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.

Delta storage pool disease (δ-SPD) is a rare platelet function disorder (PFD) characterized by deficiency of dense granules or defective granule secretion, leading to bleeding diathesis. Diagnostics of δ-SPD are difficult and lack standardization, leading to underestimation of its prevalence. Current diagnostic methods are based on granule content assays or lumi-aggregometry, which have limited availability. Therefore, there is an unmet need for a rapid, accessible test for δ-SPD. To evaluate the diagnostic value of a rapid whole blood ATP secretion test for δ-SPD. ATP secretion after PAR-1 Activating Peptide (PAR-1 AP; TRAP-6) stimulation was assessed in whole blood using luminescence in 50 healthy controls, 22 patients with a suspected PFD other than SPD (non-SPD) and 25 δ-SPD patients and corrected for platelet count. Diagnostic value of the test was determined with C-statistics, sensitivity, specificity, likelihood ratios (LLR) and predictive values (PV). PAR-1 AP mediated ATP secretion in the rapid test was lower in δ-SPD compared with healthy controls and non-SPD patients (P<.0001). The rapid test was able to discriminate between δ-SPD and non-SPD patients (C-statistic 0.88 (95%CI 0.78-0.98). At a cut-off value of the highest value of the δ-SPD group, the sensitivity was 100% and the specificity was 64%. This cut-off value corresponded with a positive LLR of 2.75, an optimal negative LLR of 0.00, positive PV of 76% and negative PV of 100%. A whole blood ATP secretion test can be used to exclude ẟ-SPD in patients presenting with a primary hemostasis defect.

BACKGROUND:Cyclic sex-hormone fluctuation impacts clotting factor concentrations, being lowest during the follicular phase of the menstrual cycle. This pattern is unexplored in women with heavy menstrual bleeding (HMB), but potentially affects the timely diagnosis of underlying bleeding disorders. AIM:Comparing clotting factor fluctuation in the follicular versus luteal phase, between women with and without HMB. METHODS:A PubMed/MEDLINE systematic review on HMB and clotting factors. Articles reporting clotting factor concentrations in premenopausal women with and without HMB were included, categorized by follicular or luteal phase if the sampling moment was specified. A meta-analysis was performed and the effect of HMB on (cyclic) clotting factor concentrations was assessed. RESULTS:A total of 21 out of 2158 articles were included. Clotting factors II, V, VII-XI, fibrinogen and von Willebrand factor (VWF) during the follicular and luteal phases were reported in women with HMB. All measurements in women with HMB were performed during the follicular or unspecified phase, hindering phase-specific assessment. Irrespective of phase, pooled measurements in women with HMB suggested elevated FVIII (pooled difference 21.8 IU/dL, 95% CI: 4.5-39.1, p = 0.01) and FV concentrations (pooled difference 15.8 IU/dL, 95% CI: 6.0-25.5, p = 0.002), but not VWF activity (pooled difference -11.0 IU/dL, 95% CI: -27.9 to 5.9, p = 0.20), compared to women without HMB. CONCLUSION:Based on meta-analysis of limited data, women with HMB tend to exhibit slightly higher FVIII and FV concentrations as compared to those without. More research is needed in the follicular phase of women with HMB to assess the effect of menstrual phases on HMB.

INTRODUCTION:Patients with musculoskeletal complaints as a result of their bleeding disorder can benefit from primary care physiotherapy. The current study aims to describe physiotherapy services provided in primary care to patients with bleeding disorders and to what extent treatment was already in concordance with treatment recommendations as published in a clinical practice guideline in April 2024. METHODS:Researchers collected data from medical notes of primary care physiotherapists in the Netherlands treating a patient with a bleeding disorder. Collected data included; patient characteristics, condition for which treatment was initiated, total number of sessions, treatment modalities provided and outcome of treatment. Data from medical files was compared with 19 treatment recommendations stated in the newly developed clinical practice guideline. RESULTS:Data from 86 treatment episodes of 62 patients by 52 different physiotherapists was collected. Treatment episodes were initiated for haemophilic arthropathy (n = 47), joint bleed (n = 24), muscle bleed (n = 9) and synovitis (n = 6). The most frequently provided treatment modalities included manual techniques (in haemophilic arthropathy) and exercise therapy (in all other conditions). The percentage in which treatment was in concordance with the recommendation ranged between 17% and 100%. CONCLUSION:The study indicated that exercise therapy was a commonly used treatment modality for all conditions. In contrast with other conditions, manual techniques were a frequently provided treatment modality in haemophilic arthropathy. Treatment was in many instances not in concordance with newly developed treatment recommendations. Dissemination and implementation of the recently developed treatment recommendations have the potential to improve primary care physiotherapy treatment for persons with bleeding disorders.

