Warfarin
Overview
Warfarin is an anticoagulant
Anticoagulant
An anticoagulant is a substance that prevents coagulation of blood. A group of pharmaceuticals called anticoagulants can be used in vivo as a medication for thrombotic disorders. Some anticoagulants are used in medical equipment, such as test tubes, blood transfusion bags, and renal dialysis...

. It is most likely to be the drug popularly referred to as a "blood thinner," yet this is a misnomer, since it does not affect the thickness or viscosity of blood. Instead, it acts on the liver to decrease the quantity of a few key proteins in blood that allow blood to clot.

It was initially marketed as a pesticide
Pesticide
Pesticides are substances or mixture of substances intended for preventing, destroying, repelling or mitigating any pest.A pesticide may be a chemical unicycle, biological agent , antimicrobial, disinfectant or device used against any pest...

 against rat
Rat
Rats are various medium-sized, long-tailed rodents of the superfamily Muroidea. "True rats" are members of the genus Rattus, the most important of which to humans are the black rat, Rattus rattus, and the brown rat, Rattus norvegicus...

s and mice
Mouse
A mouse is a small mammal belonging to the order of rodents. The best known mouse species is the common house mouse . It is also a popular pet. In some places, certain kinds of field mice are also common. This rodent is eaten by large birds such as hawks and eagles...

 and is still popular for this purpose, although more potent poisons such as brodifacoum
Brodifacoum
Brodifacoum is a highly lethal vitamin K antagonist anticoagulant poison. In recent years, it has become one of the world's most widely used pesticides...

 have since been developed.
Encyclopedia
Warfarin is an anticoagulant
Anticoagulant
An anticoagulant is a substance that prevents coagulation of blood. A group of pharmaceuticals called anticoagulants can be used in vivo as a medication for thrombotic disorders. Some anticoagulants are used in medical equipment, such as test tubes, blood transfusion bags, and renal dialysis...

. It is most likely to be the drug popularly referred to as a "blood thinner," yet this is a misnomer, since it does not affect the thickness or viscosity of blood. Instead, it acts on the liver to decrease the quantity of a few key proteins in blood that allow blood to clot.

It was initially marketed as a pesticide
Pesticide
Pesticides are substances or mixture of substances intended for preventing, destroying, repelling or mitigating any pest.A pesticide may be a chemical unicycle, biological agent , antimicrobial, disinfectant or device used against any pest...

 against rat
Rat
Rats are various medium-sized, long-tailed rodents of the superfamily Muroidea. "True rats" are members of the genus Rattus, the most important of which to humans are the black rat, Rattus rattus, and the brown rat, Rattus norvegicus...

s and mice
Mouse
A mouse is a small mammal belonging to the order of rodents. The best known mouse species is the common house mouse . It is also a popular pet. In some places, certain kinds of field mice are also common. This rodent is eaten by large birds such as hawks and eagles...

 and is still popular for this purpose, although more potent poisons such as brodifacoum
Brodifacoum
Brodifacoum is a highly lethal vitamin K antagonist anticoagulant poison. In recent years, it has become one of the world's most widely used pesticides...

 have since been developed. A few years after its introduction, warfarin was found to be effective and relatively safe for preventing thrombosis
Thrombosis
Thrombosis is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel is injured, the body uses platelets and fibrin to form a blood clot to prevent blood loss...

 and embolism
Embolism
In medicine, an embolism is the event of lodging of an embolus into a narrow capillary vessel of an arterial bed which causes a blockage in a distant part of the body.Embolization is...

 (abnormal formation and migration of blood clots) in many disorders. It was approved for use as a medication in the early 1950s and has remained popular ever since; warfarin is the most widely prescribed oral anticoagulant drug in North America.

Despite its effectiveness, treatment with warfarin has several shortcomings. Many commonly used medications interact
Drug interaction
A drug interaction is a situation in which a substance affects the activity of a drug, i.e. the effects are increased or decreased, or they produce a new effect that neither produces on its own. Typically, interaction between drugs come to mind...

 with warfarin, as do some foods (particularly fresh plant-based foods containing vitamin K
Vitamin K
Vitamin K is a group of structurally similar, fat soluble vitamins that are needed for the posttranslational modification of certain proteins required for blood coagulation and in metabolic pathways in bone and other tissue. They are 2-methyl-1,4-naphthoquinone derivatives...

), and its activity has to be monitored by blood test
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 needle, or via fingerprick....

ing for the international normalized ratio
Prothrombin time
The prothrombin time and its derived measures of prothrombin ratio and international normalized ratio are measures of the extrinsic pathway of coagulation. This test is also called "ProTime INR" and "INR PT". They are used to determine the clotting tendency of blood, in the measure of warfarin...

 (INR) to ensure an adequate yet safe dose is taken.

Warfarin and related 4-hydroxycoumarin-containing molecules decrease blood coagulation
Coagulation
Coagulation is a complex process by which blood forms clots. It is an important part of hemostasis, the cessation of blood loss from a damaged vessel, wherein a damaged blood vessel wall is covered by a platelet and fibrin-containing clot to stop bleeding and begin repair of the damaged vessel...

 by inhibiting vitamin K epoxide reductase
Vitamin K epoxide reductase
Vitamin K epoxide reductase is an enzyme that reduces vitamin K after it has been oxidised in the carboxylation of glutamic acid. Its C1 subunit is the target of anticoagulant warfarin.- See also :* Oxidoreductase...

, an enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...

 that recycles oxidized vitamin K to its reduced form after it has participated in the carboxylation
Carboxylation
Carboxylation in chemistry is a chemical reaction in which a carboxylic acid group is introduced in a substrate. The opposite reaction is decarboxylation.-Carboxylation in organic chemistry:In organic chemistry many different protocols exist for carboxylation...

 of several blood coagulation proteins, mainly prothrombin and factor VII
Factor VII
Factor VII is one of the proteins that causes blood to clot in the coagulation cascade. It is an enzyme of the serine protease class. A recombinant form of human factor VIIa has U.S. Food and Drug Administration approval for uncontrolled bleeding in hemophilia patients...

. For this reason, drugs in this class are also referred to as vitamin K antagonists. When administered, these drugs do not anticoagulate blood immediately. Instead, onset of their effect requires about a day before clotting factors being normally made by the liver have time to naturally disappear in metabolism, and the duration of action of a single dose of racemic warfarin is 2 to 5 days. Under normal pharmacological therapy the drugs are administered to decrease the action of the clotting factors they affect by 30 to 50%.

Warfarin is a synthetic derivative of dicoumarol, a 4-hydroxycoumarin-derived mycotoxin
Mycotoxin
A mycotoxin is a toxic secondary metabolite produced by organisms of the fungus kingdom, commonly known as molds. The term ‘mycotoxin’ is usually reserved for the toxic chemical products produced by fungi that readily colonize crops...

 anticoagulant originally discovered in spoiled sweet clover-based animal feeds. Dicoumarol, in turn, is derived from coumarin
Coumarin
Coumarin is a fragrant chemical compound in the benzopyrone chemical class, found in many plants, notably in high concentration in the tonka bean , vanilla grass , sweet woodruff , mullein , sweet grass , cassia cinnamon and sweet clover...

, a sweet-smelling but coagulation-inactive chemical found naturally in "sweet" clover (to which it gives its odor and name) and many other plants. The name warfarin stems from its discovery at the University of Wisconsin, incorporating the acronym for the organization which funded the key research (WARF, for Wisconsin Alumni Research Foundation
Wisconsin Alumni Research Foundation
The Wisconsin Alumni Research Foundation is the nonprofit technology transfer office of the University of Wisconsin–Madison. It is a significant source of research support, independent of federal grants...

