Activated protein C resistance test

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]

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

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] The ETP-based APC resistance test suffered from a lack of standardization which hampered study-to-study comparison but recently a validated methodology has been developed with the aim to propose a standardized and harmonized scale for the ETP-based APC resistance, the normalized activated protein C sensitivity ratio (nAPCsr).[21]

References
  1. 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. 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. 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. 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. 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.
  8. 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. 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. 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. 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. 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. 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. Douxfils, Jonathan; Morimont, Laure; Delvigne, Anne-Sophie; Devel, Philippe; Masereel, Bernard; Haguet, Hélène; Bouvy, Céline; Dogné, Jean-Michel (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.
This article is issued from Wikipedia. The text is licensed under Creative Commons - Attribution - Sharealike. Additional terms may apply for the media files.