Bleeding severity in patients with rare bleeding disorders: real-life data from the RBiN study

Blood Advances, vol. 4, pp. 5025–5034

Abstract

Patients with hereditary rare bleeding disorders (RBDs) present with diverse hemorrhagic symptoms. Correlation between factor activity levels and clinical bleeding severity is poor for most RBDs. Threshold factor activity levels have been previously described in relation to bleeding severity but have not yet been validated. The Rare Bleeding Disorders in the Netherlands (RBiN) study is a nationwide cross-sectional study of patients registered in all 6 Dutch Haemophilia Treatment Centers with a known RBD and who are age 1 to 99 years. Bleeding scores were determined, and laboratory and clinical data were extracted from patient files. In all, 263 patients were included, of whom 202 (77%) attended the scheduled study visit. The median International Society of Thrombosis and Haemostasis (ISTH) bleeding assessment tool (BAT) score was 9. Correlations between baseline factor activity levels and ISTH BAT scores were strong for deficiencies in factor II (FII) (r = -0.792) and FX (r = -0.838) and were moderate for deficiencies of fibrinogen (r = -0.683), FV (r = -0.623), FVII (r = -0.516), FXIII (r = -0.516), and α2-antiplasmin (r = -0.594). There was no correlation for FXI deficiency (r = -0.218). The RBD BAT identified more women (94% vs 83%) and children (100% vs 71%) with an RBD than the ISTH BAT did. Importantly, 48% of patients had more severe bleeding than predicted for their baseline factor activity level. In addition, 34% of patients were predicted to be asymptomatic, but they actually had grade 2 (31%) or 3 (3%) bleeding. Bleeding severity in patients with RBDs is more pronounced than previously anticipated. The previously determined threshold factor activity levels to ensure no (spontaneous) bleeding in patients with an RBD are inaccurate. This trial was registered at www.clinicaltrials.gov as #NCT03347591.

Authors 11

1. Joline L. Saes

   Radboud University Medical Center

   Affiliation as printed

   Department of Hematology, Radboud University Medical Center, Nijmegen, The Netherlands;

   Hemophilia Treatment Center Nijmegen, Eindhoven, Maastricht, The Netherlands;

2. Marieke J.A. Verhagen

   Radboud University Medical Center

   Affiliation as printed

   Department of Hematology, Radboud University Medical Center, Nijmegen, The Netherlands;

   Hemophilia Treatment Center Nijmegen, Eindhoven, Maastricht, The Netherlands;

3. Karina Meijer

   University Medical Center Groningen

   Affiliation as printed

   Department of Hematology, University Medical Center Groningen, Groningen, The Netherlands;

4. Marjon H. Cnossen

   Erasmus MC

   Affiliation as printed

   Department of Hematology, Erasmus Medical Center, Rotterdam, The Netherlands;

5. Roger E. G. Schutgens

   Utrecht University · University Medical Center Utrecht

   Affiliation as printed

   Department of Hematology, van Creveldkliniek, University Medical Center Utrecht and University Utrecht, Utrecht, The Netherlands;

6. Marjolein Peters

   Emma Kinderziekenhuis · Amsterdam University Medical Centers · University of Amsterdam

   Affiliation as printed

   Pediatric-Hematology, Emma Children’s Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands;

7. Laurens Nieuwenhuizen
   Affiliation as printed

   Department of Hematology, Maxima Medical Center Eindhoven, Eindhoven, The Netherlands;

   Hemophilia Treatment Center Nijmegen, Eindhoven, Maastricht, The Netherlands;

8. Felix J.M. van der Meer 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;

9. Ilmar C. Kruis

   Netherlands Haemophilia Society

   Affiliation as printed

   Netherlands Hemophilia Society, Nijkerk, The Netherlands; and

10. Waander L. van Heerde

    Radboud University Medical Center

    Affiliation as printed

    Department of Hematology, Radboud University Medical Center, Nijmegen, The Netherlands;

    Enzyre BV, Novio Tech Campus, Nijmegen, The Netherlands

    Hemophilia Treatment Center Nijmegen, Eindhoven, Maastricht, The Netherlands;

11. Saskia E.M. Schols

    Radboud University Medical Center

    Affiliation as printed

    Department of Hematology, Radboud University Medical Center, Nijmegen, The Netherlands;

    Hemophilia Treatment Center Nijmegen, Eindhoven, Maastricht, The Netherlands;