MTHFR and Blood Clots

MTHFR doesn’t cause blood clots directly. However, it can increase your risk factors for elevated homocysteine levels. This can increase your risk of cardiovascular events, such as deep vein thrombosis (DVT).

Homocysteine is a type of sulfur-containing amino acid that the body produces from the breakdown of another amino acid, methionine. Normally, your body is able to keep homocysteine at low levels by converting it into other products via the methionine-homocysteine pathway. This process requires the help of folate (B1), B6, and B12.

However, a mutation on the MTHFR gene—which affects 10-25 percent of the American population—may lead to a deficiency in these B vitamins. This can result in higher homocysteine levels. Elevated levels of homocysteine have been shown to increase the risk of atherosclerosis (hardening of the arteries), which can in turn increase risk factors for heart attack or stroke, as well as venous thrombosis (blood clots in the veins).

In this article, we’ll explain whether there are any links between MTHFR mutations and blood clotting disorders such as Factor V Leiden. We’ll also talk about how MTHFR affects the body and how you can reduce your risk of blood clots through diet and supplements.

First things first: the MTHFR gene mutation is not a blood clotting disorder. In fact, having one mutation in the MTHFR gene is not usually associated with an increased risk of blood clots at all. However, those with elevated homocysteine levels in the blood do have an increased risk of developing a deep vein thrombosis.

So the reason a single MTHFR gene mutation is not associated with increased risk of blood clots is because a single mutation typically doesn’t lead to high levels of homocysteine in the blood.

Other research suggests that only homozygous mutations have any detrimental effects. Having only one mutation (heterozygous)is usually not considered harmful. Even when two MTHFR mutations are present (i.e., 2 677TT mutations, or one C677T mutation and one A1298C mutation), not all people will develop high homocysteine levels.

However, a homozygous MTHFR mutation CAN increase cardiovascular risk factors that may lead to blood clotting.

A 2006 study involving women with a history of recurrent miscarriages found that inherited thrombophilias could be to blame, with 59 percent of the women having multiple homozygous gene mutations associated with blood clotting, including MTHFR. This was compared to only 10percent of women in the control category. However, the study authors pointed out that this association reflected the total number of mutations, rather than specific genes (such as MTHFR) involved.

Elevated homocysteine levels have been linked to the MTHFR mutation. For the same reason, cardiovascular disease, deep vein thrombosis (a type of blood clot),and pulmonary embolisms (PE) have also been linked to MTHFR mutations.

Some research suggests that although reduced enzyme function can lead to elevated homocysteine levels, this is not the case for everyone with MTHFR.

When homocysteine is normal, MTHFR mutations by themselves are not a risk factor for cardiovascular disease or DVT and PE. By supplementing the diet with the right nutrients, it’s possible to maintain normal homocysteine levels.

The two most-known MTHFR gene variants are C677T and A1298C. In the US, about 25% of people who are Hispanic, and 10-15%of people who are Caucasian have two copies of 677TT (or are homozygous).

C677T

Research shows that those who are homozygous 677TT often have significantly lower folate levels than heterozygous C677T. Both homozygous 677TT and compound heterozygous mutations (C677T + A1298C) are linked to higher levels of homocysteine and an increased risk of heart disease.

One study found that a higher frequency of C677T MTHFR gene mutations was associated in women with pregnancy-associated vascular pathologies, such as pre-eclampsia, vascular intrauterine growth restriction, and placenta abruption. However, the study authors concluded that the risk of these issues could be prevented with anticoagulant treatment, aspirin, and folic acid. The anticoagulation benefits were not believed to be related to the thrombogenic effect of homocysteine.

Although these mutations impair the regulation of homocysteine, supplementing with an adequate amount as well as the correct form of folate can reduce health risks associated with elevated homocysteine.

A1298C

According to research published in the American Journal of Human Genetics, heterozygous or homozygous variants of 1298A>C does not lead to increased homocysteine levels. However, a combination of 1298A>C and 677C>T may result in an outcome similar to those with homozygous 677TT.

Other studies suggest that the combined heterozygosity for the two MTHFR common mutations accounts for a proportion of folate-related neural tube defects, which is a severe birth defect.

Factor V Leiden thrombophilia (FVL) is a genetic blood clotting disorder. It is caused by a specific gene mutation that results in thrombophilia, an increased tendency to form abnormal blood clots that can block blood vessels. FVL occurs in approximately 1-5% of the general caucasian population. Factor Vis one of about 13 clotting factors responsible for the stages of normal blood coagulation, or clotting.

People with FVL have a higher than average risk of developing deep venous thrombosis (DVT). DVTs usually affect the legs, but can also occur in the thigh, pelvis, and arms. Clots can break away from their original site and become lodged in the lungs, where they may cause pulmonary embolism (PE).

Heterozygous FVL is the most common mutation found in people who experience a DVT. The risk of developing abnormal blood clots is increased in those with homozygous mutations versus heterozygous mutations.

When people with FVL develop a venous thromboembolism (VTE), these abnormal clots can be life-threatening and lead to long-term health problems.

While FVL and MTHFR are different disorders, they have some similarities in terms of how genetic variants can affect the body.

Both disorders are genetic, and both can be carried by men and women. Like MTHFR, the homozygous variant of FVL may have amore severe impact on the body.

Inheriting the FVL genetic mutation from both parents instead of just one can significantly increase the risk of abnormal blood clots. Abnormal variations of MTHFR can also be inherited as heterozygous (one variant) or homozygous (two variations). Homozygous MTHFR leads to significantly reduced MTHFR enzyme function, which can be more problematic.

