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

Joline L Saes, Marieke J A Verhagen, Karina Meijer, Marjon H Cnossen, Roger E G Schutgens, Marjolein Peters, Laurens Nieuwenhuizen, Felix J M van der Meer, Ilmar C Kruis, Waander L van Heerde, Saskia E M Schols, Joline L Saes, Marieke J A Verhagen, Karina Meijer, Marjon H Cnossen, Roger E G Schutgens, Marjolein Peters, Laurens Nieuwenhuizen, Felix J M van der Meer, Ilmar C Kruis, Waander L van Heerde, Saskia E M Schols

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.

Conflict of interest statement

Conflict-of-interest disclosure: K.M. reports grants and other funding from Bayer and Sanquin, grants from Pfizer, and other funding from Boehringer Ingelheim, Bristol-Myers Squibb, Aspen, and Uniqure outside the submitted work. M.H.C. has received grants from governmental research institutes such as the Dutch Research Institute (NWO), ZonMW, Innovation Fund, and NWO-NWA and unrestricted investigator-initiated research grants as well as educational and travel funding from Pfizer, Baxter, Baxalta, Shire, Bayer Schering Pharma, CSL Behring, Sobi Biogen, Novo Nordisk, Novartis, and Nordic Pharma and has served as steering board member for Roche and Bayer (all grants, awards and fees go to the Erasmus Medical Center as an institution and are outside the submitted work). R.E.G.S. reports grants from Bayer, Baxalta, Pfizer, and Novo Nordisk outside the submitted work. M.P. reports a grant from Pfizer outside the submitted work. F.J.M.v.d.M. reports grants from CSL Behring, Pfizer, Bayer, Novo Nordisk, Sobi, Roche, and OctaPharma outside the submitted work. W.L.H. reports personal fees from Takeda, Bayer, and CSL Behring, other funding from Enzyre, and nonfinancial support from Sobi outside the submitted work. The remaining authors declare no competing financial interests.