Warfarin, sold under the brand name Coumadin among others. It is used as an anticoagulant medication. It is commonly used to prevent

deep vein thrombosis Deep vein thrombosis (DVT) is a type of venous thrombosis involving the formation of a blood clot in a deep vein, most commonly in the legs or pelvis. A minority of DVTs occur in the arms. Symptoms can include pain, swelling, redness, and enl ...

and

pulmonary embolism Pulmonary embolism (PE) is a blockage of an pulmonary artery, artery in the lungs by a substance that has moved from elsewhere in the body through the bloodstream (embolism). Symptoms of a PE may include dyspnea, shortness of breath, chest pain ...

, and to protect against

stroke Stroke is a medical condition in which poor cerebral circulation, blood flow to a part of the brain causes cell death. There are two main types of stroke: brain ischemia, ischemic, due to lack of blood flow, and intracranial hemorrhage, hemor ...

in people who have

atrial fibrillation Atrial fibrillation (AF, AFib or A-fib) is an Heart arrhythmia, abnormal heart rhythm (arrhythmia) characterized by fibrillation, rapid and irregular beating of the Atrium (heart), atrial chambers of the heart. It often begins as short periods ...

, valvular heart disease, or artificial heart valves. Warfarin may sometimes be prescribed following a ST-segment elevation myocardial infarction and orthopedic surgery. It is usually taken by mouth, but may also be administered

intravenous Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutr ...

ly. The common

side effect In medicine, a side effect is an effect of the use of a medicinal drug or other treatment, usually adverse but sometimes beneficial, that is unintended. Herbal and traditional medicines also have side effects. A drug or procedure usually use ...

, 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 Pregnancy is the time during which one or more offspring gestation, gestates inside a woman's uterus. A multiple birth, multiple pregnancy involves more than one offspring, such as with twins. Conception (biology), Conception usually occurs ...

. 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 An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...

that reactivates vitamin K₁. Without sufficient active vitamin K₁, the plasma concentrations of clotting factors II, VII, IX, and X are reduced and thus have decreased clotting ability. The anticlotting protein C and protein S are also inhibited, but to a lesser degree. It is wrongly described as a "vitamin K antagonist". This term is incorrect. Warfarin does not antagonize the action of vitamin K1, but rather antagonizes vitamin K1 recycling, depleting active vitamin K1. 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 The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...

in 1954. In 1955, warfarin's reputation as a safe and acceptable treatment for

coronary artery disease Coronary artery disease (CAD), also called coronary heart disease (CHD), or ischemic heart disease (IHD), is a type of cardiovascular disease, heart disease involving Ischemia, the reduction of blood flow to the cardiac muscle due to a build-up ...

, arterial plaques, and ischemic strokes was bolstered when President Dwight D. Eisenhower was treated with warfarin following a highly publicized heart attack. It is on the World Health Organization's List of Essential Medicines. Warfarin is available as a generic medication and is sold under many brand names. In 2022, it was the 85th most commonly prescribed medication in the United States, with more than 8million prescriptions.

Medical uses

Warfarin is indicated for the prophylaxis and treatment of venous thrombosis and its extension, pulmonary embolism; prophylaxis and treatment of thromboembolic complications associated with atrial fibrillation and/or cardiac valve replacement; and reduction in the risk of death, recurrent myocardial infarction, and thromboembolic events such as stroke or systemic embolization after myocardial infarction. Warfarin is used to decrease the tendency for

thrombosis Thrombosis () is the formation of a Thrombus, blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel (a vein or an artery) is injured, the body uses platelets (thrombocytes) and fib ...

, or as secondary prophylaxis (prevention of further episodes) in those individuals who have already formed a blood clot (

thrombus A thrombus ( thrombi) is a solid or semisolid aggregate from constituents of the blood (platelets, fibrin, red blood cells, white blood cells) within the circulatory system during life. A blood clot is the final product of the blood coagulatio ...

). 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

, the presence of artificial heart valves, deep venous thrombosis, and

(where the embolized clots first form in veins). Warfarin is also used in antiphospholipid syndrome. It has been used occasionally after heart attacks (

myocardial infarction A myocardial infarction (MI), commonly known as a heart attack, occurs when Ischemia, blood flow decreases or stops in one of the coronary arteries of the heart, causing infarction (tissue death) to the heart muscle. The most common symptom ...

s), but is far less effective at preventing new thromboses in

coronary arteries The coronary arteries are the arteries, arterial blood vessels of coronary circulation, which transport oxygenated blood to the Cardiac muscle, heart muscle. The heart requires a continuous supply of oxygen to function and survive, much like any ...

. 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

, 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

s such as bleeding, close monitoring of the degree of anticoagulation is required by a

blood test A blood test is a medical laboratory, laboratory analysis performed on a blood sample that is usually extracted from a vein in the arm using a hypodermic needle, or via fingerprick. Multiple tests for specific blood components, such as a glucose ...

measuring an prothrombin time (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

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 Broccoli (''Brassica oleracea'' var. ''italica'') is an edible green plant in the Brassicaceae, cabbage family (family Brassicaceae, genus ''Brassica'') whose large Pseudanthium, flowering head, plant stem, stalk and small associated leafy gre ...

