Some genetic mutations can increase the risk of certain health conditions, while others have little to no effect. A mutation is a change in a gene.

One gene that may come up when people talk about blood clot risk is methylenetetrahydrofolate reductase (MTHFR). MTHFR mutations can affect how the body processes an amino acid called homocysteine, which may matter for blood clotting risk in some people.

However, MTHFR mutations do not cause hemophilia, which is a bleeding disorder caused by mutations in clotting factor genes. In addition, the most common MTHFR mutations are not considered blood clotting disorders.

In this article, we’ll explain what the MTHFR gene does, how MTHFR mutations relate to blood clots, and what this may mean 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.

The MTHFR enzyme works with vitamins B9 (folate), B6, and B12 to help break down homocysteine and turn it into another amino acid called methionine. Without enough working MTHFR enzymes, the body may have a harder time breaking down homocysteine.

This can lead to mild increases in blood homocysteine levels, which usually aren’t harmful. However, very high homocysteine levels may be linked to blood vessel complications in some people.

Types of MTHFR Mutations

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

Some gene mutations are harmless and don’t affect how your body makes proteins. Others can change your genetic code enough that your cells make proteins that don’t work as well as they should.

Two common MTHFR variants are C677T and A1298C. Many people have at least one copy of C677T or A1298C.

Because MTHFR variants are common, having one doesn’t always mean something is wrong or that you’ll develop health problems.

MTHFR Mutations and Blood Clotting Risk

Researchers believe that too much homocysteine in the blood, called hyperhomocysteinemia, may irritate blood vessels. High homocysteine levels may raise the risk of blood clots, which are clumps of blood cells, platelets, and a protein called fibrin.

One study from the journal Future Science OA found that people with hyperhomocysteinemia were 3.54 times more likely to have deep vein thrombosis (DVT), a blood clot that forms in a deep vein.

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. Low folate can sometimes lead to higher homocysteine levels.

However, folate levels by themselves don’t reliably predict who will get blood clots. Also, in many studies, lowering homocysteine with B vitamins has not always lowered the risk of heart problems or blood clots.

Current evidence shows that common MTHFR variants don’t reliably predict a person’s risk of blood clots. As a result, most major medical organizations don’t recommend MTHFR testing to check a person’s risk of blood clots.

Should You Be Tested for Homocysteine Levels?

Homocysteine levels are measured using a simple blood test. Routine homocysteine testing isn’t recommended for everyone, but a doctor may consider it if someone has had:

• Signs of low folic acid, vitamin B6, or vitamin B12 levels
• Unexplained blood clots
• Signs of blood vessel or heart disease, especially at a young age

If you’re concerned about MTHFR and blood clots, talk with your doctor about whether homocysteine testing might be helpful for you.

Types of Blood Clots With MTHFR Mutations

Blood clots may form in the veins, especially in the legs. This is called deep vein thrombosis. If part of a clot breaks free and travels to the lungs, it can cause a pulmonary embolism (PE), which can be life‑threatening if untreated.

For most people, MTHFR variants alone don’t increase the risk of DVT or PE. A person’s risk of blood clots depends on many factors, such as surgery, not moving for a long time, pregnancy, cancer, and very high homocysteine levels.

Symptoms of DVT include:

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

If you notice any of these symptoms, talk to your healthcare 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. Get medical help right away if you have symptoms of DVT and develop new symptoms 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 caused by an MTHFR mutation may also raise your risk for other complications, including:

• Atherosclerosis — Hardening of the arteries 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 group of conditions that affect memory, thinking, and daily functioning
• Osteoporosis — A condition that causes thinning of bones, making them weak and more likely to break
• Pregnancy complications — Health problems that can happen during pregnancy, such as high blood pressure or pregnancy loss

Keep in mind that the evidence linking common MTHFR variants to these problems is mixed. Because these variants are common, having one doesn’t always mean it’s causing symptoms or raising your risk of complications. Problems are more likely when certain MTHFR variants lead to abnormal homocysteine levels.

MTHFR Mutations and Hemophilia

Hemophilia is a bleeding disorder that makes it difficult for the body to form blood clots. People with hemophilia may bleed for a long time after minor injuries or medical treatments.

Hemophilia develops from gene mutations in clotting factor genes. You will usually see Roman numerals in any discussion of clotting factors.

Hemophilia A is caused by changes in the F8 gene, which helps the body make clotting factor VIII (8).

Hemophilia B is caused by changes in the F9 gene, which helps the body make clotting factor IX (9).

MTHFR Variants and Hemophilia Treatment

Some older, limited studies suggest that the MTHFR C677T variant may be linked to slightly higher thrombin levels. Thrombin is an important protein in the blood clotting process.

People with hemophilia usually don’t make enough thrombin. Having an MTHFR mutation may increase thrombin levels, reducing the number of bleeding episodes you may have.

Because blood clotting factor treatment helps the body make more thrombin, researchers have studied whether MTHFR mutations may affect hemophilia.

However, the research isn’t strong, so hemophilia treatment decisions, like clotting factor dosing, are based on factors such as weight, where the bleeding is, how serious it is, and lab results — not MTHFR status.

Do MTHFR Mutations Need Treatment?

Most of the time, MTHFR mutations don’t need treatment because a mutation alone isn’t a true blood clotting disorder. Many people with these variants have normal homocysteine levels and no related health problems.

If homocysteine levels are very high, a doctor may recommend taking folic acid supplements or folate, along with vitamins B6 and B12, to help reduce levels. They may also recommend eating foods high in folate.

These vitamins are usually used to treat a vitamin deficiency or very high homocysteine under a doctor’s guidance, not as a general way to prevent blood clots in everyone with an MTHFR variant.

Here are some foods you can add to your diet for more folate:

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

What MTHFR Mutations Mean for Your Health

MTHFR mutations are common and usually not harmful on their own. Most people with these variants don’t develop blood clots or bleeding problems.

In some cases, elevated homocysteine levels, not the MTHFR variant itself, may play a role in clotting risk, along with other factors like medical history, medications, or underlying health conditions.

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