warfarin warfarin warfarin is an anticoagulant used as a medication under several brand names including coumadin, and as a poison for rats and other pests. while the drug is described as a "blood thinner", it does not reduce viscosity but inhibits coagulation, and is commonly used to prevent blood clots in the circulatory system such as deep vein thrombosis and pulmonary embolism, and to protect against stroke in people who have atrial fibrillation, valvular heart disease, or artificial heart valves. less commonly, it is used following st-segment elevation myocardial infarction and orthopedic surgery. it is usually taken by mouth, but may also be administered intravenously. this article is about the anticoagulation medication. for the rodenticide often called "coumarins", see 4-hydroxycoumarins. warfarinclinical datapronunciation/ˈwɔːrfərɪn/ trade namescoumadin and many othersahfs/drugs.commonographmedlineplusa682277license data us dailymed: warfarin us fda: warfarin pregnancycategory au: d routes ofadministrationby mouth, intravenousatc codeb01aa03 (who) qb01aa03 (who)legal statuslegal status au: s4 (prescription only) ca: ℞-only uk: pom (prescription only) us: ℞-only pharmacokinetic databioavailability79–100% (by mouth)protein binding99%metabolismliver: cyp2c9, 2c19, 2c8, 2c18, 1a2 and 3a4elimination half-life1 week (active half-life is 20-60 hours)excretionkidney (92%)identifiers iupac name (rs)-4-hydroxy-3-(3-oxo-1-phenylbutyl)- 2h-chromen-2-one cas number81-81-2 yas salt: 129-06-6pubchem cid54678486as salt: 16204922iuphar/bps6853drugbankdb00682 nas salt: dbsalt000278chemspider10442445 yas salt: 17333193unii5q7zvv76eias salt: 6153cwm0clkeggd08682 yas salt: d00564chebichebi:10033 yas salt: chebi:10034chemblchembl1464 nas salt: chembl1200879pdb ligandrwf (pdbe, rcsb pdb)as salt: swf (pdbe, rcsb pdb)echa infocard100.001.253 chemical and physical dataformulac19h16o4molar mass308.333 g·mol−13d model (jsmol)interactive image smiles cc(=o)cc(c\1=c(/o)c2ccccc2oc/1=o)c3ccccc3 inchi inchi=1s/c19h16o4/c1-12(20)11-15(13-7-3-2-4-8-13)17-18(21)14-9-5-6-10-16(14)23-19(17)22/h2-10,15,21h,11h2,1h3 ykey:pjvwktkqmonhti-uhfffaoysa-n y ny (what is this?) (verify) the common side effect, a natural consequence of reduced clotting, is bleeding. less common side effects may include areas of tissue damage, and purple toes syndrome. use is not recommended during pregnancy. the effects of warfarin are typically monitored by checking prothrombin time (inr) every one to four weeks. many other medications and dietary factors can interact with warfarin, either increasing or decreasing its effectiveness. the effects of warfarin may be reversed with phytomenadione (vitamin k1), fresh frozen plasma, or prothrombin complex concentrate. warfarin decreases blood clotting by blocking vitamin k epoxide reductase, an enzyme that reactivates vitamin k1. without sufficient active vitamin k1, clotting factors ii, vii, ix, and x have decreased clotting ability. the anticlotting protein c and protein s are also inhibited, but to a lesser degree. a few days are required for full effect to occur, and these effects can last for up to five days. because the mechanism involves enzymes such as vkorc1, patients on warfarin with polymorphisms of the enzymes may require adjustments in therapy if the genetic variant that they have is more readily inhibited by warfarin, thus requiring lower doses. warfarin first came into large-scale commercial use in 1948 as a rat poison. it was formally approved as a medication to treat blood clots in humans by the u.s. food and drug administration in 1954. in 1955, warfarin's reputation as a safe and acceptable treatment was bolstered when president dwight d. eisenhower was treated with warfarin following a massive and highly publicized heart attack. eisenhower's treatment kickstarted a transformation in medicine whereby coronary artery disease, arterial plaques, and ischemic strokes were treated and protected against by using anticoagulants such as warfarin. it is on the world health organization's list of essential medicines. warfarin is available as a generic medication and under many trade names. in 2020, it was the 58th most commonly prescribed medication in the united states, with more than 11 million prescriptions. medical uses warfarin is used to decrease the tendency for thrombosis, or as secondary prophylaxis (prevention of further episodes) in those individuals who 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). warfarin is best suited for anticoagulation (clot formation inhibition) in