INTRODUCTION:Glanzmann's thrombasthenia is a rare inherited platelet disorder characterized by a lack of platelet aggregation. Patients tend to be diagnosed in early childhood with treatment strategies involving a multifaceted approach to prevent and manage bleeding episodes. Unfortunately, there is currently no European consensus regarding the management of GT. AIM:This initiative aimed to gain an understanding of current clinical management of GT across Europe, with the aim of aligning best practice and improving patient outcomes. METHODS:The authors, on behalf of the EAHAD Glanzmann Working Group, administered an online survey of 57 questions to European haematologists currently involved in the management of patients with GT. The survey covered topics related to diagnosis, treatment access and selection, immunization, peri-operative management and use of second-line therapies. RESULTS:Responses reflected physician consensus around some topics, including peri-operative treatment, use of recombinant factor VIIa, and concerns around antibody development. However, more varied responses were received on topics such as antibody screening (anti-αIIbβ3 antibodies screening conducted by ≤53% of respondents in all countries of interest except France), access to HLA-matched platelet concentrates (none or limited for 55% of respondents) and duration of platelet transfusions for major surgery (13%-31% for 1, 2, 3 and 4 or more days of transfusions). CONCLUSION:Establishing comprehensive guidelines to manage GT will enhance patient outcomes by ensuring patients receive high-quality and effective care as well as standardize care across different healthcare settings.

Background: Emicizumab, a bispecific antibody that mimics factor (F)VIII, has significantly improved hemophilia A management. Although emicizumab levels can be measured, tools for estimating the hemostatic efficacy of emicizumab are lacking. Thrombin generation (TG) assays can distinguish bleeding phenotypes in persons with hemophilia A on FVIII prophylaxis and may also be used during emicizumab therapy. Objectives: To assess the association between TG parameters, emicizumab levels, and bleeding in patients on emicizumab therapy. Methods: A single-center longitudinal cohort study was conducted, with samples collected during the steady-state phase of emicizumab therapy. TG was measured using tissue factor (TF; TF-TG, 1 pM) and FXIa (FXIa-TG, 200 pM). Emicizumab concentrations were determined with mass spectrometry. Only treated bleeds were recorded. Pearson correlations (rho, r) were reported. Results: Eighty-five samples from 49 patients were analyzed during a median of 1 year of emicizumab therapy. Most bleeds were traumatic (97%; n = 30), whereas 1 bleed was spontaneous. At 12 months, TF-TG (r = 0.42) showed a borderline correlation, and FXIa-TG (r = 0.15) showed no correlation with emicizumab concentrations. Although FXIa-TG showed a 9% higher endogenous thrombin potential in patients with zero vs >= 1 treated bleed (endogenous thrombin potential: 957 vs 878 nM/min, P = .045), neither the FXIa-peak height nor TF-TG showed any association with traumatic bleeding. Conclusion: TG parameters showed no clinically relevant correlations with emicizumab plasma concentrations, were not associated with traumatic bleeding, and showed considerable intrapatient variability. Therefore, TG was not considered useful for monitoring coagulation potential in patients on steady-state emicizumab prophylaxis.

