MTHFR and Blood Clotting Disorders

MTHFR and Blood Clotting Disorders

Katie Stone - Naturopath

Written By:

Katie Stone - Naturopath
Kari Asadorian - Bachelor of Science in Nursing

Medical Reviewer:

Kari Asadorian - Bachelor of Science in Nursing
Jamie Hope - Founder of Methyl-Life

Edited By:

Jamie Hope - Founder of Methyl-Life

Updated On:

February 18, 2025

Table of Contents

    How does MTHFR affect blood clotting?

    A MTHFR deficiency is the most common genetic cause of high homocysteine, and high homocysteine is one of the key factors in blood clot risk.1


    Some studies have linked certain MTHFR variants to a higher risk of thrombosis, a serious condition in which a blood clot forms in a vein or artery.2


    While some studies have found no link between MTHFR and blood clotting, it’s important to know whether you might be at risk. 

    MTHFR and thrombosis risk

    MTHFR is an enzyme that helps the body process an amino acid called homocysteine. A mutation on the MTHFR gene can mean that this enzyme cannot work properly, which causes homocysteine levels to build up in the blood. Higher homocysteine levels are associated with a higher risk of venous thromboembolism (blood clots).3


    This is in part because excess homocysteine causes oxidative stress in the blood vessels, triggering inflammation that damages the vascular endothelial cells. The blood vessels may then begin to narrow, which affects the flow of blood around the body (vascular endothelial dysfunction).4


    Homocysteine also activates the clotting system in the veins and inhibits the fibrinolytic system, which prevents the body from dissolving blood clots that have formed.5

    Although the clinical definition of hyperhomocysteinemia is more than 15 micromol/L of homocysteine in the blood, a meta-analysis found that every 5 μmol/L increase in plasma homocysteine can increase the risk of blood clots by 60%.6

    Different MTHFR variants and blood clotting

    Many studies show that people with a single MTHFR mutation and healthy homocysteine levels are not at risk for developing blood clots. This means that a MTHFR variant on its own does not cause blood clots. However, a combination of MTHFR mutations may increase the risk.


    Heterozygous or homozygous MTHFR variants, especially a compound mutation, are associated with an increased risk of clots. People with both the C677T and A1298C MTHFR mutations may have a higher risk of blood clots, even if they don’t have high homocysteine levels.7


    A 2023 study concluded that although MTHFR C677T is especially associated with vascular diseases including stroke, coronary artery disease, and hypertension, there is only a weak association between MTHFR C677T and blood clots. 


    For this reason, people with a personal or family history of blood clots should consider testing for MTHFR mutations, as this may help in taking preventive steps.8

    MTHFR supplements when you’re on blood thinners

    MTHFR supplements such as methylfolate and vitamin B12 are often recommended for people with MTHFR mutations, as these nutrients are effective in reducing homocysteine levels. Active forms of these nutrients can bypass the MTHFR mutation.


    Methylfolate has not been shown to interact with blood thinner medication. However, if you are taking anticoagulants or any other medication, consult your doctor before taking methylfolate (or any other supplement).

    How to prevent DVT when you have MTHFR

    If you have normal homocysteine levels, a MTHFR mutation doesn’t necessarily mean you are at risk of DVT or blood clots.11 However, if you have both C677T and A1298C mutations, you may be at risk of blood clots even without high homocysteine.


    Your first step in preventing DVT is to monitor your homocysteine levels. Numerous studies show that homocysteine can be reduced by supplementing with methylfolate, which is a key component of the homocysteine recycling process.


    A 2024 study found that patients with MTHFR mutations who took methylfolate, P5P (active B6) and methylcobalamin (active B12) significantly reduced both their homocysteine and LDL-C levels. This reduction also occurred in patients with homozygous MTHFR mutations.12


    Other factors shown to reduce homocysteine include quitting smoking, reducing intake of coffee and alcohol, and increasing intake of fruits and vegetables, as well as exercising regularly.13


    Maintaining a healthy diet and exercising regularly can help to reduce the risk of blood clots.14

    MTHFR, blood clotting and pregnancy

    Pregnancy can increase the risk of blood clots due to hormonal changes that affect blood vessels and coagulation factors. Recent research has shown that while pregnant women with a family history of thrombosis have a 2.18-fold higher risk of thrombosis, the MTHFR genetics did not increase the risk.15

    This reflects previous research that the risk of blood clots during pregnancy in women with a MTHFR mutation is only very small.


    However, if you have MTHFR and are pregnant or planning to conceive, it’s important to discuss any possible risks of high homocysteine as well as folate needs (particularly the bioidentical forms) with your doctor. 

    What is Factor V Leiden?

