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.

Hemophilia A (HA) is characterized by an abnormal low coagulation factor VIII (FVIII) activity level. HA patients with severe (FVIII activity level <1%) disease have an increased risk of trauma-related and spontaneous bleeding, especially in joints and muscles. Prophylactic replacement therapy with FVIII concentrate is recommended for these patients to prevent bleeding and to preserve musculoskeletal health. 1 The prophylactic scheme is now based on patient body weight and individual pharmacokinetic (PK) studies. Remarkably, there is a large inter-individual variability in PK dosing based on this algorithm. 2 Interestingly, however, some patients still experience breakthrough bleeds despite adequate FVIII trough levels, whereas others do not bleed with trough levels below threshold. 3 In addition, large heterogeneity in bleeding phenotype between patients with the same baseline FVIII activity level is observed. [3][4][5]

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