, as well as the darker varieties of

lettuce Lettuce (''Lactuca sativa'') is an annual plant of the family Asteraceae mostly grown as a leaf vegetable. The leaves are most often used raw in Green salad, green salads, although lettuce is also seen in other kinds of food, such as sandwiche ...

s and other

leafy green Leaf vegetables, also called leafy greens, vegetable greens, or simply greens, are plant leaf, leaves eaten as a vegetable, sometimes accompanied by their Petiole (botany), petioles and Shoot (botany), shoots, if tender. Leaf vegetables eaten ...

s, are also relatively high in vitamin K₁. Green vegetables such as

peas Pea (''pisum'' in Latin) is a pulse or fodder crop, but the word often refers to the seed or sometimes the pod of this flowering plant species. Peas are eaten as a vegetable. Carl Linnaeus gave the species the scientific name ''Pisum sativum ...

and green beans do not have such high amounts of vitamin K₁ as leafy greens. Certain

vegetable oil Vegetable oils, or vegetable fats, are oils extracted from seeds or from other parts of edible plants. Like animal fats, vegetable fats are ''mixtures'' of triglycerides. Soybean oil, grape seed oil, and cocoa butter are examples of seed ...

s 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: A 2006

systematic review A systematic review is a scholarly synthesis of the evidence on a clearly presented topic using critical methods to identify, define and assess research on the topic. A systematic review extracts and interprets data from published studies on ...

and

meta-analysis Meta-analysis is a method of synthesis of quantitative data from multiple independent studies addressing a common research question. An important part of this method involves computing a combined effect size across all of the studies. As such, th ...

of 14 randomized trials showed home testing led to a reduced incidence of complications (

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 Phenprocoumon (marketed under the brand names Marcoumar, Marcumar and Falithrom) is a long-acting anticoagulant to be taken by mouth, and a coumarin derivative. It acts as a vitamin K antagonist and inhibits blood clotting (coagulation) by blocki ...

. These have a shorter (acenocoumarol) or longer (phenprocoumon)

half-life Half-life is a mathematical and scientific description of exponential or gradual decay. Half-life, half life or halflife may also refer to: Film * Half-Life (film), ''Half-Life'' (film), a 2008 independent film by Jennifer Phang * ''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 Dabigatran, sold under the brand name Pradaxa among others, is an anticoagulant used to treat and prevent blood clots and to prevent stroke in people with atrial fibrillation. It is commonly used to prevent blood clots following hip or kn ...

, 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 Idarucizumab, sold under the brand name Praxbind, is a monoclonal antibody A monoclonal antibody (mAb, more rarely called moAb) is an antibody produced from a cell lineage made by cloning a unique white blood cell. All subsequent antibod ...

), 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.Brayfield A (ed), Martindale: The Complete Drug Reference nlineLondon: Pharmaceutical Press ccessed on 24 April 2017/ref> 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

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 Preterm birth, also known as premature birth, is the Childbirth, birth of a baby at fewer than 37 weeks Gestational age (obstetrics), gestational age, as opposed to full-term delivery at approximately 40 weeks. Extreme preterm is less than 28 ...

. Retrieved on 15 December 2008 through Google Book Search. 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 A birth defect is an abnormal condition that is present at childbirth, birth, regardless of its cause. Birth defects may result in disability, disabilities that may be physical disability, physical, intellectual disability, intellectual, or dev ...

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 Hypoplasia (; adjective form ''hypoplastic'') is underdevelopment or incomplete development of a tissue or organ.nasal bridge,

scoliosis Scoliosis (: scolioses) is a condition in which a person's Vertebral column, spine has an irregular curve in the coronal plane. The curve is usually S- or C-shaped over three dimensions. In some, the degree of curve is stable, while in others ...

, and calcifications in the

vertebral column The spinal column, also known as the vertebral column, spine or backbone, is the core part of the axial skeleton in vertebrates. The vertebral column is the defining and eponymous characteristic of the vertebrate. The spinal column is a segmente ...

femur The femur (; : femurs or femora ), or thigh bone is the only long bone, bone in the thigh — the region of the lower limb between the hip and the knee. In many quadrupeds, four-legged animals the femur is the upper bone of the hindleg. The Femo ...

, and heel bone, which show a peculiar stippled appearance on

X-rays An X-ray (also known in many languages as Röntgen radiation) is a form of high-energy electromagnetic radiation with a wavelength shorter than those of ultraviolet rays and longer than those of gamma rays. Roughly, X-rays have a wavelength ran ...

. 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 Developmental disability is a diverse group of chronic conditions, comprising mental or physical impairments that arise before adulthood. Developmental disabilities cause individuals living with them many difficulties in certain areas of life, espe ...

