Thromboembolic disease is common with an annual incidence of 1–3/1000 individuals. Both acquired and genetic risk factors are responsible. A risk factor for thrombosis can now be identified in over 80 percent of patients. Fifty percent of thrombotic events in patients with inherited thrombophilia are associated with an acquired risk factor. Patients with multiple inherited risk factors are at a greater risk. Two common variations of the MTHFR gene (677CàT and 1298AàC) result in amino acid substitutions and enhanced thermolability of the enzyme. The latter, in the presence of folic acid deficiency, results in elevated homocysteine levels. Thrombosis has been observed in these patients, but there is still controversy whether there is a direct association (
Bezemer I, et al. Arch Int Med 167, 497–501, 2007
; den Heijer M et al. J Thromb Haemost 3:292–299, 2005
). In the present study, we describe the spectrum of thromboembolic disease observed in 39 patients with a variety of MTHFR polymorphisms referred to a specialty center with a personal or family history of thromboses or obstetrical loss, 18 of these patients having no other risk factor other than MTHFR polymorphisms. These polymorphisms include 18 heterozygotes (11 with 677CàT; 7 with 1298AàC), 9 homozygotes (5 with 677CàT; 4 with 1298AàC) and 12 compound heterozygotes (677CàT and 1298AàC). Concomitant risk factors were found in twenty-one patients (factor V Leiden - 6; prothrombin G20210A - 3; protein C deficiency - 1; protein S deficiency - 1; PAI-1 polymorphism - 2; activated protein C resistance - 2; antiphospholipid antibody syndrome - 5; malignancy - 3; coronary artery disease - 1; hemolytic anemia - 1; factor VIII deficiency - 1). Types of thromboembolic manifestations observed in the 39 patients include venous thromboembolism (22), obstetrical loss (7), arterial thrombosis (3), myocardial infarction (3), ischemic CNS lesions (2), and palpable purpura (1), for a total of 38 manifestations. Seven of the patients had a family history of thromboembolic disease. Patients with only MTHFR polymorphisms suffered 16 types of thromboembolic events (16/38=42%). Our observations suggest that MTHFR polymorphisms alone do play a role in clinically relevant thrombotic disease and probably increase the incidence of these diseases in patients harboring other causes of thrombophilia. Therefore, continuing surveillance for this polymorphism as part of a clinical thrombophilia assessment is recommended, particularly if homocysteine levels are elevated.
