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 K
1),
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 mechanism o ...
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 K
1.
Without sufficient active vitamin K
1,
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 ...
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 apoptosis, cell death and ...
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 hear ...
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
![Vitamin K1 warfarin therapeutic window](https://upload.wikimedia.org/wikipedia/commons/1/1d/Vitamin_K1_warfarin_therapeutic_window.png)
Recommendations by many national bodies, including the
American College of Chest Physicians
The American College of Chest Physicians (CHEST) is a medical association in the United States consisting of physicians and non-physician specialists in the field of chest medicine, which includes pulmonology, critical care medicine, and sleep med ...
,
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 K
1 in the diet. Keeping vitamin K
1 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 K
1. 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 ...
,
, 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 K
1. 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 K
1 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 K
1. Foods low in vitamin K
1 include roots, bulbs, tubers, and most fruits and fruit juices. Cereals, grains, and other milled products are also low in vitamin K
1.
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 kne ...
,
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 is u ...
,
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 in ...
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
Miscarriage, also known in medical terms as a spontaneous abortion and pregnancy loss, is the death of an embryo or fetus before it is able to survive independently. Miscarriage before 6 weeks of gestation is defined by ESHRE as biochemical lo ...
, 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 c ...
. 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 can ...
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 Albini t ...
'' 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
Low-molecular-weight heparin (LMWH) is a class of anticoagulant medications. They are used in the prevention of blood clots and treatment of venous thromboembolism (deep vein thrombosis and pulmonary embolism) and in the treatment of myocardial in ...
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 calcification
Calcification is the accumulation of calcium salts in a body tissue. It normally occurs in the formation of bone, but calcium can be deposited abnormally in soft tissue,Miller, J. D. Cardiovascular calcification: Orbicular origins. ''Nature Mat ...
s in the vertebral column
The vertebral column, also known as the backbone or spine, is part of the axial skeleton. The vertebral column is the defining characteristic of a vertebrate in which the notochord (a flexible rod of uniform composition) found in all chordata, ...
, femur
The femur (; ), or thigh bone, is the proximal bone of the hindlimb in tetrapod vertebrates. The head of the femur articulates with the acetabulum in the pelvic bone forming the hip joint, while the distal part of the femur articulates with ...
, and heel bone
In humans and many other primates, the calcaneus (; from the Latin ''calcaneus'' or ''calcaneum'', meaning heel) or heel bone is a bone of the tarsus of the foot which constitutes the heel. In some other animals, it is the point of the hock.
St ...
, which show a peculiar stipple
Stippling is the creation of a pattern simulating varying degrees of solidity or shading by using small dots. Such a pattern may occur in nature and these effects are frequently emulated by artists.
Art
In printmaking, stipple engraving is ...
d appearance on X-rays
An X-ray, or, much less commonly, X-radiation, is a penetrating form of high-energy electromagnetic radiation. Most X-rays have a wavelength ranging from 10 Picometre, picometers to 10 Nanometre, nanometers, corresponding to frequency, ...
. Limb abnormalities, such as brachydactyly
Brachydactyly (Greek βραχύς = "short" plus δάκτυλος = "finger"), is a medical term which literally means "short finger". The shortness is relative to the length of other long bones and other parts of the body. Brachydactyly is an in ...
(unusually short fingers and toes) or underdeveloped extremities, can also occur. Common nonskeletal features of FWS include low birth weight
Low birth weight (LBW) is defined by the World Health Organization as a birth weight of an
infant of or less, regardless of gestational age. Infants born with LBW have added health risks which require close management, often in a neonatal intensi ...
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 and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all par ...
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 seizure
An epileptic seizure, informally known as a seizure, is a period of symptoms due to abnormally excessive or synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much of the body with los ...
s, 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
The American College of Chest Physicians (CHEST) is a medical association in the United States consisting of physicians and non-physician specialists in the field of chest medicine, which includes pulmonology, critical care medicine, and sleep med ...
, 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
Intracerebral hemorrhage (ICH), also known as cerebral bleed, intraparenchymal bleed, and hemorrhagic stroke, or haemorrhagic stroke, is a sudden bleeding into Intraparenchymal hemorrhage, the tissues of the brain, into its Intraventricular hemor ...
