PGx: Warfarin

Genotype C:C, C:G or G:G

Warfarin is one of the most commonly used anticoagulant in the prevention of blood clots and in the treatment of concomitant illnesses. Warfarin is used in the treatment of heart valve prosthesis, atrial fibrillation and recurrent stroke, heart attack, thrombosis. Warfarin is trustworthy drug that can be used in long term and its effectiveness can be monitored laboratorically. However, its use is complicated due to difficulties in determining the required dose which is very variable between individuals. In addition to genetic factors, warfarin dose is influenced by intake of vitamin K, ethnicity, age, illness, sex, drugs and body mass index. It is very important to determine the right dose of warfarin due to the narrow therapeutic range: too low dose of warfarin can lead to stroke and other complications; too high dose of warfarin can cause serious bleedings.

C : C
(VKORC1*1A/*1A) indicating warfarin sensitivity
(low warfarin dose)

C : G
(VKORC1*1A/*1B) indicating average warfarin response
(average warfarin dose)

G : G
(VKORC1*1B/*1B) indicating warfarin resistance
(high warfarin dose)

The most important laboratory indicator for monitoring the effects of warfarin is prothrombine time test (PT) which is reported as International Normalized Ratio (INR). Monitoring of INR is important to verify the effective range of warfarin dose. If INR is too low, it can increase the risk of blood clots. On the other hand, if INR is too high, it can increase the risk of serious bleedings.

Sensitivity to warfarin is associated with VKORC1 gene and with rs8050894 marker.

VKORC1 gene has two variants: VKORC1*A which indicates “low warfarin dose” and VKORC1*B which indicates “high warfarin dose”. Every person has 2 copies of VKORC1 gene – one copy from both parents. The combination of these alleles determines whether the person is sensitive, normal or resistant to warfarin. Genotype testing of VKORC1 enables to determine the most effective warfarin dose for every person. We can distinguish three different genotypes.

cardiovascular

Warfarin sensitivity

C:C (VKORC1*1A/*1A) genotype indicates to warfarin sensitivity. This genotype presents mutation in VKORC1 gene resulting in decrease of production of its enzyme and also increase of coagulation factors. In the case of this genotype, lower doses of warfarin is required. The optimal dose of warfarin is ca 2.5 mg/per day in patients with warfarin sensitivity. The required dose of warfarin in patients with warfarin sensitivity needs to be low, otherwise it increases the risk of bleedings. C:C genotype is widely common in Asia and America.

Normal warfarin response

C:G (VKORC1*1A/*1B) genotype indicates to average warfarin response. In this case, the function and production of VKORC1 enzyme is normal resulting also in normal production of coagulation factors. The optimal dose of warfarin is ca 5 mg/per day in patients with average warfarin sensitivity. However, due to the presence of VKORC1*1B allele, higher dose of warfarin is required for this genotype compared with C:C genotype. C:G genotype is common in Europe and Africa.

Warfarin resistance

G:G (VKORC1*1B/*1B) genotype indicates to warfarin resistance. This genotype presents mutation in VKORC1 gene resulting in excessive production of its enzyme and also excessive production of coagulation factors. The optimal dose of warfarin is ca 6.5 mg/per day in patients with warfarin resistance. It is important to determine high dose of warfarin in patients with warfarin resistance, otherwise it increases the risk of stroke and blood clots will not be prevented. G:G genotype is common in Africa and America.

WARFARIN TRADE NAMES

Warfarin is used worldwide by millions of people. Warfarin is marketed worldwide under many brand names and generic names: Aldocumar, Anasmol, Anticoag, Befarin, Cavamed, Cicoxil, Circuvit, Cofarin, Coumadin, Coumadine, Cumar, Farin, Foley, Haemofarin, Jantoven, Kovar, Lawarin, Maforan, Marevan, Marfarin, Marivanil, Martefarin, Morfarin, Orfarin, Panwarfin, Scheme, Simarc, Varfarin, Varfarins, Varfine, Waran, Warcok, Warf, Warfareks, Warfarin, Warfarina, Warfarine, Warfarinum, Warfen, Warfin, Warik, Warin, Warlin ja Zyfarin.

In Estonia, warfarin is marketed under the name Marevan.

