Clopidogrel resistance is a condition in which the drug clopidogrel is less effective than normal in people who are treated with it. Clopidogrel (also known as Plavix) is an antiplatelet drug, which means that it prevents blood cells called platelets from sticking together (aggregating) and forming blood clots. This drug is typically given to prevent blood clot formation in individuals with a history of stroke; heart attack; a blood clot in the deep veins of the arms or legs (deep vein thrombosis); or plaque buildup (atherosclerosis) in the blood vessels leading from the heart, which are opened by placement of a small thin tube (stent).

People with clopidogrel resistance who receive clopidogrel are at risk of serious, sometimes fatal, complications. These individuals may have another heart attack or stroke caused by abnormal blood clot formation; those with stents can develop blood clots (thromboses) within the stents, impeding blood flow.

People with clopidogrel resistance can be divided into two categories: intermediate metabolizers and poor metabolizers. Intermediate metabolizers are able to process some clopidogrel, so they receive partial benefit from the treatment but are not protected from developing a harmful blood clot. Poor metabolizers process little or no clopidogrel, so they receive very limited benefit from the treatment and are at risk of forming a harmful blood clot.

Clopidogrel resistance does not appear to cause any health problems other than those associated with clopidogrel drug treatment.

Clopidogrel resistance is a common condition, and its incidence can vary depending on ancestry. About half of individuals with Asian ancestry have clopidogrel resistance, with 10 percent of these individuals classified as poor metabolizers. Among people from western countries, nearly 30 percent are estimated to have clopidogrel resistance, with about 3 percent classified as poor metabolizers.

Many genes are involved in converting clopidogrel to its active form and in determining the drug's effects in the body. The CYP2C19 gene is particularly important for the activation of clopidogrel, and certain common variations (polymorphisms) in this gene have been associated with clopidogrel resistance. CYP2C19 gene polymorphisms account for most of the variation in clopidogrel activation due to genetic factors. Polymorphisms in other genes likely have smaller effects on clopidogrel activation.

The CYP2C19 gene provides instructions for making an enzyme that is found primarily in liver cells. It is active in a cell structure called the endoplasmic reticulum, which is involved in protein processing and transport. The CYP2C19 enzyme plays a role in the processing of many drugs, including clopidogrel. The CYP2C19 enzyme helps to convert clopidogrel to its active form, which is necessary for the drug to function in the body. In its active form, clopidogrel prevents (inhibits) the function of a receptor protein known as P2RY12 that is found on the surface of platelets. During clot formation, the P2RY12 receptor protein helps platelets cluster together to form a clot to seal off damaged blood vessels and prevent blood loss. By inhibiting the function of the P2RY12 receptor, clopidogrel decreases the formation of blood clots, including clots that can cause heart attack, stroke, and deep vein thrombosis.

The two most common CYP2C19 gene polymorphisms associated with clopidogrel resistance (known as CYP2C19*2 and CYP2C19*3) result in the production of a nonfunctional CYP2C19 enzyme that cannot convert clopidogrel to its active form. Without active clopidogrel to interfere, the P2RY12 receptor continues to promote platelet aggregation and blood clot formation, which can lead to heart attacks, strokes, and thromboses in individuals with a history of these conditions.

In addition to changes in specific genes, many other factors, including sex, age, weight, diet, and other medications, play a role in how the body reacts to clopidogrel.

Normal Function

The CYP2C19 gene is a member of the cytochrome P450 gene family. Enzymes produced from cytochrome P450 genes are involved in the formation and breakdown (metabolism) of various molecules and chemicals within cells. The CYP2C19 gene provides instructions for making an enzyme that is found primarily in liver cells in a cell structure called the endoplasmic reticulum, which is involved in protein processing and transport.

The CYP2C19 enzyme plays a role in the processing or metabolizing of at least 10 percent of commonly prescribed drugs, including a drug called clopidogrel (also known as Plavix). Clopidogrel is an antiplatelet drug, which means that it prevents blood cells called platelets from sticking together (aggregating) and forming blood clots. The CYP2C19 enzyme converts clopidogrel to its active form, which is necessary for the drug to function in the body. The active drug then stops (inhibits) a receptor protein known as P2RY12 that is found on the surface of platelets. During clot formation, the P2RY12 receptor protein helps platelets cluster together to form a clot in order to seal off damaged blood vessels and prevent blood loss.

Health Conditions Related to Genetic Changes

Clopidogrel resistance

Multiple variations (polymorphisms) in the CYP2C19 gene have been associated with clopidogrel resistance, a condition in which the drug clopidogrel is less effective than normal in people who are treated with it. The polymorphisms that are associated with clopidogrel resistance decrease the enzyme's ability to convert the drug to its active form.

The normal version of the gene, written as CYP2C19*1, provides instructions for producing a normally functioning CYP2C19 enzyme. If a person has two copies of the CYP2C19*1 version of the gene in each cell, they are able to convert clopidogrel normally. The two most common CYP2C19 gene polymorphisms associated with clopidogrel resistance (known as CYP2C19*2 and CYP2C19*3) result in the production of a nonfunctional CYP2C19 enzyme that is unable to activate clopidogrel.

Individuals with clopidogrel resistance can be classified into two groups: intermediate metabolizers or poor metabolizers. People who have one copy of the CYP2C19*1 version of the gene and one copy of either the CYP2C19*2 or CYP2C19*3 version of the gene have a reduced ability to convert clopidogrel to its active form and are classified as intermediate metabolizers. People who have the CYP2C19*2 or CYP2C19*3 versions of the gene for both copies of the gene can convert very little or none of the drug and are classified as poor metabolizers. Because conversion of clopidogrel to its active form is impaired in people with clopidogrel resistance, the drug is unable to inhibit P2RY12 receptor function. Without active clopidogrel to interfere, the P2RY12 receptor continues to promote platelet aggregation and blood clot formation, which can lead to heart attacks, strokes, and thromboses in individuals with a history of these conditions.

It is important to note that not all individuals with CYP2C19 gene mutations have clopidogrel resistance. These individuals who are at increased risk for developing clopidogrel resistance may or may not have a bad reaction when treated with the drug. In addition to changes in specific genes, many other factors, including sex, age, weight, diet, and other medications, play a role in how the body reacts to clopidogrel.

Other disorders

Polymorphisms in the CYP2C19 gene that are associated with clopidogrel resistance (described above) can also affect the processing of other drugs. Because the CYP2C19 enzyme is involved in the metabolism of many drugs, changes to the enzyme can have wide-ranging effects. Other drugs that are affected by CYP2C19 gene polymorphisms include proton pump inhibitors, used to treat stomach ulcers and other conditions; antidepressants, used to treat psychiatric disorders; anticonvulsants, used to treat seizure disorders; hypnotics and sedatives, used as sleep aids; antimalarial drugs, used to prevent malarial infections; and antiretroviral drugs, used to prevent viruses from replicating.

Most often, changes in the CYP2C19 gene lead to impaired metabolism of these drugs, which reduces their effectiveness. One change in the CYP2C19 gene (known as CYP2C19*17) increases the enzyme's ability to metabolize drugs. Individuals with two copies of the CYP2C19*17 polymorphism are typically classified as ultra-rapid metabolizers.

Other Names for This Gene

• (R)-limonene 6-monooxygenase
• (S)-limonene 6-monooxygenase
• (S)-limonene 7-monooxygenase
• CPCJ
• CYP2C
• CYPIIC17
• CYPIIC19
• cytochrome P-450 II C
• cytochrome P450 2C19 precursor
• cytochrome P450, subfamily IIC (mephenytoin 4-hydroxylase), polypeptide 19
• cytochrome P450-11A
• cytochrome P450-254C
• flavoprotein-linked monooxygenase
• mephenytoin 4'-hydroxylase
• mephenytoin 4-hydroxylase
• microsomal monooxygenase
• P450C2C
• P450IIC19
• S-mephenytoin 4-hydroxylase
• xenobiotic monooxygenase

Genomic Location

Clopidogrel resistance is inherited in an autosomal codominant pattern. Codominance means that two different versions of the gene are active (expressed), and both versions influence the genetic trait. Some people with clopidogrel resistance have a reduced ability to convert the drug to its active form because of a polymorphism in one copy of the CYP2C19 gene that results in decreased enzyme activity. These individuals are described as intermediate metabolizers. Other individuals with clopidogrel resistance convert very little or none of the drug to its active form because of polymorphisms in both copies of the CYP2C19 gene, which results in a lack of enzyme activity. These individuals are described as poor metabolizers.

It is important to note that not all individuals with CYP2C19 gene mutations have clopidogrel resistance. These individuals who are at increased risk for developing clopidogrel resistance may or may not have a bad reaction when treated with the drug.