/hemorrhagic stroke
A stroke is a disease, medical condition in which poor cerebral circulation, blood flow to the brain causes cell death. There are two main types of stroke: brain ischemia, ischemic, due to lack of blood flow, and intracranial hemorrhage, hemorr ...
) and the spinal cord
The spinal cord is a long, thin, tubular structure made up of nervous tissue, which extends from the medulla oblongata in the brainstem to the lumbar region of the vertebral column (backbone). The backbone encloses the central canal of the spi ...
. 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 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 "blood pressure" r ...
(H), abnormal kidney function
Assessment of kidney function occurs in different ways, using the presence of symptoms and signs, as well as measurements using urine tests, blood tests, and medical imaging.
Functions of a healthy kidney include maintaining a person's fluid ...
(A), previous stroke (S), known previous bleeding condition (B), previous labile
Lability refers to something that is constantly undergoing change or is likely to undergo change.
Biochemistry
In reference to biochemistry, this is an important concept as far as kinetics is concerned in metalloproteins. This can allow for th ...
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
Hemodialysis, also spelled haemodialysis, or simply dialysis, is a process of purifying the blood of a person whose kidneys are not working normally. This type of dialysis achieves the extracorporeal removal of waste products such as creatinin ...
. 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
Clopidogrel — sold under the brand name Plavix, among others — is an antiplatelet medication used to reduce the risk of heart disease and stroke in those at high risk. It is also used together with aspirin in heart attacks and following t ...
, aspirin
Aspirin, also known as acetylsalicylic acid (ASA), is a nonsteroidal anti-inflammatory drug (NSAID) used to reduce pain, fever, and/or inflammation, and as an antithrombotic. Specific inflammatory conditions which aspirin is used to treat inc ...
, or nonsteroidal anti-inflammatory drug
Non-steroidal anti-inflammatory drugs (NSAID) are members of a therapeutic drug class which reduces pain, decreases inflammation, decreases fever, and prevents blood clots. Side effects depend on the specific drug, its dose and duration of ...
s.
Warfarin necrosis
A rare but serious complication resulting from treatment with warfarin is warfarin necrosis
Warfarin-induced skin necrosis is a condition in which skin and subcutaneous tissue necrosis (tissue death) occurs due to acquired protein C deficiency following treatment with anti-vitamin K anticoagulants (4-hydroxycoumarins, such as warfarin). ...
, 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 apoptosis, cell death and ...
, an innate anticoagulant that, like the procoagulant factors whose synthesis warfarin inhibits, requires vitamin K-dependent carboxylation
Carboxylation is a chemical reaction in which a carboxylic acid is produced by treating a substrate with carbon dioxide. The opposite reaction is decarboxylation. In chemistry, the term carbonation is sometimes used synonymously with carboxylatio ...
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. Since heparins depend on the activity of antithrombin, they are considered anticoagulants. Specifically it is also used in the treatm ...
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
Gangrene is a type of tissue death caused by a lack of blood supply. Symptoms may include a change in skin color to red or black, numbness, swelling, pain, skin breakdown, and coolness. The feet and hands are most commonly affected. If the ga ...
of limbs. Its natural counterpart, purpura fulminans
Purpura fulminans is an acute, often fatal, thrombotic disorder which manifests as blood spots, bruising and discolouration of the skin resulting from coagulation in small blood vessels within the skin and rapidly leads to skin necrosis and disse ...
, 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.
Mo ...
for certain protein C mutations.
Osteoporosis
After initial reports that warfarin could reduce bone mineral density
Bone density, or bone mineral density, is the amount of bone mineral in bone tissue. The concept is of mass of mineral per volume of bone (relating to density in the physics sense), although clinically it is measured by proxy according to optica ...
, 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 bone fragility, and consequent increase in fracture risk. It is the most common reason for a broken bone ...
-related fracture
Fracture is the separation of an object or material into two or more pieces under the action of stress. The fracture of a solid usually occurs due to the development of certain displacement discontinuity surfaces within the solid. If a displa ...
. A 1999 study in 572 women taking warfarin for 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 ...
, risk of vertebral fracture
A spinal fracture, also called a vertebral fracture or a broken back, is a fracture affecting the vertebrae of the spinal column. Most types of spinal fracture confer a significant risk of spinal cord injury. After the immediate trauma, there i ...
and rib fracture
A rib fracture is a break in a rib bone. This typically results in chest pain that is worse with inspiration. Bruising may occur at the site of the break. When several ribs are broken in several places a flail chest results. Potential complicatio ...
