Activated protein C resistance test

The aPTT-based APC resistance test involves a modified aPTT test performed in the presence and absence of activated protein C (APC). The ratio of these aPTT values is calculated and is called the APC sensitivity ratio (APCsr) or simply APC ratio (APCr). This ratio is inversely related to the degree of APC resistance.{{cite journal | vauthors = Clark P | title = Changes of hemostasis variables during pregnancy | journal = Semin Vasc Med | volume = 3 | issue = 1 | pages = 13–24 | date = February 2003 | pmid = 15199489 | doi = 10.1055/s-2003-38329 | s2cid = 36952311 | url = }} The ETP-based APC resistance test involves the addition of APC to a thrombin generation assay (TGA). This results in an inhibition of thrombin generation as measured by reduction of the endogenous thrombin potential (ETP; area under the thrombin generation curve). 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. nAPCsr values range from 0 to 10. Opposite to the case of the APCsr with the aPTT-based APC resistance test, higher nAPCsr values indicate greater APC resistance. This is the result of the fact that APC prolongs the aPTT but inhibits thrombin generation.{{cite journal | vauthors = Mueck AO | title = Exogenous hormones, the risk of venous thromboembolism, and activated protein C resistance | journal = Menopause | volume = 17 | issue = 6 | pages = 1099–103 | date = 2010 | pmid = 20975607 | doi = 10.1097/gme.0b013e3181fa264c | url = }}

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.{{cite journal | vauthors = Castoldi E, Rosing J | title = Thrombin generation tests | journal = Thromb Res | volume = 127 | issue = Suppl 3| pages = S21–5 | date = February 2011 | pmid = 21262433 | doi = 10.1016/S0049-3848(11)70007-X | url = }} The initiation phase accounts for less than 5% of total thrombin generation, making aPTT-based tests poorly indicative of hypercoagulability in general.{{cite journal | vauthors = Lim HY, Leemaqz SY, Torkamani N, Grossmann M, Zajac JD, Nandurkar H, Ho P, Cheung AS | title = Global Coagulation Assays in Transgender Women on Oral and Transdermal Estradiol Therapy | journal = J Clin Endocrinol Metab | volume = 105 | issue = 7 | pages = e2369–e2377| date = July 2020 | pmid = 32413907 | doi = 10.1210/clinem/dgaa262 | s2cid = 218659931 | url = | doi-access = free }}{{cite journal | vauthors = Baglin T | title = The measurement and application of thrombin generation | journal = Br J Haematol | volume = 130 | issue = 5 | pages = 653–61 | date = September 2005 | pmid = 16115120 | doi = 10.1111/j.1365-2141.2005.05612.x | s2cid = 9701861 | url = }} 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. 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. 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.{{cite journal | vauthors = Reda S, Morimont L, Douxfils J, Rühl H | title = Can We Measure the Individual Prothrombotic or Prohemorrhagic Tendency by Global Coagulation Tests? | journal = Hamostaseologie | volume = 40 | issue = 3 | pages = 364–378 | date = August 2020 | pmid = 32726831 | doi = 10.1055/a-1153-5824 | s2cid = 220878363 | url = | doi-access = free }}{{cite journal | vauthors = Favaloro EJ, Lippi G | title = Recent Advances in Mainstream Hemostasis Diagnostics and Coagulation Testing | journal = Semin Thromb Hemost | volume = 45 | issue = 3 | pages = 228–246 | date = April 2019 | pmid = 30912101 | doi = 10.1055/s-0038-1676579 | s2cid = 85517668 | url = }}

File:Thrombin generation curves with and without activated protein C and with various oral contraceptives with activated protein C.pngs 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. The contraceptives are estetrol/drospirenone (E4/DRSP), ethinylestradiol/levonorgestrel (EE/LNG), ethinylestradiol/desogestrel (EE/DSG), and ethinylestradiol/drospirenone (EE/DRSP).]]

