Choosing Wisely:

Don’t order a factor V Leiden mutation assay as the initial test to identify a congenital cause for a thrombotic event. First, order a phenotypic activated protein C resistance (APCR) ratio assay.

Rationale and Comments: There exist several acquired APCR conditions such as elevated factor VIII and antibody-mediated APCR that can lead to thrombotic events such as deep venous thrombosis or pulmonary embolism. Further, several factor V Leiden-independent mutations may be associated with thrombosis. Best practice guidelines recommend testing for APCR using one of several phenotypic clot-based APCR ratio assays as an initial assay and following up positive APCR ratio results with the molecular factor V Leiden assay. Most currently available phenotypic tests are economical, with a greater than 95% concordance with molecular testing and up to 99% clinical sensitivity. Based on Medicare reimbursement rates, switching to initial-phase phenotypic testing and relying on its negative predictive value with follow-up genotypic testing on APCR-positive samples could result in a 75% reduction in costs. Although the factor V Leiden mutation assay is often ordered to determine the cause of venous thromboembolic disease, the APCR ratio assay provides greater clinical sensitivity at a lower cost. In instances when clot-based thrombosis risk testing is indicated during acute thrombosis, line-associated thrombosis, or anticoagulant therapy, the APCR is compromised and the factor V Leiden mutation assay is used as a primary assay.
Sponsoring Organizations:
  • American Society for Clinical Laboratory Science
  • Sources:
  • Expert consensus
  • Disciplines:
  • Hematologic
  • References: • Arachchillage DRJ, Efthymiou M, Mackie IJ, et al. Anti-protein C antibodies are associated with resistance to endogenous protein C activation and a severe thrombotic phenotype in antiphospholipid syndrome. J Thromb Haemost. 2014;12:1801-1809.
    • Elice F, Fink L, Tricot G, Barlogie B, Zangar M. Acquired resistance to activated protein C (aAPCR) in multiple myeloma is a transitory abnormality associated with an increased risk of venous thromboembolism. Brit J Haematol. 2006;134:394-405.
    • Majluf-Cruz A, Moreno-Hernández M, Ruiz-de-Chávez-Ochoa A, et al. Activated protein C resistance and factor V Leiden in Mexico. Clin Appl Thromb Hemost. 2008;14(4):428-437.
    • Moore GW, Van Cott EM, Cutler JA, Mitchell MJ, Adcock DM. Recommendations for clinical laboratory testing of activated protein C resistance; communication from the SSC of the ISTH. J Thromb Haemost. 2019;17(9):1555-1561.
    • Murphy CH, Sabath DE. Comparison of phenotypic activated protein C resistance testing with a genetic assay for factor V Leiden. Am J Clin Pathol. 2019;151:302-305.

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