warfarin
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Warfarin, sold under the brand name Coumadin among others, is a
medication A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy (pharmacotherapy) is an important part of the medical field and re ...
that is used as an
anticoagulant Anticoagulants, commonly known as blood thinners, are chemical substances that prevent or reduce coagulation of blood, prolonging the clotting time. Some of them occur naturally in blood-eating animals such as leeches and mosquitoes, where the ...
(blood thinner). It is commonly used to prevent
blood clots A thrombus (plural thrombi), colloquially called a blood clot, is the final product of the blood coagulation step in hemostasis. There are two components to a thrombus: aggregated platelets and red blood cells that form a plug, and a mesh of cr ...
such as
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 enla ...
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 p ...
, and to prevent
stroke A stroke is a medical condition in which poor blood flow to the brain causes cell death. There are two main types of stroke: ischemic, due to lack of blood flow, and hemorrhagic, due to bleeding. Both cause parts of the brain to stop functionin ...
in people who have atrial fibrillation,
valvular heart disease Valvular heart disease is any cardiovascular disease process involving one or more of the four valves of the heart (the aortic and mitral valves on the left side of heart and the pulmonic and tricuspid valves on the right side of heart). These ...
, or
artificial heart valves An artificial heart valve is a one-way valve implanted into a person's heart to replace a heart valve that is not functioning properly (valvular heart disease). Artificial heart valves can be separated into three broad classes: mechanical hear ...
. Less commonly, it is used following
ST-segment elevation myocardial infarction A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which may ...
and
orthopedic surgery Orthopedic surgery or orthopedics ( alternatively spelt orthopaedics), is the branch of surgery concerned with conditions involving the musculoskeletal system. Orthopedic surgeons use both surgical and nonsurgical means to treat musculoskeletal ...
. It is generally taken by mouth, but may also be used
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 nutrie ...
ly. The common
side effect In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...
is
bleeding Bleeding, hemorrhage, haemorrhage or blood loss, is blood escaping from the circulatory system from damaged blood vessels. Bleeding can occur internally, or externally either through a natural opening such as the mouth, nose, ear, urethra, vag ...
. Less common side effects may include areas of tissue damage and
purple toes syndrome Cholesterol embolism occurs when cholesterol is released, usually from an atherosclerotic plaque, and travels as an embolus in the bloodstream to lodge (as an embolism) causing an obstruction in blood vessels further away. Most commonly this cause ...
. Use is not recommended during
pregnancy Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occurs by sexual intercourse, but ca ...
. The effects of warfarin typically should be monitored by checking
prothrombin time The prothrombin time (PT) – along with its derived measures of prothrombin ratio (PR) and international normalized ratio (INR) – is an assay for evaluating the ''extrinsic'' pathway and common pathway of coagulation. This blood test is als ...
(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 Phytomenadione, also known as vitamin K1 or phylloquinone, is a vitamin found in food and used as a dietary supplement. It is on the World Health Organization's List of Essential Medicines. As a supplement it is used to treat certain bleeding ...
(vitamin K1),
fresh frozen plasma Fresh frozen plasma (FFP) is a blood product made from the liquid portion of whole blood. It is used to treat conditions in which there are low blood clotting factors (INR > 1.5) or low levels of other blood proteins. It may also be used as the re ...
, or
prothrombin complex concentrate Prothrombin complex concentrate (PCC), also known as factor IX complex, is a medication made up of blood clotting factors II, IX, and X. Some versions also contain factor VII. It is used to treat and prevent bleeding in hemophilia B if pure ...
. Warfarin decreases
blood clotting Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a blood clot. It potentially results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The mechanis ...
by blocking an
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
called
vitamin K epoxide reductase Vitamin K epoxide reductase (VKOR) is an enzyme () that reduces vitamin K after it has been oxidised in the carboxylation of glutamic acid residues in blood coagulation enzymes. VKOR is a member of a large family of predicted enzymes that are pre ...
that reactivates vitamin K1. Without sufficient active vitamin K1,
clotting factors Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a blood clot. It potentially results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The mechanism o ...
II, VII, IX, and X have decreased clotting ability. The anticlotting
protein C Protein C, also known as autoprothrombin IIA and blood coagulation factor XIX, is a zymogen, that is, an inactive enzyme. The activated form plays an important role in regulating anticoagulation, inflammation, and cell death and maintainin ...
and
protein S Protein S (also known as PROS) is a vitamin K-dependent plasma glycoprotein synthesized in the liver. In the circulation, Protein S exists in two forms: a free form and a complex form bound to complement protein C4b-binding protein (C4BP). In huma ...
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. Additionally, because the mechanism involves enzymes such as ''VKORC1'', patients on warfarin with polymorphisms of the enzymes may require adjustments in therapy to account 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 Rodenticides are chemicals made and sold for the purpose of killing rodents. While commonly referred to as "rat poison", rodenticides are also used to kill mice, squirrels, woodchucks, chipmunks, porcupines, nutria, beavers, and voles. Despite ...
. Warfarin was formally approved for human use 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 respon ...
to treat blood clots in 1954. In 1955, warfarin's reputation as a safe and acceptable treatment was bolstered when President
Dwight D. Eisenhower Dwight David "Ike" Eisenhower (born David Dwight Eisenhower; ; October 14, 1890 – March 28, 1969) was an American military officer and statesman who served as the 34th president of the United States from 1953 to 1961. During World War II, ...
received warfarin following a massive and highly publicized heart attack. Eisenhower's illness kickstarted a transformation in medicine where
coronary artery disease Coronary artery disease (CAD), also called coronary heart disease (CHD), ischemic heart disease (IHD), myocardial ischemia, or simply heart disease, involves the reduction of blood flow to the heart muscle due to build-up of atherosclerotic pla ...
, arterial plaques, and ischemic strokes were treated and prevented by using anticoagulants such as warfarin. It is on the
World Health Organization's List of Essential Medicines The WHO Model List of Essential Medicines (aka Essential Medicines List or EML), published by the World Health Organization (WHO), contains the medications considered to be most effective and safe to meet the most important needs in a health ...
. Warfarin is available as a
generic medication A generic drug is a pharmaceutical drug that contains the same chemical substance as a drug that was originally protected by chemical patents. Generic drugs are allowed for sale after the patents on the original drugs expire. Because the active ch ...
. In 2020, it was the 58th most commonly prescribed medication in the United States, with more than 11million prescriptions.


