cat.

D(AU) X(US)
Legal status

Prescription Only (S4)(AU) POM(UK) ℞-only(US)
Routes Oral or intravenous

Warfarin (also known under the brand names Coumadin, Jantoven, Marevan, and Waran) is an anticoagulant. It was initially marketed as a pesticide against rats and mice, and is still popular for this purpose, although more potent poisons such as brodifacoum have since been developed. A few years after its introduction, warfarin was found to be effective and relatively safe for preventing thrombosis and embolism (abnormal formation and migration of blood clots) in many disorders. It was approved for use as a medication in the early 1950s, and has remained popular ever since; warfarin is the most widely prescribed anticoagulant drug in North America.[1] Despite its effectiveness, treatment with warfarin has several shortcomings. Many commonly used medications interact with warfarin, and its activity has to be monitored by frequent blood testing for the international normalized ratio (INR) to ensure an adequate yet safe dose is taken.[2]

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 and related coumarins decrease blood coagulation by inhibiting vitamin K epoxide reductase, an enzyme that recycles oxidated vitamin K to its reduced form after it has participated in the carboxylation of several blood coagulation proteins, mainly prothrombin and factor VII. For this reason, drugs in this class are also referred to as vitamin K antagonists.[2]

Contents

History

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.[3] In 1929, North Dakota veterinarian Dr L.M. Roderick demonstrated that the condition was due to a lack of functioning prothrombin.[4]

The identity of the anticoagulant substance in moldy sweet clover remained a mystery until 1940 when Karl Paul Link and his lab of chemists working at the University of Wisconsin set out to isolate and characterize the hemorrhagic agent from the spoiled hay. It ended up taking 5 years for Link's student Harold A. Campbell to recover 6 mg of crystalline anticoagulant. Next, Link's student Mark A. Stahmann took over the project and initiated a large scale extraction, isolating 1.8 g of recrystallized anticoagulant in about 4 months. This was enough material for Stahmann and Charles F. Huebner to check their results against Campbell's and to thoroughly characterize the compound. Through degradation experiments they established that the anticoagulant was 3,3'-methylenebis-(4-hydroxycoumarin), which they later named dicumarol. They confirmed their results by synthesizing dicumarol and proving that it was identical to the naturally occurring product.[5] 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 1948, and was immediately popular; although it was developed by Link, the WARF financially supported the research and was granted the patent.[6]

After an incident in 1951, where an army inductee unsuccessfully attempted suicide with warfarin and recovered fully,[6] 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 recipient of warfarin was US president Dwight Eisenhower, who was prescribed the drug after having a heart attack in 1955.[6]

The exact mechanism of action remained unknown until it was demonstrated, in 1978, that warfarin inhibited the enzyme epoxide reductase and hence interfered with vitamin K metabolism.[7]

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.[8]

Therapeutic uses

Warfarin is prescribed to people with an increased tendency for thrombosis or as secondary prophylaxis (prevention of further episodes) in those individuals that have already formed a blood clot (thrombus). Warfarin treatment 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, the presence of artificial heart valves, deep venous thrombosis, pulmonary embolism, antiphospholipid syndrome and, occasionally, after myocardial infarction.[9]

Dosing of warfarin is complicated by the fact that it is known to interact with many commonly-used medications and even with chemicals that may be present in certain foods.[1] These interactions may enhance or reduce warfarin's anticoagulation effect. In order to optimize the therapeutic effect without risking dangerous side effects such as bleeding, close monitoring of the degree of anticoagulation is required by blood testing (INR). During the initial stage of treatment, checking may be required daily; intervals between tests can be lengthened if the patient manages stable therapeutic INR levels on an unchanged warfarin dose.[9]

When initiating warfarin therapy ("warfarinization"), the doctor will decide how strong the anticoagulant therapy needs to be. The target INR level will vary from case to case depending on the clinical indicators, but tends to be 2–3 in most conditions. In particular, target INR may be 2.5–3.5 (or even 3.0–4.5) in patients with one or more mechanical heart valves.[10]

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. The oral anticoagulant ximelagatran (trade name 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 and rivaroxaban, are under development.[11]

Contraindications

Warfarin is a teratogen, causing deformations of the face (depressed nasal bridge) and bones (stippled epiphyses), neonatal seizures, and spontaneous abortion.[12] Anticoagulation in pregnancy may therefore pose a problem in women requiring warfarin for vital indications, such as stroke prevention in those with artificial heart valves. Hence, warfarin is avoided in the first trimester, and low molecular weight heparin such as enoxaparin is substituted. Various solutions exist for the time around delivery.