) and the ending -arin, indicating its link with coumarin.

Medical uses

Warfarin is used to decrease the tendency for thrombosis
Thrombosis
Thrombosis is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel is injured, the body uses platelets and fibrin to form a blood clot to prevent blood loss...

 or as secondary prophylaxis (prevention of further episodes) in those individuals that have already formed a blood clot (thrombus
Thrombus
A thrombus , or blood clot, is the final product of the blood coagulation step in hemostasis. It is achieved via the aggregation of platelets that form a platelet plug, and the activation of the humoral coagulation system...

). Warfarin treatment can help prevent formation of future blood clots and help reduce the risk of embolism
Embolism
In medicine, an embolism is the event of lodging of an embolus into a narrow capillary vessel of an arterial bed which causes a blockage in a distant part of the body.Embolization is...

 (migration of a thrombus to a spot where it blocks blood supply to a vital organ).

The type of anticoagulation (clot formation inhibition) for which warfarin is best suited, is that in areas of slowly-running blood, such as in veins and the pooled blood behind artificial and natural valves, and pooled in dysfunctional cardiac atria. Thus, common clinical indications for warfarin use are atrial fibrillation
Atrial fibrillation
Atrial fibrillation is the most common cardiac arrhythmia . It is a common cause of irregular heart beat, identified clinically by taking a pulse. Chaotic electrical activity in the two upper chambers of the heart result in the muscle fibrillating , instead of achieving coordinated contraction...

, the presence of artificial heart valve
Artificial heart valve
An artificial heart valve is a device implanted in the heart of a patient with heart valvular disease. When one of the four heart valves malfunctions, the medical choice may be to replace the natural valve with an artificial valve. This requires open-heart surgery.Valves are integral to the normal...

s, deep venous thrombosis, and pulmonary embolism
Pulmonary embolism
Pulmonary embolism is a blockage of the main artery of the lung or one of its branches by a substance that has travelled from elsewhere in the body through the bloodstream . Usually this is due to embolism of a thrombus from the deep veins in the legs, a process termed venous thromboembolism...

 (where the embolized clots first form in veins). Warfarin is also used in antiphospholipid syndrome
Antiphospholipid syndrome
Antiphospholipid syndrome or antiphospholipid antibody syndrome , often also Hughes syndrome, is an autoimmune, hypercoagulable state caused by antibodies against cell-membrane phospholipids that provokes blood clots in both arteries and veins as well as pregnancy-related complications such as...

. It has been used occasionally after heart attacks (myocardial infarction
Myocardial infarction
Myocardial infarction or acute myocardial infarction , commonly known as a heart attack, results from the interruption of blood supply to a part of the heart, causing heart cells to die...

s), but is far less effective at preventing new thromboses in coronary arteries. Prevention of clotting in arteries is usually undertaken with antiplatelet drug
Antiplatelet drug
An antiplatelet drug is a member of a class of pharmaceuticals that decrease platelet aggregation and inhibit thrombus formation...

s, which act by a different mechanism from warfarin (which normally has no effect on platelet function).

In some countries, other coumarins are used instead of warfarin, such as acenocoumarol
Acenocoumarol
Acenocoumarol is an anticoagulant that functions as a vitamin K antagonist . It is a derivative of coumarin and is marketed under the brand names Sintrom and Sinthrome.- Dosage :...

 and phenprocoumon
Phenprocoumon
Phenprocoumon is an anticoagulant drug, a derivative of coumarin. It is a vitamin K antagonist that inhibits coagulation by blocking synthesis of coagulation factors II, VII, IX and X...

. These have a shorter (acenocoumarol) or longer (phenprocoumon) half-life
Biological half-life
The biological half-life or elimination half-life of a substance is the time it takes for a substance to lose half of its pharmacologic, physiologic, or radiologic activity, as per the MeSH definition...

, and are not completely interchangeable with warfarin. The oral anticoagulant ximelagatran
Ximelagatran
Ximelagatran is an anticoagulant that has been investigated extensively as a replacement for warfarin that would overcome the problematic dietary, drug interaction, and monitoring issues associated with warfarin therapy...

 (trade name Exanta) was expected to replace warfarin to a large degree when introduced; however, reports of hepatotoxicity
Hepatotoxicity
Hepatotoxicity implies chemical-driven liver damage.The liver plays a central role in transforming and clearing chemicals and is susceptible to the toxicity from these agents. Certain medicinal agents, when taken in overdoses and sometimes even when introduced within therapeutic ranges, may injure...

 (liver damage) prompted its manufacturer to withdraw it from further development. Other drugs offering the efficacy of warfarin without a need for monitoring, such as dabigatran
Dabigatran
Dabigatran is an oral anticoagulant from the class of the direct thrombin inhibitors...

 and rivaroxaban
Rivaroxaban
Rivaroxaban is an oral anticoagulant invented and manufactured by Bayer; in a number of countries it is marketed as Xarelto. In the United States, it is marketed by Janssen Pharmaceutica. It is the first available orally active direct factor Xa inhibitor. Rivaroxaban is well absorbed from the gut...

, are under development.

Dosing

Dosing of warfarin is complicated by the fact that it is known to interact with many commonly-used medications and even with chemicals that may be present in certain foods. These interactions may enhance or reduce warfarin's anticoagulation effect. In order to optimize the therapeutic effect without risking dangerous side effects such as bleeding, close monitoring of the degree of anticoagulation is required by blood testing (INR
Prothrombin time
The prothrombin time and its derived measures of prothrombin ratio and international normalized ratio are measures of the extrinsic pathway of coagulation. This test is also called "ProTime INR" and "INR PT". They are used to determine the clotting tendency of blood, in the measure of warfarin...

). During the initial stage of treatment, checking may be required daily; intervals between tests can be lengthened if the patient manages stable therapeutic INR levels on an unchanged warfarin dose.

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

Loading dose

Several researchers have proposed algorithms for commencing warfarin treatment:
  • The Kovacs 10 mg algorithm was better than a 5 mg algorithm.
  • The Fennerty 10 mg regimen is for urgent anticoagulation
  • The Tait 5 mg regimen is for "routine" (low-risk) anticoagulation
  • Lenzini et al. derived and prospectively validated a model including CYP2C9 and VKORC1 genotypes. This model could predict 70% of the variation in warfarin doses in a validation cohort (versus 48% without genotype). The pharmacogenetic protocol lead to a reduction in out of range INR values as compared to a historic control.
  • www.WarfarinDosing.org is a non-profit website programmed with dosing calculators and other decision support tools for clinicians' use when initiating warfarin therapy.

Maintenance dose

Recommendations by many national bodies including the American College of Chest Physicians
American College of Chest Physicians
The American College of Chest Physicians is a medical organization in the United States consisting of physicians and non-physician specialists in the field of chest medicine, which includes pulmonology, thoracic surgery, and critical care medicine....

 have been distilled to help manage dose adjustments.

The maintenance dose of warfarin can fluctuate significantly depending on the amount of vitamin K in the diet. Keeping vitamin K intake at a stable level can prevent these fluctuations. Leafy green vegetables tend to contain higher amounts of vitamin K and typically green vegetables, cabbages, and lettuces are high in vitamin K. Certain vegetable oils have high amounts of vitamin K. Foods that are low in vitamin K include roots, bulbs, tubers, some fruits and fruit juices. Cereals, grains and other milled products are also low in vitamin K.

