Thrombin generation profiling in rare coagulation factor deficiencies: associations with bleeding severity and potential for screening

Journal of Thrombosis and Haemostasis, vol. 24, pp. 913–925

Abstract

BACKGROUND: Rare coagulation factor deficiencies (RCFDs) can cause significant bleeding, but activated partial thromboplastin time (APTT) and prothrombin time (PT) may not detect abnormalities, and factor activity measurements do not predict bleeding severity. Thrombin generation assays may better reflect overall hemostatic capacity. OBJECTIVES: This study investigated whether thrombin generation can detect RCFDs and correlate with bleeding severity in patients with congenital deficiencies of factor (F)II, FV, FV/FVIII, FVII, FX, and FXI. METHODS: Thrombin generation was measured using the Nijmegen hemostasis assay in patients from the cross-sectional Dutch Rare Bleeding disorders in the Netherlands (RBiN) study (2017-2019). Parameters analyzed included thrombin potential, lag time, and thrombin potential-to-lag time (TP/LT) ratio, normalized using pooled normal plasma and expressed as percentages of the mean from 37 healthy controls. Nijmegen hemostasis assay data were correlated with bleeding severity and compared with APTT and PT. RESULTS: We included 106 patients, mostly with mild deficiencies (median factor activity 5%-53%). Overall, thrombin generation in patients was significantly reduced compared with controls, with decreased thrombin potentials (median 58%) and prolonged lag times (150%), resulting in reduced TP/LT ratios (45%). These parameters correlated with bleeding severity; across RCFDs, median TP/LT ratios ranged from 30% to 104% in patients without spontaneous bleeding (bleeding severity grade 0-1), 26% to 49% in mild spontaneous bleeding (grade 2), and 0% to 22% in severe spontaneous bleeding (grade 3). At 95% specificity, TP/LT ratio showed 68% to 100% sensitivity, outperforming APTT and PT (14%-80%) in all RCFDs except FVII and FV/FVIII deficiency. CONCLUSION: Thrombin generation profiling correlated with bleeding severity and showed higher sensitivity than conventional screening assays in detecting RCFDs, supporting its potential in screening and clinical evaluation of RFCDs.

Authors 12

1. Bauke Haisma

   Radboud University Nijmegen · Radboud University Medical Center

   Affiliation as printed

   Department of Hematology, Radboud University Medical Center, Nijmegen, the Netherlands; Hemophilia Treatment Center Nijmegen-Eindhoven-Maastricht, Nijmegen, the Netherlands

2. Sanna R. Rijpma

   Radboud University Nijmegen · Radboud University Medical Center

   Affiliation as printed

   Hemophilia Treatment Center Nijmegen-Eindhoven-Maastricht, Nijmegen, the Netherlands; Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center, Nijmegen, the Netherlands

3. Marjon H. Cnossen

   Erasmus MC · Erasmus MC - Sophia Children’s Hospital

   Affiliation as printed

   Department of Pediatric Hematology and Oncology, Erasmus Medical Center Sophia Children's Hospital, University Medical Center Rotterdam, Rotterdam, the Netherlands

4. Paul L. den Exter Aachen Department of Thrombosis and Hemostasis

   Leiden University Medical Center

   Affiliation as printed

   Department of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, the Netherlands

5. Ilmar C. Kruis

   Netherlands Haemophilia Society

   Affiliation as printed

   Netherlands Hemophilia Society, Nijkerk, the Netherlands

6. Karina Meijer

   University Medical Center Groningen

   Affiliation as printed

   Department of Hematology, University Medical Center Groningen, Groningen, the Netherlands

7. Laurens Nieuwenhuizen

   Máxima Medisch Centrum

   Affiliation as printed

   Department of Hematology, Maxima Medical Center, Eindhoven, the Netherlands

8. Nick van Es

   Amsterdam UMC Location University of Amsterdam · Amsterdam University Medical Centers

   Affiliation as printed

   Department of Vascular Medicine, Amsterdam University Medical Centers, Amsterdam, the Netherlands

9. Joline L. Saes

   Utrecht University · University Medical Center Utrecht

   Affiliation as printed

   Center for Benign Hematology, Thrombosis and Hemostasis, Van Creveldkliniek, University Medical Center Utrecht and University Utrecht, Utrecht, the Netherlands

10. Nicole M. A. Blijlevens

    Radboud University Nijmegen · Radboud University Medical Center

    Affiliation as printed

    Department of Hematology, Radboud University Medical Center, Nijmegen, the Netherlands; Hemophilia Treatment Center Nijmegen-Eindhoven-Maastricht, Nijmegen, the Netherlands

11. Waander L. van Heerde
    Affiliation as printed

    Hemophilia Treatment Center Nijmegen-Eindhoven-Maastricht, Nijmegen, the Netherlands; Enzyre, Noviotech Campus, Nijmegen, the Netherlands. Electronic address: https://x.com/waandernijmegen

12. Saskia E.M. Schols

    Radboud University Nijmegen · Radboud University Medical Center

    Affiliation as printed

    Department of Hematology, Radboud University Medical Center, Nijmegen, the Netherlands; Hemophilia Treatment Center Nijmegen-Eindhoven-Maastricht, Nijmegen, the Netherlands. Electronic address: Saskia.Schols@Radboudumc.nl