Adverse effects

Hemorrhage

The only common side effect of warfarin is hemorrhage (bleeding). 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. 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.

The risks of bleeding is increased when warfarin is combined with antiplatelet drugs such as clopidogrel, aspirin, or nonsteroidal anti-inflammatory drugs.[13] The risk may also be increased in elderly patients[14] and in patients on hemodialysis.[15]

Warfarin necrosis

Main article: warfarin necrosis

A rare but serious complication resulting from treatment with 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.[16]

Osteoporosis

After initial reports that warfarin could reduce bone mineral density, several studies have demonstrated a link between warfarin use and osteoporosis-related fracture. A 1999 study in 572 women taking wafarin for DVT, risk of vertebral fracture and rib fracture was increased; other fracture types did not occur more commonly.[17] A 2002 study looking at a randomly selected selection of 1523 patients with osteoporotic fracture found no increased exposure to anticoagulants compared to controls, and neither did stratification of the duration of anticoagulation reveal a trend towards fracture.[18]

A 2006 retrospective study of 14,564 Medicare recipients showed that warfarin use for more than one year was linked with a 60% increased risk of osteoporosis-related fracture in men; there was no association in women. The mechanism was thought to be either reduced intake of vitamin K, which is necessary for bone health, or interaction by warfarin with carboxylation of certain bone proteins.[19]

Purple toe syndrome

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.[20]

Pharmacology

3 mg (blue), 5 mg (pink) and 1 mg (brown) warfarin tablets (UK colours)

Pharmacokinetics

Warfarin consists of a racemic mixture of two active optical isomers—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.[9]

Warfarin is slower-acting than the common anticoagulant heparin, though it has a number of advantages. Heparin must be given by injection, whereas 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 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 increase thrombosis risk. For these main reasons, hospitalised patients are usually given heparin first, and are then moved on to warfarin.

Mechanism of action

Warfarin inhibits the vitamin K-dependent synthesis of biologically active forms of the calcium-dependent clotting factors II, VII, IX and 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.

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 proceed only if the carboxylase enzyme is able to convert a 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[7] (specifically the VKORC1 subunit[21][22]), 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), and individual coagulation factors as PIVKA-number (e.g. PIVKA-II). The end result of warfarin use, therefore, is to diminish blood clotting in the patient.

The initial effect of warfarin administration is to briefly 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 degradation of factor Va and 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.

Antagonism

The effects of warfarin can be reversed with vitamin K, or, when rapid reversal is needed (such as in case of severe bleeding), with prothrombin complex concentrate—which contains only the factors inhibited by warfarin—or fresh frozen plasma (depending upon the clinical indication) in addition to intravenous vitamin K.

Details on reversing warfarin are provided in clinical practice guidelines from the American College of Chest Physicians.[23] For patients with an international normalized ratio (INR) between 4.5 and 10.0, 1 mg of oral vitamin K is effective.[24]

Pharmacogenomics

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".[25]

VKORC1

Polymorphisms in the vitamin K epoxide reductase complex 1 (VKORC1) gene explain 30% of the dose variation between patients:[26] particular mutations make VKORC1 less susceptible to suppression by warfarin[22] There are two main haplotypes that explain 25% of variation: low-dose haplotype group (A) and a high-dose haplotype group (B).[27] For the three combinations of the haplotypes, the mean daily maintenance dose of warfarin was:

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).[27] VKORC1 polymorphisms lead to a more rapid achievement of a therapeutic INR, but also a shorter time to reach an INR over 4, which is associated with bleeding.[28]

