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Warfarin Sensitivity

Table of Contents

Warfarin Sensitivity

Coumadin Sensitivity; Warfarin Response

Warfarin sensitivity is a condition that is characterized by a reduced tolerance for a "blood-thinning" medication called warfarin. People with a warfarin sensitivity are more likely to experience an overdose or other serious side effects from the medication. Explore symptoms and genetics of this condition.

Warfarintablets5-3-1

Image by Gonegonegone at English Wikipedia/Wikimedia

About

Coumadin (Warfarin) and Vitamin K

Document by National Institutes of Health Clinical Center

Coumadin (Warfarin) and Vitamin K

Document by National Institutes of Health Clinical Center

What Is Warfarin Sensitivity?

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.

Source: MedlinePlus Genetics

Additional Materials (4)

Warfarin Sodium 2 mg; Taro Pharmaceuticals U.S.A., Inc.

An anticoagulant that acts by inhibiting the synthesis of vitamin K-dependent coagulation factors. Warfarin is indicated for the prophylaxis and/or treatment of venous thrombosis and its extension, pulmonary embolism, and atrial fibrillation with embolization. It is also used as an adjunct in the prophylaxis of systemic embolism after myocardial infarction. Warfarin is also used as a rodenticide.

Image by Taro Pharmaceuticals U.S.A., Inc.

Bottles of warfarin

In 2007, the FDA modified warfarin's label to indicate that genetic makeup may affect patient response to the drug. The widely used blood thinner is sold under the brand name Coumadin®. Scientists involved in the NIH Pharmacogenetics Research Network are investigating whether genetic information can be used to improve optimal dosage prediction for patients.

Image by Alisa Machalek, NIGMS/NIH

Blood Thinner Pills: Your Guide to Using Them Safely

Blood Thinner Pills: Your Guide to Using Them Safely is an easy-to-read booklet that educates people about blood thinners. It offers basic information about the medication, including reasons why a clinician might prescribe it. It also includes tips on diet, medicines and foods to avoid, important precautions for some daily activities, and when to seek help.

Document by www.ahrq.gov

Chromosomes

A research team, led by Giulio Genovese, Ph.D., of the Broad Institute at MIT and Harvard in Boston, focused on precursors for blood cancers like leukemia, lymphoma and myeloma. Though innovative drug therapies and increasing access to treatments have dramatically improved blood cancer survival, blood cancer remains one of the most common forms of cancer in the United States and worldwide. In 2014, blood cancer accounted for approximately 9.4 percent of the estimated 1,665,540 new cancer cases diagnosed across the country.

Image by Ernesto del Aguila III, NHGRI

Warfarin Sodium 2 mg; Taro Pharmaceuticals U.S.A., Inc.

Taro Pharmaceuticals U.S.A., Inc.

Bottles of warfarin

Alisa Machalek, NIGMS/NIH

Blood Thinner Pills: Your Guide to Using Them Safely

www.ahrq.gov

Chromosomes

Ernesto del Aguila III, NHGRI

Warfarin

Warfarin

Also called: Coumadin®, Jantoven®, Warfarin Sodium

Warfarin (Coumadin, Jantoven) is a prescription medicine used to prevent blood from clotting. It belongs to the family of drugs called anticoagulants (blood thinners).

Warfarin

Also called: Coumadin®, Jantoven®, Warfarin Sodium

Warfarin (Coumadin, Jantoven) is a prescription medicine used to prevent blood from clotting. It belongs to the family of drugs called anticoagulants (blood thinners).