Self-testing

Patients are making increasing use of self-testing and home monitoring of oral anticoagulation. International guidelines on home testing were published in 2005. The guidelines stated: "The consensus agrees that patient self-testing and patient self-management are effective methods of monitoring oral anticoagulation therapy, providing outcomes at least as good as, and possibly better than, those achieved with an anticoagulation clinic. All patients must be appropriately selected and trained. Currently available self-testing/self-management devices give INR results which are comparable with those obtained in laboratory testing." A 2006 systematic review
Systematic review
A systematic review is a literature review focused on a research question that tries to identify, appraise, select and synthesize all high quality research evidence relevant to that question. Systematic reviews of high-quality randomized controlled trials are crucial to evidence-based medicine...

 and meta-analysis
Meta-analysis
In statistics, a meta-analysis combines the results of several studies that address a set of related research hypotheses. In its simplest form, this is normally by identification of a common measure of effect size, for which a weighted average might be the output of a meta-analyses. Here the...

 of 14 randomized trials showed that home testing led to a reduced incidence of complications (thrombosis and major bleeding) and improved the time in the therapeutic range.

Pregnancy

Warfarin is contraindicated
Contraindication
In medicine, a contraindication is a condition or factor that serves as a reason to withhold a certain medical treatment.Some contraindications are absolute, meaning that there are no reasonable circumstances for undertaking a course of action...

 in pregnancy, as it passes through the placenta
Placenta
The placenta is an organ that connects the developing fetus to the uterine wall to allow nutrient uptake, waste elimination, and gas exchange via the mother's blood supply. "True" placentas are a defining characteristic of eutherian or "placental" mammals, but are also found in some snakes and...

l barrier and may cause bleeding in the fetus; warfarin use during pregnancy is commonly associated with spontaneous abortion
Miscarriage
Miscarriage or spontaneous abortion is the spontaneous end of a pregnancy at a stage where the embryo or fetus is incapable of surviving independently, generally defined in humans at prior to 20 weeks of gestation...

, stillbirth
Stillbirth
A stillbirth occurs when a fetus has died in the uterus. The Australian definition specifies that fetal death is termed a stillbirth after 20 weeks gestation or the fetus weighs more than . Once the fetus has died the mother still has contractions and remains undelivered. The term is often used in...

, neonatal death, and preterm birth. Coumarins (such as warfarin) are also teratogens, that is, they cause birth defects; the incidence of birth defects in infants exposed to warfarin in utero
In utero
In utero is a Latin term literally meaning "in the womb". In biology, the phrase describes the state of an embryo or fetus. In legal contexts, the phrase is used to refer to unborn children. Under common law, unborn children are still considered to exist for property transfer purposes.-See also:*...

appears to be around 5%, although higher figures (up to 30%) have been reported in some studies. Depending on when exposure occurs during pregnancy, two distinct combinations of congenital abnormalities can arise.

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
Fetal warfarin syndrome is a condition associated with administration of Warfarin during pregnancy....

 (FWS), warfarin embryopathy, or coumarin embryopathy can occur. FWS is characterized mainly by skeletal abnormalities, which include nasal hypoplasia, a depressed or narrowed nasal bridge, scoliosis
Scoliosis
Scoliosis is a medical condition in which a person's spine is curved from side to side. Although it is a complex three-dimensional deformity, on an X-ray, viewed from the rear, the spine of an individual with scoliosis may look more like an "S" or a "C" than a straight line...

, and calcification
Calcification
Calcification is the process in which calcium salts build up in soft tissue, causing it to harden. Calcifications may be classified on whether there is mineral balance or not, and the location of the calcification.-Causes:...

s in the vertebral column
Vertebral column
In human anatomy, the vertebral column is a column usually consisting of 24 articulating vertebrae, and 9 fused vertebrae in the sacrum and the coccyx. It is situated in the dorsal aspect of the torso, separated by intervertebral discs...

, femur
Femur
The femur , or thigh bone, is the most proximal bone of the leg in tetrapod vertebrates capable of walking or jumping, such as most land mammals, birds, many reptiles such as lizards, and amphibians such as frogs. In vertebrates with four legs such as dogs and horses, the femur is found only in...

, and heel bone which show a peculiar stippled appearance on X-rays
Medical radiography
Radiography is the use of ionizing electromagnetic radiation such as X-rays to view objects. Although not technically radiographic techniques, imaging modalities such as PET and MRI are sometimes grouped in radiography because the radiology department of hospitals handle all forms of imaging...

. Limb abnormalities
Dysmelia
Dysmelia is a congenital disorder referring to the limbs. -Types:Dysmelia can refer to*missing limbs: amelia, oligodactyly, congenital amputation...

, such as brachydactyly
Brachydactyly
Brachydactyly , is a medical term which literally means "shortness of the fingers and toes" . The shortness is relative to the length of other long bones and other parts of the body. Brachydactyly is an inherited, usually dominant trait...

 (unusually short fingers and toes) or underdeveloped extremities, can also occur. Common non-skeletal features of FWS include low birth weight
Low birth weight
Low birth weight is defined as a birth weight of a liveborn infant of less than 2,500 g. regardless of gestational age-Causes:LBW is either the result of preterm birth or of the infant being small for gestational age , or a combination of...

 and developmental disabilities
Developmental disability
Developmental disability is a term used in the United States and Canada to describe lifelong disabilities attributable to mental or physical impairments, manifested prior to age 18. It is not synonymous with "developmental delay" which is often a consequence of a temporary illness or trauma during...

.

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 fetal warfarin syndrome. The most common congenital abnormalities associated with warfarin use in late pregnancy are central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...

 disorders, including spasticity
Spasticity
Spasticity is a feature of altered skeletal muscle performance in muscle tone involving hypertonia, which is also referred to as an unusual "tightness" of muscles...

 and seizure
Seizure
An epileptic seizure, occasionally referred to as a fit, is defined as a transient symptom of "abnormal excessive or synchronous neuronal activity in the brain". The outward effect can be as dramatic as a wild thrashing movement or as mild as a brief loss of awareness...

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 valve
Artificial heart valve
An artificial heart valve is a device implanted in the heart of a patient with heart valvular disease. When one of the four heart valves malfunctions, the medical choice may be to replace the natural valve with an artificial valve. This requires open-heart surgery.Valves are integral to the normal...

s.

Usually, warfarin is avoided in the first trimester, and a low molecular weight heparin
Low molecular weight heparin
In medicine, low-molecular-weight heparin is a class of medication used as an anticoagulant in diseases that feature thrombosis, as well as for prophylaxis in situations that lead to a high risk of thrombosis....

 such as enoxaparin
Enoxaparin
Enoxaparin is a low molecular weight heparin marketed under the trade names Lovenox and Clexane, among others. It is an anticoagulant used to prevent and treat deep vein thrombosis or pulmonary embolism, and is given as a subcutaneous injection...

 is substituted. With heparin, risk of maternal hemorrhage and other complications is still increased, but heparins do not cross the placental barrier and therefore do not cause birth defects. Various solutions exist for the time around delivery.

Hemorrhage

The only common side effect
Adverse drug reaction
An adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dosage. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs...

 of warfarin is hemorrhage (bleeding). The risk of severe bleeding is small but definite (a median annual rate of 0.9 to 2.7% has been reported) and any benefit needs to outweigh this risk when warfarin is considered as a therapeutic measure. Risk of bleeding is augmented if the INR is out of range (due to accidental or deliberate overdose or due to interactions), and may cause hemoptysis
Hemoptysis
Hemoptysis or haemoptysis is the expectoration of blood or of blood-stained sputum from the bronchi, larynx, trachea, or lungs Hemoptysis or haemoptysis is the expectoration (coughing up) of blood or of blood-stained sputum from the bronchi, larynx, trachea, or lungs Hemoptysis or haemoptysis ...