CYP2C9

CYP2C9 is an isozyme of cytochrome P450. Polymorphisms of CYP2C9 explain another 10% of variation in warfarin dosing,[26] mainly among Caucasian patients as these variants are rare in African American and most Asian populations.[29] CYP2C9 polymorphisms do not influence time to effective INR as opposed to VKORC1, but does shorten the time to INR >4.[28]

A meta-analysis of mainly Caucasian patients found:[29]

Loading regimens

Because of warfarin's poorly-predictable pharmacokinetics, several researchers have proposed algorithms for commencing warfarin treatment:

Adjusting the maintenance dose

Recommendations by many national bodies including the American College of Chest Physicians[23] have been distilled to help manage dose adjustments.[34]

Self-testing and home monitoring

Patients are making increasing use of self-testing and home monitoring of oral anticoagulation. International guidelines were published in 2005 to govern home testing, by the International Self-Monitoring Association for Oral Anticoagulation.[2]

The international guidelines study stated: "The consensus agrees that patient self-testing and patient self-management are effective methods of monitoring oral anticoagulation therapy, providing outcomes at least as good as, and possibly better than, those achieved with an anticoagulation clinic. All patients must be appropriately selected and trained. Currently-available self-testing/self-management devices give INR results that are comparable with those obtained in laboratory testing."[2]

Interactions

Warfarin interacts with many commonly-used drugs, and the metabolism of warfarin varies greatly between patients. Some foods have also been reported to interact with warfarin.[1] Apart from the metabolic interactions, highly protein bound drugs can displace warfarin from albumin and cause an increase in INR.[35] 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.

Many commonly-used antibiotics, such as metronidazole or the macrolides, 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.[36] In addition, food that contains large quantities of vitamin K will reduce the warfarin effect.[1] Thyroid activity also appears to influence warfarin dosing requirements;[37] hypothyroidism (decreased thyroid function) makes people less responsive to warfarin treatment,[38] while hyperthyroidism (overactive thyroid) boosts the anticoagulant effect.[39] Several mechanisms have been proposed for this effect, including changes in the rate of breakdown of clotting factors and changes in the metabolism of warfarin.[40][37]

Excessive use of alcohol is also known to affect the metabolism of warfarin and can elevate the INR.[41] Patients are often cautioned against the excessive use of alcohol while taking warfarin.

Warfarin also interacts with many herbs, including—but not limited to—the following:[42]

Between 2003 and 2004, the UK Committee on Safety of Medicines received several reports of increased INR and risk of hemorrhage in people taking warfarin and cranberry juice.[43][44][45] Data establishing a causal relationship is still lacking, and a 2006 review found no cases of this interaction reported to the FDA;[45] nevertheless, several authors have recommended that both doctors and patients be made aware of its possibility.[46] The mechanism behind the interaction is still unclear.[45]

Use as a pesticide

To this day, coumarins are used as rodenticides for controlling rats and mice in residential, industrial, and agricultural areas. Warfarin is both odorless and tasteless, and 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/day over about six 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 LD50 is 50–500 mg/kg. The IDLH value is 100 mg/m³ (warfarin; various species).[47]

The use of warfarin as a rat poison is now declining because many rat populations have developed resistance to it, and poisons of considerably greater potency are now available. Other coumarins used as rodenticides include coumatetralyl and brodifacoum, which is sometimes referred to as "super-warfarin", because it is more potent, longer-acting, and effective even in rat and mouse populations that are resistant to warfarin. Unlike warfarin, which is readily excreted, newer anticoagulant poisons also accumulate in the liver and kidneys after ingestion.[48]