- Take your warfarin exactly as prescribed to lower the chance of blood clots forming in your body.
- Warfarin is very important for your health, but it can cause serious and life-threatening bleeding problems. To benefit from warfarin and also lower your chance for bleeding problems, you must:
  Get your regular blood test to check for your response to warfarin. This blood test is called a PT/INR test. The PT/INR test checks to see how fast your blood clots. Your healthcare provider will decide what PT/INR numbers are best for you. Your dose of warfarin will be adjusted to keep your PT/INR in a target range for you.
  Call your healthcare provider right away if you get any of the following signs or symptoms of bleeding problems:
  pain, swelling or discomfort
  headaches, dizziness, or weakness
  unusual bruising (bruises that develop without known cause or grow in size)
  nose bleeds
  bleeding gums
  bleeding from cuts takes a long time to stop
  menstrual bleeding or vaginal bleeding that is heavier than normal
  pink or brown urine
  red or black stools
  coughing up blood
  vomiting blood or material that looks like coffee grounds
- Many other medicines, including prescription and non-prescription medicines, vitamins and herbal supplements can interact with warfarin and:
  affect the dose you need, or
  increase warfarin side effects.
  Tell your healthcare provider about all the medicines, vitamins and herbal supplements you take. Do not stop medicines or take anything new unless you have talked to your healthcare provider. Keep a list of your medicines with you at all times to show your healthcare provider and pharmacist.
- Do not take other medicines that contain warfarin. Warfarin is the active ingredient in warfarin.
- Some foods can interact with warfarin and affect your treatment and dose.
  Eat a normal, balanced diet. Talk to your doctor before you make any diet changes. Do not eat large amounts of leafy green vegetables. Leafy green vegetables contain Vitamin K. Certain vegetable oils also contain large amounts of Vitamin K. Too much Vitamin K can lower the effect of warfarin.
  Avoid drinking cranberry juice or eating cranberry products.
  Avoid drinking alcohol.
- Always tell all of your healthcare providers that you take warfarin.
- Wear or carry information that you take warfarin.
Do not take warfarin if:
- your chance of having bleeding problems is higher than the possible benefit of treatment. Your healthcare provider will decide if warfarin is right for you. Talk to your healthcare provider about all of your health conditions.
- you are pregnant or plan to become pregnant. Warfarin can cause death or birth defects to an unborn baby. Use effective birth control if you can get pregnant.
- you are allergic to warfarin or to anything else in warfarin.
What should I tell my healthcare provider before starting warfarin?
Tell your healthcare provider about all of your health conditions, including if you:
- have bleeding problems
- fall often
- have liver or kidney problems
- have high blood pressure
- have a heart problem called congestive heart failure
- have diabetes
- drink alcohol or have problems with alcohol abuse. Alcohol can affect your warfarin dose and should be avoided.
- are pregnant or planning to become pregnant. See "Who should not take warfarin?"
- are breastfeeding. Warfarin Sodium Tablets may increase bleeding in your baby. Talk to your doctor about the best way to feed your baby. If you choose to breastfeed while taking warfarin, both you and your baby should be carefully monitored for bleeding problems.
Tell your healthcare provider about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements.
See "What is the most important information I should know about warfarin?"
- Take warfarin exactly as prescribed.Your healthcare provider will adjust your dose from time to time depending on your response to warfarin.
- You must have regular blood tests and visits with your healthcare provider to monitor your condition.
- Take warfarin at the same time every day.You can take warfarin either with food or on an empty stomach.
- If you miss a dose of warfarin, call your healthcare provider. Take the dose as soon as possible on the same day. Do not take a double dose of warfarin the next day to make up for a missed dose.
- Call your healthcare provider right away if you take too many warfarin.
- Call your healthcare provider if you are sick with diarrhea, an infection, or have a fever.
- Tell your healthcare provider about any planned surgeries, medical or dental procedures.Your warfarin may have to be stopped for a short time or you may need your dose adjusted.
- Call your healthcare provider right away if you fall or injure yourself, especially if you hit your head. Your healthcare provider may need to check you.
- Do not start, stop, or change any medicine without talking with your healthcare provider.
- Do not make changes in your diet, such as eating large amounts of green, leafy vegetables.
- Do not change your weight by dieting, without first checking with your healthcare provider.
- Avoid drinking alcohol.
- Do not do any activity or sport that may cause a serious injury.
- warfarin is very important for your health, but it can cause serious and life-threatening bleeding problems. See "What is the most important information I should know about warfarin?"
- Serious side effects of warfarin also include:
  death of skin tissue (skin necrosis or gangrene). This can happen soon after starting warfarin. It happens because blood clots form and block blood flow to an area of your body. Call your healthcare provider right away if you have pain, color, or temperature change to any area of your body. You may need medical care right away to prevent death or loss (amputation) of your affected body part.
  "purple toes syndrome". Call your healthcare provider right away if you have pain in your toes and they look purple in color or dark in color.
Other side effects with warfarin include allergic reactions, liver problems, low blood pressure, swelling, low red blood cells, paleness, fever, and rash. Call your healthcare provider if you have any side effect that bothers you.
These are not all of the side effects of warfarin. For more information, ask your healthcare provider or pharmacist.
- Store warfarin at room temperature between 68° and 77°F. Protect from light.
Keep warfarin and all medicines out of the reach of children.
1. DailyMed - WARFARIN SODIUM tablet [accessed on Nov 02, 2023]
2. Warfarin. MedlinePlus/AHFS® Drug Information. [accessed on Oct 29, 2018]

