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Hypercoagulable states can be defined as a group of inherited or acquired conditions associated with a predisposition to venous thrombosis, arterial thrombosis, or both. Venous thromboembolic disease is the most common clinical manifestation resulting from hypercoagulable states. Among them is hyperhomocysteneimia. Hyperhomocysteinemia can be precipitated by both genetic defects and acquired medical conditions, including vitamin deficiency states.

Inherited severe hyperhomocysteinemia (plasma level higher than 100 mmol/L), as seen in classic homocystinuria, may result from homozygous MTHFR or CBS deficiencies and, more rarely, from inherited errors of cobalamin (vitamin β12) metabolism. Inherited mild to moderate hyperhomocysteinemia (plasma level between 15 and 100 mmol/L) may result from heterozygous MTHFR and CBS deficiencies, but most commonly results from the C677T gene polymorphism, which is the most common mutation in the gene that codes for the MTHFR enzyme. Individuals who are heterozygous for the tlMTHFR variant have normal plasma homocysteine levels, whereas homozygous carriers may have mild to moderate fasting hyperhomocysteinemia in the setting of concomitant folate deficiency.  However, homozygosity for the tlMTHFR in the absence of hyperhomocysteinemia does not appear to be associated with an increased risk of VTEs, and most patients with hyperhomocysteinemia do not have the tlMTHFR polymorphism. Excess homocysteine in the plasma is the risk factor and is the target of therapeutic intervention, not the C677T mutation. The pathophysiology of thrombosis in hyperhomocysteinemia is also unclear. Acquired homocyteneiamia may present in the absence of MTHFR mutation.

A recent review (Abrahams and Cho et al) concludes: “Although evidence suggests that the homocysteine hypothesis is still relevant as a predictor of cardiovascular risk, we cannot conclude that measuring the homocysteine level is useful in guiding treatment. Furthermore, studies of primary and secondary prevention show no evidence that taking folic acid or other B vitamins lowers the risk of cardiovascular events.”

ACMG Recommendations:

• MTHFR polymorphism genotyping should not be ordered as part of the clinical evaluation for thrombophilia or recurrent pregnancy loss.
•  MTHFR polymorphism genotyping should not be ordered for at risk family members.
• A clinical geneticist who serves as a consultant for a patient in who an MTHFR polymorphism(s) is found should ensure that the patient has received a thorough and appropriate evaluation for his or her symptoms.
• If the patient is homozygous for the “thermolabile” variant c.665CT, the geneticist may order a fasting total plasma homocysteine, if not previously ordered, to provider more accurate counseling.
•  MTHFR status does not change the recommendation that women of childbearing age should take the standard dose of folic acid supplementation to reduce the risk of neural tube defects as per the general population guidelines.

American College of Medical Genetics Practice Guidelines: Lack of Evidence for MTHFR Polymorphism Testing. Scott E. Hickey, M.D., FACMG, Cynthia J. Curry, M.D., FACMG and Helga V. Toriello, PhD, FACMG, Genetics in Medicine 2013:15(2):153-156

Colleen M. Johnson, MD Hypercoagulable States: A Review Vascular and Endovascular Surgery, Vol. 39, No. 2, 123-133 (2005)

U.S. Preventive Services Task Force (USPSTF). Using Nontraditional Risk Factors in Coronary Heart Disease Risk Assessment: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med
October 6, 2009 vol. 151 no. 7 474-482.

TJOELLYN M. ABRAHAM, MD, LESLIE CHO, MD The homocysteine hypothesis: Still relevant to the prevention and treatment of cardiovascular disease? Cleveland Clinic Journal of Medicine December 2010 vol. 77 12 911-918

Seligsohn U, Lubetsky A. Genetic susceptibility to venous thrombosis. N Engl J Med. 2001;344:1222-1231.

De Stefano V, Casorelli I, Rossi E, et al: Interaction between hyperhomocysteinemia and inherited thrombophilic factors in venous thromboembolism. Semin Thromb Hemost 2000;26:305-311