 (coughing up blood), excessive bruising, bleeding from nose or gums, or blood in urine
Urine
Urine is a typically sterile liquid by-product of the body that is secreted by the kidneys through a process called urination and excreted through the urethra. Cellular metabolism generates numerous by-products, many rich in nitrogen, that require elimination from the bloodstream...

 or stool
Human feces
Human feces , also known as a stool, is the waste product of the human digestive system including bacteria. It varies significantly in appearance, according to the state of the digestive system, diet and general health....

.

The risks of bleeding is increased when warfarin is combined with antiplatelet drug
Antiplatelet drug
An antiplatelet drug is a member of a class of pharmaceuticals that decrease platelet aggregation and inhibit thrombus formation...

s such as clopidogrel
Clopidogrel
Clopidogrel is an oral, thienopyridine class antiplatelet agent used to inhibit blood clots in coronary artery disease, peripheral vascular disease, and cerebrovascular disease. It is marketed by Bristol-Myers Squibb and Sanofi-Aventis under the trade name Plavix. The drug works by irreversibly...

, aspirin
Aspirin
Aspirin , also known as acetylsalicylic acid , is a salicylate drug, often used as an analgesic to relieve minor aches and pains, as an antipyretic to reduce fever, and as an anti-inflammatory medication. It was discovered by Arthur Eichengrun, a chemist with the German company Bayer...

, or other nonsteroidal anti-inflammatory drugs. The risk may also be increased in elderly patients and in patients on hemodialysis
Hemodialysis
In medicine, hemodialysis is a method for removing waste products such as creatinine and urea, as well as free water from the blood when the kidneys are in renal failure. Hemodialysis is one of three renal replacement therapies .Hemodialysis can be an outpatient or inpatient therapy...

.

Warfarin necrosis

A rare but serious complication resulting from treatment with warfarin is warfarin necrosis
Warfarin necrosis
Warfarin-induced skin necrosis is a condition in which skin and subcutaneous tissue necrosis occurs due to acquired protein C deficiency following treatment with anti-vitamin K anticoagulants .Warfarin necrosis is a rare but severe complication of treatment with warfarin or related...

, which occurs more frequently shortly after commencing treatment in patients with a deficiency of protein C
Protein C
Protein C, also known as autoprothrombin IIA and blood coagulation factor XIV, is a zymogenic protein, the activated form of which plays an important role in regulating blood clotting, inflammation, cell death and maintaining the permeability of blood vessel walls in humans and other animals...

. Protein C is an innate anticoagulant that, like the procoagulant factors that warfarin inhibits, requires vitamin K-dependent carboxylation for its activity. Since warfarin initially decreases protein C levels faster than the coagulation factors, it can paradoxically increase the blood's tendency to coagulate when treatment is first begun (many patients when starting on warfarin are given heparin
Heparin
Heparin , also known as unfractionated heparin, a highly sulfated glycosaminoglycan, is widely used as an injectable anticoagulant, and has the highest negative charge density of any known biological molecule...

 in parallel to combat this), leading to massive thrombosis with skin necrosis
Necrosis
Necrosis is the premature death of cells in living tissue. Necrosis is caused by factors external to the cell or tissue, such as infection, toxins, or trauma. This is in contrast to apoptosis, which is a naturally occurring cause of cellular death...

 and gangrene
Gangrene
Gangrene is a serious and potentially life-threatening condition that arises when a considerable mass of body tissue dies . This may occur after an injury or infection, or in people suffering from any chronic health problem affecting blood circulation. The primary cause of gangrene is reduced blood...

 of limbs. Its natural counterpart, purpura fulminans
Purpura fulminans
Purpura fulminans is a haemorrhagic condition usually associated with sepsis or previous infection. It occurs mainly in babies and small children.It was first described by Guelliot in 1884.- Presentation :...

, occurs in children who are homozygous for certain protein C mutations.

Protein S deficiency can be affected in the same way as protein C deficiency is affected.

Osteoporosis

After initial reports that warfarin could reduce bone mineral density, several studies have demonstrated a link between warfarin use and osteoporosis
Osteoporosis
Osteoporosis is a disease of bones that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is deteriorating, and the amount and variety of proteins in bone is altered...

-related fracture
Bone fracture
A bone fracture is a medical condition in which there is a break in the continuity of the bone...

. A 1999 study in 572 women taking warfarin for deep venous thrombosis, risk of vertebral fracture and rib fracture was increased; other fracture types did not occur more commonly. A 2002 study looking at a randomly selected selection of 1523 patients with osteoporotic fracture found no increased exposure to anticoagulants compared to controls, and neither did stratification of the duration of anticoagulation reveal a trend towards fracture.

A 2006 retrospective study of 14,564 Medicare recipients showed that warfarin use for more than one year was linked with a 60% increased risk of osteoporosis-related fracture in men; there was no association in women. The mechanism was thought to be a combination of reduced intake of vitamin K, which is 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
Cholesterol embolism
Cholesterol embolism occurs when cholesterol is released, usually from an atherosclerotic plaque, and travels along with the bloodsteam to other places in the body, where it obstructs blood vessels...

. This condition is thought to result from small deposits of cholesterol
Cholesterol
Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...

 breaking loose and flowing into the blood vessels in the skin of the feet, which causes a blueish purple color and may be painful.

It is typically thought to affect the big toe, but it affects other parts of the feet as well, including the bottom of the foot (plantar surface). The occurrence of purple toe syndrome may require discontinuation of warfarin.

Drug interactions

Warfarin interact
Drug interaction
A drug interaction is a situation in which a substance affects the activity of a drug, i.e. the effects are increased or decreased, or they produce a new effect that neither produces on its own. Typically, interaction between drugs come to mind...

s with many commonly used drugs, and the metabolism
Drug metabolism
Drug metabolism is the biochemical modification of pharmaceutical substances by living organisms, usually through specialized enzymatic systems. This is a form of xenobiotic metabolism. Drug metabolism often converts lipophilic chemical compounds into more readily excreted polar products...

 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
Serum albumin, often referred to simply as albumin is a protein that in humans is encoded by the ALB gene.Serum albumin is the most abundant plasma protein in mammals. Albumin is essential for maintaining the osmotic pressure needed for proper distribution of body fluids between intravascular...

 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
Simvastatin is a hypolipidemic drug used to control elevated cholesterol, or hypercholesterolemia. Simvastatin is a member of the statin class of pharmaceuticals, is a synthetic derivate of a fermentation product of Aspergillus terreus.-Medical uses:The primary uses of simvastatin is for the...

), INR checks are increased or dosages adjusted until a new ideal dosage is found.

Many commonly used antibiotics, such as metronidazole
Metronidazole
Metronidazole is a nitroimidazole antibiotic medication used particularly for anaerobic bacteria and protozoa. Metronidazole is an antibiotic, amebicide, and antiprotozoal....

 or the macrolide
Macrolide
The macrolides are a group of drugs whose activity stems from the presence of a macrolide ring, 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...

s, will greatly increase the effect of warfarin by reducing the metabolism
Drug metabolism
Drug metabolism is the biochemical modification of pharmaceutical substances by living organisms, usually through specialized enzymatic systems. This is a form of xenobiotic metabolism. Drug metabolism often converts lipophilic chemical compounds into more readily excreted polar products...

 of warfarin in the body. Other broad-spectrum antibiotic
Broad-spectrum antibiotic
The term broad-spectrum antibiotic refers to an antibiotic that acts against a wide range of disease-causing bacteria. A broad-spectrum antibiotic acts against both Gram-positive and Gram-negative bacteria, in contrast to a narrow-spectrum antibiotic, which is effective against specific families of...

s can reduce the amount of the normal bacterial flora in the bowel
Gut flora
Gut flora consists of microorganisms that live in the digestive tracts of animals and is the largest reservoir of human flora. In this context, gut is synonymous with intestinal, and flora with microbiota and microflora....