These FAQs provide a summary of the most important information about Warfarin. The drug should not be used for a condition other than that for which it is prescribed. Do not give it to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information or have any questions, talk to your healthcare provider.

Additional Materials (50)

How does warfarin work?

Video by British Heart Foundation/YouTube

Understanding Coumadin (Warfarin)

Video by Beth Israel Deaconess Medical Center (BIDMC)/YouTube

Living With Warfarin

Video by Johns Hopkins Medicine/YouTube

Coumadin (Warfarin) and Vitamin K

Document by National Institutes of Health Clinical Center

Bottles of warfarin

In 2007, the FDA modified warfarin's label to indicate that genetic makeup may affect patient response to the drug. The widely used blood thinner is sold under the brand name Coumadin®. Scientists involved in the NIH Pharmacogenetics Research Network are investigating whether genetic information can be used to improve optimal dosage prediction for patients.

Image by Alisa Machalek, NIGMS/NIH

Waran (Warfarin)

Image by Bengt B

Nature | Warfarin medical animation

Video by JumpKick/YouTube

Warfarin Patient Education

Video by pharmacydave95/YouTube

Spotlight on Testing: Warfarin Pharmacogenetics

Video by ARUP Laboratories/YouTube

Warfarin Pharmacogenetics

Video by AACC/YouTube

Haemostasis 3 - Anticoagulants & Thrombolytics

Video by Handwritten Tutorials/YouTube

Blood Thinners - What You Need To Know

Video by Rehealthify/YouTube

Warfarin - Tales from the Genome

Video by Udacity/YouTube

Prescription medicine before and during pregnancy

Video by March of Dimes/YouTube

Pulmonary Embolism PART II

Video by Armando Hasudungan/YouTube

Warfarin Sodium 1 MG Oral Tablet

Image by National Library of Medicine

Warfarin Sodium 2.5 MG Oral Tablet

Image by National Library of Medicine

Warfarin Sodium 3 MG Oral Tablet

Image by National Library of Medicine

Warfarin Sodium 4 MG Oral Tablet

Image by National Library of Medicine

Warfarin Sodium 7.5 MG Oral Tablet

Image by National Library of Medicine

Warfarin Sodium 10 MG Oral Tablet

Image by National Library of Medicine

Warfarin Sodium 2 MG Oral Tablet

Image by National Library of Medicine

Warfarin Sodium 2.5 MG Oral Tablet

Image by National Library of Medicine

Warfarin Sodium 3 MG Oral Tablet

Image by National Library of Medicine

Warfarin Sodium 5 MG Oral Tablet

Image by National Library of Medicine

Warfarin Sodium 6 MG Oral Tablet

Image by National Library of Medicine

Warfarin Sodium 10 MG Oral Tablet

Image by National Library of Medicine

Warfarin Sodium 2 MG Oral Tablet

Image by National Library of Medicine

Warfarin Sodium 1 MG Oral Tablet

Image by National Library of Medicine

Warfarin Sodium 4 MG Oral Tablet

Image by National Library of Medicine

Warfarin Sodium 10 MG Oral Tablet

Image by National Library of Medicine

Warfarin Sodium 2.5 MG Oral Tablet

Image by National Library of Medicine

Warfarin Sodium 3 MG Oral Tablet

Image by National Library of Medicine

Warfarin Sodium 4 MG Oral Tablet

Image by National Library of Medicine

Warfarin Sodium 7.5 MG Oral Tablet

Image by National Library of Medicine

Warfarin Sodium 6 MG Oral Tablet

Image by National Library of Medicine

Warfarin Sodium 5 MG Oral Tablet

Image by National Library of Medicine

Warfarin Sodium 5 MG Oral Tablet

Image by National Library of Medicine

Warfarin Sodium 6 MG Oral Tablet

Image by National Library of Medicine

Warfarin Sodium 2 MG Oral Tablet

Image by National Library of Medicine

Warfarin Sodium 2.5 MG Oral Tablet

Image by National Library of Medicine

Warfarin Sodium 5 MG Oral Tablet

Image by National Library of Medicine

Warfarin Sodium 10 MG Oral Tablet

Image by National Library of Medicine

Warfarin Sodium 7.5 MG Oral Tablet [Coumadin]

Image by National Library of Medicine

Warfarin Sodium 5 MG Oral Tablet [Coumadin]

Image by National Library of Medicine

Warfarin Sodium 4 MG Oral Tablet [Coumadin]

Image by National Library of Medicine

Warfarin Sodium 3 MG Oral Tablet [Coumadin]

Image by National Library of Medicine

Warfarin Sodium 2.5 MG Oral Tablet [Coumadin]

Image by National Library of Medicine

Warfarin Sodium 2 MG Oral Tablet [Coumadin]

Image by National Library of Medicine

Warfarin Sodium 1 MG Oral Tablet [Coumadin]

Image by National Library of Medicine

1:40

How does warfarin work?

British Heart Foundation/YouTube

2:45

Understanding Coumadin (Warfarin)

Beth Israel Deaconess Medical Center (BIDMC)/YouTube

16:23

Living With Warfarin

Johns Hopkins Medicine/YouTube

Coumadin (Warfarin) and Vitamin K

National Institutes of Health Clinical Center

Bottles of warfarin

Alisa Machalek, NIGMS/NIH

Waran (Warfarin)