Sustained remissions off-treatment (SROTs) after tapering of thrombopoietin receptor agonists (TPO-RAs) have been reported in 15%-50% of patients with immune thrombocytopenia (ITP). The STIP (Stop TPO-Receptor Agonist in ITP Patients) study is a prospective trial aimed to investigate the clinical effects of romiplostim tapering. Adult patients (22/40) with ITP ≥3 months received romiplostim for 1 year, were tapered and followed for 1 year. Anti-platelet antibodies (APAs), TPO levels and indium-111 platelet scintigraphy were assessed before, during and after romiplostim. Censored survival analysis showed that the probability of SROT at 1 year after tapering was 23.6% (95% confidence interval: 11.0%-50.5%). Patients with SROT had higher platelet levels on romiplostim (median: 332.5 vs. 84.5 × 109/L) and lower romiplostim doses at the start of tapering (median: 1.0 vs. 4.5 μg/kg) compared to those with a non-sustained response (NSR). APAs were detected in 8/25 patients at baseline, of which 5 showed a substantial decrease during romiplostim. The indium-111 scan revealed an improved platelet survival at the start of tapering for 50% of patients with SROT (2/4, missing n = 1) versus none with an NSR (0/14, missing n = 3). Overall, the STIP study demonstrated a probability of SROT of 23.6% in a diverse and largely chronic group of adult patients with ITP.

Familial Platelet Disorder with associated Myeloid Malignancy (FPDMM, FPD/AML, RUNX1-FPD), caused by monoallelic deleterious germline RUNX1 variants, is characterized by bleeding diathesis and predisposition for hematologic malignancies, particularly myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Clinical data on FPDMM-associated AML (FPDMM-AML) are limited, complicating evidence-based clinical decision-making. Here, we present retrospective genetic and clinical data of the largest cohort of FPDMM patients reported to date. We describe 159 European patients (from 94 families) of whom 134 were evaluable for the development of malignant disease. Sixty developed a hematologic malignancy (44.8%), most frequently AML (36/134, 26.9%) or MDS (18/134, 13.4%). Somatic alterations of RUNX1 by gene mutation (48%) and chromosome 21 aberrations (14.3%) were the most common somatic genetic aberrations in FPDMM-AML, followed by FLT3-ITD mutations (24.1%). Somatic RUNX1 and FLT3-ITD mutations were not detected in FPDMM-associated MDS, suggesting important contributions to leukemic transformation. Remission-induction chemotherapy resulted in complete remission in 80% of FPDMM-AML patients with a 5-year overall survival (OS) of 50.4%. Survival outcome was non-inferior compared to a large cohort of newly diagnosed adult RUNX1-mutated AML (5-year OS 36.6%, p = 0.5), with relatively infrequent concurrent adverse risk somatic aberrations (ASXL1 mutation, monosomal karyotype, monosomy 5/del 5q) in FPDMM-AML. Collectively, data support the notion that step-wise leukemic evolution in FPDMM is associated with distinct genetic events and indicate that a substantial subset of FPDMM-AML patients achieves prolonged survival with conventional AML treatment, including allogeneic stem cell transplant. These findings are anticipated to inform personalized clinical decision-making in this rare disorder.

BACKGROUND:Venous thromboembolism (VTE) can recur shortly after stopping anticoagulation, highlighting the need for reliable biomarkers to identify high-risk patients during treatment. OBJECTIVES:To determine whether platelet and endothelial markers predict VTE recurrence. METHODS:We used data and samples from the randomized controlled VISTA trial (2011-2015), which included patients with unprovoked VTE who were treated with vitamin K antagonists for 6 months. After treatment cessation, patients were followed for 2 years to assess recurrence. This dataset formed the basis for the current prospective analysis, in which plasma levels of von Willebrand factor (VWF), active VWF (aVWF), soluble P-selectin, soluble thrombomodulin, CXCL4, and CXCL7 were measured before and after cessation of anticoagulation. Associations between biomarker levels and recurrence were analyzed using Cox regression. RESULTS:Plasma samples from 629 patients with a first unprovoked VTE who discontinued vitamin K antagonists were analyzed. Recurrence occurred in 75 patients (12%); 11 (15%) within 1 month, 29 (39%) within 3 months, and 46 (61%) after 3 months. Elevated levels of VWF and aVWF were associated with an increased risk of recurrence per 10-unit increase (VWF: hazard ratio, 1.03; 95% CI, 1.01-1.06; aVWF: hazard ratio, 1.02; 95% CI, 1.00-1.05). Associations were stronger for early recurrence (<3 months), while (a)VWF levels were not associated with late recurrence (>3 months). Stratification showed that VWF and aVWF were associated with increased recurrence risk in men, but not in women. CONCLUSION:Elevated levels of VWF and aVWF during anticoagulation were associated with early recurrence in men and might serve as biomarkers for predicting VTE recurrence.