References

  1. ↑ 1.0 1.1 1.2 1.3 Holbrook AM, Pereira JA, Labiris R, et al (2005). "Systematic overview of warfarin and its drug and food interactions". Arch. Intern. Med. 165 (10): 1095–106. doi:10.1001/archinte.165.10.1095. PMID 15911722. http://archinte.ama-assn.org/cgi/content/full/165/10/1095. 
  2. ↑ 2.0 2.1 2.2 2.3 Ansell J, Hirsh J, Poller L, Bussey H, Jacobson A, Hylek E (2004). "The pharmacology and management of the vitamin K antagonists: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy". Chest 126 (3 Suppl): 204S–233S. doi:10.1378/chest.126.3_suppl.204S. PMID 15383473. http://www.chestjournal.org/cgi/content/full/126/3_suppl/204S. 
  3. ↑ Schofield FW (1924). "Damaged sweet clover; the cause of a new disease in cattle simulating haemorrhagic septicemia and blackleg". J Am Vet Med Ass 64: 553–6. 
  4. ↑ Roderick LM (1931). "A problem in the coagulation of the blood; "sweet clover disease of the cattle"". Am J Physiol 96: 413–6.  PDF (subscriber only).
  5. ↑ Stahmann MA, Huebner CF, Link KP (04/01/1941). "Studies on the hemorrhagic sweet clover disease. V. Identification and synthesis of the hemorrhagic agent". J Biol Chem 138 (2): 513–27. http://www.jbc.org/cgi/reprint/138/2/513. 
  6. ↑ 6.0 6.1 6.2 Link KP (01/01/1959). "The discovery of dicumarol and its sequels". Circulation 19 (1): 97–107. PMID 13619027. http://circ.ahajournals.org/cgi/reprint/19/1/97. 
  7. ↑ 7.0 7.1 Whitlon DS, Sadowski JA, Suttie JW (1978). "Mechanism of coumarin action: significance of vitamin K epoxide reductase inhibition". Biochemistry 17 (8): 1371–7. doi:10.1021/bi00601a003. PMID 646989. 
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  19. ↑ Gage BF, Birman-Deych E, Radford MJ, Nilasena DS, Binder EF (2006). "Risk of osteoporotic fracture in elderly patients taking warfarin: results from the National Registry of Atrial Fibrillation 2". Arch. Intern. Med. 166 (2): 241–6. doi:10.1001/archinte.166.2.241. PMID 16432096. http://archinte.ama-assn.org/cgi/content/full/166/2/241. 
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  21. ↑ Li T, Chang CY, Jin DY, Lin PJ, Khvorova A, Stafford DW (2004). "Identification of the gene for vitamin K epoxide reductase". Nature 427 (6974): 541–4. doi:10.1038/nature02254. PMID 14765195. 
  22. ↑ 22.0 22.1 Rost S, Fregin A, Ivaskevicius V, et al (2004). "Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2". Nature 427 (6974): 537–41. doi:10.1038/nature02214. PMID 14765194. 
  23. ↑ 23.0 23.1 Ansell J, Hirsh J, Poller L, Bussey H, Jacobson A, Hylek E (2004). "The pharmacology and management of the vitamin K antagonists: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy". Chest 126 (3 Suppl): 204S–233S. doi:10.1378/chest.126.3_suppl.204S. PMID 15383473. http://www.chestjournal.org/cgi/content/full/126/3_suppl/204S.  (summary)
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  25. ↑ "FDA Approves Updated Warfarin (Coumadin) Prescribing Information". Retrieved on 2007-08-20.
  26. ↑ 26.0 26.1 Wadelius M, Chen LY, Downes K, et al (2005). "Common VKORC1 and GGCX polymorphisms associated with warfarin dose". Pharmacogenomics J. 5 (4): 262–70. doi:10.1038/sj.tpj.6500313. PMID 15883587. 
  27. ↑ 27.0 27.1 Rieder MJ, Reiner AP, Gage BF, et al (2005). "Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose". N. Engl. J. Med. 352 (22): 2285–93. doi:10.1056/NEJMoa044503. PMID 15930419. 
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  30. ↑ Kovacs MJ, Rodger M, Anderson DR, et al (2003). "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". Ann. Intern. Med. 138 (9): 714–9. PMID 12729425. http://annals.org/cgi/content/full/138/9/714.  (summary of 10 mg algorithm)