    Factor V Leiden (FVL) is a genetic mutation that affects Factor V, a protein in the blood involved in the coagulation process. Normally, factor V helps to stop bleeding by forming clots at the site of an injury. Another protein called activated Protein C then turns off the clotting process by deactivating Factor V. But when a person has FVL, their body cannot deactivate factor V. As a result, factor V remains active, increasing the risk of abnormal clot formation.16 The risk is even greater in people with a homozygous mutation. However, many people with FVL never develop blood clots at all.17

    MTHFR vs. Factor V Leiden

    The Factor V Leiden mutation is one of the most common genetic risk factors for venous thromboembolic disease. As the MTHFR mutation can lead to increased homocysteine levels, a combination of MTHFR and FVL mutations is a known risk factor of deep vein thrombosis.19


    Some studies have shown that people with combined MTHFR and FVL mutations have 10-50 times the risk of DVT.20 A 2014 study confirmed that FVL and MTHFR play a synergistic role in increasing the risk of hypercoagulability disorders such as DVT and thromboembolism.21


    If you have both MTHFR and FVL, it’s important that you work with relevant health professionals to monitor your risk of blood clots.

    Supplements to avoid when you have Factor V

    Women with FVL who have a history of blood clots/VTE (venous thromboembolism) should avoid both hormone replacement therapy and contraception medications that contain estrogen, as this can increase clotting risk.22

    Supplements to avoid when you have MTHFR

    People with MTHFR mutations should avoid folic acid, the synthetic form of vitamin B9. Folic acid cannot be properly metabolized as the MTHFR enzyme is not fully functional, which can then lead to low folate levels in the body.23 Fortified foods containing folic acid should also be avoided. Instead, those with MTHFR should supplement with methylfolate, the biologically active form of folate that has been shown to bypass the MTHFR mutation and reduce homocysteine levels in the body.24

    Signs of DVT and what to do if you have DVT

    DVT (a blood clot) occurs in the largest veins that are deep within the body. The legs are most often affected, but blood clots can also occur in the arms, pelvis, or abdomen.


    A clot blocks the flow of blood through the vein, causing blood to pool.


    Signs of DVT include25:

    • pain, swelling, redness, and dilated veins in the affected part of the body
    • swelling in the area of the leg affected by the clot, usually the lower leg or thigh 
    • A throbbing pain that increases when you put weight on it
    • Tenderness in the limb 
    • Heat and redness in the area 
    • Swelling or bulging of the veins


    DVT has serious consequences if not treated immediately. Seek medical assistance as soon as you notice these symptoms. This is even more urgent if you are pregnant, have a history of blood clots, have recently had surgery, or you have any other serious illnesses. If you are taking any supplements or medication, inform your health professional. 

    Product Recommendations

    L Methylfolate 15 mg - A Mood-Boosting Supplement - Methyl-Life® Supplements

    L Methylfolate 15 mg - A Mood-Boosting Supplement
    (156)

    $76.00

    • Professional Strength - Ask Your Doctor
    • High-Dose L Methylfolate 15 Mg for Natural Mood Support2
    • 3rd-Party Tested for Purity, Potency & Safety
    • 90 Vegan, Non-GMO, Chewable Mint Tablets

    Frequently Asked Questions about MTHFR and blood clotting

    Is MTHFR a blood clotting disorder?

    No, the MTHFR genetic mutation is not a blood clotting disorder. However, people with MTHFR have a greater risk of elevated homocysteine levels, which can be a cause of blood clots.26

    Are Factor V Leiden and MTHFR the same clotting disorder?

    Factor V Leiden (FVL) is a blood clotting disorder because it is a genetic mutation that impairs the body’s ability to ‘turn off’ the clotting cascade.
    But while MTHFR is also a genetic mutation, it is not a clotting disorder. MTHFR impairs the body’s ability to process folic acid, which can increase homocysteine levels in the blood. High homocysteine is an independent risk factor for blood clots and is not necessarily caused by MTHFR alone.

    Is there any connection to MTHFR and clotting issues?

    The MTHFR mutation has been indirectly linked to blood clots. This is because MTHFR makes it difficult for the body to produce methylfolate, which is necessary for breaking down homocysteine. If the body’s levels of methylfolate are low, homocysteine can accumulate in the blood, causing inflammation in the blood vessels and an increased risk of clots. However, if you have MTHFR, you can reduce your risk of blood clots by supplementing with methylfolate and monitoring your homocysteine levels.

    What type of mutation causes Factor V Leiden?