Medical uses

Warfarin is used to decrease the tendency for
thrombosis Thrombosis (from Ancient Greek "clotting") is the formation of a 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 (thro ...
, or as secondary
prophylaxis Preventive healthcare, or prophylaxis, consists of measures taken for the purposes of disease prevention.Hugh R. Leavell and E. Gurney Clark as "the science and art of preventing disease, prolonging life, and promoting physical and mental hea ...
(prevention of further episodes) in those individuals who have already formed a blood clot (
thrombus A thrombus (plural thrombi), colloquially called a blood clot, is the final product of the blood coagulation step in hemostasis. There are two components to a thrombus: aggregated platelets and red blood cells that form a plug, and a mesh of c ...
). Warfarin treatment can help prevent formation of future blood clots and help reduce the risk of
embolism An embolism is the lodging of an embolus, a blockage-causing piece of material, inside a blood vessel. The embolus may be a blood clot (thrombus), a fat globule ( fat embolism), a bubble of air or other gas (gas embolism), amniotic fluid (amniot ...
(migration of a thrombus to a spot where it blocks
blood supply The blood circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the entire body of a human or other vertebrate. It includes the cardiovascular system, or vascular system, tha ...
to a
vital organ In biology, an organ is a collection of tissues joined in a structural unit to serve a common function. In the hierarchy of life, an organ lies between tissue and an organ system. Tissues are formed from same type cells to act together in a ...
). 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 The heart is a muscular organ in most animals. This organ pumps blood through the blood vessels of the circulatory system. The pumped blood carries oxygen and nutrients to the body, while carrying metabolic waste such as carbon dioxide to t ...
atria. Thus, common clinical indications for warfarin use are atrial fibrillation, the presence of
artificial heart valve An artificial heart valve is a one-way valve implanted into a person's heart to replace a heart valve that is not functioning properly ( valvular heart disease). Artificial heart valves can be separated into three broad classes: mechanical he ...
s,
deep venous 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 enla ...
, 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 p ...
(where the embolized clots first form in veins). Warfarin is also used in
antiphospholipid syndrome Antiphospholipid syndrome, or antiphospholipid antibody syndrome (APS or APLS), is an autoimmune, hypercoagulable state caused by antiphospholipid antibodies. APS provokes blood clots (thrombosis) in both arteries and veins as well as pregnancy- ...
. It has been used occasionally after heart attacks (
myocardial infarction A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which may ...
s), but is far less effective at preventing new thromboses in
coronary arteries The coronary arteries are the arterial blood vessels of coronary circulation, which transport oxygenated blood to the heart muscle. The heart requires a continuous supply of oxygen to function and survive, much like any other tissue or organ of ...
. Prevention of clotting in arteries is usually undertaken with
antiplatelet drug An antiplatelet drug (antiaggregant), also known as a platelet agglutination inhibitor or platelet aggregation inhibitor, is a member of a class of pharmaceuticals that decrease platelet aggregation and inhibit thrombus formation. They are effecti ...
s, 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 stroke A stroke is a medical condition in which poor blood flow to the brain causes cell death. There are two main types of stroke: ischemic, due to lack of blood flow, and hemorrhagic, due to bleeding. Both cause parts of the brain to stop functionin ...
s due to atrial fibrillation, though
direct oral anticoagulant Anticoagulants, commonly known as blood thinners, are chemical substances that prevent or reduce coagulation of blood, prolonging the clotting time. Some of them occur naturally in blood-eating animals such as leeches and mosquitoes, where the ...
s (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 effect In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...
s such as bleeding, close monitoring of the degree of anticoagulation is required by a