Bengt B

5:46

Nature | Warfarin medical animation

JumpKick/YouTube

6:42

Warfarin Patient Education

pharmacydave95/YouTube

3:39

Spotlight on Testing: Warfarin Pharmacogenetics

ARUP Laboratories/YouTube

10:15

Warfarin Pharmacogenetics

AACC/YouTube

5:09

Haemostasis 3 - Anticoagulants & Thrombolytics

Handwritten Tutorials/YouTube

1:40

Blood Thinners - What You Need To Know

Rehealthify/YouTube

2:02

Warfarin - Tales from the Genome

Udacity/YouTube

3:16

Prescription medicine before and during pregnancy

March of Dimes/YouTube

13:29

Pulmonary Embolism PART II

Armando Hasudungan/YouTube

Warfarin Sodium 1 MG Oral Tablet

National Library of Medicine

Warfarin Sodium 2.5 MG Oral Tablet

National Library of Medicine

Warfarin Sodium 3 MG Oral Tablet

National Library of Medicine

Warfarin Sodium 4 MG Oral Tablet

National Library of Medicine

Warfarin Sodium 7.5 MG Oral Tablet

National Library of Medicine

Warfarin Sodium 10 MG Oral Tablet

National Library of Medicine

Warfarin Sodium 2 MG Oral Tablet

National Library of Medicine

Warfarin Sodium 2.5 MG Oral Tablet

National Library of Medicine

Warfarin Sodium 3 MG Oral Tablet

National Library of Medicine

Warfarin Sodium 5 MG Oral Tablet

National Library of Medicine

Warfarin Sodium 6 MG Oral Tablet

National Library of Medicine

Warfarin Sodium 10 MG Oral Tablet

National Library of Medicine

Warfarin Sodium 2 MG Oral Tablet

National Library of Medicine

Warfarin Sodium 1 MG Oral Tablet

National Library of Medicine

Warfarin Sodium 4 MG Oral Tablet

National Library of Medicine

Warfarin Sodium 10 MG Oral Tablet

National Library of Medicine

Warfarin Sodium 2.5 MG Oral Tablet

National Library of Medicine

Warfarin Sodium 3 MG Oral Tablet

National Library of Medicine

Warfarin Sodium 4 MG Oral Tablet

National Library of Medicine

Warfarin Sodium 7.5 MG Oral Tablet

National Library of Medicine

Warfarin Sodium 6 MG Oral Tablet

National Library of Medicine

Warfarin Sodium 5 MG Oral Tablet

National Library of Medicine

Warfarin Sodium 5 MG Oral Tablet

National Library of Medicine

Warfarin Sodium 6 MG Oral Tablet

National Library of Medicine

Warfarin Sodium 2 MG Oral Tablet

National Library of Medicine

Warfarin Sodium 2.5 MG Oral Tablet

National Library of Medicine

Warfarin Sodium 5 MG Oral Tablet

National Library of Medicine

Warfarin Sodium 10 MG Oral Tablet

National Library of Medicine

Warfarin Sodium 7.5 MG Oral Tablet [Coumadin]

National Library of Medicine

Warfarin Sodium 5 MG Oral Tablet [Coumadin]

National Library of Medicine

Warfarin Sodium 4 MG Oral Tablet [Coumadin]

National Library of Medicine

Warfarin Sodium 3 MG Oral Tablet [Coumadin]

National Library of Medicine

Warfarin Sodium 2.5 MG Oral Tablet [Coumadin]

National Library of Medicine

Warfarin Sodium 2 MG Oral Tablet [Coumadin]

National Library of Medicine

Warfarin Sodium 1 MG Oral Tablet [Coumadin]