In fact, two copies of the MTHFR 677TT, or one copy of C677T and one of A1298C, can result in a significant reduction in MTHFR enzyme activity. This leads to significantly lower levels of 5-MTHF (active folate in the body), which in turn slows down the homocysteine conversion process and leads to a build-up of homocysteine in the blood.

Women with the FVL mutation have a higher risk of developing blood clots during pregnancy. Women with MTHFR mutations also have an increased risk of complications during pregnancy.

MTHFR is not specifically related to blood coagulation. The MTHFR gene contains the DNA code to produce the methylenetetrahydrofolate reductase (MTHFR) enzyme, which is required for metabolizing folate and breaking down the amino acid homocysteine.

The MTHFR enzyme converts the folate you ingest - whether through food or supplements - into the active form of folate,L-5-Methyltetrahydrofolate (or sometimes referred to as 5-MTHF). This is the form that your body can use at the cellular level.

Factor V mutations are known to potentiate the effect of MTHFR on deep vein thrombosis. The C677T variant of the MTHFR gene increases the plasma homocysteine levels and hyperhomocysteinemia is a known risk factor of deep vein thrombosis.

Some studies have shown that the risk of DVT increases 10-50 times in those who have both MTHFR and FVL mutations combined.

A 2014 study published in the journal Molecular Cytogenetics found that FVL mutations were present in 10% of the study population, including 18 patients who were heterozygous (single mutation)and one was homozygous (double mutation).

Of these patients, 25% who were diagnosed with deep vein thrombosis were found to be positive for variants of FVL. Another 74% of the patients had MTHFR mutations (five with C677T, four with compound heterozygous [C677T + A1298C], and 11 with A1298C). Two out of four patients who were positive for both FVL and C677T MTHFR mutations turned out to have a poor prognosis and later died.

The study authors concluded that having both Factor V Leiden and MTHFR increased the risk of hypercoagulability disorders such as DVT and thromboembolism, and ultimately led to greater complications.

However, a previous study concluded that there was no evidence for interaction between FVL and hyperhomocysteinemia or C677T in venous thrombosis.

Elevated homocysteine levels are associated with an increased risk for blood clots in the veins.

There is evidence that elevated homocysteine levels are linked to thrombosis due to several factors, including higher platelet reactivity, susceptibility to clots, higher factor V activity, impaired fibrinolytic processes (the body’s ability to naturally break down clots), and vascular injury.

Recent studies have also shown that higher total plasma homocysteine concentration is associated with an increased risk of coronary artery disease, stroke, and venous thromboembolism.

Although those with MTHFR mutations who have normal homocysteine levels are not at increased risk for clots, it appears that those with MTHFR mutations who do have elevated homocysteine levels may be at risk for blood clots. High levels of homocysteine may cause vascular damage due to toxic accumulation in endothelial cells and the generation of free radicals.

With this in mind, those with elevated homocysteine levels should be aware of the symptoms of DVTs.

Signs of Deep Vein Thrombosis include:

• Pain, tenderness, or cramping in the arm or leg
• Swelling
• Warmth and redness in the skin

Treatment of venous thromboembolism (VTE) generally involves anticoagulation medication, depending on the circumstances surrounding the development of the thrombotic event.

Researchers are uncertain whether elevated homocysteine causes the blood to clot more easily, or whether it is just a marker of an increased clotting risk.

However, prevention is a much more effective means of treatment.

Numerous studies have indicated that correct doses of vitamins such as folate, vitamin B6, vitamin B12, and betaine may control or alleviate the risk of elevated homocysteine. 

Elevated homocysteine is strongly linked to low levels of plasma folate, vitamin B12, and pyridoxal-5-phosphate (the active form of B6). Previous studies have also found that elevated homocysteine levels in plasma is a risk factor for increased incidence of death in stroke patients.

Hyperhomocysteinemia is also considered a risk factor for inflammatory diseases including potentially fatal cardiovascular disease, stroke, renal disfunction.

The cardiovascular risk factors associated with MTHFR triggered some concerns that MTHFR may be a blood clotting disorder. However, although MTHFR is indeed a genetic disorder, it is not specifically a clotting disorder like FVL.

Instead, MTHFR can increase the risk of developing elevated homocysteine levels, which can, in turn, increase the risk of thromboembolic events such as ischemic stroke, heart attack, systemic artery thrombosis, deep vein thrombosis, or pulmonary embolism.

The key is for those with MTHFR to be aware of their homocysteine levels and take measures to reduce these levels where necessary. One of the best ways to reduce homocysteine levels and protect the cardiovascular system is by supplementing the body with active forms of folate, vitamin B6, and vitamin B12.

Folate plays a major role in the body’s conversion of homocysteine to methionine, which is necessary to rid the body of excess homocysteine.

Taking bioactive folate (5-MTHF) directly has been shown to significantly increase blood serum folate levels compared with folic acid supplementation. This form of folate is vital for people who have a genetic enzyme deficiency because it requires no conversion to become metabolically active.

Folic acid, on the other hand, is the synthetic (man-made) form of folate that is added to fortified foods or dietary supplements. Those who cannot convert folic acid to its biologically active form (5-methyltetrahydrofolate [5-MTHF] or L-Methylfolate) well are much less likely to benefit from folic acid supplements.

Some of the best methylfolate supplements for those with MTHFR mutations or cardiovascular risks include Methyl-Life® products (B-Methylated II, Methylated Multivitamin, Methylfolate 7.5+ or Methylfolate 15+.) This product range has been created by a team of natural health experts and used successfully by hundreds of people all over the world. The forms of L-Methylfolate used in Methyl-Life® products are among the purest, most stable, and most potent of four of the world’s industry-leading patented L-Methylfolates.