Estrogens are well known to increase APC resistance, which has been described as acquired APC resistance. However, the aPTT-based APC resistance test is much less sensitive to the procoagulatory effects of estrogens than is the ETP-based test.{{cite journal | vauthors = Tchaikovski SN, Rosing J | title = Mechanisms of estrogen-induced venous thromboembolism | journal = Thromb Res | volume = 126 | issue = 1 | pages = 5–11 | date = July 2010 | pmid = 20163835 | doi = 10.1016/j.thromres.2010.01.045 | url = }}{{cite journal | vauthors = Hemelaar M, van der Mooren MJ, Rad M, Kluft C, Kenemans P | title = Effects of non-oral postmenopausal hormone therapy on markers of cardiovascular risk: a systematic review | journal = Fertil Steril | volume = 90 | issue = 3 | pages = 642–72 | date = September 2008 | pmid = 17923128 | doi = 10.1016/j.fertnstert.2007.07.1298 | url = | doi-access = free }}{{cite journal | vauthors = Morimont L, Haguet H, Dogné JM, Gaspard U, Douxfils J | title = Combined Oral Contraceptives and Venous Thromboembolism: Review and Perspective to Mitigate the Risk | journal = Front Endocrinol (Lausanne) | volume = 12 | issue = | pages = 769187 | date = 2021 | pmid = 34956081 | pmc = 8697849 | doi = 10.3389/fendo.2021.769187 | url = | doi-access = free }}{{cite journal | vauthors = Douxfils J, Morimont L, Bouvy C | title = Oral Contraceptives and Venous Thromboembolism: Focus on Testing that May Enable Prediction and Assessment of the Risk | journal = Semin Thromb Hemost | volume = 46 | issue = 8 | pages = 872–886 | date = November 2020 | pmid = 33080636 | doi = 10.1055/s-0040-1714140 | s2cid = 224821517 | url = }}{{cite journal | vauthors = Curvers J, Thomassen MC, Nicolaes GA, Van Oerle R, Hamulyak K, Hemker HC, Tans G, Rosing J | title = Acquired APC resistance and oral contraceptives: differences between two functional tests | journal = Br J Haematol | volume = 105 | issue = 1 | pages = 88–94 | date = April 1999 | pmid = 10233368 | doi = 10.1111/j.1365-2141.1999.01302.x| s2cid = 19715963 | url = }} Pregnancy and ethinylestradiol (EE)-containing combined birth control pills increase APC resistance as measured by either the aPTT- or ETP-based test. 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. 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. The increase in APC resistance is much greater with oral estrogens than with transdermal estradiol. 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.{{cite journal | vauthors = Scheres LJ, Selier NL, Nota NM, van Diemen JJ, Cannegieter SC, den Heijer M | title = Effect of gender-affirming hormone use on coagulation profiles in transmen and transwomen | journal = J Thromb Haemost | volume = 19 | issue = 4 | pages = 1029–1037 | date = April 2021 | pmid = 33527671 | pmc = 8048491 | doi = 10.1111/jth.15256 | url = }}{{cite journal | vauthors = Toorians AW, Thomassen MC, Zweegman S, Magdeleyns EJ, Tans G, Gooren LJ, Rosing J | title = Venous thrombosis and changes of hemostatic variables during cross-sex hormone treatment in transsexual people | journal = J Clin Endocrinol Metab | volume = 88 | issue = 12 | pages = 5723–9 | date = December 2003 | pmid = 14671159 | doi = 10.1210/jc.2003-030520 | url = | doi-access = free }} EE produces a much stronger increase in APC resistance than does estradiol.{{cite journal | vauthors = Asscheman H, T'Sjoen G, Lemaire A, Mas M, Meriggiola MC, Mueller A, Kuhn A, Dhejne C, Morel-Journel N, Gooren LJ | title = Venous thrombo-embolism as a complication of cross-sex hormone treatment of male-to-female transsexual subjects: a review | journal = Andrologia | volume = 46 | issue = 7 | pages = 791–5 | date = September 2014 | pmid = 23944849 | doi = 10.1111/and.12150 | hdl = 11585/413984 | s2cid = 5363824 | url = | doi-access = free }} In relation to this, ethinylestradiol is associated with a higher risk of venous thromboembolism (VTE) than is estradiol.{{cite journal | vauthors = Kotamarti VS, Greige N, Heiman AJ, Patel A, Ricci JA | title = Risk for Venous Thromboembolism in Transgender Patients Undergoing Cross-Sex Hormone Treatment: A Systematic Review | journal = J Sex Med | volume = 18 | issue = 7 | pages = 1280–1291 | date = July 2021 | pmid = 34140253 | doi = 10.1016/j.jsxm.2021.04.006 | s2cid = 235471411 | url = }}{{cite journal | vauthors = Grandi G, Facchinetti F, Bitzer J | title = Confirmation of the safety of combined oral contraceptives containing oestradiol on the risk of venous thromboembolism | journal = Eur J Contracept Reprod Health Care | volume = 27| issue = 2| pages = 83–84 | date = February 2022 | pmid = 35133236 | doi = 10.1080/13625187.2022.2029397 | s2cid = 246651102 | url = | doi-access = free | hdl = 11380/1279881 | hdl-access = free }}

The aPTT-based APC resistance test was developed in 1993, while the ETP-based test was developed in 1997. For many years, the ETP-based APC resistance test suffered from a lack of standardization which hampered study-to-study comparison.{{cite journal |last1=Douxfils |first1=Jonathan |last2=Morimont |first2=Laure |last3=Delvigne |first3=Anne-Sophie |last4=Devel |first4=Philippe |last5=Masereel |first5=Bernard |last6=Haguet |first6=Hélène |last7=Bouvy |first7=Céline |last8=Dogné |first8=Jean-Michel |date=2020-01-28 |title=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 |url=https://pubmed.ncbi.nlm.nih.gov/31444961/ |journal=Clinical Chemistry and Laboratory Medicine |volume=58 |issue=2 |pages=294–305 |doi=10.1515/cclm-2019-0471 |issn=1437-4331 |pmid=31444961|s2cid=201644826 }} 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).

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