, which make significant quantities of vitamin K, thus potentiating the effect of warfarin. In addition, food that contains large quantities of vitamin K will reduce the warfarin effect. Thyroid
Thyroid
The thyroid gland or simply, the thyroid , in vertebrate anatomy, is one of the largest endocrine glands. The thyroid gland is found in the neck, below the thyroid cartilage...

 activity also appears to influence warfarin dosing requirements; hypothyroidism
Hypothyroidism
Hypothyroidism is a condition in which the thyroid gland does not make enough thyroid hormone.Iodine deficiency is the most common cause of hypothyroidism worldwide but it can be caused by other causes such as several conditions of the thyroid gland or, less commonly, the pituitary gland or...

 (decreased thyroid function) makes people less responsive to warfarin treatment, while hyperthyroidism
Hyperthyroidism
Hyperthyroidism is the term for overactive tissue within the thyroid gland causing an overproduction of thyroid hormones . Hyperthyroidism is thus a cause of thyrotoxicosis, the clinical condition of increased thyroid hormones in the blood. Hyperthyroidism and thyrotoxicosis are not synonymous...

 (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. Patients are often cautioned against the excessive use of alcohol while taking warfarin.

Warfarin also interacts with many herbs and spices, some used in food (such as ginger
Ginger
Ginger is the rhizome of the plant Zingiber officinale, consumed as a delicacy, medicine, or spice. It lends its name to its genus and family . Other notable members of this plant family are turmeric, cardamom, and galangal....

 and garlic
Garlic
Allium sativum, commonly known as garlic, is a species in the onion genus, Allium. Its close relatives include the onion, shallot, leek, chive, and rakkyo. Dating back over 6,000 years, garlic is native to central Asia, and has long been a staple in the Mediterranean region, as well as a frequent...

) and others used purely for medicinal purposes (such as ginseng
Ginseng
Ginseng is any one of eleven species of slow-growing perennial plants with fleshy roots, belonging to the genus Panax of the family Araliaceae....

 and Ginkgo biloba). All may increase bleeding and bruising in people taking warfarin; similar effects have been reported with borage (starflower
Borage
Borage, , also known as a starflower, is an annual herb originating in Syria, but naturalized throughout the Mediterranean region, as well as Asia Minor, Europe, North Africa, and South America. It grows to a height of , and is bristly or hairy all over the stems and leaves; the leaves are...

) oil or fish oils. St. John's Wort, sometimes recommended to help with mild to moderate depression, interacts with warfarin; it induces
Enzyme induction and inhibition
Enzyme induction is a process in which a molecule induces the expression of an enzyme.Enzyme inhibition can refer to* the inhibition of the expression of the enzyme by another molecule...

 the enzymes that break down warfarin in the body, causing a reduced anticoagulant effect.

Between 2003 and 2004, the UK Committee on Safety of Medicines received several reports of increased INR and risk of hemorrhage in people taking warfarin and cranberry juice
Cranberry
Cranberries are a group of evergreen dwarf shrubs or trailing vines in the subgenus Oxycoccus of the genus Vaccinium. In some methods of classification, Oxycoccus is regarded as a genus in its own right...

. Data establishing a causal relationship is still lacking, and a 2006 review found no cases of this interaction reported to the FDA; nevertheless, several authors have recommended that both doctors and patients be made aware of its possibility. The mechanism behind the interaction is still unclear.

Antagonism

The effects of warfarin can be reversed with vitamin K, or, when rapid reversal is needed (such as in case of severe bleeding), with prothrombin complex concentrate
Prothrombin complex concentrate
Prothrombin Complex Concentrate is a combination of blood clotting factors II, VII, IX and X, as well as protein C and S. It reverses the effect of warfarin and is used in cases of significant bleeding in patients with a coagulopathy...

—which contains only the factors inhibited by warfarin—or fresh frozen plasma
Fresh frozen plasma
The term fresh frozen plasma refers to the liquid portion of human blood that has been frozen and preserved after a blood donation and will be used for blood transfusion...

 (depending upon the clinical indication) in addition to intravenous
Intravenous therapy
Intravenous therapy or IV therapy is the infusion of liquid substances directly into a vein. The word intravenous simply means "within a vein". Therapies administered intravenously are often called specialty pharmaceuticals...

 vitamin K.

Details on reversing warfarin are provided in clinical practice guidelines from the American College of Chest Physicians
American College of Chest Physicians
The American College of Chest Physicians is a medical organization in the United States consisting of physicians and non-physician specialists in the field of chest medicine, which includes pulmonology, thoracic surgery, and critical care medicine....

. For patients with an international normalized ratio (INR) between 4.5 and 10.0, a small dose of oral vitamin K is sufficient.

Pharmacology

Pharmacokinetics


Warfarin consists of a racemic
Racemic
In chemistry, a racemic mixture, or racemate , is one that has equal amounts of left- and right-handed enantiomers of a chiral molecule. The first known racemic mixture was "racemic acid", which Louis Pasteur found to be a mixture of the two enantiomeric isomers of tartaric acid.- Nomenclature :A...

 mixture of two active enantiomer
Enantiomer
In chemistry, an enantiomer is one of two stereoisomers that are mirror images of each other that are non-superposable , much as one's left and right hands are the same except for opposite orientation. It can be clearly understood if you try to place your hands one over the other without...

s—R- and S- forms—each of which is cleared by different pathways. S-warfarin has five times the potency of the R-isomer with respect to vitamin K antagonism.

Warfarin is slower-acting than the common anticoagulant heparin
Heparin
Heparin , also known as unfractionated heparin, a highly sulfated glycosaminoglycan, is widely used as an injectable anticoagulant, and has the highest negative charge density of any known biological molecule...

, 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
Heparin-induced thrombocytopenia is the development of thrombocytopenia , due to the administration of various forms of heparin, an anticoagulant...

 (an antibody-mediated decrease in platelet
Platelet
Platelets, or thrombocytes , are small,irregularly shaped clear cell fragments , 2–3 µm in diameter, which are derived from fragmentation of precursor megakaryocytes.  The average lifespan of a platelet is normally just 5 to 9 days...

 levels), which increases the risk for thrombosis
Thrombosis
Thrombosis is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel is injured, the body uses platelets and fibrin to form a blood clot to prevent blood loss...

. 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 was stopped. Furthermore, if given initially without additional anticoagulant cover, it can increase thrombosis risk (see below). For these main reasons, hospital
Hospital
A hospital is a health care institution providing patient treatment by specialized staff and equipment. Hospitals often, but not always, provide for inpatient care or longer-term patient stays....

ised patients are usually given heparin with warfarin initially, the heparin covering the 3–5 day lag period and being withdrawn after a few days.

Mechanism of action

Warfarin inhibits the vitamin K
Vitamin K
Vitamin K is a group of structurally similar, fat soluble vitamins that are needed for the posttranslational modification of certain proteins required for blood coagulation and in metabolic pathways in bone and other tissue. They are 2-methyl-1,4-naphthoquinone derivatives...

-dependent synthesis of biologically active forms of the calcium
Calcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...

