INTRODUCTION:About 40%-70% of persons with a clinically relevant bleeding tendency who are referred to haemostasis experts are classified as having a 'bleeding disorder of unknown cause' (BDUC) as no biological entity can be found after extensive laboratory testing. Currently, guidelines are under development regarding diagnostic assessment and management to minimize variation in clinical practice. AIM:Investigate current practices regarding BDUC in the Netherlands. METHODS:An online survey on the best BDUC definition, associated bleeding phenotype, clinical and diagnostic approaches, treatment, registration, and follow-up was distributed amongst healthcare providers working in Dutch haemophilia treatment centres (HTCs). RESULTS:The survey was completed by 39/54 (72%) respondents. Twenty percent did not register BDUC patients in their HTC. Healthcare professionals indicated that follow-up should depend on bleeding phenotype severity and bleeding history, and other potential causes for an increased bleeding tendency should be excluded. Moreover, the use of laboratory tests within the routine diagnostic pathway was demonstrated to be heterogeneous. Regarding treatment, tranexamic acid was most frequently prescribed for minor and major surgical interventions (79% and 86%), dental extractions (93%) and childbirth (93%). Desmopressin was prescribed for major surgical procedures by 79%. CONCLUSION:Our survey shows that Dutch current practice varies but is generally in line with recent ISTH SSC recommendations. Additionally, it describes other clinically relevant topics not included in the international survey, such as follow-up and exclusion of other causes for bleeding. This survey therefore adds to international efforts to unify BDUC definition, diagnostic approach, treatment and follow-up, and to attain broadly supported guidelines.

Background α2-Antiplasmin (A2AP) deficiency is a rare and often unidentified disorder characterized by increased fibrinolysis and subsequent bleeding. Global hemostasis assays may increase insight into the altered coagulation and fibrinolysis in these patients. Objectives To explore thrombin and plasmin generation profiles in A2AP-deficient patients, corresponding A2AP activity levels and associated bleeding phenotypes. Methods The Nijmegen hemostasis assay was used to assess thrombin and plasmin generation in 23 A2AP-deficient patients (median age, 50 years; 70% women) from the cross-sectional Rare Bleeding disorders in the Netherlands study. Analyzed parameters included thrombin peak height, thrombin potential, fibrin lysis time, plasmin peak height, plasmin velocity index, and plasmin potential. These parameters were expressed as percentages of a reference obtained from 37 healthy controls (median age, 46 years; 57% women). The Nijmegen hemostasis assay data were correlated with A2AP activity levels and International Society on Thrombosis and Hemostasis Bleeding Assessment Tool scores using Pearson correlation coefficients. Results Patients’ A2AP activity levels ranged from 23% to 83% (reference range, 89%-122%). Plasmin generation increased, as evidenced by significantly shorter fibrin lysis times (73%; P < .001) and higher plasmin peak heights (203%; P < .001), plasmin velocity indices (302%; P < .001) and plasmin potentials (154%; P < .001) in A2AP-deficient patients than those in healthy controls. Moreover, significantly higher thrombin potentials (146%; P < .001) and thrombin peak heights (132%; P < .001) were observed. Enhanced plasmin generation parameters showed statistically significant correlations with lower A2AP activity levels and higher International Society on Thrombosis and Hemostasis Bleeding Assessment Tool scores. Conclusion A2AP-deficient patients exhibited augmented plasmin generation profiles that correlated with A2AP activity level and bleeding phenotype. Interestingly, increased thrombin generation profiles were also found in these patients.

Background: Desmopressin is frequently used perioperatively in persons with nonsevere hemophilia A. However, increase in factor (F)VIII:C after desmopressin use is interindividually highly variable. Tachyphylaxis has only been reported in test setting for persons with hemophilia A, with a remaining response of approximately 70% after a second dose compared with that after a first dose. Objectives: To study tachyphylaxis of FVIII:C response after multiple administration(s) of desmopressin in perioperative persons with nonsevere hemophilia A. Methods: We studied FVIII:C levels after desmopressin before (day 0 [D0]) and on days 1 (D1) and 2 (D2) after surgery in 26 patients of the DAVID and Little DAVID studies. We studied tachyphylaxis by comparing the responses at D1 and D2 with that at D0. We also assessed the reproducibility of the D0 response in comparison to an earlier performed desmopressin test. Results: The median absolute FVIII:C increase was 0.50 IU/mL (0.35-0.74; n = 23) at D0, 0.21 IU/mL (0.14-0.28; n = 17) at D1, and 0.23 IU/mL (0.16-0.30; n = 11) at D2. The median percentage of FVIII increase after the second administration (D1) compared with the first (D0) was 42.9% (29.2%-52.5%; n = 17) and that of the third (D2) compared with the first (D0) was 36.4% (23.7%-46.9%; n = 11). The FVIII:C desmopressin response at D0 was comparable with the desmopressin test response in 74% of the patients. Conclusion: Tachyphylaxis in the surgical setting was considerably more pronounced than previously reported, with FVIII:C at D1 and D2 of 36% to 43% of the initial response. Our results may have important implications for monitoring repeated desmopressin treatment when used perioperatively.

