Warfarin sensitivity is a condition in which individuals have a low tolerance for the drug warfarin. Warfarin is an anticoagulant, which means that it thins the blood, preventing blood clots from forming. Warfarin is often prescribed to prevent blood clots in people with heart valve disease who have replacement heart valves, people with an irregular heart beat (atrial fibrillation), or those with a history of heart attack, stroke, or a prior blood clot in the deep veins of the arms or legs (deep vein thrombosis).

Many people with warfarin sensitivity take longer than normal to break down (metabolize) warfarin. The medication remains active in their body longer than usual, so they require lower doses. These individuals are classified as "slow metabolizers" of warfarin. Other people with warfarin sensitivity do not need as much drug to prevent clots because their clot-forming process is naturally slower than average and can be stopped by low warfarin doses. If people with warfarin sensitivity take the average dose (or more) of warfarin, they are at risk of an overdose, which can cause abnormal bleeding in the brain, gastrointestinal tract, or other tissues, and may lead to serious health problems or death.

Warfarin sensitivity does not appear to cause any health problems other than those associated with warfarin drug treatment.

Many genes are involved in the metabolism of warfarin and in determining the drug's effects in the body. Certain common changes (polymorphisms) in the CYP2C9 and VKORC1 genes account for most of the variation in warfarin metabolism due to genetic factors. Polymorphisms in other genes, some of which have not been identified, have a smaller effect on warfarin metabolism. The polymorphisms associated with warfarin sensitivity often differ by population and ethnic background.

The CYP2C9 gene provides instructions for making an enzyme that breaks down various substances in the body. The CYP2C9 enzyme breaks down steroids, fatty acids, and certain drugs, including warfarin. Several CYP2C9 gene polymorphisms decrease the activity of the CYP2C9 enzyme and slow the body's metabolism of warfarin. As a result, the drug remains active in the body for a longer period of time, leading to warfarin sensitivity.

The VKORC1 gene provides instructions for making a vitamin K epoxide reductase enzyme. The VKORC1 enzyme helps turn on (activate) clotting proteins in the pathway that forms blood clots. Warfarin prevents (inhibits) the action of the VKORC1 enzyme and slows the activation of clotting proteins and clot formation. Certain VKORC1 gene polymorphisms decrease the amount of functional VKORC1 enzyme available to help activate clotting proteins. Individuals develop warfarin sensitivity because a lower warfarin dose is needed to inhibit the VKORC1 enzyme, as there is less functional enzyme that needs to be suppressed.

While changes in specific genes, particularly CYP2C9 and VKORC1, affect how the body reacts to warfarin, many other factors, including sex, age, weight, diet, and other medications, also play a role in the body's interaction with this drug.

Normal Function

The CYP2C9 gene provides instructions for making an enzyme that is found in a cell structure called the endoplasmic reticulum, which is involved in protein processing and transport. The CYP2C9 enzyme breaks down (metabolizes) compounds including steroid hormones and fatty acids. The CYP2C9 enzyme also plays a major role in breaking down the drug warfarin, which thins the blood and prevents blood clots from forming. This enzyme also assists in metabolizing other drugs such as ibuprofen, which reduces inflammation.

Health Conditions Related to Genetic Changes

Warfarin sensitivity

Certain common CYP2C9 gene variations (polymorphisms) have been associated with warfarin sensitivity, a condition in which individuals require lower doses of the drug warfarin than are usually prescribed. Warfarin is an anticoagulant, which means that it thins the blood, preventing blood clots from forming.

The CYP2C9 gene polymorphisms associated with warfarin sensitivity change single protein building blocks (amino acids) in the CYP2C9 enzyme. The altered enzyme slows the breakdown (metabolism) of warfarin, allowing the drug to remain active in the body for a longer period of time. People with warfarin sensitivity take longer than usual to metabolize warfarin and may require lower doses of the drug than are usually prescribed.