blood test A blood test is a 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 test or a cholester ...
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 Point-of-care testing (POCT or bedside testing) is defined as medical diagnostic testing at or near the point of care—that is, at the time and place of patient care. This contrasts with the historical pattern in which testing was wholly or most ...
is available and has increased the ease of INR testing in the outpatient setting. Instead of a
blood draw In medicine, venipuncture or venepuncture is the process of obtaining intravenous access for the purpose of venous blood sampling (also called ''phlebotomy'') or intravenous therapy. In healthcare, this procedure is performed by medical labo ...
, 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 In pharmacokinetics, a maintenance dose is the maintenance rate g/hof drug administration equal to the rate of elimination at steady state. This is not to be confused with dose regimen, which is a type of drug therapy in which the dose gof ...
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 vegetable Leaf vegetables, also called leafy greens, pot herbs, vegetable greens, or simply greens, are plant leaves eaten as a vegetable, sometimes accompanied by tender petioles and shoots. Leaf vegetables eaten raw in a salad can be called salad gre ...
s tend to contain higher amounts of vitamin K1. Green parts of members of the family
Apiaceae Apiaceae or Umbelliferae is a family of mostly aromatic flowering plants named after the type genus ''Apium'' and commonly known as the celery, carrot or parsley family, or simply as umbellifers. It is the 16th-largest family of flowering plants ...
, such as
parsley Parsley, or garden parsley (''Petroselinum crispum'') is a species of flowering plant in the family Apiaceae that is native to the central and eastern Mediterranean region (Sardinia, Lebanon, Israel, Cyprus, Turkey, southern Italy, Greece, Por ...
,
cilantro Coriander (;
, and
dill Dill (''Anethum graveolens'') is an annual herb in the celery family Apiaceae. It is the only species in the genus ''Anethum''. Dill is grown widely in Eurasia, where its leaves and seeds are used as a herb or spice for flavouring food. Growth ...
are extremely rich sources of vitamin K;
cruciferous vegetables Cruciferous vegetables are vegetables of the family Brassicaceae (also called Cruciferae) with many genera, species, and cultivars being raised for food production such as cauliflower, cabbage, kale, garden cress, bok choy, broccoli, Brussels spr ...
such as
cabbage Cabbage, comprising several cultivars of ''Brassica oleracea'', is a leafy green, red (purple), or white (pale green) biennial plant grown as an annual vegetable crop for its dense-leaved heads. It is descended from the wild cabbage ( ''B.&nb ...
and
broccoli Broccoli (''Brassica oleracea'' var. ''italica'') is an edible green plant in the cabbage family (family Brassicaceae, genus ''Brassica'') whose large flowering head, stalk and small associated leaves are eaten as a vegetable. Broccoli is cl ...
, as well as the darker varieties of
lettuce Lettuce (''Lactuca sativa'') is an annual plant of the family Asteraceae. It is most often grown as a leaf vegetable, but sometimes for its stem and seeds. Lettuce is most often used for salads, although it is also seen in other kinds of food, ...
s and other
leafy green Leaf vegetables, also called leafy greens, pot herbs, vegetable greens, or simply greens, are plant leaves eaten as a vegetable, sometimes accompanied by tender petioles and shoots. Leaf vegetables eaten raw in a salad can be called salad gr ...
s, are also relatively high in vitamin K1. Green vegetables such as
peas The pea is most commonly the small spherical seed or the seed-pod of the flowering plant species ''Pisum sativum''. Each pod contains several peas, which can be green or yellow. Botanically, pea pods are fruit, since they contain seeds and d ...
and
green beans Green beans are young, unripe fruits of various cultivars of the common bean (''Phaseolus vulgaris''), although immature or young pods of the runner bean (''Phaseolus coccineus''), yardlong bean ( ''Vigna unguiculata'' subsp. ''sesquipedalis' ...
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 fruits. Like animal fats, vegetable fats are ''mixtures'' of triglycerides. Soybean oil, grape seed oil, and cocoa butter are examples of seed oils, or fat ...
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.