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 The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...

disorders, including

spasticity Spasticity () is a feature of altered skeletal muscle performance with a combination of paralysis, increased tendon reflex activity, and hypertonia. It is also colloquially referred to as an unusual "tightness", stiffness, or "pull" of muscles. ...

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. 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 The spinal cord is a long, thin, tubular structure made up of nervous tissue that extends from the medulla oblongata in the lower brainstem to the lumbar region of the vertebral column (backbone) of vertebrate animals. The center of the spinal c ...

. 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 Blood pressure (BP) is the pressure of Circulatory system, circulating blood against the walls of blood vessels. Most of this pressure results from the heart pumping blood through the circulatory system. When used without qualification, the term ...

(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 recommended in clinical practice guidelines, they are only moderately effective in predicting bleeding risk and do not perform well in predicting hemorrhagic stroke. Bleeding risk may be increased in people on hemodialysis. Another score used to assess bleeding risk on anticoagulation, specifically Warfarin or Coumadin, is the ATRIA score, which uses a weighted additive scale of clinical findings to determine bleeding risk stratification. The risks of bleeding are increased further when warfarin is combined with antiplatelet drugs such as clopidogrel, aspirin, or nonsteroidal anti-inflammatory drugs.

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, an innate anticoagulant that, like the procoagulant factors whose synthesis 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 Heparin, also known as unfractionated heparin (UFH), is a medication and naturally occurring glycosaminoglycan. Heparin is a blood anticoagulant that increases the activity of antithrombin. It is used in the treatment of myocardial infarction, ...

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 Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism. Mos ...

for certain protein C mutations.

Osteoporosis

After initial reports that warfarin could reduce bone mineral density, several studies demonstrated a link between warfarin use and

osteoporosis Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to more porous bone, and consequent increase in Bone fracture, fracture risk. It is the most common reason f ...

-related

fracture Fracture is the appearance of a crack or complete separation of an object or material into two or more pieces under the action of stress (mechanics), stress. The fracture of a solid usually occurs due to the development of certain displacemen ...

. A 1999 study in 572 women taking warfarin for deep venous thrombosis, risk of vertebral fracture and rib fracture was increased; other fracture types did not occur more commonly. A 2002 study looking at a randomly selected selection of 1,523 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. 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

-related fracture in men, but no association in women was seen. The mechanism was thought to be a combination of reduced intake of vitamin K (a vitamin necessary for bone health) and inhibition by warfarin of vitamin K-mediated carboxylation of certain bone proteins, rendering them nonfunctional.

Purple toe syndrome

Another rare complication that may occur early during warfarin treatment (usually within 3 to 8 weeks of commencement) is purple toe syndrome. This condition is thought to result from small deposits of

cholesterol Cholesterol is the principal sterol of all higher animals, distributed in body Tissue (biology), tissues, especially the brain and spinal cord, and in Animal fat, animal fats and oils. Cholesterol is biosynthesis, biosynthesized by all anima ...

breaking loose and causing embolisms in blood vessels in the skin of the feet, which causes a blueish-purple colour and may be painful. It is typically thought to affect the

big toe Toes are the Digit (anatomy), digits of the foot of a tetrapod. Animal species such as cats that walk on their toes are described as being ''digitigrade''. Humans, and other animals that walk on the soles of their feet, are described as being ' ...

, 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.

Calcification

Several studies have also implicated warfarin use in valvular and vascular calcification. No specific treatment is available, but some modalities are under investigation.

Overdose

The major side effect of warfarin use is bleeding. Risk of bleeding is increased if the INR is out of range (due to accidental or deliberate overdose or due to interactions). Many drug interactions can increase the effect of warfarin, also causing an overdose. In patients with supratherapeutic INR but INR less than 10 and no bleeding, it is enough to lower the dose or omit a dose, monitor the INR and resume warfarin at an adjusted lower dose when the target INR is reached. For people who need rapid reversal of warfarin – such as due to serious bleeding – or who need emergency surgery, the effects of warfarin can be reversed with vitamin K, prothrombin complex concentrate (PCC), or fresh frozen plasma (FFP). Generally, four-factor PCC can be given more quickly than FFP, the amount needed is a smaller volume of fluid than FFP, and does not require ABO blood typing. Administration of PCCs results in rapid hemostasis, similar to that of FFP, namely, with comparable rates of thromboembolic events, but with reduced rates of volume overload. Blood products should not be routinely used to reverse warfarin overdose, when vitamin K could work alone. While PCC has been found in lab tests to be better than FFP, when rapid reversal is needed, as of 2018, whether a difference in outcomes such as death or disability exists is unclear. When warfarin is being given and INR is in therapeutic range, simple discontinuation of the drug for five days is usually enough to reverse the effect and cause INR to drop below 1.5.