Background: Spleen rupture is described as a rare hemorrhagic manifestation of afibrinogenemia.Pathogenesis and best management are still not well defined.Aims: We report the clinical characteristics and the management of spleen rupture in the Lebanese cohort with afibrinogenemia.Methods: It is a retrospective observational descriptive study in a welldefined cohort, "the Lebanese patient with afibrinogenemia," during a follow up period of 21 years.Variables studied were sex, age, gene mutation, bleeding score and thrombotic event, occurrence of spleen rupture, radiological finding of spleen, management of spleen rupture, and outcome.All patients provided written informed consent and university ethic committee give his approval.Results: 17 (23%) out of 73 patients had spontaneous spleen rupture with no obvious trigger factor.There was 5/31 (16%) women and 12/42 (28.5%) men.Mean age of occurrence was 16.3 years [6;42].Hom FGG R134X and hom FGA L212X were the 2 gene mutation.Mean bleeding score was 22.7 [12;34].Ten had previous history of thromboembolic event while 17 out of the 73 in the studied population Presenting symptoms were sudden abdominal pain, hypotension and hemoperitoneum.Abdominal ultrasound and CT scan identifies patches of spleen parenchyma necrosis with hemoperitoneum Splenectomy was performed in 11 patients, 4 had conservative treatment.Two died from hemorrhagic shock before any treatment.Splenectomy was complicated in 4 patients by a portal thrombosis.The four patients were treated with Low-Molecular-Weight-Heparin with no recanalization.Fibrinogen substitution was given as conservative treatment for 1 to 3 weeks than a prophylaxis regimen every 15 days.2 patient received Low-Molecular-Weight-Heparin.Spleen returned to normal in one to 3 weeks.Recurrence was observed in one patient who stopped prophylaxis with a follow up of 3 years. Conclusion(s):Spleen rupture is significantly associated with thromboembolic events ( p < 0,001) and could be an expression of thromboembolic event.Conservative treatment is effective.

Background: Bone diseases, such as low bone mineral density (BMD) and osteoporosis are emerging concerns in people with hemophilia (PWH).As a consequence, PWH might experience fractures more frequently than the general population.Aims: Our primary aim was to compare the incidence of bone fractures in PWH and people with no bleeding disorders.The secondary aim was to identify the risk factors associated with bone fractures in PWH.Methods: This was a retrospective, case-control, study based on data from the Canadian Bleeding Disorders Registry and administrative data from the Institute for Clinical Evaluative Sciences (ICES).PWH were eligible if born before Jan 1, 2017, and alive on April 1, 1993.They were followed up to March 31, 2018.Age-and sex-matched controls with no bleeding disorders were randomly selected with a 20:1 case:control ratio.We analyzed the data using multivariate regression models, adjusting for age, severity, and inhibitor status, and comorbidities (Charlson Comorbidity index).

In resource-rich countries, almost all severe hemophilia patients receive prophylactic replacement therapy with factor concentrates to prevent spontaneous bleeding in joints and muscles to decrease the development of arthropathy and risk of long-term disability. Pharmacokinetic (PK)-guided dosing can be applied to individualize factor replacement therapy, as interindividual differences in PK parameters influence factor VIII (FVIII) and FIX activity levels. PK-guided dosing may therefore lead to more optimal safeguarding of FVIII/FIX levels during prophylaxis and on demand treatment. The OPTI-CLOT TARGET study is a multicenter, nonrandomized, prospective cohort study that aims to investigate the reliability and feasibility of PK-guided prophylactic dosing of factor concentrates in hemophilia-A and -B patients in daily clinical practice. At least 50 patients of all ages on prophylactic treatment using standard half-life (SHL) and extended half-life (EHL) factor concentrates will be included during 9 months and will receive PK-guided treatment. As primary endpoint, a minimum of four FVIII/FIX levels will be compared with FVIII/FIX levels as predicted by Bayesian forecasting. Secondary endpoints are the association of FVIII and FIX levels with bleeding episodes and physical activity, expectations and experiences, economic analyses, and optimization of population PK models. This study will lead to more insight in the reliability and feasibility of PK-guided dosing in hemophilia patients. Moreover, it will contribute to personalization of treatment by greater knowledge of dosing regimens needed to prevent and treat bleeding in the individual patient and provide evidence to more clearly associate factor activity levels with bleeding risk.

BackgroundIn 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)).MethodsWe 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.FindingsWe 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.InterpretationWomen 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.FundingThe WiN study was supported (in part) by research funding from the Dutch Hemophilia Foundation (Stichting Haemophilia), Shire (Takeda), and CSL Behring (unrestricted grant).

Women with Von Willebrand disease (VWD) have an increased risk of developing postpartum hemorrhage (PPH). Our aim is to evaluate peripartum management strategies in relation to maternal and neonatal bleeding complications in VWD. Electronic databases were searched up to January 2019. Seventy-one case-reports and -series and 16 cohort studies were selected, including 811 deliveries. Cohort studies reported primary PPH in 32% and secondary PPH in 13% of the women. The overall primary PPH incidence in the individual patient data was 34%, similar between women who received prophylactic treatment to prevent PPH and those who didn't. Neonatal bleeding events were reported in 4.6% of deliveries. Overall, the available evidence on peripartum management in women with VWD was of low quality. The ongoing high risk for PPH is evident, despite prophylactic treatment, as well as the need for higher quality evidence from larger prospective cohort studies to improve management strategies.