Skip to main content

Laboratory Testing for Activated Protein C Resistance (APCR): An Update

  • Protocol
  • First Online:
Hemostasis and Thrombosis

Abstract

Activated protein C resistance (APCR) reflects a hemostatic state defined by a reduced ability of activated protein C (APC) to affect an anticoagulant response. This state of hemostatic imbalance is characterized by a heightened risk of venous thromboembolism. Protein C is an endogenous anticoagulant that is produced by the hepatocytes and undergoes proteolysis-mediated activation to APC. APC in turn degrades activated Factors V and VIII. APCR describes a state of resistance by activated Factors V and VIII to APC-mediated cleavage of these factors, thereby promoting amplified thrombin production and a potentially procoagulant state. This resistance of APC may be inherited or acquired. Mutations in Factor V are responsible for the most frequent form hereditary APCR. The predominant mutation, a G1691A missense mutation at Arginine 506, the so-called Factor V Leiden [FVL], causes a deletion of an APC-targeted cleavage site in Factor Va, thereby rendering it resistant to inactivation by APC. There are a variety of laboratory assays for APCR, but this chapter focuses on a procedure using a commercially available clotting assay that utilizes a snake venom and ACL TOP analyzers.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 219.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 199.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 279.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  1. Dahlback B, Carlsson M, Svensson PJ (1993) Familial thrombophilia due to a previously unrecognised mechanism characterised by poor anticoagulant response to activated protein C: prediction of a cofactor to activated protein C. Proc Natl Acad Sci 90:1004–1008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Coppola A, Tufano A, Cerbone AM, Di Minno G (2009) Inherited thrombophilia: implications for prevention and treatment of venous thromboembolism. Semin Thromb Hemost 35:683–694

    Article  CAS  PubMed  Google Scholar 

  3. Lippi G, Danese E, Favaloro EJ, Montagnana M, Franchini M (2015) Diagnostics in venous thromboembolism: from origin to future prospects. Semin Thromb Hemost 41:374–381

    Article  PubMed  Google Scholar 

  4. Bertina RM, Koeleman BPC, Koster T et al (1994) Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 69:64–67

    Article  Google Scholar 

  5. Voorberg J, Roelse J, Koopman R et al (1994) Association of idiopathic venous thromboembolism with single point-mutation at Arg506 of factor V. Lancet 343:1535–1536

    Article  CAS  PubMed  Google Scholar 

  6. Zoller B, Dahlback B (1994) Linkage between inherited resistance to activated protein C and factor V gene mutation in venous thrombosis. Lancet 343:1536–1538

    Article  CAS  PubMed  Google Scholar 

  7. Zoller B, Svensson PJ, He X, Dahlback B (1994) Identification of the same factor V gene mutation in 47 out of 50 thrombosis-prone families with inherited resistance to activated protein C. J Clin Invest 94:2521–2524

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Pajič T (2023) Testing for Factor V Leiden (FVL) and prothrombin G20210A genetic variants. In: Favaloro EJ, Gosselin RC (eds) Hemostasis and thrombosis: methods and protocols. Methods in molecular biology. Springer, New York, pp 233–251. https://doi.org/10.1007/978-1-0716-3175-1_14

  9. Mohammed S, Favaloro EJ (2017) Laboratory testing for activated protein C resistance (APCR). Methods Mol Biol 1646:137–143. https://doi.org/10.1007/978-1-4939-7196-1_10

    Article  CAS  PubMed  Google Scholar 

  10. Favaloro EJ, Mirochnik O, McDonald D (1999) Functional activated protein C resistance assays: correlation with factor V DNA analysis is better with RVVT- than APTT- based assays. Br J Biomed Sci 56:23–33

    CAS  PubMed  Google Scholar 

  11. Favaloro EJ, Orsag I, Bukuya M, McDonald D (2002) A nine-year retrospective assessment of laboratory testing for activated protein C resistance: evolution of a novel approach to thrombophilia investigations. Pathology 34:348–355

    Article  CAS  PubMed  Google Scholar 

  12. Graf LL, Welsh CH, Qamar Z, Marlar RA (2003) Activated protein C resistance assay detects thrombotic risk factors other than Factor V Leiden. Am J Clin Pathol 119:52–60

    Article  CAS  PubMed  Google Scholar 

  13. Favaloro EJ, Mohammed S, Pati N, Manyuk H, McDonald D (2011) A clinical audit of congenital thrombophilia investigation in tertiary practice. Pathology 43:266–272