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 Literature review, 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 publ ...
and
meta-analysis A meta-analysis is a statistical analysis that combines the results of multiple scientific studies. Meta-analyses can be performed when there are multiple scientific studies addressing the same question, with each individual study reporting me ...
of 14
randomized trial In science, randomized experiments are the experiments that allow the greatest reliability and validity of statistical estimates of treatment effects. Randomization-based inference is especially important in experimental design and in survey sampl ...
s showed home testing led to a reduced incidence of complications (
thrombosis Thrombosis (from Ancient Greek "clotting") is the formation of a 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 (thro ...
and major bleeding), and improved the time in the therapeutic range.


Alternative anticoagulants

In some countries, other
coumarin Coumarin () or 2''H''-chromen-2-one is an aromatic organic chemical compound with formula . Its molecule can be described as a benzene molecule with two adjacent hydrogen atoms replaced by a lactone-like chain , forming a second six-membered h ...
s are used instead of warfarin, such as
acenocoumarol Acenocoumarol is an anticoagulant that functions as a vitamin K antagonist (like warfarin). It is a derivative of coumarin Coumarin () or 2''H''-chromen-2-one is an aromatic organic chemical compound with formula . Its molecule can be descri ...
and
phenprocoumon Phenprocoumon (marketed under the brand names Marcoumar, Marcumar and Falithrom) is a long-acting blood thinner drug to be taken by mouth, and a derivative of coumarin. It acts as a vitamin K antagonist and inhibits blood clotting (coagulation) b ...
. These have a shorter (acenocoumarol) or longer (phenprocoumon)
half-life Half-life (symbol ) is the time required for a quantity (of substance) to reduce to half of its initial value. The term is commonly used in nuclear physics to describe how quickly unstable atoms undergo radioactive decay or how long stable ato ...
, 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. Specifically it is used to prevent blood clots following hip or kn ...
,
apixaban Apixaban, sold under the brand name Eliquis, is an anticoagulant medication used to treat and prevent blood clots and to prevent stroke in people with nonvalvular atrial fibrillation through directly inhibiting factor Xa. Specifically it i ...
,
edoxaban Edoxaban, sold under the brand name Lixiana among others, is an anticoagulant medication and a direct factor Xa inhibitor. It is taken by mouth. Compared with warfarin it has fewer drug interactions. It was developed by Daiichi Sankyo an ...
, and
rivaroxaban Rivaroxaban, sold under the brand name Xarelto among others, is an anticoagulant medication (blood thinner) used to treat and prevent blood clots. Specifically it is used to treat deep vein thrombosis and pulmonary emboli and prevent blood clo ...
, have been approved in a number of countries for classical warfarin uses. Complementing these drugs are
reversal agent An antidote is a substance that can counteract a form of poisoning. The term ultimately derives from the Greek term φάρμακον ἀντίδοτον ''(pharmakon) antidoton'', "(medicine) given as a remedy". Antidotes for anticoagulants are s ...
s available for dabigatran (
idarucizumab Idarucizumab, sold under the brand name Praxbind, is a monoclonal antibody used as a reversal agent for dabigatran. Idarucizumab was developed by Boehringer Ingelheim. One study sponsored by the manufacturer found that idarucizumab effectively ...
), and for apixaban, and rivaroxaban (
andexanet alfa Andexanet alfa, sold under the trade name Andexxa among others, is an antidote for the medications rivaroxaban and apixaban, when reversal of anticoagulation is needed due to uncontrolled bleeding. It has not been found to be useful for other fac ...
). 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 Ciraparantag (aripazine) is a drug under investigation as an antidote for a number of anticoagulant (anti-blood clotting) drugs, including factor Xa inhibitors ( rivaroxaban, apixaban and edoxaban), dabigatran, and heparins (including fondaparin ...
).