The two most common CYP2C9 polymorphisms in people of European ancestry are known as CYP2C9*2 and CYP2C9*3. Both of these polymorphisms lead to a decrease in warfarin metabolism to such degrees that prescription doses are typically reduced by one-third and one-fifth, respectively. In individuals with African ancestry, the four most common CYP2C9 polymorphisms associated with warfarin sensitivity are known as CYP2C9*5, CYP2C9*6, CYP2C9*8, and CYP2C9*11. These polymorphisms lead to a decrease in warfarin metabolism that would necessitate a reduction in prescription doses by one-third to one-sixth. In other populations, the effects of these polymorphisms are less certain but are an active area of research.

In rare cases in which individuals have more than one CYP2C9 polymorphisms, the enzyme activity is severely decreased and metabolism of warfarin is very slow. If people with warfarin sensitivity take the average dose (or more) of warfarin, they are at risk of an overdose, which can cause abnormal bleeding in the brain, gastrointestinal tract, or other tissues, and may lead to serious health problems or death.

Other Names for This Gene

• CYPIIC9
• cytochrome P-450MP
• cytochrome P450 2C9
• cytochrome P450 MP-4
• cytochrome P450 MP-8
• cytochrome P450 PB-1
• cytochrome P450, family 2, subfamily C, polypeptide 9
• cytochrome P450, family 2, subfamily C, polypeptide 9 gene
• P450 MP-4
• S-mephenytoin 4-hydroxylase
• S-mephenytoin 4-hydroxylase, human
• warfarin-7-hydroxylase, human

Genomic Location

Normal Function

The F9 gene provides instructions for making a protein called coagulation factor IX. Coagulation factors are a group of related proteins that are essential for the formation of blood clots. After an injury, clots protect the body by sealing off damaged blood vessels and preventing further blood loss.

Coagulation factor IX is made in the liver. This protein circulates in the bloodstream in an inactive form until an injury that damages blood vessels occurs. In response to injury, coagulation factor IX is activated by another coagulation factor called factor XIa. The active protein (sometimes written as coagulation factor IXa) interacts with coagulation factor VIII and other molecules. These interactions set off a chain of additional chemical reactions that form a blood clot.

Health Conditions Related to Genetic Changes

Hemophilia

Mutations in the F9 gene cause a type of hemophilia called hemophilia B. More than 900 alterations in this gene have been identified. The most common mutations change single DNA building blocks (base pairs) in the gene. A small percentage of mutations delete or insert multiple base pairs or rearrange segments of DNA within the gene.

Mutations in the F9 gene lead to the production of an abnormal version of coagulation factor IX or reduce the amount of this protein. The altered or missing protein cannot participate effectively in the blood clotting process. As a result, blood clots cannot form properly in response to injury. These problems with blood clotting lead to excessive bleeding that can be difficult to control. Mutations that completely eliminate the activity of coagulation factor IX result in severe hemophilia. Mutations that reduce but do not eliminate the protein's activity usually cause mild or moderate hemophilia.

Several mutations near the beginning of the F9 gene sequence cause an unusual form of hemophilia known as hemophilia B Leyden. People with these mutations are born with very low levels of functional coagulation factor IX, but hormonal changes cause the levels of this protein to increase gradually during puberty. As a result, adults with hemophilia B Leyden rarely experience episodes of abnormal bleeding.

Warfarin sensitivity

MedlinePlus Genetics provides information about Warfarin sensitivity

Other disorders

Several rare mutations in the F9 gene cause an increased sensitivity (hypersensitivity) to a drug called warfarin. This medication is an anticoagulant, which means it is used to prevent the formation or growth of abnormal blood clots. Warfarin works by reducing the amount of active factor IX and three other coagulation proteins.

The mutations responsible for warfarin hypersensitivity each change a single base pair in the F9 gene. These mutations do not cause hemophilia B, and people with these genetic changes only have bleeding problems if they are treated with warfarin. Warfarin reduces the amount of coagulation factor IX to very low levels in these individuals, which prevents the blood from clotting normally and can lead to recurrent, severe bleeding problems. To avoid these complications, people with warfarin hypersensitivity can be treated with other anticoagulant medications.

