Hyperfibrinolytic bleeding can be caused by a deficiency of one of the inhibitors of fibrinolysis (plasminogen activator inhibitor type 1 [PAI-1] or α2-antiplasmin [α2-AP]), or an excess of one of the activators of fibrinolysis: tissue-type plasminogen activator or urokinase-type plasminogen activator. This review focuses on the clinical implications of these disorders. The bleeding phenotype of fibrinolytic disorders is characterized by delayed bleeding after trauma, surgery and dental procedures. Bleeding in areas of high fibrinolytic activity is also common, such as menorrhagia and epistaxis. Patients with α2-AP deficiency present with the most severe bleeding episodes. Recently, it was discovered that hyperfibrinolytic disorders are associated with a high rate of obstetric complications such as miscarriage and preterm birth, especially in PAI-1 deficient patients. Hyperfibrinolytic disorders are probably underdiagnosed because of lack of knowledge and lack of accurate diagnostic tests. A substantial part of the large group of patients diagnosed as 'bleeding of unknown origin' could actually have a hyperfibrinolytic disorder. In the case of a high index of suspicion (i.e. because of a positive family history, recurrent bleeding or uncommon type of bleeding such as an intramedullary hematoma), further testing should not be withheld because of normal results of standard hemostatic screening assays. Timely diagnosis is important because these disorders can generally be treated well with antifibrinolytic agents.

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.

Background In recent years, more awareness is raised about sex-specific dilemmas in inherited bleeding disorders. However, no large studies have been performed to assess differences in diagnosis, bleeding phenotype and management of men and women with bleeding disorders. Therefore, we investigated sex differences in a large cohort of well-defined patients with autosomal inherited bleeding disorders (von Willebrand disease (VWD), rare bleeding disorders (RBDs) and congenital platelet defects (CPDs)). Methods We included patients from three nationwide cross-sectional studies on VWD, RBDs and CPDs in the Netherlands, respectively the WiN, RBiN and TiN study. In all studies a bleeding score (BS) was obtained, and patients filled in an extensive questionnaire on the management and burden of their disorder. Findings We included 1092 patients (834 VWD; 196 RBD; 62 CPD), of whom 665 (60.9%) were women. Women were more often referred because of a bleeding diathesis than men (47.9% vs 36.6%, p = 0.002). Age of first bleeding was similar between men and women, respectively 8.9 ± 13.6 (mean ±sd) years and 10.6 ± 11.3 years ( p = 0.075). However, the diagnostic delay, which was defined as time from first bleeding to diagnosis, was longer in women (11.6 ± 16.4 years) than men (7.7 ± 16.6 years, p = 0.002). Similar results were found when patients referred for bleeding were analyzed separately. Of women aging 12 years or older, 469 (77.1%) had received treatment because of sex-specific bleeding. Interpretation Women with autosomal inherited bleeding disorders are more often referred for bleeding, have a longer diagnostic delay, and often require treatment because of sex-specific bleeding. Funding The WiN study was supported (in part) by research funding from the Dutch Hemophilia Foundation (Stichting Haemophilia), Shire (Takeda), and CSL Behring (unrestricted grant).

Introduction The diagnostic trajectory of patients with increased bleeding tendency can be very costly and time‐consuming. In addition, previous studies have shown that half of these patients remain without final diagnosis despite all efforts. Aim This study aimed to improve insight into the current diagnostic process of these patients. Methods A total of 117 adult patients, referred to an academic hospital because of being suspected to have an increased bleeding tendency, were included. Different parameters were compared between patients receiving final diagnosis, patients without final diagnosis but a high Tosetto bleeding assessment tool (BAT) score (classified as bleeding of unknown cause, or BUC) and a control group consisting of patients without final diagnosis and a low BAT score. Results The BAT score was significantly higher in patients in the BUC group as compared to patients reaching final diagnosis (8.1 vs 4.9). Interestingly, the two subcategories most prevalently increased were surgery and post‐partum haemorrhage‐associated bleeding (surgery: 2.1 vs 1.1; post‐partum haemorrhage: 0.7 vs 0.0). Laboratory screening results were more often abnormal in patients reaching final diagnosis compared to patients remaining without diagnosis and a high BAT score (n = 32 (78%) vs n = 14 (46%), 95% CI 1.5‐12), especially concerning the PFA (=27 (66%) vs n = 10 (33%), 95% CI 1.4‐10) and von Willebrand factor activity levels (n = 11 (27%) vs n = 1 (3%), 95% CI 1.3‐91). Conclusion Isolated high bleeding score on surgical or post‐partum bleeding correlates with a lower chance of receiving final diagnosis. Withholding extensive haemostatic testing should be considered. Better screening and confirmative haemostatic assays are still needed.

Introduction Bleeding assessment tools and laboratory phenotyping often remain inconclusive in patients with a haemorrhagic diathesis. Aim To describe the phenotype and genetic profile of patients with a bleeding tendency. Methods Whole exome sequencing (WES) was incorporated in the routine diagnostic pathway of patients with thrombocytopenia (n = 17), platelet function disorders (n = 19) and an unexplained bleeding tendency (n = 51). The analysis of a panel of 126 OMIM (Online Mendelian Inheritance in Man) genes involved in thrombosis and haemostasis was conducted, and if negative, further exome‐wide analysis was performed if informed consent given. Results Eighteen variants were detected in 15 patients from a total of 87 patients (17%). Causative variants were observed in MYH9 (two cases), SLFN14, P2RY12 and GP9. In addition, one case was considered solved due to combined carriership of F7 and F13A1 variants and one with combined carriership of F2, F8 and VWF, all variants related to secondary haemostasis protein aberrations. Two variants of uncertain significance (VUS) were found in two primary haemostasis genes: GFI1B and VWF. Eight patients were carriers of autosomal recessive disorders. Exome‐wide analysis was performed in 54 cases and identified three variants in candidate genes. Conclusion Based on our findings, we conclude that performing WES at the end of the diagnostic trajectory can be of additive value to explain the complete bleeding phenotype in patients without a definite diagnosis after conventional laboratory tests. Discovery of combinations of (novel) genes that predispose to bleeding will increase the diagnostic yield in patients with an unexplained bleeding diathesis.