areas of slowly running blood (such as in veins and the pooled blood behind artificial and natural valves), and in blood pooled in dysfunctional cardiac atria. thus, common clinical indications for warfarin use are atrial fibrillation, the presence of artificial heart valves, deep venous thrombosis, and pulmonary embolism (where the embolized clots first form in veins). warfarin is also used in antiphospholipid syndrome. it has been used occasionally after heart attacks (myocardial infarctions), but is far less effective at preventing new thromboses in coronary arteries. prevention of clotting in arteries is usually undertaken with antiplatelet drugs, which act by a different mechanism from warfarin (which normally has no effect on platelet function). it can be used to treat people following ischemic strokes due to atrial fibrillation, though direct oral anticoagulants (doacs) may offer greater benefits. dosing dosing of warfarin is complicated because it is known to interact with many commonly used medications and certain foods. these interactions may enhance or reduce warfarin's anticoagulation effect. to optimize the therapeutic effect without risking dangerous side effects such as bleeding, close monitoring of the degree of anticoagulation is required by a blood test measuring an inr. during the initial stage of treatment, inr is checked daily; intervals between tests can be lengthened if the patient manages stable therapeutic inr levels on an unchanged warfarin dose. newer point-of-care testing is available and has increased the ease of inr testing in the outpatient setting. instead of a blood draw, the point-of-care test involves a simple finger prick. maintenance dose vitamin k1-warfarin interaction effect: when warfarin levels are high, people have more risk of bleeding. conversely, lower levels of warfarin lead to increased risk of blood clots. a narrow range exists where the benefits of warfarin are greater than the risks, its therapeutic window. certain drugs, herbal medicines, and foods can interact with warfarin, increasing or decreasing a previously stable warfarin level. recommendations by many national bodies, including the american college of chest physicians, have been distilled to help manage dose adjustments. the maintenance dose of warfarin can fluctuate significantly depending on the amount of vitamin k1 in the diet. keeping vitamin k1 intake at a stable level can prevent these fluctuations. leafy green vegetables tend to contain higher amounts of vitamin k1. green parts of members of the family apiaceae, such as parsley, cilantro, and dill are extremely rich sources of vitamin k; cruciferous vegetables such as cabbage and broccoli, as well as the darker varieties of lettuces and other leafy greens, are also relatively high in vitamin k1. green vegetables such as peas and green beans do not have such high amounts of vitamin k1 as leafy greens. certain vegetable oils have high amounts of vitamin k1. foods low in vitamin k1 include roots, bulbs, tubers, and most fruits and fruit juices. cereals, grains, and other milled products are also low in vitamin k1. several studies reported that the maintenance dose can be predicted based on various clinical data. self-testing anticoagulation with warfarin can also be monitored by patients at home. international guidelines on home testing were published in 2005. the guidelines 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. a 2006 systematic review and meta-analysis of 14 randomized trials showed home testing led to a reduced incidence of complications (thrombosis and major bleeding), and improved the time in the therapeutic range. alternative anticoagulants 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. several types of anticoagulant drugs offering the efficacy of warfarin without a need for monitoring, such as dabigatran, apixaban, edoxaban, and rivaroxaban, have been approved in a number of countries for classical warfarin uses. complementing these drugs are reversal agents available for dabigatran (idarucizumab), and for apixaban, and rivaroxaban (andexanet alfa). andexanet alfa is suggested for edoxaban, but use of it is considered off label due to limited evidence. a reversal agent for dabigatran, apixaban, edoxaban, and rivaroxaban is in development (ciraparantag). contraindications all anticoagulants are generally contraindicated in situations in which the reduction in clotting that they cause might lead to serious and potentially life-threatening bleeds. this includes people with active bleeding