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 ulcer Peptic ulcer disease (PUD) is a break in the inner Gastric mucosa, lining of the stomach, the first part of the small intestine, or sometimes the lower esophagus. An ulcer in the stomach is called a gastric ulcer, while one in the first part of t ...
s), 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 Lumbar puncture (LP), also known as a spinal tap, is a medical procedure in which a needle is inserted into the spinal canal, most commonly to collect cerebrospinal fluid (CSF) for diagnostic testing. The main reason for a lumbar puncture is to ...
(e.g., spinal injections,
epidural Epidural administration (from Ancient Greek ἐπί, , upon" + ''dura mater'') is a method of medication administration in which a medicine is injected into the epidural space around the spinal cord. The epidural route is used by physicians an ...
s, 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 Heparin-induced thrombocytopenia (HIT) is the development of thrombocytopenia (a low platelet count), due to the administration of various forms of heparin, an anticoagulant. HIT predisposes to thrombosis (the abnormal formation of blood clots ...
until
platelet count Platelets, also called thrombocytes (from Greek θρόμβος, "clot" and κύτος, "cell"), are a component of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping, thereby ini ...
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 Necrosis () is a form of cell injury which results in the premature death of cells in living tissue by autolysis. Necrosis is caused by factors external to the cell or tissue, such as infection, or trauma which result in the unregulated dige ...
, which is a rare but serious side effect associated with warfarin.


Pregnancy

Warfarin is
contraindicated In medicine, a contraindication is a condition that serves as a reason not to take a certain medical treatment due to the harm that it would cause the patient. Contraindication is the opposite of indication, which is a reason to use a certain tre ...
in pregnancy, as it passes through the
placenta The placenta is a temporary embryonic and later fetal organ that begins developing from the blastocyst shortly after implantation. It plays critical roles in facilitating nutrient, gas and waste exchange between the physically separate mater ...
l barrier and may cause bleeding in the fetus; warfarin use during pregnancy is commonly associated with spontaneous abortion,
stillbirth Stillbirth is typically defined as fetal death at or after 20 or 28 weeks of pregnancy, depending on the source. It results in a baby born without signs of life. A stillbirth can result in the feeling of guilt or grief in the mother. The term ...
,
neonatal death Perinatal mortality (PNM) refers to the death of a fetus or neonate and is the basis to calculate the perinatal mortality rate. Variations in the precise definition of the perinatal mortality exist, specifically concerning the issue of inclusion ...
, 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 we ...
. Retrieved on 15 December 2008 through
Google Book Search Google Books (previously known as Google Book Search, Google Print, and by its code-name Project Ocean) is a service from Google Inc. that searches the full text of books and magazines that Google has scanned, converted to text using optical ...
.
Coumarins (such as warfarin) are also teratogens, that is, they cause
birth defect A birth defect, also known as a congenital disorder, is an abnormal condition that is present at birth regardless of its cause. Birth defects may result in disabilities that may be physical, intellectual, or developmental. The disabilities ca ...
s; the incidence of birth defects in infants exposed to warfarin ''
in utero ''In Utero'' is the third and final studio album by American rock band Nirvana. It was released on September 21, 1993, by DGC Records. After breaking into the mainstream with their second album, ''Nevermind'' (1991), Nirvana hired Steve Albin ...
'' 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, also known as a congenital disorder, is an abnormal condition that is present at birth regardless of its cause. Birth defects may result in disabilities that may be physical, intellectual, or developmental. The disabilities can ...
abnormalities can arise.