-dependent clotting factors II
Thrombin
Thrombin is a "trypsin-like" serine protease protein that in humans is encoded by the F2 gene. Prothrombin is proteolytically cleaved to form thrombin in the first step of the coagulation cascade, which ultimately results in the stemming of blood loss...

, VII
Factor VII
Factor VII is one of the proteins that causes blood to clot in the coagulation cascade. It is an enzyme of the serine protease class. A recombinant form of human factor VIIa has U.S. Food and Drug Administration approval for uncontrolled bleeding in hemophilia patients...

, IX
Factor IX
Factor IX is one of the serine proteases of the coagulation system; it belongs to peptidase family S1. Deficiency of this protein causes hemophilia B. It was discovered in 1952 after a young boy named Stephen Christmas was found to be lacking this exact factor, leading to...

 and X
Factor X
Factor X, also known by the eponym Stuart-Prower factor or as prothrombinase, is an enzyme of the coagulation cascade. It is a serine endopeptidase .-Physiology:...

, as well as the regulatory factors protein C
Protein C
Protein C, also known as autoprothrombin IIA and blood coagulation factor XIV, is a zymogenic protein, the activated form of which plays an important role in regulating blood clotting, inflammation, cell death and maintaining the permeability of blood vessel walls in humans and other animals...

, protein S
Protein S
Protein S is a vitamin K-dependent plasma glycoprotein synthesized in the endothelium. In the circulation, Protein S exists in two forms: a free form and a complex form bound to complement protein C4b. In humans, protein S is encoded by the PROS1 gene...

, and protein Z
Protein Z
Protein Z also known as PROZ is a protein which in humans 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 vitamin K-dependent, and its functionality is therefore impaired in warfarin therapy...

. Other proteins not involved in blood clotting, such as osteocalcin
Osteocalcin
Osteocalcin, also known as bone gamma-carboxyglutamic acid-containing protein , is a noncollagenous protein found in bone and dentin. In humans, the osteocalcin is encoded by the BGLAP gene.- Function :...

, or matrix Gla protein
Matrix gla protein
Matrix gla protein is a protein found in numerous body tissues that requires vitamin K for its optimum function. It is present in bone , as well as in heart, kidney and lung...

, may also be affected.

The precursors of these factors require carboxylation
Carboxylation
Carboxylation in chemistry is a chemical reaction in which a carboxylic acid group is introduced in a substrate. The opposite reaction is decarboxylation.-Carboxylation in organic chemistry:In organic chemistry many different protocols exist for carboxylation...

 of their glutamic acid
Glutamic acid
Glutamic acid is one of the 20 proteinogenic amino acids, and its codons are GAA and GAG. It is a non-essential amino acid. The carboxylate anions and salts of glutamic acid are known as glutamates...

 residues to allow the coagulation factors to bind to phospholipid
Phospholipid
Phospholipids are a class of lipids that are a major component of all cell membranes as they can form lipid bilayers. Most phospholipids contain a diglyceride, a phosphate group, and a simple organic molecule such as choline; one exception to this rule is sphingomyelin, which is derived from...

 surfaces inside blood vessels, on the vascular endothelium
Endothelium
The endothelium is the thin layer of cells that lines the interior surface of blood vessels, forming an interface between circulating blood in the lumen and the rest of the vessel wall. These cells are called endothelial cells. Endothelial cells line the entire circulatory system, from the heart...

. The enzyme that carries out the carboxylation of glutamic acid is gamma-glutamyl carboxylase
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 proteins...

. The carboxylation reaction will proceed only if the carboxylase enzyme is able to convert a reduced form of vitamin K (vitamin K hydroquinone) to vitamin K epoxide at the same time. The vitamin K epoxide is in turn recycled back to vitamin K and vitamin K hydroquinone by another enzyme, the vitamin K epoxide reductase
Vitamin K epoxide reductase
Vitamin K epoxide reductase is an enzyme that reduces vitamin K after it has been oxidised in the carboxylation of glutamic acid. Its C1 subunit is the target of anticoagulant warfarin.- See also :* Oxidoreductase...

 (VKOR). Warfarin inhibits epoxide reductase (specifically the VKORC1 subunit), thereby diminishing available vitamin K and vitamin K hydroquinone in the tissues, which inhibits the carboxylation activity of the glutamyl carboxylase. When this occurs, the coagulation factors are no longer carboxylated at certain glutamic acid
Glutamic acid
Glutamic acid is one of the 20 proteinogenic amino acids, and its codons are GAA and GAG. It is a non-essential amino acid. The carboxylate anions and salts of glutamic acid are known as glutamates...

 residues, and are incapable of binding to the endothelial surface of blood vessels, and are thus biologically inactive. As the body's stores of previously-produced active factors degrade (over several days) and are replaced by inactive factors, the anticoagulation effect becomes apparent. The coagulation factors are produced, but have decreased functionality due to undercarboxylation; they are collectively referred to as PIVKAs (proteins induced [by] vitamin K absence/antagonism), and individual coagulation factors as PIVKA-number (e.g. PIVKA-II
Des-gamma carboxyprothrombin
Des-gamma carboxyprothrombin , also known as protein induced by vitamin K absence/antagonist-II , is an abnormal form of the coagulation protein, prothrombin. Normally, the prothrombin precursor undergoes post-translational carboxylation by gamma-glutamyl carboxylase in the liver prior to...

). The end result of warfarin use, therefore, is to diminish blood clotting in the patient.

When warfarin is newly started, it may promote clot formation temporarily. This is because the level of protein C
Protein C
Protein C, also known as autoprothrombin IIA and blood coagulation factor XIV, is a zymogenic protein, the activated form of which plays an important role in regulating blood clotting, inflammation, cell death and maintaining the permeability of blood vessel walls in humans and other animals...

 and protein S
Protein S
Protein S is a vitamin K-dependent plasma glycoprotein synthesized in the endothelium. In the circulation, Protein S exists in two forms: a free form and a complex form bound to complement protein C4b. In humans, protein S is encoded by the PROS1 gene...

 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
Protein C
Protein C, also known as autoprothrombin IIA and blood coagulation factor XIV, is a zymogenic protein, the activated form of which plays an important role in regulating blood clotting, inflammation, cell death and maintaining the permeability of blood vessel walls in humans and other animals...

 (for which it is the co-factor) and therefore reduced degradation of factor V
Factor V
Factor V is a protein of the coagulation system, rarely referred to as proaccelerin or labile factor. In contrast to most other coagulation factors, it is not enzymatically active but functions as a cofactor...

a and factor VIII
Factor VIII
Factor VIII is an essential blood clotting factor also known as anti-hemophilic factor . In humans, Factor VIII is encoded by the F8 gene...

a. Although loading doses of warfarin over 5 mg also produce a precipitous decline in factor VII
Factor VII
Factor VII is one of the proteins that causes blood to clot in the coagulation cascade. It is an enzyme of the serine protease class. A recombinant form of human factor VIIa has U.S. Food and Drug Administration approval for uncontrolled bleeding in hemophilia patients...

, 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 hemostasis 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, it is beneficial to co-administer heparin
Heparin
Heparin , also known as unfractionated heparin, a highly sulfated glycosaminoglycan, is widely used as an injectable anticoagulant, and has the highest negative charge density of any known biological molecule...

, an anticoagulant that acts upon antithrombin
Antithrombin
Antithrombin is a small protein molecule that inactivates several enzymes of the coagulation system. Antithrombin is a glycoprotein produced by the liver and consists of 432 amino acids. It contains three disulfide bonds and a total of four possible glycosylation sites...

 and helps reduce the risk of thrombosis, with warfarin therapy for four to five days, in order to have the benefit of anticoagulation from heparin until the full effect of warfarin has been achieved.

