The aPTT-based APC resistance test involves a modified aPTT test performed in the presence and absence ofactivated 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 athrombin generation assay (TGA).[5] This results in an inhibition ofthrombin generation as measured by reduction of theendogenous 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 ofcoagulation, the ETP-based test is aglobal assay and measures the initiation, propagation, and termination phases of coagulation.[5][9] The initiation phase accounts for less than 5% of totalthrombin generation, making aPTT-based tests poorly indicative of hypercoagulability in general.[10][11] The aPTT-based assay is more sensitive to levels ofprothrombin andfactor VIII, whereas the ETP-based test is more sensitive to levels oftissue factor pathway inhibitor (TFPI) andprotein S.[5] The ETP-based test has traditionally been performed using methods such as thecalibrated automated thrombogram (CAT) and has been limitedly available due to its technical difficulty.[2] Recently however, a fully automated commercial test system called theST 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]
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] andethinylestradiol (EE)-containingcombined 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 theprogestin, which may be due to varying degrees ofandrogenic antagonism of ethinylestradiol-mediated procoagulation.[5][4] In contrast to EE-containing birth control pills, studies have not found increased APC resistance withmenopausal hormone therapy or withestetrol- orestradiol-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 withoral estrogens than withtransdermalestradiol.[14] Increased APC resistance with both the aPTT-based and ETP-based tests has been observed withfeminizing hormone therapy intransgender 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 ofvenous thromboembolism (VTE) than is estradiol.[18][19][20]
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 ofstandardization which hampered study-to-study comparison.[21] By 2020 however, a validated methodology was developed aiming to propose a standardized andharmonized scale for ETP-based APC resistance, the normalized activated protein C sensitivity ratio (nAPCsr).[21]
^abcAmiral 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.PMID29162399.
^abcdefDouxfils 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.PMID33080636.S2CID224821517.
^abMueck AO (2010). "Exogenous hormones, the risk of venous thromboembolism, and activated protein C resistance".Menopause.17 (6):1099–103.doi:10.1097/gme.0b013e3181fa264c.PMID20975607.
^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.PMID34140253.S2CID235471411.
^abDouxfils J, Morimont L, Delvigne AS, Devel P, Masereel B, Haguet H, Bouvy C, Dogné JM (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.ISSN1437-4331.PMID31444961.S2CID201644826.