  31. ↑ Fennerty A, Campbell IA, Routledge PA (1988). "Anticoagulants in venous thromboembolism". BMJ 297 (6659): 1285–8. PMID 3144365.  Full text at PMC: 1834928
  32. ↑ Tait RC, Sefcick A (1998). "A warfarin induction regimen for out-patient anticoagulation in patients with atrial fibrillation". Br. J. Haematol. 101 (3): 450–4. doi:10.1046/j.1365-2141.1998.00716.x. PMID 9633885.  summary
  33. ↑ Millican E, Jacobsen-Lenzini PA, Milligan PE, et al (2007). "Genetic-based dosing in orthopaedic patients beginning warfarin therapy". Blood 110 (5): 1511–5. doi:10.1182/blood-2007-01-069609. PMID 17387222.  Online tool based on the study.
  34. ↑ "Point-of-Care Guides: May 15, 2005. American Family Physician". Retrieved on 2007-08-20.
  35. ↑ Gage BF, Fihn SD, White RH (October 2000). "Management and dosing of warfarin therapy". Am. J. Med. 109 (6): 481–8. PMID 11042238. 
  36. ↑ 37.0 37.1 Kurnik D, Loebstein R, Farfel Z, Ezra D, Halkin H, Olchovsky D (March 2004). "Complex drug-drug-disease interactions between amiodarone, warfarin, and the thyroid gland". Medicine (Baltimore) 83 (2): 107–13. doi:10.1097/01.md.0000123095.65294.34. PMID 15028964. http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=0025-7974&volume=83&issue=2&spage=107. 
  37. ↑ Stephens MA, Self TH, Lancaster D, Nash T (December 1989). "Hypothyroidism: effect on warfarin anticoagulation". South Med J 82 (12): 1585–6. PMID 2595433. http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=0038-4348&volume=82&issue=12&spage=1585. 
  38. ↑ Chute JP, Ryan CP, Sladek G, Shakir KM (1997). "Exacerbation of warfarin-induced anticoagulation by hyperthyroidism". Endocr Pract 3 (2): 77–9. PMID 15251480. http://aace.metapress.com/openurl.asp?genre=article&issn=1530-891X&volume=3&issue=2&spage=77. 
  39. ↑ Kellett HA, Sawers JS, Boulton FE, Cholerton S, Park BK, Toft AD (January 1986). "Problems of anticoagulation with warfarin in hyperthyroidism". Q J Med 58 (225): 43–51. PMID 3704105. http://qjmed.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=3704105. 
  40. ↑ Weathermon R, Crabb DW (1999). "Alcohol and medication interactions". Alcohol Res Health 23 (1): 40–54. PMID 10890797. 
  41. ↑ Austin, Steve and Batz, Forrest (1999). Lininger, Schuyler W.. ed.. A-Z guide to drug-herb-vitamin interactions: how to improve your health and avoid problems when using common medications and natural supplements together. Roseville, Calif: Prima Health. pp. 224. ISBN 0-7615-1599-2. 
  42. ↑ "Cranberry juice clot drug warning". BBC news (2003-09-18). Retrieved on 2008-05-18.
  43. ↑ Suvarna R, Pirmohamed M, Henderson L (December 2003). "Possible interaction between warfarin and cranberry juice". BMJ 327 (7429): 1454. doi:10.1136/bmj.327.7429.1454. PMID 14684645. 
  44. ↑ 45.0 45.1 45.2 Aston JL, Lodolce AE, Shapiro NL (September 2006). "Interaction between warfarin and cranberry juice". Pharmacotherapy 26 (9): 1314–9. doi:10.1592/phco.26.9.1314. PMID 16945054.  Free full text with registration at Medscape
  45. ↑ Pham DQ, Pham AQ (March 2007). "Interaction potential between cranberry juice and warfarin". Am J Health Syst Pharm 64 (5): 490–4. doi:10.2146/ajhp060370. PMID 17322161. 
  46. ↑ United States Occupational Safety and Health Administration (OSHA) (August 16, 1996). "Documentation for Immediately Dangerous To Life or Health Concentrations (IDLHs): Warfarin". Centers for Disease Control and Prevention. Retrieved on 2008-07-07.
  47. ↑ Charles T. Eason; Mark Wickstrom (2001). "2. Anticoagulant poisons". Vertebrate pesticide toxicology manual (poisons). New Zealand Department of Conservation. pp. pp. 41–74. ISBN 0-478-22035-9. 

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