American Society for Clinical Laboratory Science

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Released June 10, 2020

Don’t order a factor V Leiden (FVL) 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.

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, have 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 FVL 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 FVL mutation assay is used as a primary assay.

These items are provided solely for informational purposes and are not intended as a substitute for consultation with a medical professional. Patients with any specific questions about the items on this list or their individual situation should consult their physician.

How The List Was Created

George Fritsma, MS, MLS (ASCP), and the late Cindy Johns, MS, MLS (ASCP) hosted a plenary presentation “Enhancing Laboratory Communication to Reduce Extra-analytical Errors” at the ASCLS Clinical Laboratory Educators’ Conference in Boston in February 2017. Their talk referenced the ABIMF Choosing Wisely initiative. Subsequent discussions resulted in the ASCLS Board of Directors appointing a Choosing Wisely task force that evolved to a standing committee. The committee is composed of ASCLS members representing all medical laboratory science disciplines.

The committee collaborated with respective ASCLS Scientific Assemblies in developing and reviewing recommendations, which the Board of Directors reviewed and accepted for publication. The recommendations were subsequently reviewed in collaboration with the ASCP Test Utilization Steering Committee prior to submission.



American Society for Clinical Laboratory Science (ASCLS) recommendations were developed under the leadership of ASCLS’s Choosing Wisely Committee and the ASCLS president and executive vice president. The Committee examined numerous options based on evidence available through an extensive review of  the literature and member proposals. Subject matter experts from the ASCLS Scientific Assemblies reviewed and recommended approval of their respective recommendations, which are subsequently approved by the ASCLS Board of Directors. The recommendations were subsequently reviewed in collaboration with the ASCP Test Utilization Steering Committee prior to submission.


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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 Applied Thromb/Hemostas 2008: 428–37.

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. Accepted for Publication, doi: 10.1111/jth.14532.

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;151:302–5.