National Library of Medicine

Causes

CT scan of the chest showing hemothorax caused by warfarin use

Image by Cevik Y

CT scan of the chest showing hemothorax caused by warfarin use

CT scan of the chest showing a hemothorax caused by warfarin use.

Image by Cevik Y

What Causes Warfarin Sensitivity?

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.

Source: MedlinePlus Genetics

Additional Materials (2)

CT scan showing hemothorax caused by warfarin use

CT scan showing hemothorax caused by warfarin use

Image by Cevik Y/Wikimedia

Cartoon Model of CYP2C9, after PDB: 1R9O.

Cartoon Model of CYP2C9, after PDB: 1R9O.

Image by Nothingserious (talk)/Wikimedia

CT scan showing hemothorax caused by warfarin use

Cevik Y/Wikimedia

Cartoon Model of CYP2C9, after PDB: 1R9O.

Nothingserious (talk)/Wikimedia

CYP2C9 Gene

Ideogram of human chromosome 10

Image by Office of Biological and Environmental Research of the U.S. Department of Energy Office of Science, the Biological and Environmental Research Information System, Oak Ridge National Laboratory.

Ideogram of human chromosome 10

Selected genes, traits, and disorders associated with the chromosome listed; (blue and violet) regions reflecting the unique patterns of light and dark bands seen on human chromosomes stained to allow viewing through a light microscope; (red) the centromere, or constricted portion, of each chromosome; (yellow) chromosomal regions that vary in staining intensity and sometimes are called hererochromatin (meaning “different color”); (lines between yellow) variable regions, called stalks, that connect a very small chromosome arm (a “satellite”) to the chromosome.

Image by Office of Biological and Environmental Research of the U.S. Department of Energy Office of Science, the Biological and Environmental Research Information System, Oak Ridge National Laboratory.

CYP2C9 Gene: Cytochrome P450 Family 2 Subfamily C Member 9

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

The CYP2C9 gene is found on chromosome 10.

Source: MedlinePlus Genetics

F9 Gene

Ideogram of human chromosome X

Image by Office of Biological and Environmental Research of the U.S. Department of Energy Office of Science, the Biological and Environmental Research Information System, Oak Ridge National Laboratory.

Ideogram of human chromosome X

Selected genes, traits, and disorders associated with the chromosome listed; (blue and violet) regions reflecting the unique patterns of light and dark bands seen on human chromosomes stained to allow viewing through a light microscope; (red) the centromere, or constricted portion, of each chromosome; (yellow) chromosomal regions that vary in staining intensity and sometimes are called hererochromatin (meaning “different color”); (lines between yellow) variable regions, called stalks, that connect a very small chromosome arm (a “satellite”) to the chromosome.

