From the Guidelines
Vitamin B12 and folate deficiencies increase the risk of thrombosis primarily by elevating homocysteine levels in the blood, which damages the endothelial lining of blood vessels and promotes a prothrombotic environment. When these essential vitamins are lacking, the body cannot properly metabolize homocysteine, leading to hyperhomocysteinemia. This excess homocysteine has been associated with increased circulating Hcy levels, and these are the first therapeutic targets in the treatment of homocysteinaemia, as shown in a study published in the European Heart Journal 1.
Mechanisms of Thrombosis
The mechanisms by which homocysteine increases the risk of thrombosis include:
- Damaging the endothelial lining of blood vessels
- Promoting platelet aggregation
- Impairing fibrinolysis
- Increasing tissue factor expression
- Activating inflammatory pathways and oxidative stress, further damaging blood vessels and promoting clot formation, as suggested by the study on homocysteine and coronary atherosclerosis 1.
Clinical Significance
The relationship between vitamin B12 and folate deficiencies and thrombosis risk is clinically significant, as studies show that individuals with B12 or folate deficiencies have a higher risk of venous thromboembolism compared to those with normal levels. However, a meta-analysis of eight RCTs concluded that homocysteine-lowering interventions did not reduce the risk of fatal/non-fatal myocardial infarction, stroke, or death by any cause 1.
Treatment and Screening
Treatment involves supplementation with vitamin B12 (typically 1000 mcg daily) and folate (1-5 mg daily), which can normalize homocysteine levels within weeks. For patients with unexplained thrombotic events, especially at young ages or unusual sites, screening for these vitamin deficiencies is recommended as part of a comprehensive hypercoagulability workup. Oral administration of folic acid (0.5–5.0 mg/day) reduces fasting Hcy levels by 25–30%, while supplementation with vitamin B12 (0.02–1 mg/day) yields an additional 7% reduction in Hcy levels, as shown in the study on homocysteine and coronary atherosclerosis 1.
From the Research
Vitamin B12 and Folate Deficiency
Vitamin B12 and folate deficiencies can increase the risk of thrombosis due to several factors.
- Hyperhomocysteinemia is a known risk factor for thrombosis, and vitamin B12 and folate play a crucial role in homocysteine metabolism 2.
- A study found that patients with acquired vitamin B12 and/or folate deficiency had a high risk of thrombosis, and hyperhomocysteinemia was responsible for arterial thrombotic risk in these patients 2.
- The association between homocysteine, vitamin B12, folic acid, and MTHFR C677T is weak, which raises doubt about the current routine evaluation of hyperhomocysteinemia as part of thrombophilia workup 3.
Mechanism of Thrombosis
The mechanism of thrombosis in vitamin B12 and folate deficiency is not fully understood, but it is thought to be related to the following factors:
- Hyperhomocysteinemia, which can damage the endothelium and promote thrombosis 2, 4.
- Impaired methylation and DNA synthesis, which can lead to changes in blood vessel function and coagulation 5, 6.
- Increased levels of methylmalonic acid and homocysteine, which can be used as diagnostic biomarkers for vitamin B12 deficiency 5, 6.
Clinical Implications
Vitamin B12 and folate deficiencies can have significant clinical implications, including: