MTHFR Mutation and DVT Risk
MTHFR mutations alone (heterozygous or homozygous) do NOT cause DVT and should not be considered a clinically significant thrombophilic risk factor in isolation. 1, 2
The Evidence Against MTHFR as a DVT Risk Factor
The relationship between MTHFR mutations and DVT is controversial and largely refuted by high-quality guidelines:
Heterozygous MTHFR C677T mutation, found in 30-40% of the general population, is not associated with venous thrombosis according to major genetic medicine guidelines 1
The MTHFR 1298 A→C mutation shows no increased risk for DVT, with odds ratios of 1.07 for heterozygotes and 0.83 for homozygotes—essentially no effect 3
Do not attribute thrombotic risk to MTHFR heterozygous status alone, as this is a common clinical pitfall 1
What Actually Matters: Hyperhomocysteinemia
The critical distinction is that elevated homocysteine levels (>15 μmol/L), not the MTHFR genotype itself, confer increased DVT risk 1:
- Homocysteine levels >15 μmol/L increase DVT odds by 2.5-fold 1
- Risk begins to increase as fasting plasma homocysteine exceeds 10 μmol/L 1
- Hyperhomocysteinemia is the relevant thrombotic risk factor, not the genetic variant 1
When MTHFR May Contribute to Risk
MTHFR mutations can increase DVT risk only in specific contexts:
Combined with Other Thrombophilias
- Homozygous MTHFR C677T (TT genotype) combined with Factor V Leiden increases risk 17.3-fold, compared to 6.3-fold for Factor V Leiden alone 4
- The combination of hyperhomocysteinemia with Factor V Leiden increases DVT risk 20-fold 1
- Homozygous TT MTHFR genotype shows independent association with DVT (OR 1.6-1.7), particularly in patients with other predisposing risk factors 5
Compound Heterozygosity
- Compound heterozygous state (677CT/1298AC) is associated with 3.5-fold increased risk for thrombosis 6
- This specific combination appears to be an independent risk factor in some populations 6
Clinical Approach to MTHFR and DVT
Testing Recommendations
Routine genetic thrombophilia testing, including MTHFR, is NOT recommended for adults with first unprovoked DVT, as it does not change management or improve outcomes 2
If a patient has DVT and MTHFR mutation is identified, measure homocysteine levels to determine if hyperhomocysteinemia is present 1
Confirm elevated homocysteine with repeat fasting measurement due to testing complexity 1
Management Based on Homocysteine Levels
If hyperhomocysteinemia is present (>15 μmol/L):
Measure serum and erythrocyte folate, serum cobalamin (B12), and serum/urine methylmalonic acid to determine the etiology 1
Folate deficiency requires oral folate supplementation; B12 deficiency requires parenteral cobalamin 1
Folate supplementation can lower homocysteine levels even in states of mild relative deficiency 1
Monitor treatment efficacy by measuring homocysteine levels after supplementation 1
When to Consider Thrombophilia Testing
Testing may be considered in specific high-risk scenarios 2:
- Patients under 50 years old with any venous thrombosis
- Unusual thrombosis sites (cerebral, mesenteric, portal veins)
- Recurrent thrombosis
- Strong family history of VTE in first-degree relatives
Key Clinical Pitfalls to Avoid
Never attribute DVT solely to MTHFR mutation status—this is the most common error in clinical practice 1
Do not test asymptomatic family members for MTHFR mutations, as the absolute VTE risk remains low and prophylactic anticoagulation carries significant bleeding risk (3% annual major bleeding rate with 0.6% case fatality) 2
Recognize that Factor V Leiden and Prothrombin G20210A are the clinically significant hereditary thrombophilias, not MTHFR 7
Factor V Leiden increases DVT risk 4-7 fold (heterozygous) and 9-80 fold (homozygous) 7
Prothrombin G20210A increases DVT risk 2-4 fold 7