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.
Factor V Leiden
activated protein C resistance
blood coagulation test
combined hormonal contraceptive
endogenous thrombin potential
protein S deficiency
Journal
Clinical chemistry and laboratory medicine
ISSN: 1437-4331
Titre abrégé: Clin Chem Lab Med
Pays: Germany
ID NLM: 9806306
Informations de publication
Date de publication:
28 01 2020
28 01 2020
Historique:
received:
06
05
2019
accepted:
30
07
2019
pubmed:
25
8
2019
medline:
7
4
2021
entrez:
25
8
2019
Statut:
ppublish
Résumé
Background Regulatory bodies recommend the use of an assay based on the assessment of the endogenous thrombin potential (ETP) for the investigation of the activated protein C resistance (APCr) in the development of steroid contraceptives in women. However, the assays described in the literature are home-made and not standardized regarding the method, the reagents, the reference plasma and the quality controls. In the absence of any commercially available method, we aimed at validating the ETP-based APCr assay. Methods The validation was performed according to regulatory standards. The method targets a 90% inhibition of the ETP in healthy donors in the presence of APC compared to the same condition in the absence of APC. As a large-scale production of a pool of plasma from well-selected healthy donors is impossible, algorithms were applied to a commercial reference plasma to correlate with the selected pool. Results Repeatability and intermediate precision passed the acceptance criteria. The assay demonstrated a curvilinear dose response to protein S and APC concentrations (R2 > 0.99). Analysis of plasma samples from 47 healthy individuals (22 women not taking combined hormonal contraceptives [CHC], and 25 men not Factor V Leiden carriers) confirmed the validity of the test, with a mean inhibition percentage of 90%. Investigations in 15 women taking different contraceptives and in two subjects with Factor V Leiden confirmed the good sensitivity and performance of the assay. Conclusions This validation provides the pharmaceutical industry, the regulatory bodies and physicians with a reproducible, sensitive and validated gold-standard ETP-based APCr assay.
Identifiants
pubmed: 31444961
doi: 10.1515/cclm-2019-0471
pii: cclm-2019-0471
doi:
Substances chimiques
Contraceptive Agents
0
Protein C
0
factor V Leiden
0
Factor V
9001-24-5
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
294-305Références
Guideline on Clinical investigation of Steroid Contraceptives in Women – EMEA/CPMP/EWP/519/98 Rev 1. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003349.pdf. Accessed: 25 Apr 2005.
Nicolaes GA, Thomassen MC, Tans G, Rosing J, Hemker HC. Effect of activated protein C on thrombin generation and on the thrombin potential in plasma of normal and APC-resistant individuals. Blood Coagul Fibrinolysis 1997;8:28–38.
Curvers J, Thomassen MC, Nicolaes GA, Van Oerle R, Hamulyak K, Hemker HC, et al. Acquired APC resistance and oral contraceptives: differences between two functional tests. Br J Haematol 1999;105:88–94.
Rosing J, Middeldorp S, Curvers J, Christella M, Thomassen LG, Nicolaes GA, et al. Low-dose oral contraceptives and acquired resistance to activated protein C: a randomised cross-over study. Lancet 1999;354:2036–40.
Curvers J, Thomassen MC, Rimmer J, Hamulyak K, van der Meer J, Tans G, et al. Effects of hereditary and acquired risk factors of venous thrombosis on a thrombin generation-based APC resistance test. Thromb Haemost 2002;88:5–11.
Tchaikovski SN, van Vliet HA, Thomassen MC, Bertina RM, Rosendaal FR, Sandset PM, et al. Effect of oral contraceptives on thrombin generation measured via calibrated automated thrombography. Thromb Haemost 2007;98:1350–6.
Hemker HC, Giesen P, Al Dieri R, Regnault V, de Smedt E, Wagenvoord R, et al. Calibrated automated thrombin generation measurement in clotting plasma. Pathophysiol Haemost Thromb 2003;33:4–15.
Brugge JM, Tans G, Rosing J, Castoldi E. Protein S levels modulate the activated protein C resistance phenotype induced by elevated prothrombin levels. Thromb Haemost 2006;95:236–42.
Dargaud Y, Luddington R, Gray E, Lecompte T, Siegemund T, Baglin T, et al. Standardisation of thrombin generation test – which reference plasma for TGT? An international multicentre study. Thromb Res 2010;125:353–6.
Dargaud Y, Luddington R, Gray E, Negrier C, Lecompte T, Petros S, et al. Effect of standardization and normalization on imprecision of calibrated automated thrombography: an international multicentre study. Br J Haematol 2007;139:303–9.
Loeffen R, Kleinegris MC, Loubele ST, Pluijmen PH, Fens D, van Oerle R, et al. Preanalytic variables of thrombin generation: towards a standard procedure and validation of the method. J Thromb Haemost 2012;10:2544–54.
Perrin J, Depasse F, Lecompte T, French-speaking CATg, under the aegis of G, French-speaking CATg, et al. Large external quality assessment survey on thrombin generation with CAT: further evidence for the usefulness of normalisation with an external reference plasma. Thromb Res 2015;136:125–30.