First trimester of pregnancy

Usually, warfarin is avoided in the
first trimester Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occurs by sexual intercourse, but ca ...
, and a low-molecular-weight heparin such as
enoxaparin Enoxaparin sodium, sold under the brand name Lovenox among others, is an anticoagulant medication (blood thinner). It is used to treat and prevent deep vein thrombosis (DVT) and pulmonary embolism (PE) including during pregnancy and following c ...
is substituted. With heparin, risks of
maternal haemorrhage Obstetrical bleeding is bleeding in pregnancy that occurs Antepartum bleeding, before, during, or Postpartum bleeding, after childbirth. Bleeding before childbirth is that which occurs after 24 weeks of pregnancy. Bleeding may be vaginal or less c ...
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 Fetal warfarin syndrome is a Birth defect, disorder of the embryo which occurs in a child whose mother took the medication warfarin (brand name: Coumadin) during pregnancy. Resulting abnormalities include low birth weight, Failure to thrive, slower ...
(FWS), warfarin embryopathy, or coumarin embryopathy can occur. FWS is characterized mainly by
skeletal A skeleton is the structural frame that supports the body of an animal. There are several types of skeletons, including the exoskeleton, which is the stable outer shell of an organism, the endoskeleton, which forms the support structure inside ...
abnormalities, which include nasal
hypoplasia Hypoplasia (from Ancient Greek ὑπo- ''hypo-'' 'under' + πλάσις ''plasis'' 'formation'; adjective form ''hypoplastic'') is underdevelopment or incomplete development of a tissue or organ.nasal bridge The nasal bridge is the upper, bony part of the human nose, which overlies the nasal bones. Association with epicanthic folds Low-rooted nasal bridges are closely associated with epicanthic folds. A lower nasal bridge is more likely to cause an ...
,
scoliosis Scoliosis is a condition in which a person's spine has a sideways curve. The curve is usually "S"- or "C"-shaped over three dimensions. In some, the degree of curve is stable, while in others, it increases over time. Mild scoliosis does not t ...
, and calcifications in the vertebral column, femur, and calcaneus, heel bone, which show a peculiar stippled appearance on medical radiography, X-rays. Dysmelia, 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 disability, 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 renal function, 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 drug An antiplatelet drug (antiaggregant), also known as a platelet agglutination inhibitor or platelet aggregation inhibitor, is a member of a class of pharmaceuticals that decrease platelet aggregation and inhibit thrombus formation. They are effecti ...
s 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 Protein C, also known as autoprothrombin IIA and blood coagulation factor XIX, is a zymogen, that is, an inactive enzyme. The activated form plays an important role in regulating anticoagulation, inflammation, and cell death and maintainin ...
, 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 in parallel to combat this), leading to massive thrombosis with skin
necrosis Necrosis () is a form of cell injury which results in the premature death of cells in living tissue by autolysis. Necrosis is caused by factors external to the cell or tissue, such as infection, or trauma which result in the unregulated dige ...
and gangrene of limbs. Its natural counterpart, purpura fulminans, occurs in children who are homozygous 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-related bone fracture, fracture. A 1999 study in 572 women taking warfarin for Deep vein thrombosis, deep venous thrombosis, risk of Vertebral compression fracture, 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 (United States), Medicare recipients showed that warfarin use for more than one year was linked with a 60% increased risk of osteoporosis-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 cholesterol embolism, purple toe syndrome. This condition is thought to result from small deposits of cholesterol 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, 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 Prothrombin complex concentrate (PCC), also known as factor IX complex, is a medication made up of blood clotting factors II, IX, and X. Some versions also contain factor VII. It is used to treat and prevent bleeding in hemophilia B if pure ...
(PCC), or
fresh frozen plasma Fresh frozen plasma (FFP) is a blood product made from the liquid portion of whole blood. It is used to treat conditions in which there are low blood clotting factors (INR > 1.5) or low levels of other blood proteins. It may also be used as the re ...
(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 drug interaction, interacts with many commonly used drugs, and the drug metabolism, metabolism 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 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), international normalized ratio, 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 antibiotics, such as metronidazole or the macrolides, 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 gut flora, 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.
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 respon ...
(FDA) product insert on warfarin states that alcohol should be avoided. The Cleveland Clinic 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 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 oil, borage (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 enzyme induction and inhibition, 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 the 3-position substituent. However, the existence of many 4-hydroxycoumadin anticoagulants (for example
phenprocoumon Phenprocoumon (marketed under the brand names Marcoumar, Marcumar and Falithrom) is a long-acting blood thinner drug to be taken by mouth, and a derivative of coumarin. It acts as a vitamin K antagonist and inhibits blood clotting (coagulation) b ...
) 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 and consists of two enantiomers. 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 enantiomers—''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 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 Heparin-induced thrombocytopenia (HIT) is the development of thrombocytopenia (a low platelet count), due to the administration of various forms of heparin, an anticoagulant. HIT predisposes to thrombosis (the abnormal formation of blood clots ...
(an antibody-mediated decrease in platelet 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

