Thrombophilia: How To Test? How To Manage?

By Julie Hambleton, MD

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Hyperhomocysteinemia

The early descriptions of patients with hyperhomocysteinemia involved homozygous mutations in genes encoding for enzymes of homocysteine metabolism resulting in a severe multisystem disease with neurologic and vascular manifestations. Severe elevations in plasma homocysteine are also associated with homozygous defects of the methylenetetrahydrofolate reductase (MTHFR) gene or of various enzymes that participate in the vitamin B₁₂ cycle. However, these mutations are uncommon. The more common causes of hyperhomocysteinemia are subtle in presentation and may be caused by less severe defects in genes encoding for enzymes or from inadequate status of those vitamins that are involved in homocysteine metabolism. Inadequate folate, vitamin B₁₂, or pyridoxine may result in a substantial increase in plasma homocysteine concentrations. More recently, a thermolabile polymorphism of the MTHFR gene was found to be associated with elevated homocysteine levels in the setting of folate deficiency.

Mild (16 to 24 mmol/L) and moderate (25 to 100 mmol/L) hyperhomocysteinemia both have been shown to be independent risk factors for stroke, myocardial infarction, peripheral arterial disease, and extracranial carotid artery stenosis. Hyperhomocysteinemia has also been shown to be a risk factor for venous thromboembolic disease. Furthermore, it appears to augment the independent risk of VTE associated with oral contraceptive use, pregnancy, trauma, surgery, immobilization, and other disorders of thrombophilia, most notably factor V Leiden mutation and the lupus anticoagulant.

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