Activated protein C resistance test
SynonymsAPC resistance test; Activated protein C resistance assay; APC resistance assay; APCR test; APCR assay
Test ofActivated protein C resistance, coagulation, hypercoagulability

The activated protein C resistance (APCR) test is a coagulation test used in the evaluation and diagnosis of activated protein C (APC) resistance, a form of hypercoagulability.[1][2] Hereditary APC resistance is usually caused by the factor V Leiden mutation, whereas acquired APC resistance has been linked to antiphospholipid antibodies, pregnancy, and estrogen therapy.[3][4][5][6] APC resistance can be measured using either an activated partial thromboplastin time (aPTT)-based test or an endogenous thrombin potential (ETP)-based test.[5][4][2]

Methodology

The aPTT-based APC resistance test involves a modified aPTT test performed in the presence and absence of activated protein C (APC).[1][5] The ratio of these aPTT values is calculated and is called the APC sensitivity ratio (APCsr) or simply APC ratio (APCr).[1][5] This ratio is inversely related to the degree of APC resistance.[7] The ETP-based APC resistance test involves the addition of APC to a thrombin generation assay (TGA).[5] This results in an inhibition of thrombin generation as measured by reduction of the endogenous thrombin potential (ETP; area under the thrombin generation curve).[5] The result is expressed as a normalized APC sensitivity ratio (nAPCsr), which corresponds to the ratio of the ETP measured in the presence and absence of APC divided by the same ratio in reference plasma.[5] nAPCsr values range from 0 to 10.[5] Opposite to the case of the APCsr with the aPTT-based APC resistance test, higher nAPCsr values indicate greater APC resistance.[5][8] This is the result of the fact that APC prolongs the aPTT but inhibits thrombin generation.[8]

Whereas the aPTT-based APC resistance test only measures the initiation phase of coagulation, the ETP-based test is a global assay and measures the initiation, propagation, and termination phases of coagulation.[5][9] The initiation phase accounts for less than 5% of total thrombin generation, making aPTT-based tests poorly indicative of hypercoagulability in general.[10][11] The aPTT-based assay is more sensitive to levels of prothrombin and factor VIII, whereas the ETP-based test is more sensitive to levels of tissue factor pathway inhibitor (TFPI) and protein S.[5] The ETP-based test has traditionally been performed using methods such as the calibrated automated thrombogram (CAT) and has been limitedly available due to its technical difficulty.[2] Recently however, a fully automated commercial test system called the ST Genesia has been introduced, and it has been said that this should allow for adoption of TGAs and ETP-based APC resistance tests in routine clinical settings.[2][12]

Influences

Thrombin generation curves in the absence (HPP -APC) and presence (HPP +APC) of activated protein C (APC) in healthy pooled plasma and in plasma of women on various combined oral contraceptives.[5] The contraceptives are estetrol/drospirenone (E4/DRSP), ethinylestradiol/levonorgestrel (EE/LNG), ethinylestradiol/desogestrel (EE/DSG), and ethinylestradiol/drospirenone (EE/DRSP).[5]

Estrogens are well known to increase APC resistance, which has been described as acquired APC resistance.[2][5][4][13][14] However, the aPTT-based APC resistance test is much less sensitive to the procoagulatory effects of estrogens than is the ETP-based test.[13][14][5][4][2][15] Pregnancy[7] and ethinylestradiol (EE)-containing combined birth control pills increase APC resistance as measured by either the aPTT- or ETP-based test.[4][5][15] EE-containing birth control pills show different degrees of influence on the ETP-based test depending on the progestin, which may be due to varying degrees of androgenic antagonism of ethinylestradiol-mediated procoagulation.[5][4] In contrast to EE-containing birth control pills, studies have not found increased APC resistance with menopausal hormone therapy or with estetrol- or estradiol-containing birth control pills using the aPTT-based test, though increased APC resistance has been shown with the ETP-based test.[14] The increase in APC resistance is much greater with oral estrogens than with transdermal estradiol.[14] Increased APC resistance with both the aPTT-based and ETP-based tests has been observed with feminizing hormone therapy in transgender women, which involves higher doses of estradiol than are used in other contexts.[16][17] EE produces a much stronger increase in APC resistance than does estradiol.[18][17] In relation to this, ethinylestradiol is associated with a higher risk of venous thromboembolism (VTE) than is estradiol.[18][19][20]