Brito MB, Ferriani RA, Meijers JC, Garcia AA, Quintana SM, Silva de Sa MF, et al. Effects of the etonogestrel-releasing contraceptive implant inserted immediately postpartum on maternal hemostasis: a randomized controlled trial. Thromb Res 2012;130:355–60.
Johnson JV, Lowell J, Badger GJ, Rosing J, Tchaikovski S, Cushman M. Effects of oral and transdermal hormonal contraception on vascular risk markers: a randomized controlled trial. Obstet Gynecol 2008;111:278–84.
Raps M, Helmerhorst F, Fleischer K, Thomassen S, Rosendaal F, Rosing J, et al. Sex hormone-binding globulin as a marker for the thrombotic risk of hormonal contraceptives. J Thromb Haemost 2012;10:992–7.
Raps M, Rosendaal F, Ballieux B, Rosing J, Thomassen S, Helmerhorst F, et al. Resistance to APC and SHBG levels during use of a four-phasic oral contraceptive containing dienogest and estradiol valerate: a randomized controlled trial. J Thromb Haemost 2013;11:855–61.
Westhoff CL, Pike MC, Cremers S, Eisenberger A, Thomassen S, Rosing J. Endogenous thrombin potential changes during the first cycle of oral contraceptive use. Contraception 2017;95: 456–63.
Tans G, van Hylckama Vlieg A, Thomassen MC, Curvers J, Bertina RM, Rosing J, et al. Activated protein C resistance determined with a thrombin generation-based test predicts for venous thrombosis in men and women. Br J Haematol 2003;122: 465–70.
Lebreton A, Sinegre T, Pereira B, Lamblin G, Duron C, Abergel A. Plasma hypercoagulability in the presence of thrombomodulin but not of activated protein C in patients with cirrhosis. J Gastroenterol Hepatol 2017;32:916–24.
ICH Topic Q 2 (R1) – Validation of Analytical Procedures: Text and Methodology (CPMP/ICH/381/95). Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002662.pdf. Accessed: 1995.
Bioanalytical Method Validation – Guidance for Industry. Available at: https://www.fda.gov/downloads/drugs/guidances/ucm070107.pdf. Accessed: 6 Feb 2018.
CLSI. User evaluation of between-reagent lot variation, in CLSI document EP26-A. Wayne, PA: Clinical and Laboratory Standards Institute, 2013.
CLSI. Statistical quality control for quantitative measurement procedures: principles and definitions. in CLSI Guideline C24. Wayne, PA: Clinical and Laboratory Standards Institute, 2016.
Curvers J, Christella M, Thomassen LG, de Ronde H, Bertina RM, Rosendaal FR, et al. Effects of (pre-)analytical variables on activated protein C resistance determined via a thrombin generation-based assay. Thromb Haemost 2002;87:483–92.
de Visser MC, van Hylckama Vlieg A, Tans G, Rosing J, Dahm AE, Sandset PM, et al. Determinants of the APTT- and ETP-based APC sensitivity tests. J Thromb Haemost 2005;3:1488–94.
Dargaud Y, Wolberg AS, Luddington R, Regnault V, Spronk H, Baglin T, et al. Evaluation of a standardized protocol for thrombin generation measurement using the calibrated automated thrombogram: an international multicentre study. Thromb Res 2012;130:929–34.
Kluft C, Meijer P. External quality assessment for thrombin generation tests: an exploration. Semin Thromb Hemost 2010;36:791–6.
CLSI. Defining, establishing, and verifying reference intervals in the clinical laboratory; Approved Guideline – Third Edition, in CLSI document EP28-A3C. Wayne, PA: Clinical and Laboratory Standards Institute, 2010.
Bagot CN, Marsh MS, Whitehead M, Sherwood R, Roberts L, Patel RK, et al. The effect of estrone on thrombin generation may explain the different thrombotic risk between oral and transdermal hormone replacement therapy. J Thromb Haemost 2010;8:1736–44.
Tripodi A. Thrombin generation assay and its application in the clinical laboratory. Clin Chem 2016;62:699–707.
Rodgers SE, Wong A, Gopal RD, Dale BJ, Duncan EM, McRae SJ. Evaluation of pre-analytical variables in a commercial thrombin generation assay. Thromb Res 2014;134:160–4.
Bagot CN, Leishman E. Establishing a reference range for thrombin generation using a standard plasma significantly improves assay precision. Thromb Res 2015;136:139–43.
Lacroix R, Judicone C, Poncelet P, Robert S, Arnaud L, Sampol J, et al. Impact of pre-analytical parameters on the measurement of circulating microparticles: towards standardization of protocol. J Thromb Haemost 2012;10:437–46.
Douxfils J, Morimont L, Bouvy C, de Saint-Hubert M, Devalet B, Devroye C, et al. Assessment of the analytical performances and sample stability on ST Genesia system using the STG-DrugScreen application. J Thromb Haemost 2019;17:1273–87.