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
Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to bone fragility, and consequent increase in fracture risk. It is the most common reason for a broken bone am ...
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 osteoporosis
Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to bone fragility, and consequent increase in fracture risk. It is the most common reason for a broken bone ...
-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 any of a class of certain organic molecules called lipids. It is a sterol (or modified steroid), a type of lipid. Cholesterol is biosynthesized by all animal cells and is an essential structural component of animal cell mem ...
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 digits (fingers) 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 '' pl ...
, but it affects other parts of the feet, as well, including the bottom of the foot (plantar
Standard anatomical terms of location are used to unambiguously describe the anatomy of animals, including humans. The terms, typically derived from Latin or Greek roots, describe something in its standard anatomical position. This position prov ...
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
Calcification is the accumulation of calcium salts in a body tissue. It normally occurs in the formation of bone, but calcium can be deposited abnormally in soft tissue,Miller, J. D. Cardiovascular calcification: Orbicular origins. ''Nature Mat ...
. 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
Blood compatibility testing is conducted in a medical laboratory to identify potential incompatibilities between blood group systems in blood transfusion. It is also used to diagnose and prevent some complications of pregnancy that can occur whe ...
. 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 el, μεταβολή ''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 cell ...
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 chemical ...
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 elevated lipid levels. It is also used to decrease the risk of heart ...
), INR checks are increased or dosages adjusted until a new ideal dosage is found.
When taken with nonsteroidal anti-inflammatory drug
Non-steroidal anti-inflammatory drugs (NSAID) are members of a therapeutic drug class which reduces pain, decreases inflammation, decreases fever, and prevents blood clots. Side effects depend on the specific drug, its dose and duration of ...
s (NSAIDs), warfarin increases the risk for gastrointestinal bleeding
Gastrointestinal bleeding (GI bleed), also called gastrointestinal hemorrhage (GIB), is all forms of bleeding in the gastrointestinal tract, from the mouth to the rectum. When there is significant blood loss over a short time, symptoms may incl ...
. This increased risk is due to the antiplatelet effect of NSAIDs and possible damage to the gastrointestinal mucosa
A mucous membrane or mucosa is a membrane that lines various cavities in the body of an organism and covers the surface of internal organs. It consists of one or more layers of epithelial cells overlying a layer of loose connective tissue. It is ...
.
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 bacterial infections, and antibiotic medications are widely used in the treatment and prevention of ...
s, such as metronidazole
Metronidazole, sold under the brand name Flagyl 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 vaginosis. It is ef ...
or the macrolide
The Macrolides are a class of natural products that consist of a large macrocyclic lactone ring to which one or more deoxy sugars, usually cladinose and desosamine, may be attached. The lactone rings are usually 14-, 15-, or 16-membered. Macrol ...
s, greatly increase the effect of warfarin by reducing the metabolism of warfarin in the body. Other broad-spectrum antibiotic
A broad-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 used when a bacterial inf ...
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
The thyroid, or thyroid gland, is an endocrine gland in vertebrates. In humans it is in the neck and consists of two connected lobes. The lower two thirds of the lobes are connected by a thin band of tissue called the thyroid isthmus. The thy ...
activity also appears to influence warfarin dosing requirements; hypothyroidism
Hypothyroidism (also called ''underactive thyroid'', ''low thyroid'' or ''hypothyreosis'') is a disorder of the endocrine system in which the thyroid gland does not produce enough thyroid hormone. It can cause a number of symptoms, such as po ...
(decreased thyroid function) makes people less responsive to warfarin treatment, while hyperthyroidism
Hyperthyroidism is the condition that occurs due to excessive production of thyroid hormones by the thyroid gland. Thyrotoxicosis is the condition that occurs due to excessive thyroid hormone of any cause and therefore includes 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
Cleveland Clinic is a nonprofit American academic medical center based in Cleveland, Ohio. Owned and operated by the Cleveland Clinic Foundation, an Ohio nonprofit corporation established in 1921, it runs a 170-acre (69 ha) campus in Cleveland, ...
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
A spice is a seed, fruit, root, bark, or other plant substance primarily used for flavoring or coloring food. Spices ...
and garlic
Garlic (''Allium sativum'') is a species of bulbous flowering plant in the genus ''Allium''. Its close relatives include the onion, shallot, leek, chive, Allium fistulosum, Welsh onion and Allium chinense, Chinese onion. It is native to South A ...