Background Limited data exist on persons with rare bleeding disorders possessing a heterozygous genotype, as most studies focus on biallelic genotypes and more severe coagulation factor deficiencies. A growing body of evidence suggests that persons with a heterozygous genotype experience clinically relevant bleeding symptoms. Objectives This study aimed to explore the incidence of bleeding symptoms and postoperative bleeding in persons with a heterozygous genotype. Methods This cross-sectional substudy of the Rare Bleeding Disorders in the Netherlands study (2017-2019) included persons with rare coagulation factor deficiencies and disorders of fibrinolysis with a heterozygous or biallelic genotype. Clinical data and laboratory samples were collected during a single study visit along with questionnaires. Results In total, 86 persons with a heterozygous genotype and 55 with a biallelic genotype were included. Median factor activity levels in persons with a heterozygous genotype approached 50% with considerable heterogeneity (range, 11%-93%). In 75%, persons with a heterozygous genotype reported bleeding severity of grade II or III. Female-specific bleeding was common. In total, 425 surgical procedures were performed. Persons with a heterozygous genotype were less likely to receive periprocedural treatment, and omission of periprocedural treatment was associated with postoperative bleeding in procedures with intermediate-high bleeding risk. Postoperative bleeding was comparable for persons with a heterozygous genotype (35%; 59/171) and a biallelic genotype (35%; 86/247; P = .926). Conclusion In our population with rare bleeding disorders, the majority of persons possessing a heterozygous genotype exhibited spontaneous bleeding symptoms. Especially in intermediate-high risk procedures, a proactive approach to periprocedural hemostatic treatment in persons with a heterozygous genotype seems beneficial.

Background Delta storage pool disease (δ-SPD) is a rare platelet function disorder (PFD) characterized by a deficiency of dense granules or defective granule secretion, leading to bleeding diathesis. Diagnostics of δ-SPD are difficult and lack standardization, leading to underestimation of its prevalence. Current diagnostic methods are based on granule content assays or lumi-aggregometry, which have limited availability. Therefore, there is an unmet need for a rapid, accessible test for δ-SPD. Objectives To evaluate the diagnostic value of a rapid whole-blood adenosine triphosphate (ATP) secretion test for δ-SPD. Methods ATP secretion after PAR-1 activating peptide (PAR-1 AP; TRAP-6) stimulation was assessed in whole blood using luminescence in 50 healthy controls, 22 patients with a suspected PFD other than storage pool disease (non-SPD) and 25 patients with δ-SPD and corrected for platelet count. Diagnostic value of the test was determined with C-statistics, sensitivity, specificity, likelihood ratios (LLRs), and predictive values (PVs). Results PAR-1 AP mediated ATP secretion in the rapid test was lower in δ-SPD than in healthy controls and non-SPD patients (P < .0001). The rapid test was able to discriminate between δ-SPD and non-SPD patients (C-statistic 0.88; 95% CI, 0.78-0.98). At a cutoff value of the highest value of the δ-SPD group, the sensitivity was 100% and the specificity was 64%. This cutoff value corresponded with a positive LLR of 2.75, an optimal negative LLR of 0.00, positive PV of 76%, and negative PV of 100%. Conclusion A whole-blood ATP secretion test can be used to exclude ẟ-SPD in patients presenting with a primary hemostasis defect.

