Activated Protein C Resistance (APC)

Resistance to activated protein C (APC) is a relatively frequent finding in patients with unexplained or familial venous thromboembolism (VTE), detected by a simple clotting test, the APC resistance assay. This abnormality is associated in over 95% of cases with a single point mutation in the factor V gene, termed factor V Leiden. This defect is highly prevalent, occurring in the heterozygous form in 5% of healthy Caucasians, and in 30-50% of patients with recurrent VTE. It is the most common hereditary cause of thrombosis, imparting an 8-fold increased risk of VTE in heterozygotes and an 80-fold increased risk of VTE in homozygotes. The APC resistance clotting test is an important component of laboratory panels for venous thrombosis. A normal result rules out factor V Leiden, while an abnormal result should be followed up with a PCR assay to confirm the presence of factor V Leiden.

Up until recently, most APC resistance assays were based on the APTT. While the newer versions of the APTT-based assays have offered good sensitivity (98-100%) and specificity (98-100%) for factor V Leiden diagnosis, they have had a number of disadvantages. Most significantly, lupus anticoagulants interfere with these assays, which is a problem in view of the high prevalence of both APC resistance and lupus anticoagulants in thrombophilic populations. High factor VIII levels may also affect the APTT-based assays. Furthermore, the APTT-based assays do not always provide perfect discrimination between normal individuals and those with factor V Leiden.

A new APC resistance assay became available in July 2005, using snake venoms to activate factor V and prothrombin, thus involving the lower portion of the clotting pathway and eliminating interference by factor VIII, and in the absence of phospholipid-based complexes, eliminating interference by lupus anticoagulants. Furthermore, the new assay has so far been shown to be 100% sensitive and specific for factor V Leiden, with excellent and wide discrimination between normal individuals and carriers of the factor V Leiden mutation. The assay is not affected by anticoagulation with heparin (standard or low molecular weight) or warfarin.

APC resistance assay is available as part of the venous thrombosis panels, or as an individual test. Results are reported as an “APC resistance ratio.” The reference range is ¾2.5. If an abnormal result is obtained (<2.5), the laboratory will automatically follow up with a confirmatory PCR assay for factor V Leiden.

Specimen requirement is one 5mL blue-top tube. Both the coagulation and PCR tests can be performed on the same sample.

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