Interactions

Warfarin interacts with many commonly used drugs, and the

metabolism Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the co ...

of warfarin varies greatly between patients. Some foods have also been reported to interact with warfarin. Apart from the metabolic interactions, highly protein bound drugs can displace warfarin from

serum albumin Serum albumin, often referred to simply as blood albumin, is an albumin (a type of globular protein) found in vertebrate blood. Human serum albumin is encoded by the ''ALB'' gene. Other mammalian forms, such as bovine serum albumin, are chem ...

and cause an increase in the INR. 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 Simvastatin, sold under the brand name Zocor among others, is a statin, a type of lipid-lowering medication. It is used along with exercise, diet, and weight loss to decrease hyperlipidemia, elevated lipid levels. It is also used to decrease t ...

), INR checks are increased or dosages adjusted until a new ideal dosage is found. When taken with nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin increases the risk for gastrointestinal bleeding. This increased risk is due to the antiplatelet effect of NSAIDs and possible damage to the gastrointestinal mucosa. Many commonly used

antibiotic An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting pathogenic bacteria, bacterial infections, and antibiotic medications are widely used in the therapy ...

s, such as

metronidazole Metronidazole, sold under the brand name Flagyl and Metrogyl among others, is an antibiotic and antiprotozoal medication. It is used either alone or with other antibiotics to treat pelvic inflammatory disease, endocarditis, and bacterial vagino ...

or the macrolides, greatly increase the effect of warfarin by reducing the metabolism of warfarin in the body. Other

broad-spectrum antibiotic A broad-antimicrobial spectrum, spectrum antibiotic is an antibiotic that acts on the two major bacterial groups, Gram-positive and Gram-negative, or any antibiotic that acts against a wide range of disease-causing bacteria. These medications are ...

s can reduce the amount of the normal bacterial flora in the bowel, which make significant quantities of vitamin K₁, thus potentiating the effect of warfarin. In addition, food that contains large quantities of vitamin K₁ will reduce the warfarin effect. Thyroid activity also appears to influence warfarin dosing requirements; hypothyroidism (decreased thyroid function) makes people less responsive to warfarin treatment, while hyperthyroidism (overactive thyroid) boosts the anticoagulant effect. 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. Excessive use of alcohol is also known to affect the metabolism of warfarin and can elevate the INR, and thus increase the risk of bleeding. The U.S.

(FDA) product insert on warfarin states that alcohol should be avoided. The

Cleveland Clinic Cleveland Clinic is an American Nonprofit organization, nonprofit Academic health science center, academic Medical centers in the United States, medical center based in Cleveland, Ohio. Owned and operated by the Cleveland Clinic Foundation, an O ...

suggests that when taking warfarin one should not drink more than "one beer, 6 oz of wine, or one shot of alcohol per day". Warfarin also interacts with many herbs and spices, some used in food (such as

ginger Ginger (''Zingiber officinale'') is a flowering plant whose rhizome, ginger root or ginger, is widely used as a spice and a folk medicine. It is an herbaceous perennial that grows annual pseudostems (false stems made of the rolled bases of l ...

and garlic) and others used purely for medicinal purposes (such as ginseng and '' Ginkgo biloba''). All may increase bleeding and bruising in people taking warfarin; similar effects have been reported with borage ( starflower) oil. St. John's wort, sometimes recommended to help with mild to moderate depression, reduces the effectiveness of a given dose of warfarin; it induces the enzymes that break down warfarin in the body, causing a reduced anticoagulant effect. Between 2003 and 2004, the UK Committee on Safety of Medicines received several reports of increased INR and risk of haemorrhage in people taking warfarin and cranberry juice.Free full text with registration at Medscape
Data establishing a causal relationship are still lacking, and a 2006 review found no cases of this interaction reported to the USFDA; nevertheless, several authors have recommended that both doctors and patients be made aware of its possibility. The mechanism behind the interaction is still unclear.

Chemistry

X-ray crystallographic studies of warfarin show that it exists in tautomeric form, as the cyclic hemiketal, which is formed from the 4-hydroxycoumarin and the

ketone In organic chemistry, a ketone is an organic compound with the structure , where R and R' can be a variety of carbon-containing substituents. Ketones contain a carbonyl group (a carbon-oxygen double bond C=O). The simplest ketone is acetone ( ...

in the 3-position substituent. However, the existence of many 4-hydroxycoumadin anticoagulants (for example

) that possess no ketone group in the 3-substituent to form such a structure, suggests that the hemiketal must tautomerise to the 4-hydroxy form in order for warfarin to be active.