Background Glanzmann thrombasthenia (GT) is an inherited platelet function disorder caused by mutations in the fibrinogen receptor αIIbβ3. The deficiency can be quantitative (type I/II) or qualitative (type III). It causes lack of platelet aggregation and leads to a moderate to severe bleeding tendency. Besides the absence or functional alteration of the integrins αIIb and β3, little is known about the proteomic landscape of platelets from GT patients. Objectives To evaluate the platelet proteome in GT. Methods Label-free quantification of platelet proteins was performed in 13 genetically confirmed GT patients (11 type I and 2 type III) and 13 healthy controls with liquid chromatography coupled with tandem mass spectrometry. αIIbβ3 expression was quantified with whole blood flow cytometry. Medical ethics committee approval was obtained and all participants provided informed consent. Results Of 3664 identified proteins, 2677 were considered quantified. Dynamic range spanned 5 orders of magnitude, and the mean coefficient of variation was 1.2%, indicating data were robust. Flow cytometry-based αIIb expression correlated well with αIIb abundance according to liquid chromatography-tandem mass spectrometry. Twenty-nine proteins were less abundant, and 32 proteins were more abundant in GT patients than in controls. Downregulated proteins were enriched for α-granule proteins, including secreted protein acidic and cyteine rich, amyloid β precursor-like protein 2, TIMP metallopeptidase inhibitor 1, and TREM-like transcript-1, in addition to the subunits of integrin αIIbβ3, fibrinogen, and plasminogen. Upregulated proteins were mostly plasma proteins annotated to blood microparticles. Conclusion GT platelets show reduced abundance of specific platelet α-granule proteins compared with healthy controls.

To illustrate the challenges in the management of women with Glanzmann thrombasthenia (GT) planning a pregnancy, we conducted a literature review and present a case series of eight women giving detailed descriptions of reproductive health problems, platelet alloimmunisation, treatment to prevent post-partum haemorrhage and neonatal outcomes. ART, assisted reproductive therapy; PPH, post-partum haemorrhage; rFVIIa, recombinant activated factor VII.

Thrombotic complications are common in Coronavirus disease 2019 (COVID-19) patients, with pulmonary embolism (PE) being the most frequent. Randomised trials have provided inconclusive results on the optimal dosage of thromboprophylaxis in critically ill COVID-19 patients. We utilized data from the multicentre CAPACITY-COVID patient registry to assess the effect of differential application of Low Molecular Weight Heparin (LMWH) dose protocols on PE and in-hospital mortality risk in critically ill COVID-19 patients. An instrumental variable analysis was performed to estimate the intention-to-treat effect, utilizing differences in thromboprophylaxis prescribing behaviour between hospitals. We included 939 patients with PCR confirmed SARS-CoV-2 infection from 34 hospitals. Two-hundred-and-one patients (21%) developed a PE. The adjusted cause-specific HR of PE was 0.92 (95% CI: 0.73-1.16) per doubling of LMWH dose. The adjusted cause-specific HR for in-hospital mortality was 0.82 (95% CI: 0.65-1.02) per doubling of LMWH dose. This dose-response relationship was shown to be non-linear. To conclude, this study did not find evidence for an effect of LMWH dose on the risk of PE, but suggested a non-linear decreased risk of in-hospital mortality for higher doses of LMWH. However, uncertainty remains, and the dose-response relationship between LMWH dose and in-hospital mortality needs further investigation in well-designed studies.

BACKGROUND:Efanesoctocog is a B-domain-deleted, Fc-fusion factor (F)VIII linked to the D'D3 domain of von Willebrand factor and 2 XTEN polypeptides, designed for an ultra-extended half-life for prophylaxis in hemophilia A, but also aiding in managing acute bleeding or surgery in patients on long-term emicizumab. However, no current laboratory method accurately measures FVIII levels in the presence of emicizumab. OBJECTIVES:To test whether the bovine chromogenic FVIII assay, specifically calibrated for efanesoctocog, could provide an accurate assessment of efanesoctocog activity. METHODS:Seven centers across 5 countries received 12 plasma samples to measure in triplicate using 2 calibration methods across 3 independent days. Samples (n = 6) contained either only efanesoctocog (FVIII activity [FVIII:C]= 5 to 150 IU/dL), or efanesoctocog (FVIII:C = 5 to 150 IU/dL) in combination with emicizumab (50 μg/mL; n = 5). One sample contained efanesoctocog (FVIII:C = 50 IU/dL) and a high dose of emicizumab (80 μg/mL); another sample contained efanesoctocog (FVIII:C = 50 IU/dL) with a low dose of emicizumab (20 μg/mL). Each center used its own analyzers, along with their usual reagents. RESULTS:Chromogenic assay (CSA) calibrated with standard calibrators highly overestimates FVIII:C. However, specific calibration with efanesoctocog enabled accurate measurement of FVIII:C, with low inter- and intra-laboratory variability, and no interference from emicizumab. All CSA reagents used in the study demonstrated low variability across different laboratories (interlaboratory coefficient of variation ranges between 9% and 20%). CONCLUSION:Specific calibration of the FVIII CSA using efanesoctocog and bovine reagents allows for accurate measurement of FVIII:C in patients receiving efanesoctocog, even in the presence of emicizumab.

