The phenomenon known as acquired activated protein C resistance

Resistance to the effect of activated protein C (APC), added to plasma from patients with a history of deep-vein thrombosis, was reported by Amer et al (1990), and the significance of inherited resistance was recognized by Dahlback et al (1993). In the majority of subjects, inherited resistance results from the Leiden mutation (factor V Leiden, FVL) in the gene coding for coagulation factor V (Bertina et al, 1994), although a number of other genetic variations have been described in the factor V gene associated with an APC resistance phenotype. Inherited resistance has been identified as a significant risk factor for venous thrombosis (Griffin et al, 1993; Koster et al, 1993), late fetal loss (Martinelli et al, 2000) and pre-eclampsia (Dizon-Townson et al, 1996). In recent years, the potential significance of resistance occurring in the absence of known mutations of the factor V gene has been recognized. A number of authors have coined the term acquired APC resistance for this phenomenon. The investigation of APC resistance by Dahlback et al (1993) was based on the effect of APC on an activated partial thromboplastin time (aPTT). Since then, it has been recognized that the originally described aPTT-based test is not specific for the Leiden mutation. Indeed, in the intervening years, many strategies have been devised to render coagulation-based APC resistance assessments more specific for FVL (de Ronde & Bertina, 1994; Jorquera et al, 1994; Varadi et al, 1995; Nicolaes et al, 1996). Despite this drive to improve specificity, studies that used the original aPTT-based test or techniques that remain sensitive to a variety of causes of APC resistance (Gable et al, 1997; Nicolaes et al, 1997) have shown that the degree of resistance (in FVL-negative subjects) relates to: X thrombin generation (Clark et al, 1999; Lowe et al, 1999); X venous thrombosis risk (de Visser et al, 1999); X cerebrovascular disease risk (van der Bom et al, 1996; Kiechl et al, 1999); X pre-eclampsia risk (Clark et al, 2001a); X the presence of antiphospholipid activity (Hampton et al, 1994); X combined oral contraceptive use (Osterud et al, 1994; Henkens et al, 1995; Olivieri et al, 1995), in particular thirdgeneration oral contraceptive use (Rosing et al, 1997). A substantial number of questions are posed by these observations. These are typified by the debate resulting from the observation that use of the third-generation combined oral contraceptive pill (COCP) is associated with more APC resistance than second-generation COCPs (Rosing et al, 1997). The authors used an APC resistance test based upon the thrombin generation resulting from tissue factoractivated plasma. However, a comparable differential of resistance has not been seen with aPTT-APC resistance tests (Henkens et al, 1995; Olivieri et al, 1995; Schramm & Heinemann, 1997), a finding that has subsequently been confirmed by Rosing's own group (Curvers et al, 1999). Although this variance has highlighted the difficulty of diagnosing acquired APC resistance, it is likely to afford an opportunity to understand the mechanism of the additional risk of venous thrombosis (venous thromboembolim, VTE) associated with third-generation COCPs (Vandenbroucke & Rosendaal, 1997). From this debate, it is clear that the detection of acquired APC resistance requires consideration of the method of testing and the population under study. The APC resistance phenotype does, however, correlate with markers of in vivo thrombin generation (Freyburger et al, 1997; Clark et al, 1999; Lowe et al, 1999) and may indicate an overall prothrombotic phenotype. What information, then, does APC resistance testing give us and, given the myriad of influences upon it, can APC resistance testing (in non-FVL subjects) be tamed to provide a useful tool in the assessment of thrombotic risk?