Hormone replacement therapy and the factor V Leiden mutation.

Abstract

In 1993, individuals with a hereditary predisposition to venous thromboembolism whose plasmas exhibited a poor response to activated protein C (APC) in an activated partial thromboplastin time assay were identified.1 The molecular basis for this laboratory phenotype of resistance to APC was a guanine to adenine mutation at nucleotide 1691 in the factor V gene.2 This results in the replacement of arginine (R) at position 506 by glutamine in the resulting protein, a defect which has been termed factor V Leiden. R506 is the first of three sites at which APC normally cleaves and inactivates procoagulant factor Va. The Q506 substitution causes factor Va to be inactivated approximately l0-fold more slowly than normal, thereby making the cofactor relatively resistant to the anticoagulant action of APC.3 This allows for increased factor Va availability within the prothrombinase complex, thereby enhancing thrombin generation and the development of a hypercoagulable state. See page 1012 Factor V Leiden is the most common inherited risk factor for venous thromboembolism, increasing the risk of venous thrombosis by 4- to 10-fold in heterozygotes and 50- to 100-fold in homozygotes.4,5⇓ Heterozygosity can be identified in 12% to 20% of unselected white patients presenting with venous thrombosis and 40% to 50% of patients with a strong positive family history. Approximately 3% to 7% of normal white patients are heterozygous carriers of factor V Leiden, but the mutation is rare in …