Stereochemistry

Warfarin contains a

stereocenter In stereochemistry, a stereocenter of a molecule is an atom (center), axis or plane that is the focus of stereoisomerism; that is, when having at least three different groups bound to the stereocenter, interchanging any two different groups cr ...

and consists of two

enantiomer In chemistry, an enantiomer (Help:IPA/English, /ɪˈnænti.əmər, ɛ-, -oʊ-/ Help:Pronunciation respelling key, ''ih-NAN-tee-ə-mər''), also known as an optical isomer, antipode, or optical antipode, is one of a pair of molecular entities whi ...

s. This is a racemate, i.e., a 1: 1 mixture of ('' R '') – and the ('' S '') – form:

Pharmacology

Pharmacokinetics

Warfarin consists of a racemic mixture of two active

s—''R''- and ''S''- forms—each of which is cleared by different pathways. S-warfarin is two to five times more potent than the R-isomer in producing an anticoagulant response. Both the enantiomers of warfarin undergo CYP-mediated metabolism by many different CYPs to form 3',4',6,7,8 and 10-hydroxy warfarin metabolites, major being 7-OH warfarin formed from S-warfarin by CYP2C9 and 10-OH warfarin from R-warfarin by CYP3A4. Warfarin is slower-acting than the common anticoagulant

, 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 An antibody (Ab) or immunoglobulin (Ig) is a large, Y-shaped protein belonging to the immunoglobulin superfamily which is used by the immune system to identify and neutralize antigens such as pathogenic bacteria, bacteria and viruses, includin ...

-mediated decrease in

platelet Platelets or thrombocytes () are a part of blood whose function (along with the coagulation#Coagulation factors, coagulation factors) is to react to bleeding from blood vessel injury by clumping to form a thrombus, blood clot. Platelets have no ...

levels), which increases the risk for thrombosis. It takes several days for warfarin to reach the therapeutic effect, since the circulating coagulation factors are not affected by the drug (thrombin has a half-life time of days). Warfarin's long half-life means that it remains effective for several days after it is stopped. Furthermore, if given initially without additional anticoagulant cover, it can increase thrombosis risk (see below).

Mechanism of action

Warfarin is one of several drugs often referred to as a "blood thinner"; this is not technically correct, as these drugs reduce coagulation of blood, increasing the clotting time, without affecting the

viscosity Viscosity is a measure of a fluid's rate-dependent drag (physics), resistance to a change in shape or to movement of its neighboring portions relative to one another. For liquids, it corresponds to the informal concept of ''thickness''; for e ...

("thickness") as such of blood. Warfarin inhibits the vitamin K-dependent synthesis of biologically active forms of the 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

gamma Gamma (; uppercase , lowercase ; ) is the third letter of the Greek alphabet. In the system of Greek numerals it has a value of 3. In Ancient Greek, the letter gamma represented a voiced velar stop . In Modern Greek, this letter normally repr ...

carboxylation of their

glutamic acid Glutamic acid (symbol Glu or E; known as glutamate in its anionic form) is an α- amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can ...

residues to allow the coagulation factors to bind to

phospholipid Phospholipids are a class of lipids whose molecule has a hydrophilic "head" containing a phosphate group and two hydrophobic "tails" derived from fatty acids, joined by an alcohol residue (usually a glycerol molecule). Marine phospholipids typ ...

surfaces inside blood vessels, on the vascular

endothelium The endothelium (: endothelia) is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the r ...

. The

that carries out the carboxylation of glutamic acid is gamma-glutamyl carboxylase. The carboxylation reaction proceeds 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 ''VKOR'' (specifically the VKORC1 subunit), thereby diminishing available vitamin K and vitamin K hydroquinone in the tissues, which decreases the carboxylation activity of the glutamyl carboxylase. When this occurs, the coagulation factors are no longer carboxylated at certain

residues, and are incapable of binding to the endothelial surface of blood vessels, and are thus biologically inactive. As the body's 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 yvitamin K absence), and individual coagulation factors as PIVKA-''number'' (e.g., PIVKA-II). When warfarin is newly started, it may ''promote'' clot formation temporarily, because the level of proteins C and S are also dependent on vitamin K activity. Warfarin causes decline in protein C levels in first 36 hours. In addition, reduced levels of protein S lead to a reduction in activity of protein C (for which it is the co-factor), so reduces degradation of factor Va and factor VIIIa. Although loading doses of warfarin over 5 mg also produce a precipitous decline in factor VII, resulting in an initial prolongation of the INR, full antithrombotic effect does not take place until significant reduction in factor II occurs days later. The haemostasis system becomes temporarily biased towards thrombus formation, leading to a prothrombotic state. Thus, when warfarin is loaded rapidly at greater than 5 mg per day, to co-administering

, an anticoagulant that acts upon antithrombin and helps reduce the risk of thrombosis, is beneficial, with warfarin therapy for four to five days, to have the benefit of anticoagulation from heparin until the full effect of warfarin has been achieved.

Pharmacogenomics

Warfarin activity is determined partially by genetic factors. Polymorphisms in two genes (''VKORC1'' and ''CYP2C9'') play a particularly large role in response to warfarin. '' VKORC1'' polymorphisms explain 30% of the dose variation between patients: particular

mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, ...

s make VKORC1 less susceptible to suppression by warfarin. There are two main haplotypes that explain 25% of variation: low-dose haplotype group (A) and a high-dose haplotype group (B). ''VKORC1'' polymorphisms explain why African Americans are on average relatively resistant to warfarin (higher proportion of group B

haplotype A haplotype (haploid genotype) is a group of alleles in an organism that are inherited together from a single parent. Many organisms contain genetic material (DNA) which is inherited from two parents. Normally these organisms have their DNA orga ...

s), while Asian Americans are generally more sensitive (higher proportion of group A haplotypes). Group A ''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. '' CYP2C9'' polymorphisms explain 10% of the dose variation between patients, mainly among Caucasian patients as these variants are rare in African American and most Asian populations. These ''CYP2C9'' polymorphisms do not influence time to effective INR as opposed to ''VKORC1'', but do shorten the time to INR > 4. Despite the promise of pharmacogenomic testing in warfarin dosing, its use in clinical practice is controversial. In August 2009, the

Centers for Medicare and Medicaid Services The Centers for Medicare & Medicaid Services (CMS) is a federal agency within the United States Department of Health and Human Services (HHS) that administers the Medicare program and works in partnership with state governments to administer ...

concluded, "the available evidence does not demonstrate that pharmacogenomic testing of ''CYP2C9'' or ''VKORC1''

allele An allele is a variant of the sequence of nucleotides at a particular location, or Locus (genetics), locus, on a DNA molecule. Alleles can differ at a single position through Single-nucleotide polymorphism, single nucleotide polymorphisms (SNP), ...

s to predict warfarin responsiveness improves health outcomes in Medicare beneficiaries." A 2014

showed that using genotype-based dosing did not confer benefit in terms of time within therapeutic range, excessive anticoagulation (as defined by INR greater than 4), or a reduction in either major bleeding or thromboembolic events.

History

In the early 1920s, an outbreak occurred of a previously unrecognized cattle disease in the

northern United States The Northern United States, commonly referred to as the American North, the Northern States, or simply the North, is a geographical and historical region of the United States. History Early history Before the 19th century westward expansion, the ...

and Canada. Cattle were haemorrhaging after minor procedures, and on some occasions spontaneously. For example, 21 of 22 cows died after dehorning, and 12 of 25 bulls died after

castration Castration is any action, surgery, surgical, chemical substance, chemical, or otherwise, by which a male loses use of the testicles: the male gonad. Surgical castration is bilateral orchiectomy (excision of both testicles), while chemical cas ...

. All of these animals had bled to death. In 1921, Frank Schofield, a Canadian veterinary pathologist, determined that the cattle were ingesting moldy

silage Silage is fodder made from green foliage crops which have been preserved by fermentation (food), fermentation to the point of souring. It is fed to cattle, sheep and other ruminants. The fermentation and storage process is called ''ensilage'', ' ...

made from sweet clover, and that this was functioning as a potent anticoagulant. Only spoiled hay made from sweet clover (grown in northern states of the US and in Canada since the turn of the century) produced the disease. Schofield separated good clover stalks and damaged clover stalks from the same hay mow, and fed each to a different rabbit. The rabbit that had ingested the good stalks remained well, but the rabbit that had ingested the damaged stalks died from a haemorrhagic illness. A duplicate experiment with a different sample of clover hay produced the same result. In 1929,

North Dakota North Dakota ( ) is a U.S. state in the Upper Midwest, named after the indigenous Dakota people, Dakota and Sioux peoples. It is bordered by the Canadian provinces of Saskatchewan and Manitoba to the north and by the U.S. states of Minneso ...

veterinarian Lee M. Roderick demonstrated that the condition was due to a lack of functioning prothrombin. The identity of the anticoagulant substance in spoiled sweet clover remained a mystery until 1940. In 1933, Karl Paul Link and his laboratory of chemists working at the

University of Wisconsin A university () is an institution of tertiary education and research which awards academic degrees in several academic disciplines. ''University'' is derived from the Latin phrase , which roughly means "community of teachers and scholars". Uni ...

set out to isolate and characterize the haemorrhagic agent from the spoiled hay. Five years were needed before Link's student, Harold A. Campbell, recovered 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 dicoumarol. They confirmed their results by synthesizing dicoumarol and proving in 1940 that it was identical to the naturally occurring agent. Dicoumarol was a product of the plant molecule coumarin (not to be confused with Coumadin, a later tradename for warfarin). Coumarin is now known to be present in many plants, and produces the notably sweet smell of freshly cut grass or hay and plants such as sweet grass; in fact, the plant's high content of coumarin is responsible for the original common name of "sweet clover", which is named for its sweet smell, not its bitter taste. They are present notably in woodruff (''Galium odoratum'',

Rubiaceae Rubiaceae () is a family (biology), family of flowering plants, commonly known as the coffee, madder, or bedstraw family. It consists of terrestrial trees, shrubs, lianas, or herbs that are recognizable by simple, opposite leaves with Petiole ( ...

