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Quick Question: FVL Order

Our Quick Question for May, 2019 was “A rheumatologist orders a thrombophilia profile that includes a genotypic factor V Leiden mutation assay. You…

A. Proceed with the FVL assay: 40% (14)
B. First perform the phenotypic APCR: 51% (18)
C. Cancel the order: 9% (3)

George posted this because the American Society for Clinical Laboratory Science Choosing Wisely task force has developed the following recommendation for the American Board of Internal Medicine Foundation Choosing Wisely initiative. Our survey results indicate a clear division between those who would proceed with the genotypic molecular assay and those who would substitute the phenotypic activated protein C resistance ratio assay. We’d like to see arguments supporting both approaches. Three of us would simply cancel the order, perhaps reflecting the general over-use of thrombophilia profiles. Let’s add this approach to the mix.

Don’t order a factor V Leiden (FVL) mutation assay to identify a congenital cause for a thrombotic event. Order the phenotypic activated protein C resistance (APCR) ratio assay.
There exist several acquired activated protein C resistance conditions such as anti-protein C autoantibodies in antiphospholipid syndrome and multiple myeloma, and a few rare additional factor V mutations besides the Leiden mutation that may associate with thrombosis.[i],[ii],[iii] Best practice approaches recommend testing for APCR as an initial assay and following up positive APCR results with the molecular factor V Leiden assay. Phenotypic testing has near 100% sensitivity, specificity, and predictive values for the results of FVL molecular testing.[iv] Based on Medicare reimbursement rates, switching to initial-phase phenotypic testing with follow-up genotypic testing could result in a 75% reduction in costs.4

1 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: 1801–9.
2 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.
3 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.
4 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.



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