Does having a Methylenetetrahydrofolate Reductase (MTHFR) mutation increase the risk of thrombosis (blood clots)?

MTHFR Mutation and Risk of Blood Clots

The MTHFR mutation alone is not a significant independent risk factor for thrombosis (blood clots), and routine testing for this mutation is not recommended for thrombophilia evaluation. 1

Understanding MTHFR Mutation and Clotting Risk

The methylenetetrahydrofolate reductase (MTHFR) gene mutation has been extensively studied for its potential relationship with thrombosis. While early research suggested a possible link, more comprehensive evidence indicates:

• MTHFR mutations (particularly C677T) are common genetic variants found in 5-15% of the general population 2
• The mutation can lead to mildly elevated homocysteine levels in some individuals
• Meta-analyses show only a modest association between MTHFR C677T and venous thrombosis (OR 1.20-1.26) 1
• The association is weaker than other established thrombophilia risk factors

Evidence Analysis

The American Heart Association/American Stroke Association guidelines provide clear direction on this issue:

1. Multiple meta-analyses have examined the relationship between MTHFR C677T and thrombosis:

   • First meta-analysis: OR 1.24 (95% CI: 1.08-1.42) 1
   • Second meta-analysis: OR 1.20 (95% CI: 1.02-1.41) 1
   • Third meta-analysis focusing on homozygous TT genotype: OR 1.26 (95% CI: 1.14-1.40) 1

2. Studies show inconsistent results:

   • Some studies found no association between MTHFR mutations and thrombosis 3, 4, 5
   • Others found a modest association, particularly in younger patients 2, 6
   • Geographic variations exist, with North American studies showing no effect, possibly due to higher folate intake 6

Clinical Management Approach

If you have an MTHFR mutation:

1. Evaluate for other risk factors: The presence of MTHFR mutation alone does not warrant anticoagulation therapy 1

2. Check for venous thrombosis: If you have both MTHFR mutation and arterial ischemic stroke/TIA, evaluation for deep vein thrombosis is recommended 1

3. Consider homocysteine levels: If homocysteine is elevated (>10 μmol/L), consider vitamin supplementation 1, 7

   • Standard multivitamin with B6 (1.7 mg/d), B12 (2.4 μg/d), and folate (400 μg/d) 1
   • This may reduce homocysteine levels but has not been proven to reduce thrombosis risk

4. Anticoagulation decisions: Base these on standard thrombosis risk factors, not solely on MTHFR status 1

   • If venous thrombosis is present: Short or long-term anticoagulation is indicated
   • Without venous thrombosis: Standard antiplatelet therapy is reasonable

Important Caveats

• MTHFR testing is not recommended as part of routine thrombophilia workup
• The association between MTHFR and thrombosis is weaker in older adults with other vascular risk factors
• The effect may be more significant in younger patients (<55 years) 1
• Folate fortification in food (common in North America) may mitigate any potential risk 6
• Focus on modifiable risk factors for thrombosis rather than MTHFR status

In clinical practice, the presence of an MTHFR mutation should not significantly alter management decisions regarding thrombosis prevention unless accompanied by other significant risk factors or actual thrombotic events.