Hypercoagulable states can be defined as a group of inherited or acquired conditions associated with a predisposition to venous thrombosis, arterial thrombosis, or both. Venous thromboembolic disease is the most common clinical manifestation resulting from hypercoagulable states. Among them is hyperhomocysteneimia. Hyperhomocysteinemia can be precipitated by both genetic defects and acquired medical conditions, including vitamin deficiency states.
Inherited severe hyperhomocysteinemia (plasma level higher than 100 mmol/L), as seen in classic homocystinuria, may result from homozygous MTHFR or CBS deficiencies and, more rarely, from inherited errors of cobalamin (vitamin β12) metabolism. Inherited mild to moderate hyperhomocysteinemia (plasma level between 15 and 100 mmol/L) may result from heterozygous MTHFR and CBS deficiencies, but most commonly results from the C677T gene polymorphism, which is the most common mutation in the gene that codes for the MTHFR enzyme. Individuals who are heterozygous for the tlMTHFR variant have normal plasma homocysteine levels, whereas homozygous carriers may have mild to moderate fasting hyperhomocysteinemia in the setting of concomitant folate deficiency. However, homozygosity for the tlMTHFR in the absence of hyperhomocysteinemia does not appear to be associated with an increased risk of VTEs, and most patients with hyperhomocysteinemia do not have the tlMTHFR polymorphism. Excess homocysteine in the plasma is the risk factor and is the target of therapeutic intervention, not the C677T mutation. The pathophysiology of thrombosis in hyperhomocysteinemia is also unclear. Acquired homocyteneiamia may present in the absence of MTHFR mutation.
Colleen M. Johnson, MD Hypercoagulable States: A Review Vascular and Endovascular Surgery, Vol. 39, No. 2, 123-133 (2005)
Seligsohn U, Lubetsky A. Genetic susceptibility to venous thrombosis. N Engl J Med. 2001;344:1222-1231.
De Stefano V, Casorelli I, Rossi E, et al: Interaction between hyperhomocysteinemia and inherited thrombophilic factors in venous thromboembolism. Semin Thromb Hemost 2000;26:305-311
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