Image by Office of Biological and Environmental Research of the U.S. Department of Energy Office of Science, the Biological and Environmental Research Information System, Oak Ridge National Laboratory.

F9 Gene: Coagulation Factor IX

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

The F9 gene is found on the X chromosome.

Source: MedlinePlus Genetics

VKORC1 Gene

Ideogram of human chromosome 16

Image by Office of Biological and Environmental Research of the U.S. Department of Energy Office of Science, the Biological and Environmental Research Information System, Oak Ridge National Laboratory.

Ideogram of human chromosome 16

Selected genes, traits, and disorders associated with the chromosome listed; (blue and violet) regions reflecting the unique patterns of light and dark bands seen on human chromosomes stained to allow viewing through a light microscope; (red) the centromere, or constricted portion, of each chromosome; (yellow) chromosomal regions that vary in staining intensity and sometimes are called hererochromatin (meaning “different color”); (lines between yellow) variable regions, called stalks, that connect a very small chromosome arm (a “satellite”) to the chromosome.

Image by Office of Biological and Environmental Research of the U.S. Department of Energy Office of Science, the Biological and Environmental Research Information System, Oak Ridge National Laboratory.

VKORC1 Gene: Vitamin K Epoxide Reductase Complex Subunit 1

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 VKORC1 gene is found on chromosome 16.

Source: MedlinePlus Genetics

Inheritance

Autosomal Dominant and Baby

Image by TheVisualMD / Domaina

Autosomal Dominant and Baby

Autosomal dominant : an autosomal dominant pattern.

Image by TheVisualMD / Domaina

How Is Warfarin Sensitivity Inherited?

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.

Source: MedlinePlus Genetics

Testing

Warfarin Sensitivity, CYP2C9 and VKORC1 Test

Also called: CYP2C9 and VKORC1 Genotyping, Pharmacogenetic testing of CYP2C9 and VKORC1 alleles for warfarin

The CYP2C9 and VKORC1 genotypes are the most important known genetic determinants of warfarin dosing. The test is meant to identify individuals with genetic variations that affect metabolism and/or sensitivity to warfarin.

Warfarin Sensitivity, CYP2C9 and VKORC1 Test

Also called: CYP2C9 and VKORC1 Genotyping, Pharmacogenetic testing of CYP2C9 and VKORC1 alleles for warfarin

The CYP2C9 and VKORC1 genotypes are the most important known genetic determinants of warfarin dosing. The test is meant to identify individuals with genetic variations that affect metabolism and/or sensitivity to warfarin.