Background: While prophylactic emicizumab therapy is highly effective in preventing bleeding in hemophilia A and generally well-tolerated, the high costs impose a significant financial burden on healthcare systems. Several case series have suggested that current bodyweight-based dosing of emicizumab could be safely reduced, providing similar effectiveness at a lower cost. Aim: Determine whether individualized PK-guided reduced dosing of emicizumab targeting a Ctrough emicizumab concentration of 30±5 μg/mL is non-inferior to conventional bodyweight-based dosing in the prevention of bleeding in hemophilia A patients. Methods: The DosEmi study is an ongoing phase IV, multicenter, prospective, open-label, crossover study comparing 12 months of conventional dosing of emicizumab vs 12 months of PK-guided reduced dosing targeting at concentrations of 30±5 μg/mL (ClinicalTrial.gov - NCT06320626). Study participants were recruited from eight Dutch hemophilia treatment centers from September 1st 2022 onwards. Eligible participants have severe or moderate congenital hemophilia A (FVIII < 6 IU/mL) with and without FVIII-inhibitors; receiving conventional dosing of emicizumab (according to label of 6 mg/kg/4 weeks at varying intervals) for a duration of ≥ 12 months prior to inclusion with good bleeding control, defined as: no spontaneous joint/muscle bleeds in the previous six months and/or a maximum of two treated (traumatic) bleeds in the previous six months. Emicizumab concentrations were determined by a validated liquid chromatography-tandem mass spectrometry method after 12 months on conventional dosing, only patients with an emicizumab trough levels of ≥ 40 μg/mL were eligible for dose reduction. Patients with emicizumab trough levels of 25-39 μg/mL continued their current dose regimen and were followed observationally for 12 months. Patients with emicizumab trough levels of < 25 μg/mL were adjusted in dosing regimen according to local protocol. The interim analysis was scheduled to compare the proportion of patients without treated bleeds during six months of follow-up on conventional dosing to six months on PK-guided dosing using survival analysis, with a predefined non-inferiority criterion of an absolute risk difference of <16%. Patient characteristics were summarized as numbers (%) and medians with interquartile range (IQR, P25-P75). Results: On July 1st 2024, 72 patients were included in the study. Emicizumab concentrations were measured in 30 patients, and the emicizumab dose was reduced in 27 out of 30 patients. The median age of study participants was 52 (IQR 33 - 62) years. All patients had severe hemophilia A, and the majority of patients had no FVIII inhibitors (n=25, 93%). Overall, the emicizumab dose was decreased from a median of 6 (IQR 5.2 - 6.4) mg/kg/4wks to 3.4 (IQR 2.8 - 3.9) mg/kg/4wks. The median follow up during PK-guided dosing was 4.6 (IQR: 3.2 - 10.5) months, of which 13 patients completed the entire six months on PK-guided dosing. Bleeding control remained stable over the follow-up period. The proportion of patients without treated bleeds was 76% during conventional dosing versus 71% during the PK-guided dosing (p=0.222). Similar results were observed with regard to the proportion of patients without treated joint bleeds, 82% versus 87% respectively (p=0.609). All bleeds were traumatic except in one patient who developed a spontaneous ultrasound confirmed muscle bleed on PK-guided dosing. Regarding the safety, no emicizumab related adverse events nor thrombotic events were observed after dose reduction Conclusion: With an absolute risk difference of +5% for absence of bleeding and -4% for absence of joint bleeding, these preliminary interim results suggest that PK-guided reduced dosing of emicizumab at concentrations of 30±5 μg/mL is non inferior to conventional dosing in preventing bleeding in patients with congenital hemophilia A. The definite results from this prespecified interim analysis evaluating the full six months of PK-guided dosing in 25 adult patients will be available in December 2024.