) and others used purely for medicinal purposes (such as ginseng
Ginseng () is the root of plants in the genus ''Panax'', such as Korean ginseng ('' P. ginseng''), South China ginseng ('' P. notoginseng''), and American ginseng ('' P. quinquefolius''), typically characterized by the presence of ginsenosides an ...
and ''Ginkgo biloba
''Ginkgo biloba'', commonly known as ginkgo or gingko ( ), also known as the maidenhair tree, is a species of tree native to China. It is the last living species in the order Ginkgoales, which first appeared over 290 million years ago. Fossils ...
''). All may increase bleeding and bruising in people taking warfarin; similar effects have been reported with borage
Borage ( or ; ''Borago officinalis''), also known as starflower, is an annual herb in the flowering plant family Boraginaceae. It is native to the Mediterranean region, and has naturalized in many other locales.
It grows satisfactorily in gard ...
( starflower) oil. St. John's wort
''Hypericum perforatum'', known as St. John's wort, is a flowering plant in the family Hypericaceae and the type species of the genus ''Hypericum''.
Possibly a hybrid between ''Hypericum maculatum, H. maculatum'' and ''Hypericum attenuatum, H. ...
, sometimes recommended to help with mild to moderate depression, reduces the effectiveness of a given dose of warfarin; it induces
Electromagnetic or magnetic induction is the production of an electromotive force (emf) across an electrical conductor in a changing magnetic field.
Michael Faraday is generally credited with the discovery of induction in 1831, and James Cler ...
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
The Committee on Safety of Medicines (CSM) was an independent advisory committee that advised the UK Licensing Authority on the quality, efficacy, and safety of medicines.
Following the thalidomide tragedy of 1957 to 1961, in 1963 the government ...
received several reports of increased INR and risk of haemorrhage in people taking warfarin and cranberry juice
Cranberry juice is the liquid juice of the cranberry, typically manufactured to contain sugar, water, and other fruit juices. Cranberry – a fruit native to North America – is recognized for its bright red color, tart taste, and versat ...
.[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
Crystallography is the experimental science of determining the arrangement of atoms in crystalline solids. Crystallography is a fundamental subject in the fields of materials science and solid-state physics (condensed matter physics). The word ...
studies of warfarin show that it exists in tautomer
Tautomers () are structural isomers (constitutional isomers) of chemical compounds that readily interconvert.
The chemical reaction interconverting the two is called tautomerization. This conversion commonly results from the relocation of a hydr ...
ic form, as the cyclic hemiketal
A hemiacetal or a hemiketal has the general formula R1R2C(OH)OR, where R1 or R2 is hydrogen or an organic substituent. They generally result from the addition of an alcohol to an aldehyde or a ketone, although the latter are sometimes called hemi ...
, which is formed from the 4-hydroxycoumarin and the ketone
In organic chemistry, a ketone is a functional group with the structure R–C(=O)–R', where R and R' can be a variety of carbon-containing substituents. Ketones contain a carbonyl group –C(=O)– (which contains a carbon-oxygen double bo ...
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
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 c ...
and consists of two enantiomer
In chemistry, an enantiomer ( /ɪˈnænti.əmər, ɛ-, -oʊ-/ ''ih-NAN-tee-ə-mər''; from Ancient Greek ἐνάντιος ''(enántios)'' 'opposite', and μέρος ''(méros)'' 'part') – also called optical isomer, antipode, or optical ant ...
s. This is a racemate
In chemistry, a racemic mixture, or racemate (), is one that has equal amounts of left- and right-handed enantiomers of a chiral molecule or salt. Racemic mixtures are rare in nature, but many compounds are produced industrially as racemates. ...
, i.e., a 1: 1 mixture of ('' R '') – and the ('' S '') – form:
Pharmacology
Pharmacokinetics
Warfarin consists of a racemic
In chemistry, a racemic mixture, or racemate (), is one that has equal amounts of left- and right-handed enantiomers of a chiral molecule or salt. Racemic mixtures are rare in nature, but many compounds are produced industrially as racemates. ...
mixture of two active enantiomer
In chemistry, an enantiomer ( /ɪˈnænti.əmər, ɛ-, -oʊ-/ ''ih-NAN-tee-ə-mər''; from Ancient Greek ἐνάντιος ''(enántios)'' 'opposite', and μέρος ''(méros)'' 'part') – also called optical isomer, antipode, or optical ant ...
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 heparin
Heparin, also known as unfractionated heparin (UFH), is a medication and naturally occurring glycosaminoglycan. Since heparins depend on the activity of antithrombin, they are considered anticoagulants. Specifically it is also used in the treatm ...
, 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 in ...
(an antibody
An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the ...
-mediated decrease in platelet
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 ...
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
The viscosity of a fluid is a measure of its resistance to deformation at a given rate. For liquids, it corresponds to the informal concept of "thickness": for example, syrup has a higher viscosity than water.
Viscosity quantifies the inte ...
of blood.
Warfarin inhibits the vitamin K-dependent synthesis of biologically active forms of the 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 mechanism o ...
factors II, VII VII or vii may refer to: the Roman numeral 7
Art and entertainment
* The Vii, a video game console
* vii, leading-tone triad, see diminished triad
* ''VII'' (Blitzen Trapper album)
* ''VII'' (Just-Ice album)
* ''VII'' (Teyana Taylor album)
* ...
, IX and X, as well as the regulatory factors protein C, protein S, and protein Z
Protein Z (PZ or PROZ) is a Protein in humans which is encoded by the ''PROZ'' gene.
Protein Z is a member of the coagulation cascade, the group of blood proteins that leads to the formation of blood clots. It is a glycoprotein. Protein Z functi ...
. Other proteins not involved in blood clotting, such as osteocalcin
Osteocalcin, also known as bone gamma-carboxyglutamic acid-containing protein (BGLAP), is a small (49-amino-acid) noncollagenous protein hormone found in bone and dentin, first identified as a calcium-binding protein.
Because osteocalcin has gl ...
, or matrix Gla protein
Matrix Gla protein (MGP) is member of a family of vitamin K2 dependent, Gla-containing proteins. MGP has a high affinity binding to calcium ions, similar to other Gla-containing proteins. The protein acts as an inhibitor of vascular mineralizat ...
, may also be affected.
The precursors of these factors require gamma
Gamma (uppercase , lowercase ; ''gámma'') 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 re ...
carboxylation of their glutamic acid
Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) 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 synt ...
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 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 rest of the vessel ...
. 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
Gamma-glutamyl carboxylase is an enzyme that in humans is encoded by the ''GGCX'' gene, located on chromosome 2 at 2p12.
Function
Gamma-glutamyl carboxylase is an enzyme that catalyzes the posttranslational modification of vitamin K-dependent pro ...
. 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
In organic chemistry, an epoxide is a cyclic ether () with a three-atom ring. This ring approximates an equilateral triangle, which makes it strained, and hence highly reactive, more so than other ethers. They are produced on a large scale for ...
at the same time. The vitamin K epoxide is, in turn, recycled back to vitamin K and vitamin K hydroquinone
Hydroquinone, also known as benzene-1,4-diol or quinol, is an aromatic organic compound that is a type of phenol, a derivative of benzene, having the chemical formula C6H4(OH)2. It has two hydroxyl groups bonded to a benzene ring in a ''para'' ...
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
Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) 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 synt ...
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 Des-gamma carboxyprothrombin (DCP), also known as protein induced by vitamin K absence/antagonist-II (PIVKA-II), is an abnormal form of the coagulation protein, prothrombin. Normally, the prothrombin precursor undergoes post-translational carboxylat ...
).
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
Heparin, also known as unfractionated heparin (UFH), is a medication and naturally occurring glycosaminoglycan. Since heparins depend on the activity of antithrombin, they are considered anticoagulants. Specifically it is also used in the treatm ...
, an anticoagulant that acts upon antithrombin
Antithrombin (AT) is a small glycoprotein that inactivates several enzymes of the coagulation system. It is a 432-amino-acid protein produced by the liver. It contains three disulfide bonds and a total of four possible glycosylation sites. α-An ...
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
The human gene ''VKORC1'' encodes for the enzyme, Vitamin K epOxide Reductase Complex (VKORC) subunit 1. This enzymatic protein complex is responsible for reducing vitamin K 2,3-epoxide to its active form, which is important for effective clottin ...
'' 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, mi ...