{"label":"CYP2C9 Genotype Reference Range","scale":"lin","step":0.25,"hideunits":true,"items":[{"flag":"normal","label":{"short":"C12","long":"CYP2C9*1\/*2","orientation":"horizontal"},"values":{"min":0,"max":1},"text":"No action is required for this gene-drug interaction.","conditions":[]},{"flag":"borderline","label":{"short":"C13","long":"CYP2C9*1\/*3","orientation":"horizontal"},"values":{"min":1,"max":2},"text":"The CYP2C9 enzyme metabolizes warfarin and the variants CYP2C9*1 and *3 are associated with lower dose requirements. 65% of the standard initial dose is recommended by the Dutch Pharmacogenetics Working Group (DPWG).","conditions":["Warfarin sensitivity"]},{"flag":"borderline","label":{"short":"C22","long":"CYP2C9*2\/*2","orientation":"horizontal"},"values":{"min":2,"max":3},"text":"The CYP2C9 enzyme metabolizes warfarin and the variants CYP2C9*2 are associated with lower dose requirements. 65% of the standard initial dose is recommended by the Dutch Pharmacogenetics Working Group (DPWG).","conditions":["Warfarin sensitivity"]},{"flag":"abnormal","label":{"short":"C23","long":"CYP2C9*2\/*3","orientation":"horizontal"},"values":{"min":3,"max":4},"text":"The CYP2C9 enzyme metabolizes warfarin and the variants CYP2C9*2 and *3 are associated with lower dose requirements. 45% of the standard initial dose is recommended by the Dutch Pharmacogenetics Working Group (DPWG).","conditions":["Warfarin sensitivity"]},{"flag":"abnormal","label":{"short":"C33","long":"CYP2C9*3\/*3","orientation":"horizontal"},"values":{"min":4,"max":5},"text":"The CYP2C9 enzyme metabolizes warfarin and the variants CYP2C9*3 are associated with lower dose requirements. 20% of the standard initial dose is recommended by the Dutch Pharmacogenetics Working Group (DPWG).","conditions":["Warfarin sensitivity"]}],"value":0.5}[{"normal":0},{"borderline":0},{"borderline":1},{"abnormal":0},{"abnormal":1}]
Use the slider below to see how your results affect your health.
Your result is CYP2C9*1/*2.
No action is required for this gene-drug interaction.
Related conditions
{"label":"VKORC1 Genotype Reference Range","scale":"lin","step":0.25,"hideunits":true,"items":[{"flag":"normal","label":{"short":"VKORC1 C\/T","long":"VKORC1 C\/T","orientation":"horizontal"},"values":{"min":1,"max":2},"text":"No action is required for this gene-drug interaction. VKORC1 1173C>T is equivalent to c.-1639G>A. VKORC1 C\/T corresponds to VKORC1, c.-1639 G\/A.","conditions":[]},{"flag":"abnormal","label":{"short":"VKORC1 T\/T","long":"VKORC1 T\/T","orientation":"horizontal"},"values":{"min":2,"max":3},"text":"The genetic variation results in increased sensitivity to warfarin. This results in an increase in the risk of excessively severe inhibition of blood clotting (INR >4) during the first month of the treatment. 60% of the standard initial dose is recommended by the Dutch Pharmacogenetics Working Group (DPWG). VKORC1 1173C>T is equivalent to c.-1639G>A. VKORC1 T\/T corresponds to VKORC1, c.-1639 A\/A.","conditions":["Warfarin sensitivity"]}],"value":1.5}[{"normal":0},{"abnormal":0}]
Use the slider below to see how your results affect your health.
Your result is VKORC1 C/T.
No action is required for this gene-drug interaction. VKORC1 1173C>T is equivalent to c.-1639G>A. VKORC1 C/T corresponds to VKORC1, c.-1639 G/A.
Related conditions
1. Warfarin sensitivity - Genetics Home Reference - NIH [accessed on Oct 22, 2018]
2. Warfarin Therapy and VKORC1 and CYP Genotype - Medical Genetics Summaries - NCBI Bookshelf [accessed on Oct 22, 2018]
3. CPIC® Guideline for Pharmacogenetics-Guided Warfarin Dosing – CPIC [accessed on Oct 22, 2018]
4. VKORC1 Pharmacogenomics Summary [accessed on Oct 22, 2018]
5. Pharmacogenetic testing of CYP2C9 and VKORC1 alleles for warfarin | Genetics in Medicine [accessed on Oct 22, 2018]
6. Warfarin Pharmacogenetics: CYP2C9 and VKORC1 Genotypes Predict Different Sensitivity and Resistance Frequencies in the Ashkenazi and Sephardi Jewish Populations - ScienceDirect [accessed on Oct 22, 2018]
7. https://www.labcorp.com/tests/related-documents/L4627 [accessed on Oct 22, 2018]
8. 511460: Warfarin (P450 2C9 and VKORC1) | LabCorp [accessed on Oct 22, 2018]
9. Warfarin Sensitivity, CYP2C9 and VKORC1, 3 Variants [accessed on Oct 22, 2018]
10. CYP2C9 And VKORC1 Testing and Genotyping – Indications | Genelex [accessed on Oct 22, 2018]

Additional Materials (10)

Spotlight on Testing: Warfarin Pharmacogenetics

Video by ARUP Laboratories/YouTube

Warfarin Pharmacogenetics

Video by AACC/YouTube

Coumadin (Warfarin) and Vitamin K

Document by National Institutes of Health Clinical Center

Bottles of warfarin

In 2007, the FDA modified warfarin's label to indicate that genetic makeup may affect patient response to the drug. The widely used blood thinner is sold under the brand name Coumadin®. Scientists involved in the NIH Pharmacogenetics Research Network are investigating whether genetic information can be used to improve optimal dosage prediction for patients.

