Mutations (changes) in your genes can increase your risk of developing certain health conditions — including hemophilia. Mutations in the methylenetetrahydrofolate reductase (MTHFR) gene may raise your risk of blood clots. However, it’s important to note that having the mutation itself doesn’t mean you have a clotting disorder.

In this article, we’ll give an overview of the MTHFR gene and its role in the body. We’ll also discuss how MTHFR mutations are associated with blood clots and what this means for people living with hemophilia. To learn more about MTHFR mutations and whether you may have one, talk to your doctor or hematologist (blood specialist).

What Is the MTHFR Mutation?

Your genes act as instruction manuals, telling your cells how to make proteins. When genes undergo mutations, their instructions sometimes become incorrect or unreadable. This means your cells can no longer make the protein correctly, or even at all.

The MTHFR gene provides instructions for making the MTHFR protein. This is an enzyme responsible for processing the amino acid homocysteine. You can think of amino acids as the building blocks of proteins.

Specifically, the MTHFR enzyme works with vitamins B9 (folate), B6, and B12 to break down homocysteine into another amino acid called methionine. Without enough functioning MTHFR enzymes, you can’t properly process homocysteine. As a result, the homocysteine levels in your blood rise and can lead to complications.

Types of MTHFR Mutations

When reading about MTHFR mutations, you may come across sources that refer to them as “MTHFR variants.” For the purpose of this article, these terms mean the same thing. You may also see researchers use the term “polymorphism,” which also refers to a variation of a gene.

Some gene mutations are harmless and don’t affect your ability to make proteins correctly. Others change your genetic code enough that your cells make abnormal proteins that don’t work as well as they should.

Mutations in the MTHFR gene can result in low quantities of enzymes, rendering them less effective at breaking down homocysteine. Researchers have found that the genetic variants MTHFR C677T and A1298C may increase a person’s risk of several complications. Your overall risk can depend on how many copies of the MTHFR gene are mutated.

Everyone inherits two copies of each gene — one from their mother and one from their father. If you have an MTHFR mutation on one gene copy, it’s referred to as heterozygous (the prefix “hetero-” means “different”). If you have a mutation in both copies of the MTHFR gene, it’s referred to as homozygous (“homo-”’ means “same”).

MTHFR Mutations and Blood Clotting Risk

Researchers believe that too much homocysteine (called hyperhomocysteinemia) in the bloodstream irritates the blood vessels. This may raise your risk of blood clots or clumps of blood cells, platelets, and fibrin proteins. In fact, around 10 percent of people have hyperhomocysteinemia when they experience venous (deep-vein) thrombosis (blood clots) — also called venous thromboembolism (VTE).

People with hyperhomocysteinemia typically have low levels of B vitamins. Folate is one vitamin that’s important for creating new red blood cells and keeping you healthy. Without enough folate, you’re more likely to develop thrombosis.

It’s worth noting that newer studies haven’t been able to find an exact link between MTHFR mutations and the risk of blood clots. More research is needed to figure out the exact role of MTHFR mutations in blood clotting risk.

Furthermore, polymorphisms of the MTHFR gene (variants that have little to no effect on a person’s health) are found in 60 percent to 70 percent of the general population. Due to the limited and controversial evidence, current guidelines by the International Society of Thrombosis and Haemostasis do not recommend MTHFR testing as part of routine thrombophilia assessment.

Types of Blood Clots With MTHFR Mutations

People with MTHFR mutations and high homocysteine levels may develop blood clots in the veins. These are the blood vessels that bring oxygen-depleted blood from your body back to your heart.

Blood clots tend to form in the extremities — usually in the legs. These clots are known as deep vein thrombosis (DVT) — a form of VTE — because they form in the body’s innermost veins. If a blood clot breaks free and travels to the lungs, it’s called a pulmonary embolism (PE). While people with MTHFR mutations are more likely to develop these blood clots, the overall risk is only slightly higher than those without mutations.

Symptoms of DVT to be aware of include:

• Leg pain
• Swelling
• Warmth
• Changes in skin color

If you notice any of these symptoms, talk to your health care provider. You’ll want treatment as soon as possible to avoid complications.

PE is serious and can become life-threatening if it’s left untreated. Seek medical attention immediately if you have symptoms of DVT and develop new signs of PE, like:

• Chest pain when taking a breath or coughing
• Shortness of breath
• Fainting
• Coughing up blood
• Fast pulse

Other Complications With MTHFR Mutations

Elevated homocysteine levels can also raise your risk for other complications, including:

• Atherosclerosis, hardening of your arteries (blood vessels that carry oxygen-rich blood from your heart to the rest of your body)
• Cardiovascular disease, including heart disease, heart attack, and stroke
• Dementia, a condition that affects memory as you age
• Osteoporosis, which causes thin and brittle bones
• Pregnancy loss

MTHFR Mutations and Hemophilia

Hemophilia is a bleeding disorder that makes it difficult for the body to form blood clots. People with hemophilia can have uncontrollable bleeding problems after minor injuries or medical treatments.

Hemophilia develops from gene mutations in clotting factor genes. Hemophilia A is caused by changes in the F8 gene that provides instructions for making clotting factor VIII (8). People with hemophilia B have mutations in the F9 gene, responsible for making clotting factor IX (9).

Some studies have found that people with both hemophilia and MTHFR C677T mutations have milder bleeding episodes. Researchers believe this is because the C677T mutation increases thrombin levels.

Thrombin is an important protein in the blood clotting process. Normally, people with hemophilia don’t make enough thrombin. Having an MTHFR mutation can increase thrombin levels, reducing the number of bleeding episodes you may have.

The same phenomenon has also been seen in people with von Willebrand disease (VWD) — another bleeding disorder. One study found that people with VWD who also have MTHFR mutations have milder bleeding symptoms.

How Are MTHFR Mutations Treated?

Remember, the MTHFR mutation itself isn’t a thrombophilia (blood clotting disorder). Some people with MTHFR mutations have normal homocysteine levels. This is because they have a gene variant that doesn’t affect how well the MTHFR protein works.

If you have an MTHFR mutation but you don’t have hyperhomocysteinemia, you likely won’t need any treatment. For people who have MTHFR mutations and high homocysteine levels, treatment is usually necessary.

Your doctor will likely have you take folic acid supplements, along with a multivitamin that also has folate. They may recommend eating foods high in folate as well. Good sources of dietary folate include:

• Dark, leafy vegetables like Brussels sprouts, spinach, broccoli, and asparagus
• Beans
• Sunflower seeds
• Whole grains
• Fortified cereals
• Fresh fruits
• Eggs

Final Thoughts

Although MTHFR mutations may influence blood clotting and make conditions like hemophilia more complicated, not everyone with these mutations will have health issues. Some people might be at higher risk because they have more homocysteine in their blood, but many others remain healthy. Talk to your doctor to understand your genes and figure out the best treatment plan for you.

Find Your Team

On MyHemophiliaTeam, the social network for people with hemophilia and their loved ones, more than 6,500 members come together to ask questions, give advice, and share their stories with others who understand life with hemophilia.

Are you living with an MTHFR mutation? How has it affected your life with hemophilia? Share your experience in the comments below, or start a conversation by posting on your Activities page.