The discovery of activated protein C resistance

Abstract

Venous thrombosis is a multifactorial disease, with the pathogenesis involving genetic and environmental risk factors. The most common genetic risk factor known to date is a single point mutation in the gene of coagulation factor V (FV), which results in the replacement of Arg506 with Gln (FV Leiden). Arg506 is one of several cleavage sites in FV for anticoagulant activated protein C (APC) and the mutation results in the loss of the cleavage site. Via a complicated series of reactions, this results in impaired APC-mediated degradation of both FVa and FVIIIa. The associated hypercoagulable condition, which causes a lifelong increased risk of thrombosis, is known as APC resistance. APC resistance was discovered in my laboratory in the late 1980s and we published the first report almost exactly 10 years ago. This started an avalanche of research activities and several thousand articles have since been published on this topic. Analyses for APC resistance and FV Leiden have made their way into clinical medicine and are now performed routinely all over the world. I have been asked to write a personal historical annotation about the discovery of APC resistance, the early research activities and the rapid progress in this field. © 2003 International Society on Thrombosis and Haemostasis.