Intraindividual consistency of the activated protein C resistance phenotype

Abstract

Summary Resistance to activated protein C (APC) has been demonstrated to be a risk factor for venous thromboembolism, but it is not known whether this phenotype is consistent over time. We reinvestigated 2580 subjects from the Vicenza Thrombophilia and Atherosclerosis (VITA) Project to evaluate the prevalence of a consistent APC resistance phenotype in the population. Among the 433 subjects with an APC resistance at first visit, the phenotype was confirmed in all the 74 factor V (FV) Leiden carriers and in 124 of 359 FV Leiden negative subjects (34%). The prevalence of a confirmed phenotype, not associated with FV Leiden, was 4·8% in our population. In a subgroup of subjects previously investigated for heritability of the APC resistance, we confirmed the APC resistance phenotype in seven of 39 (17·9%) subjects with an APC resistant sibling but only in 20 of 408 (4·9%) subjects without a sibling with the same phenotype (P = 0·005). Among the 124 FV Leiden negative subjects with a persistent APC resistance phenotype, 40 (32%) had a plasma factor VIII coagulant activity level above 150 IU/dl and eight (6·4%) were carriers of the G20210A prothrombin allele. APC resistance not due to FV Leiden is a frequent and consistent phenotype in the general population, with a possibly strong genetic influence.

APC resistance: biological basis and acquired influences

“…Soon after the discovery of APC resistance it was observed that not all individuals with a poor APC‐response carry the FV Leiden mutation, which suggested the existence of additional causes of APC resistance [4,34]. APC resistance in the absence of FV Leiden is in fact very prevalent in the general population (10–15% of individuals, as determined with the aPTT‐based test [47,48]) and is also associated with an increased risk of venous thrombosis [8–10]. The underlying causes may be genetic or acquired and depend on the APC resistance assay used.…”

“…Genetic factors other than FV Leiden also importantly contribute to plasma APC resistance, as illustrated by a large population survey indicating that ∼5% of individuals who do not carry FV Leiden are APC‐resistant at repeated testing [47]. The heritability (i.e.…”

“…The effect of FVIII levels is specific for the intrinsically triggered aPTT‐based assay. Remarkably, while elevated FVIII levels are a prevalent cause of APC resistance [8,47–50], mutations affecting the APC‐cleavage sites in FVIIIa have never been identified in APC‐resistant individuals [78–80]. Elevated FIX(a) and FX(a) levels may cause APC resistance via increased protection of their cofactors FVIIIa and FVa from APC‐mediated inactivation [18,19,26].…”

APC Resistance

“…Research showed that in 10-15% of individuals who are APC resistant (as determined via an APTT-based assay), the FVLeiden mutation is not present (Taralunga et al, 2004;Tosetto et al, 2004). This implies that besides FVLeiden, other factors exist that may modify the outcome of an APC resistance assay.…”

“…In the APTT-based APC resistance assays other factors besides OC use and pregnancy were found to be prevalent among cases on non-FVLeiden APC resistance. These include high FVIII levels, elevated prothrombin levels, malignancy and the presence of lupus anticoagulants (Henkens et al, 1995;Cumming et al, 1995;Laffan & Manning, 1996;Aznar et al, 1997;Tosetto et al, 1997;de Visser et al, 1999;Castaman et al, 2001;Tosetto et al, 2004;Taralunga et al, 2004;Sarig et al, 2005). Several allelic variants of the FV gene have been described that contribute to the APC resistance phenotype and to venous thrombosis.…”