), and at lower levels in licorice,

lavender ''Lavandula'' (common name lavender) is a genus of 47 known species of perennial flowering plants in the sage family, Lamiaceae. It is native plant, native to the Old World, primarily found across the drier, warmer regions of the Mediterranean ...

, and various other species. The name coumarin comes via the French ''coumarou'' from ''kumarú'', the Tupi name for the tree of the tonka bean, which notably contains a high concentration of coumarin. However, coumarins themselves do not influence clotting or warfarin-like action, but must first be metabolized by various fungi into compounds such as 4-hydroxycoumarin, then further (in the presence of naturally occurring formaldehyde) into dicoumarol, to have any anticoagulant properties. Over the next few years, numerous similar chemicals (specifically 4-hydroxycoumarins with a large

aromatic In organic chemistry, aromaticity is a chemical property describing the way in which a conjugated system, conjugated ring of unsaturated bonds, lone pairs, or empty orbitals exhibits a stabilization stronger than would be expected from conjugati ...

substituent at the 3 position) were found to have the same anticoagulant properties. The first drug in the class to be widely commercialized was dicoumarol itself, patented in 1941 and later used as a pharmaceutical. Karl 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 warfarin was developed by Link, the Wisconsin Alumni Research Foundation financially supported the research and was assigned the patent. After an incident in 1951, in which an army inductee attempted suicide with multiple doses of warfarin in rodenticide, but recovered fully after presenting to a naval hospital and being treated with vitamin K (by then known as a specific antidote), 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. An early recipient of warfarin was US President

Dwight Eisenhower Dwight David "Ike" Eisenhower (born David Dwight Eisenhower; October 14, 1890 – March 28, 1969) was the 34th president of the United States, serving from 1953 to 1961. During World War II, he was Supreme Commander of the Allied Expeditionar ...

, who was prescribed the drug after having a heart attack in 1955. The exact

mechanism of action In pharmacology, the term mechanism of action (MOA) refers to the specific biochemical Drug interaction, interaction through which a Medication, drug substance produces its pharmacological effect. A mechanism of action usually includes mention o ...

remained unknown until it was demonstrated, in 1978, that warfarin inhibits the enzyme vitamin K epoxide reductase, and hence interferes with vitamin K metabolism. Lavrenty Beria and I. V. Khrustalyov are thought to have conspired to use warfarin to poison Soviet leader

Joseph Stalin Joseph Vissarionovich Stalin (born Dzhugashvili; 5 March 1953) was a Soviet politician and revolutionary who led the Soviet Union from 1924 until Death and state funeral of Joseph Stalin, his death in 1953. He held power as General Secret ...

. Warfarin is tasteless and colourless, and produces symptoms similar to those that Stalin exhibited.

Occupational safety

Warfarin used for pest control is a hazardous substance harmful to health. People can be exposed to warfarin in the workplace by breathing it in, swallowing it, skin absorption, and eye contact. The Occupational Safety and Health Administration has set the legal limit ( permissible exposure limit) for warfarin exposure in the workplace as 0.1 mg/m³ over an 8-hour workday. The National Institute for Occupational Safety and Health has set a recommended exposure limit of 0.1 mg/m³ over an 8-hour workday. At levels of 100 mg/m³, warfarin is immediately dangerous to life and health. It is classified as an extremely hazardous substance in the United States as defined in Section 302 of the U.S.

Emergency Planning and Community Right-to-Know Act The Emergency Planning and Community Right-to-Know Act of 1986 is a United States federal law passed by the 99th United States Congress located at Title 42, Chapter 116 of the U.S. Code, concerned with emergency response preparedness. On Octobe ...

(42 U.S.C. 11002), and is subject to strict reporting requirements by facilities which produce, store, or use it in significant quantities.

Society and culture

The name "warfarin" is derived from the acronym for "Wisconsin Alumni Research Foundation", plus "-arin", indicating its link with coumarin. Warfarin is a derivative of dicoumarol, an anticoagulant originally discovered in spoiled sweet clover. Dicoumarol, in turn, is from coumarin, a sweet-smelling but coagulation-inactive chemical found in "sweet" clover and tonka beans (also known as ''cumaru'' from which coumarin's name derives).

Brand names

Warfarin as a drug is marketed under many brand and generic names, including Aldocumar, Anasmol, Anticoag, Befarin, Cavamed, Cicoxil, Circuvit, Cofarin, Coumadin, Coumadine, Cumar, Farin, Foley, Haemofarin, Jantoven, Kovar, Lawarin, Maforan, Marevan, Marfarin, Marivanil, Martefarin, Morfarin, Orfarin, Panwarfin, Scheme, Simarc, Varfarin, Varfarins, Varfine, Waran, Warcok, Warf, Warfareks, Warfarin, Warfarina, Warfarine, Warfarinum, Warfen, Warfin, Warik, Warin, Warlin, and Zyfarin.

