Abstract Heavy menstrual bleeding (HMB) is a common yet underrecognized manifestation in girls and women with bleeding disorders and in those receiving antithrombotic therapy. HMB remains poorly defined and insufficiently explored and managed in clinical encounters. We explore HMB using the Limbourg Brothers' miniature as a historical and visual point to examine how menstrual bleeding has long remained visible yet unspoken. We argue that the burden of recognition still falls too heavily on the individual, particularly when clinicians fail to ask the right questions or when symptoms are normalized within families and society. We further propose that menstrual health should be treated as a core quality indicator in thrombosis and hemostasis clinics. We call for more recognition, standardized assessment, and proactive management so that women and girls are no longer left to seek help from the margins.

The impact of hemophilia in affected women and girls is insufficiently recognized, resulting in suboptimal evaluation of bleeding symptoms, delay in diagnosis, and missed management opportunities. The aim of this collaborative International Society on Thrombosis and Haemostasis (ISTH) Scientific Subcommittee on Pediatric and Neonatal Thrombosis and Haemostasis, Factor (F)VIII, FIX, and Rare Coagulation Disorders, and Women’s Health Issues in Thrombosis and Haemostasis project is to provide guidance recommendations regarding screening and diagnosis of hemophilia carriers (HC)/women and girls with hemophilia (WGwH) in addition to the previously published revised nomenclature by the Scientific Subcommittee of the ISTH. We provide several guidance recommendations regarding the nomenclature, utilization of the ISTH-Bleeding Assessment Tool as a tool to quantify bleeding phenotype, FVIII/FIX assays for testing, assay discrepancy, genetic testing, and testing during pregnancy and postpartum, to help guide hemophilia providers to streamline the screening and diagnosis of HC/WGwH in a uniform manner. We hope that once the screening and diagnosis of HC/WGwH become a uniform standard practice globally, this will pave the way for global harmonization of terminologies and improved management, bringing gender equity in hemophilia care a step forward.

BACKGROUND:Pregnant women with von Willebrand disease (VWD) receive prophylactic von Willebrand factor (VWF) concentrate based on third trimester VWF/factor (F)VIII levels to reduce the risk of severe postpartum hemorrhage (PPH, ≥ 1000 mL). Due to high severe PPH rates, Dutch guidelines were revised in 2018. Consensus was reached to increase the third trimester threshold for prophylaxis from < 50 to < 80 IU/dL, and peak target levels during childbirth from ≥ 100 to ≥ 150 IU/dL. OBJECTIVES:To assess the severe PPH incidence after guideline revision. METHODS:Pregnant Dutch women with VWD were prospectively enrolled (2018-2024). VWF/FVIII activity levels and hematologic and obstetric outcomes were compared with those of a historical cohort (2012-2017). Statistics included descriptives and logistic regression to correct for confounders. RESULTS:Severe PPH occurred in 18.1% (n = 29/160) without thrombosis or exsanguinations. Prophylaxis in those with third trimester levels of < 80 IU/dL led to PPH rates similar to those with spontaneous a rise > 80 IU/dL. Compared with the historical cohort (prophylaxis cutoff, < 50 IU/dL), severe PPH incidence did not decrease (n = 20/151 vs n = 29/160; odds ratio [OR], 1.45; 95% CI, 0.78-2.69). Moreover, in the third trimester 50- to 80-IU/dL subgroup and third trimester < 50-IU/dL subgroup, the risk for severe PPH was similar (n = 31/160 vs n = 23/151; OR, 0.86; 95% CI, 0.23-3.28; and n = 64/160 vs n = 48/151; OR, 2.59; 95% CI, 0.78-8.60, respectively), despite increased peak target levels of 150 IU/dL. CONCLUSION:Increasing the third trimester VWF and FVIII cutoff to < 80 IU/dL and aiming for ≥ 150 IU/dL at delivery did not decrease severe PPH. More research is needed on optimal peripartum hemostatic prophylaxis in VWD.

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.

ABSTRACT:Previous reports have highlighted that some patients with low von Willebrand factor (VWF) with significant bleeding were diagnosed based on an isolated but persistent reduction in plasma VWF activity levels in the 30 to 50 IU/dL range. These patients had plasma VWF antigen (VWF:Ag) levels >50 IU/dL and thus had qualitative low VWF (low VWF-QL) rather than quantitative low VWF. Although the clinical importance of functional VWF defects in type 2 von Willebrand disease (VWD) is well recognized, the translational implications of mild functional defects in patients with low VWF-QL have not been defined. To address this clinically important question, we combined low VWF data sets from the low VWF in Ireland cohort and the low VWF in Erasmus MC studies. Overall, we observed that low VWF-QL was common and accounted for ∼50% of our combined low VWF cohort. Importantly, our findings demonstrated that many of these patients with mild isolated functional VWF defects in the 30 to 50 IU/dL range had significant bleeding phenotypes, although their plasma VWF:Ag levels were within the normal range. In addition, we further showed that low VWF-QL is a distinct clinicopathological entity compared to type 2 VWD. Finally, our studies highlighted that low VWF-QL is predominantly caused by abnormalities in VWF biosynthesis within endothelial cells that are occurring largely independent of identifiable pathological VWF sequence variants. Cumulatively, these novel observations have important clinical implications for the diagnosis and management of patients with mild functional VWF defects.

