Advertisement

Thrombin generation profile in non-thrombotic factor V Leiden carriers

  • Paul BilloirEmail author
  • Thomas Duflot
  • Marielle Fresel
  • Marie Hélène Chrétien
  • Virginie Barbay
  • Véronique Le Cam Duchez
Article

Abstract

Factor V Leiden (FVL) mutation is the most common genetic risk factor for venous thromboembolism. In families with a history of thrombosis, FVL can be present in 18%. Thrombin generation test is commonly used as an evaluation tool of thrombotic risk. The objective of this study was to evaluate the thrombogenic potential of FVL in asymptomatic carriers and in patients with personal or familial history of thrombosis. This was a retrospective single center study including 160 patients. Among them, 43 had personal history of thrombosis and 117 had familial history of thrombosis. Thrombin generation (TG) was realized in frozen platelet poor plasma with 1 pM of tissue factor and 4 µM of phospholipid. FVL mutation was associated with a global increase of TG. No difference was observed between patients with provoked thrombosis and patients with first-degree familial history of thrombosis (endogenous thrombin potential (ETP): 1501.0 ± 316.4 nM min and thrombin peak: 253.4 ± 71.5 nM vs. 1520.4 ± 283.8 nM min and 268.6 ± 68.0 nM). An increase of TG was observed in patients with unprovoked thrombosis (n = 23) and in patients with provoked thrombosis (n = 20) (ETP: 1819.5 ± 319.8 nM min and peak: 332.3 ± 55.8 nM). In the unprovoked thrombosis group, patients with a pulmonary embolism had a higher ETP than patients with deep vein thrombosis (DVT) (2036 ± 343 nM min vs. 1707 ± 261 nM min). With a predictive score formula (s = 0.1315 × Age + 0.0105 × ETP) with a threshold of 22.1 as risk to develop an unprovoked thrombosis among patients with second-degree familial history. The results of our analysis suggest that measurement of thrombin generation in patients with FVL mutation may identify subjects with an increased risk of unprovoked thrombosis. Further studies are needed to examine the usefulness of predicting thrombotic presentation in asymptomatic carriers.

Keywords

Factor V Leiden mutation Thrombin generation Unprovoked thrombosis Hypercoagulable states Asymptomatic carrier 

Notes

Acknowledgements

The authors are grateful to Nikki Sabourin-Gibbs, Rouen University Hospital, for editing the manuscript.

Compliance with ethical standards

Conflict of interest

The authors state that they have no conflict of interest.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

11239_2019_1821_MOESM1_ESM.tif (43 kb)
Supplementary material 1 (TIF 42 KB)

References

  1. 1.
    Rees DC, Cox M, Clegg JB (1995) World distribution of factor V Leiden. Lancet (Lond Engl) 346:1133–1134CrossRefGoogle Scholar
  2. 2.
    De Stefano V, Chiusolo P, Paciaroni K, Leone G (1998) Epidemiology of factor V Leiden: clinical implications. Semin Thromb Hemost 24:367–379.  https://doi.org/10.1055/s-2007-996025 CrossRefGoogle Scholar
  3. 3.
    Heit JA (2015) Epidemiology of venous thromboembolism. Nat Rev Cardiol 12:464–474.  https://doi.org/10.1038/nrcardio.2015.83 CrossRefGoogle Scholar
  4. 4.
    Campello E, Spiezia L, Simioni P (2016) Diagnosis and management of factor V Leiden. Expert Rev Hematol 9:1139–1149.  https://doi.org/10.1080/17474086.2016.1249364 CrossRefGoogle Scholar
  5. 5.
    Hemker HC, Al Dieri R, De Smedt E, Béguin S (2006) Thrombin generation, a function test of the haemostatic-thrombotic system. Thromb Haemost 96:553–561CrossRefGoogle Scholar
  6. 6.
    Wielders S, Mukherjee M, Michiels J, Rijkers DT, Cambus JP, Knebel RW, Kakkar V, Hemker HC, Béguin S (1997) The routine determination of the endogenous thrombin potential, first results in different forms of hyper- and hypocoagulability. Thromb Haemost 77:629–636CrossRefGoogle Scholar
  7. 7.
    R Core Team (2018) R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. https://www.R-project.org/ (n.d.)
  8. 8.
    Robin X, Turck N, Hainard A, Tiberti N, Lisacek F, Sanchez J-C, Müller M (2011) pROC: an open-source package for R and S + to analyze and compare ROC curves. BMC Bioinform 12:77.  https://doi.org/10.1186/1471-2105-12-77 CrossRefGoogle Scholar
  9. 9.
    Wickham H (2016) ggplot2: Elegant Graphics for data analysis. Springer, New York (n.d.)CrossRefGoogle Scholar
  10. 10.
    Bezemer ID, van der Meer FJM, Eikenboom JCJ, Rosendaal FR, Doggen CJM (2009) The value of family history as a risk indicator for venous thrombosis. Arch Intern Med 169:610–615.  https://doi.org/10.1001/archinternmed.2008.589 CrossRefGoogle Scholar
  11. 11.
    Lensen RP, Rosendaal FR, Koster T, Allaart CF, de Ronde H, Vandenbroucke JP, Reitsma PH, Bertina RM (1996) Apparent different thrombotic tendency in patients with factor V Leiden and protein C deficiency due to selection of patients. Blood 88:4205–4208Google Scholar
  12. 12.
    Chaireti R, Jennersjö C, Lindahl TL (2009) Thrombin generation and D-dimer concentrations in a patient cohort investigated for venous thromboembolism. Relations to venous thrombosis, factor V Leiden and prothrombin G20210A. The LIST study. Thromb Res 124:178–184.  https://doi.org/10.1016/j.thromres.2008.12.033 CrossRefGoogle Scholar
  13. 13.
    van Langevelde K, Flinterman LE, van Hylckama Vlieg A, Rosendaal FR, Cannegieter SC (2012) Broadening the factor V Leiden paradox: pulmonary embolism and deep-vein thrombosis as 2 sides of the spectrum. Blood 120:933–946.  https://doi.org/10.1182/blood-2012-02-407551 CrossRefGoogle Scholar
  14. 14.
    Segal JB, Brotman DJ, Necochea AJ, Emadi A, Samal L, Wilson LM, Crim MT, Bass EB (2009) Predictive value of factor V Leiden and prothrombin G20210A in adults with venous thromboembolism and in family members of those with a mutation: a systematic review. JAMA 301:2472–2485.  https://doi.org/10.1001/jama.2009.853 CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Normandie Univ, UNIROUEN, INSERM U1096, Rouen University HospitalRouenFrance
  2. 2.Department of Pharmacology, CHU de RouenRouenFrance
  3. 3.INSERM U1096, Normandie University, UNIROUENRouenFrance
  4. 4.Rouen University HospitalRouenFrance
  5. 5.Service d’Hématologie BiologiqueCentre Hospitalier Universitaire Charles NicolleRouenFrance

Personalised recommendations