History

The aPTT-based APC resistance test was developed in 1993, while the ETP-based test was developed in 1997.[5] For many years, the ETP-based APC resistance test suffered from a lack of standardization which hampered study-to-study comparison.[21] By 2020 however, a validated methodology was developed aiming to propose a standardized and harmonized scale for ETP-based APC resistance, the normalized activated protein C sensitivity ratio (nAPCsr).[21]

References

  1. 1 2 3 Amiral J, Vissac AM, Seghatchian J (December 2017). "Laboratory assessment of Activated Protein C Resistance/Factor V-Leiden and performance characteristics of a new quantitative assay". Transfus Apher Sci. 56 (6): 906–913. doi:10.1016/j.transci.2017.11.021. PMID 29162399.
  2. 1 2 3 4 5 6 Reda S, Morimont L, Douxfils J, Rühl H (August 2020). "Can We Measure the Individual Prothrombotic or Prohemorrhagic Tendency by Global Coagulation Tests?". Hamostaseologie. 40 (3): 364–378. doi:10.1055/a-1153-5824. PMID 32726831. S2CID 220878363.
  3. ↑ Kujovich JL (January 2011). "Factor V Leiden thrombophilia". Genet Med. 13 (1): 1–16. doi:10.1097/GIM.0b013e3181faa0f2. PMID 21116184. S2CID 220861191.
  4. 1 2 3 4 5 6 Douxfils J, Morimont L, Bouvy C (November 2020). "Oral Contraceptives and Venous Thromboembolism: Focus on Testing that May Enable Prediction and Assessment of the Risk". Semin Thromb Hemost. 46 (8): 872–886. doi:10.1055/s-0040-1714140. PMID 33080636. S2CID 224821517.
  5. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Morimont L, Haguet H, Dogné JM, Gaspard U, Douxfils J (2021). "Combined Oral Contraceptives and Venous Thromboembolism: Review and Perspective to Mitigate the Risk". Front Endocrinol (Lausanne). 12: 769187. doi:10.3389/fendo.2021.769187. PMC 8697849. PMID 34956081.
  6. ↑ Bremme KA (June 2003). "Haemostatic changes in pregnancy". Best Pract Res Clin Haematol. 16 (2): 153–68. doi:10.1016/s1521-6926(03)00021-5. PMID 12763484.
  7. 1 2 Clark P (February 2003). "Changes of hemostasis variables during pregnancy". Semin Vasc Med. 3 (1): 13–24. doi:10.1055/s-2003-38329. PMID 15199489. S2CID 36952311.
  8. 1 2 Mueck AO (2010). "Exogenous hormones, the risk of venous thromboembolism, and activated protein C resistance". Menopause. 17 (6): 1099–103. doi:10.1097/gme.0b013e3181fa264c. PMID 20975607.
  9. ↑ Castoldi E, Rosing J (February 2011). "Thrombin generation tests". Thromb Res. 127 (Suppl 3): S21–5. doi:10.1016/S0049-3848(11)70007-X. PMID 21262433.
  10. ↑ Lim HY, Leemaqz SY, Torkamani N, Grossmann M, Zajac JD, Nandurkar H, Ho P, Cheung AS (July 2020). "Global Coagulation Assays in Transgender Women on Oral and Transdermal Estradiol Therapy". J Clin Endocrinol Metab. 105 (7): e2369–e2377. doi:10.1210/clinem/dgaa262. PMID 32413907. S2CID 218659931.
  11. ↑ Baglin T (September 2005). "The measurement and application of thrombin generation". Br J Haematol. 130 (5): 653–61. doi:10.1111/j.1365-2141.2005.05612.x. PMID 16115120. S2CID 9701861.