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 or ...
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
Cytochrome P450 family 2 subfamily C member 9 (abbreviated CYP2C9) is an enzyme protein. The enzyme is involved in metabolism, by oxidation, of both xenobiotics, including drugs, and endogenous compounds, including fatty acids. In humans, the prote ...
'' polymorphisms explain 10% of the dose variation between patients, mainly among Caucasian
Caucasian may refer to:
Anthropology
*Anything from the Caucasus region
**
**
** ''Caucasian Exarchate'' (1917–1920), an ecclesiastical exarchate of the Russian Orthodox Church in the Caucasus region
*
*
*
Languages
* Northwest Caucasian l ...
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 INR >4.
Despite the promise of pharmacogenomic
Pharmacogenomics is the study of the role of the genome in drug response. Its name ('' pharmaco-'' + ''genomics'') reflects its combining of pharmacology and genomics. Pharmacogenomics analyzes how the genetic makeup of an individual affects the ...
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 M ...
concluded, "the available evidence does not demonstrate that pharmacogenomic testing of ''CYP2C9'' or ''VKORC1'' allele
An allele (, ; ; modern formation from Greek ἄλλος ''állos'', "other") is a variation of the same sequence of nucleotides at the same place on a long DNA molecule, as described in leading textbooks on genetics and evolution.
::"The chro ...
s to predict warfarin responsiveness improves health outcomes in 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
The Northern United States, commonly referred to as the American North, the Northern States, or simply the North, is a geographical or historical region of the United States.
History Early history
Before the 19th century westward expansion, the "N ...
and Canada. Cattle were haemorrhaging
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 ...
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, surgical, chemical, or otherwise, by which an individual loses use of the testicles: the male gonad. Surgical castration is bilateral orchiectomy (excision of both testicles), while chemical castration uses pharmaceut ...
. All of these animals had bled to death.
In 1921, Frank Schofield
Frank W. Schofield (1889–1970) was a British-born Canadian veterinarian and Protestant missionary who was involved in the Korean independence movement against the Japanese Empire.
Schofield graduated in 1910 from the Ontario Veterinary Colleg ...
, a Canadian veterinary
Veterinary medicine is the branch of medicine that deals with the prevention, management, diagnosis, and treatment of disease, disorder, and injury in animals. Along with this, it deals with animal rearing, husbandry, breeding, research on nutri ...
pathologist
Pathology is the study of the causal, causes and effects of disease or injury. The word ''pathology'' also refers to the study of disease in general, incorporating a wide range of biology research fields and medical practices. However, when us ...
, determined that the cattle were ingesting moldy silage
Silage () is a type of fodder made from green foliage crops which have been preserved by fermentation to the point of acidification. It can be fed to cattle, sheep and other such ruminants (cud-chewing animals). The fermentation and storage p ...
made from sweet clover
''Melilotus'', known as melilot, sweet clover, and kumoniga (from the Cumans),Bulgarian Folk Customs, Mercia MacDermott, pg 27 is a genus in the family Fabaceae (the same family that also includes the ''Trifolium'' clovers). Members are known a ...
, 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 Native Americans in the United States, indigenous Dakota people, Dakota Sioux. North Dakota is bordered by the Canadian provinces of Saskatchewan and Manitoba to the north a ...
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
Karl Paul Gerhard Link (31 January 1901 – 21 November 1978) was an American biochemist best known for his discovery of the anticoagulant warfarin.
Training and early career
He was born in LaPorte, Indiana to a Lutheran minister of German descen ...
and his laboratory of chemists working at the University of Wisconsin
A university () is an institution of higher (or tertiary) education and research which awards academic degrees in several academic disciplines. Universities typically offer both undergraduate and postgraduate programs. In the United States, t ...
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
Dicoumarol ( INN) or dicumarol (USAN) is a naturally occurring anticoagulant drug that depletes stores of vitamin K (similar to warfarin, a drug that dicoumarol inspired). It is also used in biochemical experiments as an inhibitor of reductases. ...
. 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 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
The Rubiaceae are a 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 interpetiolar stipules ...
), and at lower levels in licorice
Liquorice (British English) or licorice (American English) ( ; also ) is the common name of ''Glycyrrhiza glabra'', a flowering plant of the bean family Fabaceae, from the root of which a sweet, aromatic flavouring can be extracted.
