lunes, 25 de agosto de 2014

Activated Protein C Resistance Assay and Factor V Leiden — NEJM

Activated Protein C Resistance Assay and Factor V Leiden — NEJM

Activated Protein C Resistance Assay and Factor V Leiden

N Engl J Med 2014; 371:685-686August 14, 2014DOI: 10.1056/NEJMc1405664

To the Editor:

The factor V Leiden (F5) R506Q mutation is associated with a genetic disorder1 that has a solid phenotype and a poor response to activated protein C,2 which may lead to venous thromboembolism, pulmonary thromboembolism, or both (with the use of combined oral contraceptives), and miscarriage.3 The clinical phenotype of factor V Leiden is still determined by means of activated partial-thromboplastin time–based first- and second-generation activated protein C resistance assays. Discrepancies between activated protein C resistance and factor V Leiden assays can be due to lupus anticoagulants, heparin, protein C, protein S, antithrombin, fibrinogen, factor VIII, and factor X. We hypothesize that the use of a third-generation activated protein C resistance assay alone is both reliable and economical.
Factor V Leiden polymerase-chain-reaction–based genetic testing is usually considered to be a superior screening method for detecting thrombophilia. Thus, it is generally performed in persons with a history of thrombophilia and before the use of hormonal contraception. Moreover, genetic and functional testing is performed because of concerns that 50% of cases of thrombophilia occur despite negative findings in all preclinical tests. In our study, we found that genetic testing does not provide additional information, and, as exemplified in the following index cases,4,5 can be misleading (Figure 1BFIGURE 1Results of Activated Protein C Resistance Testing to Detect Factor V Leiden Polymorphisms.).
If heterozygosity for the factor V Leiden polymorphism is genetically verified but activated protein C resistance testing yields normal results, an increased risk of thromboembolism is assumed because the genetic test is considered to be more precise. A careful investigation of the family pedigree of such an index person, including all relatives who were heterozygous for the factor V Leiden mutation, revealed no thromboembolism. DNA sequencing yielded a novel mutation that was registered and described as factor V Graz.4 In this instance, conventional factor V Leiden genetic testing led to an assignment of risk that is not warranted.
Conversely, strongly increased activated protein C resistance that is generally detected in homozygotes with the factor V Leiden genotype is also occasionally detected in persons with a genetic test that shows heterozygosity. This pseudo-homozygosity is clinically relevant because it indicates an increased risk of thrombophilia that has been attributed to other factor V gene mutations.5 The genetic test fails to indicate the real risk, but the functional activated protein C resistance test allows the clinically relevant risk to be managed sufficiently.
Inaccurate test results may also be seen in recipients of bone marrow transplants from donors with different factor V Leiden genotypes.
The functional activated protein C resistance test costs approximately $5; the genetic test costs approximately $60. In our cohort, $2,611,260 was saved without sacrificing reliability (see theSupplementary Appendix, available with the full text of this letter at Nevertheless, the strongest argument for functional activated protein C resistance testing is its reliable prediction of the increased clinical risk of thrombosis.
As compared with genetic testing, we found that third-generation functional testing for activated protein C resistance was more reliable and more economical for clinical use.
Florian Prüller, M.D.
Eva-Christine Weiss, M.D.
Reinhard B. Raggam, M.D.
Mila Cervar-Zivkovic, M.D.
Wilfried Renner, Ph.D.
Jasmin Wagner, M.D.
Medical University of Graz, Graz, Austria
Simon Michaelis, M.D.
Academic Teaching Hospital Feldkirch, Feldkirch, Austria
Winfried März, M.D.
Synlab Services, Mannheim, Germany
Harald Mangge, M.D.
Medical University of Graz, Graz, Austria
Disclosure forms provided by the authors are available with the full text of this letter at
5 References

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