  12. ↑ Favaloro EJ, Lippi G (April 2019). "Recent Advances in Mainstream Hemostasis Diagnostics and Coagulation Testing". Semin Thromb Hemost. 45 (3): 228–246. doi:10.1055/s-0038-1676579. PMID 30912101. S2CID 85517668.
  13. 1 2 Tchaikovski SN, Rosing J (July 2010). "Mechanisms of estrogen-induced venous thromboembolism". Thromb Res. 126 (1): 5–11. doi:10.1016/j.thromres.2010.01.045. PMID 20163835.
  14. 1 2 3 4 Hemelaar M, van der Mooren MJ, Rad M, Kluft C, Kenemans P (September 2008). "Effects of non-oral postmenopausal hormone therapy on markers of cardiovascular risk: a systematic review". Fertil Steril. 90 (3): 642–72. doi:10.1016/j.fertnstert.2007.07.1298. PMID 17923128.
  15. 1 2 Curvers J, Thomassen MC, Nicolaes GA, Van Oerle R, Hamulyak K, Hemker HC, Tans G, Rosing J (April 1999). "Acquired APC resistance and oral contraceptives: differences between two functional tests". Br J Haematol. 105 (1): 88–94. doi:10.1111/j.1365-2141.1999.01302.x. PMID 10233368. S2CID 19715963.
  16. ↑ Scheres LJ, Selier NL, Nota NM, van Diemen JJ, Cannegieter SC, den Heijer M (April 2021). "Effect of gender-affirming hormone use on coagulation profiles in transmen and transwomen". J Thromb Haemost. 19 (4): 1029–1037. doi:10.1111/jth.15256. PMC 8048491. PMID 33527671.
  17. 1 2 Toorians AW, Thomassen MC, Zweegman S, Magdeleyns EJ, Tans G, Gooren LJ, Rosing J (December 2003). "Venous thrombosis and changes of hemostatic variables during cross-sex hormone treatment in transsexual people". J Clin Endocrinol Metab. 88 (12): 5723–9. doi:10.1210/jc.2003-030520. PMID 14671159.
  18. 1 2 Asscheman H, T'Sjoen G, Lemaire A, Mas M, Meriggiola MC, Mueller A, Kuhn A, Dhejne C, Morel-Journel N, Gooren LJ (September 2014). "Venous thrombo-embolism as a complication of cross-sex hormone treatment of male-to-female transsexual subjects: a review". Andrologia. 46 (7): 791–5. doi:10.1111/and.12150. hdl:11585/413984. PMID 23944849. S2CID 5363824.
  19. ↑ Kotamarti VS, Greige N, Heiman AJ, Patel A, Ricci JA (July 2021). "Risk for Venous Thromboembolism in Transgender Patients Undergoing Cross-Sex Hormone Treatment: A Systematic Review". J Sex Med. 18 (7): 1280–1291. doi:10.1016/j.jsxm.2021.04.006. PMID 34140253. S2CID 235471411.
  20. ↑ Grandi G, Facchinetti F, Bitzer J (February 2022). "Confirmation of the safety of combined oral contraceptives containing oestradiol on the risk of venous thromboembolism". Eur J Contracept Reprod Health Care. 27 (2): 83–84. doi:10.1080/13625187.2022.2029397. PMID 35133236. S2CID 246651102.
  21. 1 2 Douxfils J, Morimont L, Delvigne A, Devel P, Masereel B, Haguet H, Bouvy C, Dogné J (2020-01-28). "Validation and standardization of the ETP-based activated protein C resistance test for the clinical investigation of steroid contraceptives in women: an unmet clinical and regulatory need". Clinical Chemistry and Laboratory Medicine. 58 (2): 294–305. doi:10.1515/cclm-2019-0471. ISSN 1437-4331. PMID 31444961. S2CID 201644826.
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