    Factor V Leiden is caused by a single-point mutation in the factor V gene. Specifically, one building block (guanine) is swapped for another (adenine) at a specific spot (position 1691). This change alters a single amino acid in the protein, replacing arginine with glutamine at position 506.27 Factor V is a clotting protein, and this mutation makes it resistant to being deactivated. If Factor V remains active in the blood, there is a higher risk of abnormal blood clot formation (thrombophilia), raising the risk of deep vein thrombosis (DVT) and pulmonary embolism.

    References

    1. Dean L.; Methylenetetrahydrofolate Reductase Deficiency; Medical Genetics Summaries; 2012 Mar

      https://www.ncbi.nlm.nih.gov/books/NBK66131/

    2. Cirstoveanu C., Calin N., Heriseanu C., Filip C., Vasile C.M., Margarint I., Marcu V., Dimitriu M., Ples L., Bizubac M.; Consistent Correlation between MTHFR and Vascular Thrombosis in Neonates—Case Series and Clinical Considerations; Journal of Clinical Medicine; 2023 Jul

      https://pmc.ncbi.nlm.nih.gov/articles/PMC10381825/

    3. Chandler PD, Pradhan AD, Cook NR, et al.; Homocysteine Is Associated With Future Venous Thromboembolism in Women; Arteriosclerosis, Thrombosis, and Vascular Biology; 2021

      https://www.ahajournals.org/doi/10.1161/ATVBAHA.121.316397

    4. Streiff MB.; Hyperhomocysteinemia; MSD Manual Professional Edition; 2023 Aug

      https://www.msdmanuals.com/professional/hematology-and-oncology/thrombotic-disorders/hyperhomocysteinemia

    5. Lee R, Frenkel EP; Hyperhomocysteinemia and Thrombosis; Hematology/Oncology Clinics of North America; 2003 Feb

      https://pubmed.ncbi.nlm.nih.gov/12627664/

    6. Den Heijer M, Lewington S, Clarke R; Homocysteine, MTHFR and risk of venous thrombosis: a meta-analysis of published epidemiological studies; Journal of Thrombosis and Haemostasis; 2005 Feb

      https://pubmed.ncbi.nlm.nih.gov/15670035/

    7. Liu F., Silva D., Viteri Malone M., Seetharaman K.; MTHFR A1298C and C677T Polymorphisms Are Associated with Increased Risk of Venous Thromboembolism: A Retrospective Chart Review Study; Acta Haematologica; 2017 Dec

      https://pubmed.ncbi.nlm.nih.gov/29212064/

    8. Liu F., Silva D., Viteri Malone M., Seetharaman K.; MTHFR A1298C and C677T Polymorphisms Are Associated with Increased Risk of Venous Thromboembolism: A Retrospective Chart Review Study; Acta Haematologica; 2017 Dec

      https://pubmed.ncbi.nlm.nih.gov/29212064

    9. Carboni L.; Active Folate Versus Folic Acid: The Role of 5-MTHF (Methylfolate) in Human Health; Integrative Medicine (Encinitas); 2022 Jul

      https://pmc.ncbi.nlm.nih.gov/articles/PMC9380836/

    10. Drugs.com; L-Methylfolate Formula Drug Interactions; Drugs.com; 2025 Feb.

      https://www.drugs.com/drug-interactions/l-methylfolate,l-methylfolate-formula.html

    11. Romanitan MO, Popa-Cherecheanu M, Vasile VA, et al.; Highlights on Genetic Polymorphism Associated with Thromboembolic Risk; Implications in Ophthalmic and Autoimmune Disorders—A Review; Diagnostics; 2023 Mar.

      https://pmc.ncbi.nlm.nih.gov/articles/PMC10093669

    12. Pokushalov E., Ponomarenko A., Bayramova S., et al.;"Effect of Methylfolate, Pyridoxal-5′-Phosphate, and Methylcobalamin Supplementation on Homocysteine and Low-Density Lipoprotein Cholesterol Levels in Patients with Methylenetetrahydrofolate Reductase, Methionine Synthase, and Methionine Synthase Reductase Polymorphisms: A Randomized Controlled Trial"; Nutrients; 2024 May.