SIDE EFFECTS OF WARFARIN

The most common side effects of warfarin are blood clots and bleedings caused by insufficient warfarin dose. Patients who are using warfarin must always inform their doctor in the case of accident or falling due to the fact that even small injuries can cause serious bleedings in patients with coagulation disorder. Less common side effects of warfarin are osteoporosis, tissue damage and purple toe syndrome. If you have been prescribed warfarin then you should pay attention to these symptoms and seek medical attention if you notice one of them:

  • Bleeding from the gums
  • Red or brown urine
  • Bloody stool
  • Nosebleed
  • Vomiting or coughing up blood
  • Severe headache, migrane, dizziness, weakness
  • Fall or injury to the head
  • Pain or swelling of the joints

Patients who are using warfarin can decrease the risk of bleeding by:

  • Using a soft-bristle toothbrush
  • Flossing with waxed floss
  • Shaving with electric razor rather than a blade
  • Being careful when using sharp objects, like knives, scissors
  • Avoiding activities that can cause a risk of falling and injuries
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INTERACTIONS

Warfarin can interact with a lot of drugs, foods and vitamins. Due to that the metabolism of warfarin is very variable between individuals. Warfarin interaction with other drugs might lower the effectiveness of it which can cause increase in bleedings. Due to interactions it is useful to take genetic warfarin sensitivity test to determine the effective dose of warfarin.

Drugs Supplements Foods
Many antibiotics Coenzyme Q10 Alcohol
Antifungal medications, such as Diflucan Green tea Foods that have vitamin K levels, such as soy beans, spinach, broccoli
Aspirin and aspirin-containing drugs Vitamin E Cranberry and cranberry juice
Ibuprofen Garlic Garlic
Acetaminophen, such as Tylenol Black licorice
Cold and allergy drugs
Abnormal heart rhythm medicines, such as amiodarone
Antacids and laxatives
References

Updated: 07.07.2018

Disclaimer

The information provided in this article is based on published SNP (single nucleotide polymorphism) data and is for educational purposes only. Most published studies about genetic variants in the DNA explain only a small part of the heritability of a trait or disease risk, and often do not take into account how different variants may interact with each other. In addition, many published studies do not account for medical history or environmental, dietary, microbial, or lifestyle factors, which may alter true risk for any trait or disease.

The relevance of each article may vary based on ethnicity. Nothing in the genetic article should be used for medical self-diagnosis or self-treatment. The information provided should not be considered complete, nor should it be relied on to suggest diagnosis or treatment of a particular individual. You should always get the advice of your doctor or other appropriate health care professional if you have any questions about diagnosis, treatment, prevention, mitigation, or cure of any medical condition, phenotype, condition, impairment, or the status of your health.

Glossary

ALLELE
An allele is a variant form of a gene that is located at a specific position, or genetic locus, on a specific chromosome. Humans have two alleles at each genetic locus, with one allele inherited from each parent.
CHROMOSOME
A chromosome is a thread-like structure of DNA that carries hereditary information, or genes. Human cells have 22 chromosome pairs plus two sex chromosomes, giving a total of 46 per cell.
DISEASE PREVALENCE
The proportion of individuals in a population having a disease or characteristic. Prevalence is a statistical concept referring to the number of cases of a disease that are present in a particular population at a given time, whereas incidence refers to the number of new cases that develop in a given period of time.
DNA
DNA, or deoxyribonucleic acid, is the main component of chromosomes and the carrier of genetic information in nearly all living organisms. DNA is made up of molecules called nucleotides. Each nucleotide contains a phosphate group, a sugar group and a nitrogen base. The four types of nitrogen bases are adenine (A), thymine (T), guanine (G) and cytosine (C).
GENE
A hereditary unit consisting of a sequence of DNA that occupies a specific location on a chromosome. Genes are transferred from a parent to offspring, and are responsible for the physical and heritable characteristics or phenotype of an individual.
GENETIC VARIANT
An alteration in the most common DNA nucleotide sequence. The variant can be benign, pathogenic or of unknown significance. SNPs are the most common type of genetic variation.
GENOTYPE
The genetic makeup of an individual organism. It may also refer to just a particular gene or set of genes carried by an individual. The genotype determines the phenotype, or observable traits of the organism.
ODDS RATIO
The odds ratio is a way of comparing whether the odds of a certain outcome is the same for two different groups. In this report, the odds ratio estimates the probability of a condition occurring in a group of people with a certain genetic variant compared to a group of people without that variant.

An odds ratio of 1 means that the two groups are equally likely to develop the condition. An odds ratio higher than 1 means that the people with the genetic variant are more likely to develop the condition, while an odds ratio of less than 1 means that the the people with the variant are less likely to develop the condition.
PHENOTYPE
A description of an individual’s physical characteristics, including appearance, development and behaviour. The phenotype is determined by the individual’s genotype as well as environmental factors.
POPULATION ALLELE FREQUENCY
The allele frequency represents the incidence of a gene variant in a population. Alleles are variant forms of a gene that are located at the same position, or genetic locus, on a chromosome.
SNP
Single nucleotide polymorphisms, frequently called SNPs, are the most common type of genetic variation among people. A SNP is a variation in a single nucleotide that occurs at a specific position in the genome.

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