Other Names for This Gene

• Christmas factor
• coagulation factor IX (plasma thromboplastic component, Christmas disease, hemophilia B)
• FA9_HUMAN
• Factor 9
• FIX
• HEMB
• Plasma thromboplastin component
• PTC

Genomic Location

Normal Function

The VKORC1 gene provides instructions for making a vitamin K epoxide reductase enzyme. The VKORC1 enzyme is made primarily in the liver. It spans the membrane of a cellular structure called the endoplasmic reticulum, which is involved with protein processing and transport. The VKORC1 enzyme helps turn on (activate) clotting proteins in the pathway that forms blood clots. Specifically, the VKORC1 enzyme converts one form of vitamin K into a different form of vitamin K that assists in activating clotting proteins.

Health Conditions Related to Genetic Changes

Warfarin resistance

Multiple variations (polymorphisms) in the VKORC1 gene have been associated with warfarin resistance, a condition in which individuals require higher doses of the drug warfarin than are usually prescribed. Warfarin is an anticoagulant, which means that it thins the blood and prevents blood clots from forming. It acts by attaching (binding) to the VKORC1 enzyme and blocking (inhibiting) the activation of the clotting proteins.

The most common VKORC1 gene polymorphism in people with warfarin resistance changes a single protein building block (amino acid) in the VKORC1 enzyme. Specifically, the amino acid aspartic acid is replaced with the amino acid tyrosine at position 36 (written as Asp36Tyr or D36Y). This polymorphism leads to the formation of a VKORC1 enzyme with a decreased ability to bind to warfarin. As a result, a higher dose of warfarin is needed to inhibit the VKORC1 enzyme and stop the clotting process. If people with warfarin resistance require anticoagulant treatment and take the average warfarin dose (or less), they will remain at risk of developing a potentially harmful blood clot.

Warfarin sensitivity

Multiple polymorphisms in the VKORC1 gene have been associated with warfarin sensitivity, a condition in which individuals require lower doses of the drug warfarin than are usually prescribed.

The most common VKORC1 gene polymorphism in people with warfarin sensitivity, known as VKORC1A, changes a single DNA building block (nucleotide) in an area near the VKORC1 gene, which controls the production of the enzyme. Specifically, the nucleotide guanine is replaced with the nucleotide adenine (written as -1639G>A). The VKORC1A polymorphism is particularly common in individuals of Asian and European descent. This change reduces the amount of VKORC1 enzyme that is available to convert vitamin K into a form that can activate clotting proteins. Because there is a decreased amount of VKORC1 enzyme, a lower dose of warfarin is needed to inhibit the actions of the enzyme, resulting in warfarin sensitivity. If people with warfarin sensitivity take the average warfarin dose (or more), they are at risk of an overdose, which can cause abnormal bleeding in the brain, gastrointestinal tract, or other tissues, and may lead to serious health problems or death.

Other Names for This Gene

• FLJ00289
• vitamin K 1 2,3-epoxide reductase subunit 1
• vitamin K epoxide reductase complex, subunit 1
• VKOR

Genomic Location

The polymorphisms associated with this condition are inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to result in warfarin sensitivity. However, different polymorphisms affect the activity of warfarin to varying degrees. Additionally, people who have more than one polymorphism in a gene or polymorphisms in multiple genes associated with warfarin sensitivity have a lower tolerance for the drug's effect or take even longer to clear the drug from their body.

The prevalence of warfarin sensitivity is unknown. However, it appears to be more common in people who are older and those with lower body weights.

Of the approximately 2 million people in the U.S. who are prescribed warfarin annually, 35,000 to 45,000 individuals go to hospital emergency rooms with warfarin-related adverse drug events. While it is unclear how many of these events are due to warfarin sensitivity, the most common sign is excessive internal bleeding, which often occurs when individuals with warfarin sensitivity are given too much of the medication.