    Article  PubMed  Google Scholar 

  14. Favaloro EJ (2006) More on ‘universal’ versus ‘selected’ screening for thrombophilia: the hidden costs of false-positive diagnosis. Br J Haematol 134:239–240

    Article  PubMed  Google Scholar 

  15. Favaloro EJ, McDonald D, Lippi G (2009) Laboratory evaluation of thrombophilia: the good, the bad and the ugly. Semin Thromb Hemost 35:695–710

    Article  CAS  PubMed  Google Scholar 

  16. Favaloro EJ (2014) The futility of thrombophilia testing. Clin Chem Lab Med 52:499–503

    Article  CAS  PubMed  Google Scholar 

  17. Favaloro EJ, Lippi G (2017) Interference of direct oral anticoagulants (DOACs) in hemostasis assays: high potential for diagnostic false positives and false negatives. Blood Transfus 15(6):491–494. https://doi.org/10.2450/2016.0301-16

    Article  PubMed  PubMed Central  Google Scholar 

  18. Gosselin RC, Adcock DM, Bates SM et al (2018) International Council for Standardization in Haematology (ICSH) Recommendations for Laboratory Measurement of Direct Oral Anticoagulants. Thromb Haemost 118(3):437–450. https://doi.org/10.1055/s-0038-1627480

    Article  PubMed  Google Scholar 

  19. Douxfils J, Adcock D, Bates SM et al (2021) 2021 Update of the International Council for Standardization in Haematology Recommendations for Laboratory Measurement of Direct Oral Anticoagulants. Thromb Haemost 121(8):1008–1020. https://doi.org/10.1055/a-1450-8178

    Article  PubMed  Google Scholar 

  20. Favaloro EJ, Gilmore G, Bonar R, Dean E, Arunachalam S, Mohammed S, Baker R (2020) Laboratory testing for activated protein C resistance: rivaroxaban induced interference and a comparative evaluation of andexanet alfa and DOAC Stop to neutralise interference. Clin Chem Lab Med 58(8):1322–1331. https://doi.org/10.1515/cclm-2019-1160

    Article  CAS  PubMed  Google Scholar 

  21. Exner T, Rigano J, Favaloro EJ (2020) The effect of DOACs on laboratory tests and their removal by activated carbon to limit interference in functional assays. Int J Lab Hematol 42(Suppl 1):41–48. https://doi.org/10.1111/ijlh.13196

    Article  PubMed  Google Scholar 

  22. Favaloro EJ, Mohammed S, Vong R et al (2021) A multi-laboratory assessment of congenital thrombophilia assays performed on the ACL Top 50 family for harmonisation of thrombophilia testing in a large laboratory network. Clin Chem Lab Med 59(10):1709–1718. https://doi.org/10.1515/cclm-2021-0499

    Article  CAS  PubMed  Google Scholar 

  23. Favaloro EJ, Soltani S, McDonald J, Grezchnik E, Easton L (2006) Activated protein C resistance: the influence of ABO-blood group, gender and age. Thromb Res 117:665–670

    Article  CAS  PubMed  Google Scholar 

  24. Dean E, Favaloro EJ (2020) The changing face of activated protein C resistance testing – a 10-year retrospective. Ann Blood 5:6. https://doi.org/10.21037/aob.2020.02.06

    Article  Google Scholar 

  25. Favaloro EJ, Mohammed S, Vong R, Leonardo Pasalic P (2023) Harmonization of hemostasis testing across a large laboratory network: an example from Australia. In: Favaloro EJ, Gosselin RC (eds) Hemostasis and thrombosis: methods and protocols. Methods in molecular biology. Springer, New York, pp 71–91. https://doi.org/10.1007/978-1-0716-3175-1_5

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Emmanuel J. Favaloro .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2023 The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature

About this protocol

Check for updates. Verify currency and authenticity via CrossMark

Cite this protocol

Favaloro, E.J., Mohammed, S., Vong, R., Pasalic, L. (2023). Laboratory Testing for Activated Protein C Resistance (APCR): An Update. In: Favaloro, E.J., Gosselin, R.C. (eds) Hemostasis and Thrombosis. Methods in Molecular Biology, vol 2663. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-3175-1_11

Download citation

  • DOI: https://doi.org/10.1007/978-1-0716-3175-1_11

  • Published:

  • Publisher Name: Humana, New York, NY

  • Print ISBN: 978-1-0716-3174-4

  • Online ISBN: 978-1-0716-3175-1

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics