Maximising the diagnostic potential of APTT-based screening assays for activated protein C resistance

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Abstract

Introduction:

Activated protein C resistance (APC-R) due to FV Leiden is the most common hereditary thrombophilia. Rarer FV mutations can also confer APC-R, and acquired APC-R is encountered in a number of conditions. APC-R screening with clotting tests is common, yet they are prone to interferences and elevated baseline clotting times can invalidate testing.

Methods:

APTT-based classic APC-R (CAPC-R) screening, and modified screening (MAPC-R) employing dilution in FV-deficient plasma were performed on an automated analyser. Baseline clotting times and APC-R ratios of 1340 patients being screened for hereditary and acquired thrombophilia were assessed for analytical and diagnostic validity.

Results:

Most patients (1117/1340) had normal baseline clotting times, and in 270 of these cases, this was despite the presence of a lupus anticoagulant (LA). FV Leiden was genetically confirmed in all patients with reduced CAPC-R and MAPC-R ratios. A subgroup with normal CAPC-R but reduced MAPC-R also identified FV Leiden, but also other patients with minimally reduced MAPC-R ratios not due to FV Leiden. Reduced CAPC-R and normal modified APC-R identified possible acquired APC-R in 49 patients. LA-positive patients with elevated baseline clotting times did not affect distinction between APC-R and normality, although therapeutic anticoagulation did invalidate CAPC-R, and occasionally MAPC-R too.

Conclusions:

Many departments only screen with MAPC-R to detect just FV mutations. Concurrent performance of CAPC-R and MAPC-R increases diagnostic capability by detecting acquired APC-R. Elevated baseline clotting times can invalidate APC-R ratios, although prolongation by LA alone may not.

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