Background: In the Netherlands, pregnant women with von Willebrand Disease (VWD) receive prophylactic clotting factor suppletion when third trimester von Willebrand factor activity or Factor VIII levels are < 80 IU/dL to decrease the risk of postpartum hemorrhage (PPH). PPH (≥ 500 mL) and severe PPH (≥ 1000 mL) can lead to adverse outcomes like anemia, prolonged hospitalization, and slow recovery. Furthermore, prophylactic clotting factor suppletion necessitated childbirth in a hemophilia treatment center, increased intravenous infusions, and prolonged hospital stay which possibly affects quality of life (QoL) and childbirth satisfaction. Aim: assess patient reported outcomes (PROMs) by the Short Form 36 (SF-36), Mackeys Childbirth Satisfaction Rating Scale (MCSRS) and the Labor And DeliverY indeX (LADY-X) at week 1 and 6 postpartum in women with VWD with and without (severe) PPH. Method: Pregnant women with VWD (age ≥ 18 years) with an ongoing pregnancy who visited a Dutch hemophilia treatment center were eligible. PROMs data were combined with data on PPH and clotting factor prophylaxis from the PRegnancy and Inherited bleeding DisordErS (PRIDES) study. Participants completed the Short Form 36 (SF-36) for QoL assessment, Mackeys Childbirth Satisfaction Rating Scale (MCSRC) for childbirth satisfaction and the Labor And DeliverY indeX (LADY-X) for childbirth experience. The SF-36 and MCSRS were completed at week 1, and the SF-36 and LADY-X at week 6 postpartum. We used descriptive statistics for baseline parameters. Linear regression compared SF-36 scores at week 1, 6 and the delta between them for women with and without (severe) PPH. LADY-X and MCSRS scores were analysed by using the Mann-Whitney U test and regression analysis to control for clotting factor suppletion. Outcomes were compared to a general Dutch cohort study (2004-2007) by one sample t-tests and Odds Ratios. Results: between September 2018 and March 2024, 81 women with VWD, mostly VWD type 1 (76.5%, n=62/81), completed at least one questionnaire. Vaginal deliveries occurred in 78.8% (n=63/81). The incidences of PPH and severe PPH were 36.3% (n=29/81) and 16.3% (n=13/81), respectively. Overall, 23.5% (n=19/81) completed the SF-36 at both week 1 and 6 postpartum. Of these women, 36.8% (n=7/19) had PPH and 15.8% (n=3/19) severe PPH. Week 1 was completed by 79.0% (n=63/81), 36.5% (n=23/63) with PPH and 14.3% (n=9/63) with severe PPH. Week 6 was completed by 58.7% (n=47/81), 34.0% (n=16/47) had PPH and 12.8% (n=6/47) severe PPH. QoL scores did not differ between women with and without a (severe) PPH at week 1 and 6 postpartum. No difference was found in the change of SF-36 scores between week 1 and 6 in women with and without (severe) PPH. Compared to the general population, women with VWD had lower scores on the ‘Role limitations due to emotional problems’ domain at week 1 (mean difference -41.8, p-value < .001). At week 6, women with VWD had a lower QoL on 7/8 domains (p-values <0.05). Overall, 63 women with VWD completed the MCSRS, including 36.5% (n=23/63) with PPH. There were no differences in MCSRS scores for each domain between women with and without PPH. Women with severe PPH (14.3%, n=9/63) had lower satisfaction score on the ‘Baby’ domain (beta -1.93, 95% CI: -3.75 - -0.11). Compared to the general population, women with VWD reported higher childbirth satisfaction on all MSCRS domains (p-values < 0.001). 62 women completed the LADY-X, 32.8% (n=20/62) with PPH and 13.1% (n=8/62) with severe PPH. No significant differences were found between women with and without (severe) PPH. Women with VWD reported more concern about their baby in comparison to the general population (OR 0.21, 95% CI 0.12-0.39). Conclusions: Overall, women with VWD with (severe) PPH report similar QoL at week 1 and week 6 postpartum as compared to those without (severe) PPH. Childbirth satisfaction was lower in women with severe PPH on the ‘Baby’ domain and childbirth experience did not differ between women with and without (severe) PPH. Compared to the general population, women with VWD had a lower QoL at week 6 postpartum and more concerns about their newborn. However, women with VWD report higher childbirth satisfaction on almost all MCSRS domains. These results should be interpreted cautiously due to comparisons with a historical cohort.