Chemical synthesis

The succinct synthesis of warfarin starts with condensation of ortho-hydroxyacetophenone
(1–2) with ethyl carbonate to give the b-ketoester as the intermediate shown in the enol
Enol
Enols are alkenes with a hydroxyl group affixed to one of the carbon atoms composing the double bond. Alkenes with a hydroxyl group on both sides of the double bond are called enediols. Deprotonated anions of enols are called enolates...

 form. Attack of the phenoxide on the ester grouping leads to cyclization and formation of the coumarin
Coumarin
Coumarin is a fragrant chemical compound in the benzopyrone chemical class, found in many plants, notably in high concentration in the tonka bean , vanilla grass , sweet woodruff , mullein , sweet grass , cassia cinnamon and sweet clover...

. Conjugate addition of the anion from that product to methyl styryl ketone gives the corresponding Michael adduct
Michael reaction
The Michael reaction or Michael addition is the nucleophilic addition of a carbanion or another nucleophile to an alpha, beta unsaturated carbonyl compound. It belongs to the larger class of conjugate additions. This is one of the most useful methods for the mild formation of C-C bonds...

 and thus warfarin.

Molecular structure

X-ray crystallographic studies of warfarin show that it exists in tautomer
Tautomer
Tautomers are isomers of organic compounds that readily interconvert by a chemical reaction called tautomerization. This reaction commonly results in the formal migration of a hydrogen atom or proton, accompanied by a switch of a single bond and adjacent double bond...

ic form, as the cyclic hemiketal, which is formed from the 4-hydroxycoumadin and the ketone in the 3-position substituent. However, the existence of many 4-hydroxycoumadin anticoagulants (for example phenprocoumon
Phenprocoumon
Phenprocoumon is an anticoagulant drug, a derivative of coumarin. It is a vitamin K antagonist that inhibits coagulation by blocking synthesis of coagulation factors II, VII, IX and X...

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

Pharmacogenomics

Warfarin activity is determined partially by genetic factors. The American Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...

 "highlights the opportunity for healthcare providers to use genetic tests to improve their initial estimate of what is a reasonable warfarin dose for individual patients". Polymorphism
Polymorphism (biology)
Polymorphism in biology occurs when two or more clearly different phenotypes exist in the same population of a species — in other words, the occurrence of more than one form or morph...

s in two genes (VKORC1 and CYP2C9) are particularly important.
  • VKORC1
    VKORC1
    Vitamin K epoxide reductase complex subunit 1 is an enzyme that in humans is encoded by the VKORC1 gene.-Further reading:...

     polymorphisms explain 30% of the dose variation between patients: particular mutations make VKORC1 less susceptible to suppression by warfarin. There are two main haplotypes that explain 25% of variation: low-dose haplotype group (A) and a high-dose haplotype group (B). VKORC1 polymorphisms explain why African Americans are on average relatively resistant to warfarin (higher proportion of group B haplotypes), while Asian American
    Asian American
    Asian Americans are Americans of Asian descent. The U.S. Census Bureau definition of Asians as "Asian” refers to a person having origins in any of the original peoples of the Far East, Southeast Asia, or the Indian subcontinent, including, for example, Cambodia, China, India, Indonesia, Japan,...

    s 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
    CYP2C9
    Cytochrome P450 2C9 is a protein that in humans is encoded by the CYP2C9 gene.- Function :CYP2C9 is an important cytochrome P450 enzyme with a major role in the oxidation of both xenobiotic and endogenous compounds. CYP2C9 makes up about 18% of the cytochrome P450 protein in liver microsomes...

    polymorphisms explain 10% of the dose variation between patients, mainly among Caucasian patients as these variants are rare in African American and most Asian populations. These CYP2C9 polymorphisms do not influence time to effective INR as opposed to VKORC1, but does shorten the time to INR >4.


Despite the promise of pharmacogenomic testing in warfarin dosing, its use in clinical practice is controversial. In August 2009 the Centers for Medicare and Medicaid Services
Centers for Medicare and Medicaid Services
The Centers for Medicare & Medicaid Services , previously known as the Health Care Financing Administration , is a federal agency within the United States Department of Health and Human Services that administers the Medicare program and works in partnership with state governments to administer...

 concluded that "the available evidence does not demonstrate that pharmacogenomic testing of CYP2C9 or VKORC1 alleles to predict warfarin responsiveness improves health outcomes in Medicare
Medicare (United States)
Medicare is a social insurance program administered by the United States government, providing health insurance coverage to people who are aged 65 and over; to those who are under 65 and are permanently physically disabled or who have a congenital physical disability; or to those who meet other...

 beneficiaries." Two randomized controlled trials have found that even though genetic testing may predict stable doses of warfarin, the testing does not increase time in therapeutic range (i.e., time in the desired level of anticoagulation). A recent study found that prospective warfarin genotyping reduced hospitalization rates for patients just starting warfarin therapy.

History

In the early 1920s, there was an outbreak of a previously unrecognised cattle
Cattle
Cattle are the most common type of large domesticated ungulates. They are a prominent modern member of the subfamily Bovinae, are the most widespread species of the genus Bos, and are most commonly classified collectively as Bos primigenius...

 disease in the northern United States and Canada. Cattle were haemorrhaging after minor procedures, and on some occasions, spontaneously. For example, 21 out of 22 cows died after dehorning, and 12 out of 25 bulls died after castration. All of these animals had bled to death.

In 1921, Frank Schofield, a Canadian veterinary pathologist, determined that the cattle were ingesting mouldy silage
Silage
Silage is fermented, high-moisture fodder that can be fed to ruminants or used as a biofuel feedstock for anaerobic digesters. It is fermented and stored in a process called ensiling or silaging, and is usually made from grass crops, including corn , sorghum or other cereals, using the entire...

 made from sweet clover that functioned as a potent anticoagulant. Only spoiled hay made from sweet clover (grown in northern states of the USA and in Canada since the turn of the century) produced the disease. Schofield separated good clover stalks and damaged clover stalks from the same hay mow, and fed each to a different rabbit. The rabbit that had ingested the good stalks remained well, but the rabbit that had ingested the damaged stalks died from a haemorrhagic illness. A duplicate experiment with a different sample of clover hay produced the same result. In 1929, North Dakota veterinarian Dr L.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 Link
Karl Paul Gerhard Link was an American biochemist best known for his discovery of the anticoagulant warfarin.-Training and early career:...

 and his lab of chemists working at the University of Wisconsin
University of Wisconsin–Madison
The University of Wisconsin–Madison is a public research university located in Madison, Wisconsin, United States. Founded in 1848, UW–Madison is the flagship campus of the University of Wisconsin System. It became a land-grant institution in 1866...

 set out to isolate and characterize the hemorrhagic agent from the spoiled hay. It took five years for Link's student Harold A. Campbell to recover 6 mg of crystalline anticoagulant. Next, Link's student Mark A. Stahmann took over the project and initiated a large-scale extraction, isolating 1.8 g of recrystallized anticoagulant in about 4 months. This was enough material for Stahmann and Charles F. Huebner to check their results against Campbell's and to thoroughly characterize the compound. Through degradation experiments they established that the anticoagulant was 3,3'-methylenebis-(4-hydroxycoumarin), which they later named dicoumarol. They confirmed their results by synthesizing dicoumarol and proving in 1940 that it was identical to the naturally occurring agent.

Dicoumarol was a product of the plant molecule coumarin
Coumarin
Coumarin is a fragrant chemical compound in the benzopyrone chemical class, found in many plants, notably in high concentration in the tonka bean , vanilla grass , sweet woodruff , mullein , sweet grass , cassia cinnamon and sweet clover...

 (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 like sweet grass; in fact, the plant's high content of coumarin is responsible for the original common name of "sweet clover", which is named for its sweet smell, not its bitter taste. They are present notably in woodruff (Galium odoratum, Rubiaceae
Rubiaceae
The Rubiaceae is a family of flowering plants, variously called the coffee family, madder family, or bedstraw family. The group contains many commonly known plants, including the economically important coffee , quinine , and gambier , and the horticulturally valuable madder , west indian jasmine ,...

), and at lower levels in licorice, lavender
Lavender
The lavenders are a genus of 39 species of flowering plants in the mint family, Lamiaceae. An Old World genus, distributed from Macaronesia across Africa, the Mediterranean, South-West Asia, Arabia, Western Iran and South-East India...

, and various other species. 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
Formaldehyde is an organic compound with the formula CH2O. It is the simplest aldehyde, hence its systematic name methanal.Formaldehyde is a colorless gas with a characteristic pungent odor. It is an important precursor to many other chemical compounds, especially for polymers...

) into dicoumarol, in order to have any anticoagulant properties. Fungal attack of the damaged and dying clover stalks explained the presence of the anticoagulant only in spoiled clover silages; dicoumarol is considered to be a fermentation product and mycotoxin
Mycotoxin
A mycotoxin is a toxic secondary metabolite produced by organisms of the fungus kingdom, commonly known as molds. The term ‘mycotoxin’ is usually reserved for the toxic chemical products produced by fungi that readily colonize crops...

.

Over the next few years, numerous similar chemicals (specifically 4-hydroxycoumarins with a large aromatic substitutent at the 3' position) were found to have the same anticoagulant properties. The first drug in the class to be widely commercialized was dicoumarol itself, patented in 1941 and later used as a pharmaceutical. Karl Link continued working on developing more potent coumarin-based anticoagulants for use as rodent poisons, resulting in warfarin in 1948. The name "warfarin" stems from the acronym WARF, for Wisconsin Alumni Research Foundation
Wisconsin Alumni Research Foundation
The Wisconsin Alumni Research Foundation is the nonprofit technology transfer office of the University of Wisconsin–Madison. It is a significant source of research support, independent of federal grants...

+ the ending -arin indicating its link with coumarin. Warfarin was first registered for use as a rodenticide in the US in 1948, and was immediately popular. Although warfarin was developed by Link, the WARF financially supported the research and was assigned the patent.

After an incident in 1951, where a US Army
United States Army
The United States Army is the main branch of the United States Armed Forces responsible for land-based military operations. It is the largest and oldest established branch of the U.S. military, and is one of seven U.S. uniformed services...

 inductee unsuccessfully attempted suicide
Suicide
Suicide is the act of intentionally causing one's own death. Suicide is often committed out of despair or attributed to some underlying mental disorder, such as depression, bipolar disorder, schizophrenia, alcoholism, or drug abuse...

 with multiple doses of warfarin in rodenticide and recovered fully after presenting to a hospital, and being treated with vitamin K (by then known as a specific antidote), studies began in the use of warfarin as a therapeutic anticoagulant. It was found to be generally superior to dicoumarol, and in 1954 was approved for medical use in humans. An early recipient of warfarin was US president Dwight Eisenhower, who was prescribed the drug after having a heart attack in 1955.

The exact mechanism of action
Mechanism of action
In pharmacology, the term mechanism of action refers to the specific biochemical interaction through which a drug substance produces its pharmacological effect...

 remained unknown until it was demonstrated, in 1978, that warfarin inhibits
Enzyme inhibitor
An enzyme inhibitor is a molecule that binds to enzymes and decreases their activity. Since blocking an enzyme's activity can kill a pathogen or correct a metabolic imbalance, many drugs are enzyme inhibitors. They are also used as herbicides and pesticides...

 the enzyme epoxide reductase
Vitamin K epoxide reductase
Vitamin K epoxide reductase is an enzyme that reduces vitamin K after it has been oxidised in the carboxylation of glutamic acid. Its C1 subunit is the target of anticoagulant warfarin.- See also :* Oxidoreductase...

 and hence interferes with vitamin K metabolism.

A theory published in 2003 posits that Lavrenty Beria, Nikita Khrushchev
Nikita Khrushchev
Nikita Sergeyevich Khrushchev led the Soviet Union during part of the Cold War. He served as First Secretary of the Communist Party of the Soviet Union from 1953 to 1964, and as Chairman of the Council of Ministers, or Premier, from 1958 to 1964...

 and others conspired to use warfarin to poison the Soviet leader Joseph Stalin
Joseph Stalin
Joseph Vissarionovich Stalin was the Premier of the Soviet Union from 6 May 1941 to 5 March 1953. He was among the Bolshevik revolutionaries who brought about the October Revolution and had held the position of first General Secretary of the Communist Party of the Soviet Union's Central Committee...

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

Use as a pesticide

To this day, the so-called "coumarins" (4-hydroxycoumarin derivatives) are used as rodenticides for controlling rat
Rat
Rats are various medium-sized, long-tailed rodents of the superfamily Muroidea. "True rats" are members of the genus Rattus, the most important of which to humans are the black rat, Rattus rattus, and the brown rat, Rattus norvegicus...

s and mice
Mouse
A mouse is a small mammal belonging to the order of rodents. The best known mouse species is the common house mouse . It is also a popular pet. In some places, certain kinds of field mice are also common. This rodent is eaten by large birds such as hawks and eagles...

 in residential, industrial, and agricultural areas. Warfarin is both odorless and tasteless, and is effective when mixed with food bait
Bait (luring substance)
Bait is any substance used to attract prey, e.g. in a mousetrap.-In Australia:Baiting in Australia refers to specific campaigns to control foxes, wild dogs and dingos by poisoning in areas where they are a problem...

, because the rodent
Rodent
Rodentia is an order of mammals also known as rodents, characterised by two continuously growing incisors in the upper and lower jaws which must be kept short by gnawing....

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
Talc is a mineral composed of hydrated magnesium silicate with the chemical formula H2Mg34 or Mg3Si4O102. In loose form, it is the widely-used substance known as talcum powder. It occurs as foliated to fibrous masses, its crystals being so rare as to be almost unknown...

 and used as a tracking powder, which accumulates on the animal's skin and fur, and is subsequently consumed during grooming. The is 50–500 mg/kg. The IDLH
IDLH
IDLH is an initialism for Immediately Dangerous to Life or Health, and is defined by the US National Institute for Occupational Safety and Health as exposure to airborne contaminants that is "likely to cause death or immediate or delayed permanent adverse health effects or prevent escape from such...

 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. Other 4-hydroxycoumarins used as rodenticides include coumatetralyl
Coumatetralyl
Coumatetralyl is an anticoagulant of the warfarin type. Symptoms of overexposure relate to failure of the blood clotting mechanism and include bleeding gums and failure of blood clotting after skin wounds. After one exposure the toxicity of coumatetralyl is relatively low, however if overexposure...

 and brodifacoum
Brodifacoum
Brodifacoum is a highly lethal vitamin K antagonist anticoagulant poison. In recent years, it has become one of the world's most widely used pesticides...

, 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
Bioaccumulation
Bioaccumulation refers to the accumulation of substances, such as pesticides, or other organic chemicals in an organism. Bioaccumulation occurs when an organism absorbs a toxic substance at a rate greater than that at which the substance is lost...

 in the liver and kidneys after ingestion.

External links

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