conditions (such as gastrointestinal ulcers), or disease states with increased risk of bleeding (e.g., low platelets, severe liver disease, uncontrolled hypertension). for patients undergoing surgery, treatment with anticoagulants is generally suspended. similarly, spinal and lumbar puncture (e.g., spinal injections, epidurals, etc.) carry increased risk, so treatment is suspended prior to these procedures. warfarin should not be given to people with heparin-induced thrombocytopenia until platelet count has improved or normalised. warfarin is usually best avoided in people with protein c or protein s deficiency, as these thrombophilic conditions increase the risk of skin necrosis, which is a rare but serious side effect associated with warfarin. pregnancy further information: fetal warfarin syndrome and anticoagulation in pregnancy warfarin is contraindicated in pregnancy, as it passes through the placental barrier and may cause bleeding in the fetus; warfarin use during pregnancy is commonly associated with spontaneous abortion, stillbirth, neonatal death, and preterm birth. coumarins (such as warfarin) are also teratogens, that is, they cause birth defects; the incidence of birth defects in infants exposed to warfarin in utero appears to be around 5%, although higher figures (up to 30%) have been reported in some studies. depending on when exposure occurs during pregnancy, two distinct combinations of congenital abnormalities can arise. first trimester of pregnancy usually, warfarin is avoided in the first trimester, and a low-molecular-weight heparin such as enoxaparin is substituted. with heparin, risks of maternal haemorrhage and other complications are still increased, but heparins do not cross the placental barrier, so do not cause birth defects. various solutions exist for the time around delivery. when warfarin (or another 4-hydroxycoumarin derivative) is given during the first trimester—particularly between the sixth and ninth weeks of pregnancy—a constellation of birth defects known variously as fetal warfarin syndrome (fws), warfarin embryopathy, or coumarin embryopathy can occur. fws is characterized mainly by skeletal abnormalities, which include nasal hypoplasia, a depressed or narrowed nasal bridge, scoliosis, and calcifications in the vertebral column, femur, and heel bone, which show a peculiar stippled appearance on x-rays. limb abnormalities, such as brachydactyly (unusually short fingers and toes) or underdeveloped extremities, can also occur. common nonskeletal features of fws include low birth weight and developmental disabilities. second trimester and later warfarin administration in the second and third trimesters is much less commonly associated with birth defects, and when they do occur, are considerably different from fws. the most common congenital abnormalities associated with warfarin use in late pregnancy are central nervous system disorders, including spasticity and seizures, and eye defects. because of such later pregnancy birth defects, anticoagulation with warfarin poses a problem in pregnant women requiring warfarin for vital indications, such as stroke prevention in those with artificial heart valves. according to the american college of chest physicians, warfarin may be used in lactating women who wish to breastfeed their infants. available data does not suggest that warfarin crosses into the breast milk. similarly, inr levels should be checked to avoid adverse effects. adverse effects bleeding the only common side effect of warfarin is hemorrhage. the risk of severe bleeding is small but definite (a typical yearly rate of 1–3% has been reported), and any benefit needs to outweigh this risk when warfarin is considered. all types of bleeding occur more commonly, but the most severe ones are those involving the brain (intracerebral hemorrhage/hemorrhagic stroke) and the spinal cord. risk of bleeding is increased if the inr is out of range (due to accidental or deliberate overdose or due to interactions). this risk increases greatly once the inr exceeds 4.5. several risk scores exist to predict bleeding in people using warfarin and similar anticoagulants. a commonly used score (has-bled) includes known predictors of warfarin-related bleeding: uncontrolled high blood pressure (h), abnormal kidney function (a), previous stroke (s), known previous bleeding condition (b), previous labile inr when on anticoagulation (l), elderly as defined by age over 65 (e), and drugs associated with bleeding (e.g., aspirin) or alcohol misuse (d). while their use is