While warfarin is one of several drugs popularly referred to as a "blood thinner", this is a misnomer, since it does not affect the viscosity of blood. Warfarin inhibits the vitamin K-dependent synthesis of biologically active forms of the clotting factors thrombin, II, factor VII, VII, factor IX, IX and factor X, X, as well as the regulatory factors protein C, protein S, and protein Z. Other proteins not involved in blood clotting, such as osteocalcin, or matrix gla protein, matrix Gla protein, may also be affected. The precursors of these factors require gamma 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 Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
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 reduction (chemistry), reduced form of vitamin K (vitamin K hydroquinone) to vitamin K epoxide at the same time. The vitamin K epoxide is, in turn, recycled back to vitamin K and vitamin K hydroquinone by another enzyme, the
vitamin K epoxide reductase Vitamin K epoxide reductase (VKOR) is an enzyme () that reduces vitamin K after it has been oxidised in the carboxylation of glutamic acid residues in blood coagulation enzymes. VKOR is a member of a large family of predicted enzymes that are pre ...
(''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 glutamic acid 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 [by] vitamin K absence), and individual coagulation factors as PIVKA-''number'' (e.g., Des-gamma carboxyprothrombin, 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 heparin, 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. Polymorphism (biology), 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 mutations 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 haplotypes), 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 race, 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 does shorten the time to International normalized ratio, 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 concluded, "the available evidence does not demonstrate that pharmacogenomic testing of ''CYP2C9'' or ''VKORC1'' alleles to predict warfarin responsiveness improves health outcomes in Medicare (United States), Medicare beneficiaries." A 2014
meta-analysis A meta-analysis is a statistical analysis that combines the results of multiple scientific studies. Meta-analyses can be performed when there are multiple scientific studies addressing the same question, with each individual study reporting me ...
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 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. All of these animals had bled to death. In 1921, Frank Schofield, a Canadian veterinary pathologist, determined that the cattle were ingesting moldy silage 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 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–Madison, University of Wisconsin 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 Coumarin () or 2''H''-chromen-2-one is an aromatic organic chemical compound with formula . Its molecule can be described as a benzene molecule with two adjacent hydrogen atoms replaced by a lactone-like chain , forming a second six-membered h ...
(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 Hierochloe odorata, 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 Galium odoratum, woodruff (''Galium odoratum'', Rubiaceae), and at lower levels in licorice, lavender, and various other species. The name coumarin comes from the French pronunciation of ''coumarou'', the Indian name for the tree of the Dipteryx odorata, 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 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 rodenticide, 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, who was prescribed the drug after having a heart attack in 1955. The exact mechanism of action remained unknown until it was demonstrated, in 1978, that warfarin enzyme inhibitor, 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. Warfarin is tasteless and colourless, and produces symptoms similar to those that Stalin exhibited.


Pest control


Rodents

Coumarins (4-hydroxycoumarin derivatives) are used as rodenticides for controlling rats and mouse, mice in residential, industrial, and agricultural areas. Warfarin is both odorless and tasteless, and is effective when mixed with food bait (luring substance), 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 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). The use of warfarin itself 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. Resistance is due to an autosomal dominant (genetics), dominant on chromosome 1 in Norway rats. This has convergent evolution, 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 bioaccumulation, accumulate in the liver and kidneys after ingestion. However, such rodenticides may also accumulate in birds of prey and other animals that eat the poisoned rodents or baits.


Vampire bats

Warfarin is used to cull vampire bat populations 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 showed that culling programs did not lead to lower transmission rates of rabies to livestock and humans.


Occupational safety

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 IDLH, immediately dangerous to life and health. It is classified as an List of extremely hazardous substances, extremely hazardous substance in the United States as defined in Section 302 of the U.S. Emergency Planning and Community Right-to-Know Act (42 U.S.C. 11002), and is subject to strict reporting requirements by facilities which produce, store, or use it in significant quantities.


Names

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 Dipteryx odorata, tonka beans (also known as ''cumaru'' from which coumarin's name derives). The 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.


Research

Long-term use of VKOR inhibitors as anticoagulation therapy was associated with lower cancer incidence.


References


Further reading

*


External links

*
Historical information on warfarin
from the Wisconsin Alumni Research Foundation
CDC – NIOSH Pocket Guide to Chemical Hazards
* {{Authority control 4-Hydroxycoumarins Anticoagulant rodenticides Coumarin drugs Teratogens World Health Organization essential medicines Wikipedia medicine articles ready to translate