The liq ...
, lavender
''Lavandula'' (common name lavender) is a genus of 47 known species of flowering plants in the mint family, Lamiaceae. It is native to the Old World and is found in Cape Verde and the Canary Islands, and from Europe across to northern and easte ...
, and various other species. The name coumarin comes from the French pronunciation of ''coumarou'', the Indian name for the tree of the tonka bean
''Dipteryx odorata'' (commonly known as "cumaru", "kumaru", or "Brazilian teak") is a species of flowering tree in the pea family, Fabaceae. The tree is native to Central America and northern South America and is semi-deciduous. Its seeds are kn ...
, 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
Formaldehyde ( , ) (systematic name methanal) is a naturally occurring organic compound with the formula and structure . The pure compound is a pungent, colourless gas that polymerises spontaneously into paraformaldehyde (refer to section F ...
) into dicoumarol, to have any anticoagulant properties.
Over the next few years, numerous similar chemicals (specifically 4-hydroxycoumarins with a large aromatic
In chemistry, aromaticity is a chemical property of cyclic ( ring-shaped), ''typically'' planar (flat) molecular structures with pi bonds in resonance (those containing delocalized electrons) that gives increased stability compared to satur ...
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
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 ...
. 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 Wisconsin Alumni Research Foundation is the independent nonprofit technology transfer organization serving the University of Wisconsin–Madison and Morgridge Institute for Research. It provides significant research support, granting tens ...
+ the ending "-arin" indicating its link with coumarin. Warfarin was first registered for use as a rodenticide
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. Despi ...
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
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 ...
), 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 an American military officer and statesman who served as the 34th president of the United States from 1953 to 1961. During World War II, ...
, 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 interaction through which a drug substance produces its pharmacological effect. A mechanism of action usually includes mention of the specific molecular targe ...
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
Lavrentiy Pavlovich Beria (; rus, Лавре́нтий Па́влович Бе́рия, Lavréntiy Pávlovich Bériya, p=ˈbʲerʲiə; ka, ლავრენტი ბერია, tr, ; – 23 December 1953) was a Georgian Bolsheviks ...
and I. V. Khrustalyov are thought to have conspired to use warfarin to poison Soviet leader Joseph Stalin
Joseph Vissarionovich Stalin (born Ioseb Besarionis dze Jughashvili; – 5 March 1953) was a Georgian revolutionary and Soviet political leader who led the Soviet Union from 1924 until his death in 1953. He held power as General Secreta ...
. Warfarin is tasteless and colourless, and produces symptoms similar to those that Stalin exhibited.
Pest control
Rodents
Coumarins (4-hydroxycoumarin derivatives) are used as rodenticide
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. Despi ...
s 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 Rodentia (), which are characterized by a single pair of continuously growing incisors in each of the upper and lower jaws. About 40% of all mammal species are rodents. They are na ...
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
Talc, or talcum, is a Clay minerals, clay mineral, composed of hydrated magnesium silicate with the chemical formula Mg3Si4O10(OH)2. Talc in powdered form, often combined with corn starch, is used as baby powder. This mineral is used as a thi ...
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
The term immediately dangerous to life or health (IDLH) is defined by the US National Institute for Occupational Safety and Health (NIOSH) as exposure to airborne contaminants that is "likely to cause death or immediate or delayed permanent advers ...
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
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 allosome, allosomal (sex chromosome) pairs, which may have different structures. The DNA in au ...
dominant on chromosome 1 in Norway rat
The brown rat (''Rattus norvegicus''), also known as the common rat, street rat, sewer rat, wharf rat, Hanover rat, Norway rat, Norwegian rat and Parisian rat, is a widespread species of common rat. One of the largest muroids, it is a brown o ...
s. This has arisen independently and become fixed several times around the world. Other 4-hydroxycoumarins used as rodenticides include coumatetralyl
Coumatetralyl is an anticoagulant of the 4-hydroxycoumarin vitamin K antagonist type used as a rodenticide.
Common applications
Coumatetralyl is commonly used with grains and other cereals as a rodent poison in conjunction with a tracking po ...
and brodifacoum
Brodifacoum is a highly lethal 4-hydroxycoumarin vitamin K antagonist anticoagulant poison. In recent years, it has become one of the world's most widely used pesticides. It is typically used as a rodenticide, but is also used to control larger ...