Image by Alisa Machalek, NIGMS/NIH

Anticoagulant Heparin

Anticoagulants (often called blood thinners) like heparin and warfarin don't break up existing clots, but they do keep them from getting bigger and help stop new clots from forming. In life-threatening situations, thrombolytics (clot-busting drugs) like urokinase and alteplase may be administered to actually dissolve clots.

Image by TheVisualMD

Warfarin tablets

Warfarin tablets, 5, 3 and 1mg, photo by Gonegonegone, taken this date. Pink = 5mg, blue = 3mg, brown = 1mg.

Image by Gonegonegone at English Wikipedia

Anticoagulants

The leech produces an anticoagulant that prevents the stored blood from clotting, plus other agents that inhibit microbial decay of the blood.

Image by Veronidae

A sample of Heparin Sodium for injection

A sample of Heparin Sodium for injection

Image by LHcheM

Sensitive content

This media may include sensitive content

Prothrombin Time (PT): Deep Vein Thrombosis (DVT)

Deep vein thrombosis, or DVT, is a blood clot that forms in a vein deep in the body, typically the lower leg or thigh. If such clots travel to the lungs, they can cause pulmonary embolisms, which can damage tissue and impair the lungs' ability to supply oxygen to the body. Although anyone can develop DVT, such clots are often associated with prolonged bed rest, long periods of sitting in a cramped position, old age, or blood clotting disorders. Obesity, surgery, pregnancy, heart failure, cancer, smoking, and being tall can also elevate risk.

Image by TheVisualMD

Waran (Warfarin)

Image by Bengt B

3:39

Spotlight on Testing: Warfarin Pharmacogenetics

ARUP Laboratories/YouTube

10:15

Warfarin Pharmacogenetics

AACC/YouTube

Coumadin (Warfarin) and Vitamin K

National Institutes of Health Clinical Center

Bottles of warfarin

Alisa Machalek, NIGMS/NIH

Anticoagulant Heparin

TheVisualMD

Warfarin tablets

Gonegonegone at English Wikipedia

Anticoagulants

Veronidae

A sample of Heparin Sodium for injection

LHcheM

Sensitive content

This media may include sensitive content

Prothrombin Time (PT): Deep Vein Thrombosis (DVT)

TheVisualMD

Waran (Warfarin)

Bengt B

Statistics

Population statistics

Image by ArtsyBeeKids/Pixabay

Population statistics

Image by ArtsyBeeKids/Pixabay

How Common Is Warfarin Sensitivity?

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.

Source: MedlinePlus Genetics

Related HealthJournals

Warfarin Resistance

Warfarin resistance is a condition that is characterized by a high tolerance for a "blood-thinning" medication called warfarin. Affected people will still be at an elevated risk for blood clots when given the standard dose of warfarin. Explore symptoms and genetics of this condition.

Genetic Testing

Genetic testing is a type of medical test that identifies changes in chromosomes, genes, or proteins. Over 2000 tests are available. Genetic testing may be done for many reasons, from newborn baby screening to diagnosing certain diseases. Read about why you might consider testing.

Pharmacogenomics

Pharmacogenomics is the study of how genes affect a person’s response to drugs. It combines pharmacology (the science of drugs) and genomics (the study of genes and their functions) to develop effective, safe medications and doses that will be tailored to a person’s genetic makeup. Learn more about this precise approach to medicine.

Blood Thinners

Anticoagulant and antiplatelet drugs are blood thinners, medications that reduce the risk of heart attacks and help keep blood clots from forming. There are different types of blood thinners. The most common blood thinner that doctors prescribe is warfarin (Coumadin®). Learn more about blood thinners and how to use them safely.

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Warfarin Sensitivity

Warfarin sensitivity is a condition that is characterized by a reduced tolerance for a "blood-thinning" medication called warfarin. People with a warfarin sensitivity are more likely to experience an overdose or other serious side effects from the medication. Explore symptoms and genetics of this condition.

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