      https://pmc.ncbi.nlm.nih.gov/articles/PMC11173557/

    13. Al Fatly M., Mulder MT, Roeters van Lennep J, Blom HJ, Berk KAC.; The effect of diet-induced weight loss on circulating homocysteine levels in people with obesity and type 2 diabetes; Nutrition Journal; 2024 Jan

      https://pmc.ncbi.nlm.nih.gov/articles/PMC10763019

    14. Evans CR, Hong CP, Folsom AR, et al.; Lifestyle moderates genetic risk of venous thromboembolism: the Atherosclerotic Risk in Communities study; Arteriosclerosis, Thrombosis, and Vascular Biology; 2020 Sep

      https://pmc.ncbi.nlm.nih.gov/articles/PMC8498945/

    15. Coriu L., Ungureanu R., Talmaci R., Uscatescu V., Cirstoiu M., Coriu D., Copaciu E.; Hereditary Thrombophilia and Thrombotic Events in Pregnancy: Single-Center Experience; Journal of Medicine and Life; 2014 Oct-Dec

      https://pmc.ncbi.nlm.nih.gov/articles/PMC4316141/

    16. Albagoush SA, Koya S, Chakraborty RK, Schmidt AE.; Factor V Leiden Mutation; StatPearls [Internet]; Treasure Island (FL): StatPearls Publishing; 2023 Jan

      https://www.ncbi.nlm.nih.gov/books/NBK534802

    17. Albagoush SA, Koya S, Chakraborty RK, Schmidt AE.; Factor V Leiden Mutation; StatPearls [Internet]; Treasure Island (FL): StatPearls Publishing; 2023 Jan

      https://www.ncbi.nlm.nih.gov/books/NBK534802

    18. I. Pabinger, C. Ay, D. Dunkler, J. Thaler, E.‐M. Reitter, C. Marosi, C. Zielinski, C. Mannhalter; "Factor V Leiden mutation increases the risk for venous thromboembolism in cancer patients – results from the Vienna Cancer And Thrombosis Study (CATS)"; Journal of Thrombosis and Haemostasis; 2015 Jan

      https://www.sciencedirect.com/science/article/pii/S1538783622034183

    19. Bansal P.; Factor V Leiden and MTHFR mutations as a combined risk factor for hypercoagulability in referred patients population from Western India; Molecular Cytogenetics; 2014 Jan

      https://pmc.ncbi.nlm.nih.gov/articles/PMC4044653/

    20. Bansal P.; Factor V Leiden and MTHFR mutations as a combined risk factor for hypercoagulability in referred patients population from Western India; Molecular Cytogenetics; 2014 Jan

      https://pmc.ncbi.nlm.nih.gov/articles/PMC4044653/

    21. Bansal P.; Factor V Leiden and MTHFR mutations as a combined risk factor for hypercoagulability in referred patients population from Western India; Molecular Cytogenetics; 2014 Jan

      https://pmc.ncbi.nlm.nih.gov/articles/PMC4044653/

    22. Pastori D., Menichelli D., Valeriani E., Pignatelli P.; Factor V Leiden Thrombophilia; GeneReviews® [Internet]; University of Washington, Seattle; 2024 May

      https://www.ncbi.nlm.nih.gov/books/NBK1368/

    23. Carboni L.; Active Folate Versus Folic Acid: The Role of 5-MTHF (Methylfolate) in Human Health; Integrative Medicine (Encinitas); 2022 Jul

      https://pmc.ncbi.nlm.nih.gov/articles/PMC9380836/

    24. Carboni L.; Active Folate Versus Folic Acid: The Role of 5-MTHF (Methylfolate) in Human Health; Integrative Medicine (Encinitas); 2022 Jul

      https://pmc.ncbi.nlm.nih.gov/articles/PMC9380836/

    25. Paul C Kruger, John W Eikelboom, James D Douketis, Graeme J Hankey; "Deep vein thrombosis: update on diagnosis and management"; Medical Journal of Australia, Vol. 210, Iss. 11 p. 516-524; 2019 Jun

      https://onlinelibrary.wiley.com/doi/full/10.5694/mja2.50201

    26. Park WC, Chang JH.; Clinical Implications of Methylenetetrahydrofolate Reductase Mutations and Plasma Homocysteine Levels in Patients with Thromboembolic Occlusion; Vascular Specialist International; 2014 Dec

      https://pmc.ncbi.nlm.nih.gov/articles/PMC4480315/

    27. Albagoush SA, Koya S, Chakraborty RK, Schmidt AE.; Factor V Leiden Mutation; StatPearls [Internet]; Treasure Island (FL): StatPearls Publishing; 2023 Jan

      https://www.ncbi.nlm.nih.gov/books/NBK534802

    28. Banner Image Designed by Freepik

      https://www.freepik.com/

    Katie Stone - Naturopath

    About the Author

    Katie is a qualified Naturopath (BNatMed) and freelance writer from New Zealand. She specializes in all things health and wellness, particularly dietary supplements and nutrition. Katie is also a dedicated runner and has completed more half-marathons than she can count!

    Related Articles

    Can Folate Help Prevent Congenital Heart Defects? - Can Folate Help Prevent Congenital Heart Defects?

    Can Folate Help Prevent Congenital Heart Defects?

    Browse Categories