Clopidogrel resistance

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

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.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

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.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

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.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

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.

Which doctor should you see?

The suggested department for discussing Clopidogrel resistance is Clinical Genetics, with a clinical geneticist as the relevant type of clinician. Paediatrician (children) or physician (adults), with clinical geneticist referral.

This is an editorial referral starting point. The appropriate clinic depends on the person’s age, symptoms, previous diagnosis and local services. The first clinician can decide whether another specialty or a team is needed; a department label does not confirm the diagnosis.

How to prepare for an assessment

Bring a short timeline of the main symptoms: when they first appeared, whether they are constant or episodic, what seems to change them, and how they affect daily activities. Include previous reports, discharge summaries, current medicines and supplements, allergies, and any relevant family history. A dated record is more useful than trying to match every feature in an online article.

Ask the clinician what is already established and what remains uncertain. If a test is suggested, ask what question it answers, what its limitations are and how the result would change the next step. The information here is not an instruction to arrange every possible test. In children, bring growth, developmental and school information if it is relevant to the concern.

• Does the exact genetic or chromosome finding explain the observed features?
• Would a genetic counsellor help the family understand the result?
• Which organ-specific assessments are appropriate for this particular diagnosis?

Treatment discussions and follow-up

Where the source describes treatments, these are an overview of possible care, not a prescription for an individual. Ask which option applies to the confirmed diagnosis, what benefit is expected, what adverse effects to watch for and how progress will be assessed. Availability, approvals and local practice can differ from the country described in the source.

Before leaving the appointment, clarify the next review date, who will communicate results, and whom to contact if the situation changes. Discuss difficulties with sleep, work, school, mobility, eating or emotional wellbeing when these are relevant. Practical support may require coordination between the treating clinician and other services.

When to seek emergency help

Severe breathing difficulty, collapse, new stroke-like symptoms, a seizure that is prolonged or repeated without recovery, uncontrolled major bleeding, or an immediate risk of self-harm require emergency help. In India, call 112 or reach the nearest emergency department. This is a general, non-exhaustive warning list; it is not a condition-specific triage tool.