Veterinary use

Warfarin is used as a poison for rats and other pests.

Pest control

Warfarin was introduced as a rodenticide, only later finding medical uses; in both cases it was used as an anticoagulant. The use of warfarin itself as a rat poison is declining, because many rat populations have developed resistance to it, and poisons of considerably greater potency have become available. However, warfarin continued to be considered a valuable tool for rodent control which minimised risk to other species.

Rodents

Coumarins (4-hydroxycoumarin derivatives) are used as rodenticides for controlling rats and

mice A mouse (: mice) is a small rodent. Characteristically, mice are known to have a pointed snout, small rounded ears, a body-length scaly tail, and a high breeding rate. The best known mouse species is the common house mouse (''Mus musculus' ...

in residential, industrial, and agricultural areas. Warfarin is both odorless and tasteless, and is effective when mixed with food bait, because the

rodent Rodents (from Latin , 'to gnaw') are mammals of the Order (biology), order Rodentia ( ), which are characterized by a single pair of continuously growing incisors in each of the upper and Mandible, lower jaws. About 40% of all mammal specie ...

s 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 for warfarin is 50–100mg/kg for a single dose, after 5–7 days. 1mg/kg for repeated daily doses for 5 days, after 5–8 days. The IDLH value is 100 mg/m³ (warfarin; various species). Resistance to warfarin as a poison has developed in many rat populations due to an

autosomal An autosome is any chromosome that is not a sex chromosome. The members of an autosome pair in a diploid cell have the same morphology, unlike those in allosomal (sex chromosome) pairs, which may have different structures. The DNA in autosome ...

dominant on chromosome 1 in

brown rat The brown rat (''Rattus norvegicus''), also known as the common rat, street rat, sewer rat, wharf rat, Hanover rat, Norway rat and Norwegian rat, is a widespread species of common rat. One of the largest Muroidea, muroids, it is a brown or grey ...

s. This has arisen independently and become fixed several times around the world. Other 4-hydroxycoumarins 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 The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...

and

kidney In humans, the kidneys are two reddish-brown bean-shaped blood-filtering organ (anatomy), organs that are a multilobar, multipapillary form of mammalian kidneys, usually without signs of external lobulation. They are located on the left and rig ...

s after ingestion. However, such rodenticides may also accumulate in

birds of prey Birds of prey or predatory birds, also known as (although not the same as) raptors, are hypercarnivorous bird species that actively predation, hunt and feed on other vertebrates (mainly mammals, reptiles and smaller birds). In addition to speed ...

and other animals that eat the poisoned rodents or baits.

Vampire bats

Warfarin is used to cull populations of

vampire bat Vampire bats, members of the subfamily Desmodontinae, are Phyllostomidae, leaf-nosed bats currently found in Central and South America. Their food source is the blood of other animals, a dietary trait called hematophagy. Three extant bat species ...

s, in which rabies is often prevalent, in areas where human–wildlife conflict is a concern. Vampire bats are captured with mist nets and coated with a combination of petroleum jelly and warfarin. The bat returns to its roost and other members of the roost become poisoned as well by ingesting the warfarin after reciprocal grooming. Suspected vampire bat roosts may also be coated in the warfarin solution, though this kills other bat species and remains in the environment for years. The efficacy of killing vampire bats to reduce rabies transmission is questionable; a study in

Peru Peru, officially the Republic of Peru, is a country in western South America. It is bordered in the north by Ecuador and Colombia, in the east by Brazil, in the southeast by Bolivia, in the south by Chile, and in the south and west by the Pac ...

showed that culling programs did not lead to lower transmission rates of rabies to livestock and humans.

Brand names

Warfarin as a pest control poison is marketed under many brand and generic names, including Cov-R-Tox, Co-Rax, d-Con, Dethmor, Killgerm Sewercide, Mar-Fin, Rattunal, Rax, Rodex, Rodex Blox, Rosex, Sakarat, Sewarin, Solfarin, Sorex Warfarin, Tox-Hid, Warf, warfarin, and Warfarat. Warfarin is called coumafene in France, zoocoumarin in the Netherlands and Russia, and coumarin in Japan.

References

External links

* {{Authority control 4-Hydroxycoumarins Anticoagulant rodenticides Coumarin drugs Teratogens World Health Organization essential medicines Wikipedia medicine articles ready to translate

Medical uses

Dosing

Maintenance dose

Self-testing

Alternative anticoagulants

Contraindications

Pregnancy

First trimester of pregnancy

Second trimester and later

Adverse effects

Bleeding

Warfarin necrosis

Osteoporosis

Purple toe syndrome

Calcification

Overdose

Interactions

Chemistry

Stereochemistry

Pharmacology

Pharmacokinetics

Mechanism of action

Pharmacogenomics

History

Occupational safety

Society and culture

Brand names

Veterinary use

Pest control

Rodents

Vampire bats

Brand names

References

Further reading

External links