, 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 Organ (anatomy), organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of proteins and biochemicals necessary for ...
and kidney
The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; blood ...
s after ingestion. However, such rodenticides may also accumulate in birds of prey
Birds of prey or predatory birds, also known as raptors, are hypercarnivorous bird species that actively hunt and feed on other vertebrates (mainly mammals, reptiles and other smaller birds). In addition to speed and strength, these predators ...
and other animals that eat the poisoned rodents or baits.
Vampire bats
Warfarin is used to cull vampire bat
Vampire bats, species of the subfamily Desmodontinae, are leaf-nosed bats found in Central and South America. Their food source is blood of other animals, a dietary trait called hematophagy. Three extant bat species feed solely on blood: the com ...
populations in areas where human–wildlife conflict
Human–wildlife conflict (HWC) refers to the negative interactions between human and wild animals, with undesirable consequences both for people and their resources, on the one hand, and wildlife and their habitats on the other (IUCN 2020). HWC ...
is a concern. Vampire bats are captured with mist net
Mist nets are used by hunters and poachers, but also by ornithologists and chiropterologists to capture wild birds and bats for banding or other research projects. Mist nets are typically made of nylon or polyester mesh suspended between two ...
s and coated with a combination of petroleum jelly
Petroleum jelly, petrolatum, white petrolatum, soft paraffin, or multi-hydrocarbon, CAS number 8009-03-8, is a semi-solid mixture of hydrocarbons (with carbon numbers mainly higher than 25), originally promoted as a topical ointment for its h ...
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
Social grooming is a behavior in which social animals, including humans, clean or maintain one another's body or appearance. A related term, allogrooming, indicates social grooming between members of the same species. Grooming is a major soci ...
. 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
, image_flag = Flag of Peru.svg
, image_coat = Escudo nacional del Perú.svg
, other_symbol = Great Seal of the State
, other_symbol_type = Seal (emblem), National seal
, national_motto = "Fi ...
showed that culling programs did not lead to lower transmission rates of rabies
Rabies is a viral disease that causes encephalitis in humans and other mammals. Early symptoms can include fever and tingling at the site of exposure. These symptoms are followed by one or more of the following symptoms: nausea, vomiting, vi ...
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
The Occupational Safety and Health Administration'' (OSHA ) is a large regulatory agency of the United States Department of Labor that originally had federal visitorial powers to inspect and examine workplaces. Congress established the agenc ...
has set the legal limit (permissible exposure limit
The permissible exposure limit (PEL or OSHA PEL) is a legal limit in the United States for exposure of an employee to a chemical substance or physical agent such as high level noise. Permissible exposure limits are established by the Occupational S ...
) for warfarin exposure in the workplace as 0.1 mg/m3 over an 8-hour workday. The National Institute for Occupational Safety and Health
The National Institute for Occupational Safety and Health (NIOSH, ) is the United States federal agency responsible for conducting research and making recommendations for the prevention of work-related injury and illness. NIOSH is part of the C ...
has set a recommended exposure limit
A recommended exposure limit (REL) is an occupational exposure limit that has been recommended by the United States National Institute for Occupational Safety and Health. The REL is a level that NIOSH believes would be protective of worker safety ...
of 0.1 mg/m3 over an 8-hour workday. At levels of 100 mg/m3, warfarin is immediately dangerous to life and health
The term immediately dangerous to life or health (IDLH) is defined by the US National Institute for Occupational Safety and Health (NIOSH) as exposure to airborne contaminants that is "likely to cause death or immediate or delayed permanent advers ...
.
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 October ...
(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 tonka beans
''Dipteryx odorata'' (commonly known as "cumaru", "kumaru", or "Brazilian teak") is a species of flowering tree in the pea family, Fabaceae. The tree is native to Central America and northern South America and is semi-deciduous. Its seeds are kno ...
(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
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External links
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Historical information on warfarin
from the Wisconsin Alumni Research Foundation
The Wisconsin Alumni Research Foundation is the independent nonprofit technology transfer organization serving the University of Wisconsin–Madison and Morgridge Institute for Research. It provides significant research support, granting tens ...
CDC – NIOSH Pocket Guide to Chemical Hazards
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4-Hydroxycoumarins
Anticoagulant rodenticides
Coumarin drugs
Teratogens
World Health Organization essential medicines
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