Background:Sexuality is a fundamental aspect of quality of life, often impacted by chronic or inherited diseases like von Willebrand disease (VWD), an inherited bleeding disorder characterized by mucosal bleeding, including heavy menstrual bleeding (HMB). To date, no studies have investigated the impact of VWD on sexuality. Objectives:This study aimed to identify sexual restrictions and symptoms in VWD patients, differentiating between men and women and between premenopausal and nonmenstruating women. Methods:We performed a nationwide, multicenter, prospective cohort study, the Willebrand in the Netherlands-Prospective study, including adult VWD patients (>18 years) who completed questionnaires on sexuality and health-related quality of life (SF-36). Additional data were collected via blood tests and a self-reported bleeding assessment tool (International Society on Thrombosis and Haemostasis Bleeding Assessment Tool). Results:We included 549 VWD patients with a median age of 51 years (IQR, 37-66 years), of whom the majority were women (n = 347; 63.2%). Patients were diagnosed with type 1 (57.2%), type 2 (39.2%), or type 3 VWD (3.6%). Sexual restrictions due to VWD were reported by 3.5% of men (n = 7) and 9.8% of women (n = 34; P < .01). Bleeding during sexual activity was reported by 33.1% (n = 115) of women. Premenopausal patients more often reported sexual restrictions than nonmenstruating patients (15.5% vs 5.2%, P = .01), with HMB as the most important determinant (odds ratio, 1.60; 95% CI, 1.12-2.46). Most patients (n = 455; 82.9%) reported that sexuality was not discussed during routine clinic visits. Conclusion:Women with VWD experience more sexual restrictions than men and report more postcoital bleeding than the general population. Premenopausal women are particularly affected, mostly due to HMB. This highlights the need for health care providers to address sexual health during consultations and treat HMB to improve overall care for VWD patients.

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.

Background Type 2B von Willebrand disease (VWD) is a bleeding disorder caused by gain-of-function variants in the VWF gene. The laboratory and clinical phenotype of type 2B VWD is heterogeneous. Objectives We investigated associations between genotype and phenotype over a median of 16 years follow-up in a large cohort of well-characterized patients. Methods We included 64 genetically confirmed type 2B VWD patients from the national multicenter “Willebrand in the Netherlands” study and retrospectively collected clinical and laboratory data from electronic patient records. We analyzed associations between genotype and thrombocytopenia, bleeding phenotype, and events leading to endothelial activation and von Willebrand factor (VWF) secretion, including surgery, desmopressin administration, pregnancy, and delivery. Results Thrombocytopenia manifested in 67.2% of patients, with varying occurrences between genetic variants (p.Arg1306Trp: 75.0%, p.Arg1308Cys: 58.3%). The most important determinant of thrombocytopenia was the p.Arg1306Trp VWF variant (odds ratio, 25.1). Platelet counts strongly varied over time and were continuously <150 × 109/L in 37.5% of patients with p.Arg1306Trp vs 8.3% in p.Arg1308Cys. In our analysis, endothelial activation was not an independent determinant (odds ratio, 1.3) for thrombocytopenia occurrence. No association was found between thrombocytopenia and cumulative bleeding scores or annual bleeding rates. Four women showed declining platelet counts in all full-term pregnancies (n = 8) during the third trimester with a sharp decrease in the week before delivery. Postpartum hemorrhage, defined as >500 mL estimated blood loss at delivery, occurred in 5 of 8 deliveries, despite prophylactic treatment with VWF concentrates. Conclusion This study reveals a strong association between VWF variant p.Arg1306Trp and thrombocytopenia in type 2B VWD patients.

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.

INTRODUCTION:In patients with an increased bleeding tendency, extensive diagnostic blood testing is often performed. When results of tier 1 assays of primary haemostasis are normal, protocols recommend additional testing to rule out rare disorders including coagulation factor XIII (FXIII) and α2-antiplasmin (α2AP) deficiency. AIM:To evaluate the added diagnostic value of FXIII and α2AP levels in patients with a bleeding disorder of unknown cause (BDUC). METHODS:A retrospective monocentre cohort study between August 2011 and August 2023 was conducted. In all patients with bleeding tendencies and normal diagnostic tests for von Willebrand disease and platelet function, FXIII and α2AP were measured. RESULTS:We included 158 consecutive patients; mean ISTH-BAT scores were 8.2 (SD ± 3.7) in children, 6.2 (SD ± 2.1) in men and 10.6 (SD ± 3.3) in women. Median age was 37 (range 5-79) years, 88.6% of patients were female. Patients displayed median FXIII activity of 111% (IQR = 97-131) and median α2AP activity of 112% (IQR = 103-119). Three (1.9%) patients had FXIII levels < 50%, respectively 43%, 45% and 46%. Corresponding ISTH-BAT scores were 7, 12 and 14. No α2AP levels < 60% was observed. No significant association was found between FXIII levels and ISTH-BAT scores. CONCLUSION:In our cohort of BDUC patients, no clinical relevant FXIII deficiencies were detected; absolute values were well above the 30% cutoff considered adequate for normal haemostasis. No α2AP deficiencies were detected. These data suggest that in BDUC patients, measuring FXIII or AP activity is of limited value.

Background: Between 2002 and 2011, the incidence of severe primary postpartum hemorrhage (PPH) in Dutch women with von Willebrand disease (VWD) and hemophilia carriers (HCs) was 8% vs 4.5% in the general population. Objectives: To determine the contemporary incidence of severe primary PPH in women with VWD and HCs. Methods: All women with VWD or HCs who delivered between 2012 and 2017 were selected from all 6 Dutch hemophilia treatment centers. Data on patient and disease characteristics, peripartum hematologic and obstetric management, and outcomes were retrospectively collected. Incidence of severe primary (>= 1000 mL of blood loss <= 24 hours after childbirth) and primary (>= 500 mL within <= 24 hours after childbirth) PPH was compared with the (1) previous cohort and (2) general Dutch population and between (3) women with VWD and HCs with third-trimester coagulation activity levels <50 international units (IU)/dL vs >= 50 IU/dL and (4) women treated with vs without peripartum hemostatic prophylaxis. Results: Three-hundred forty-eight deliveries (151 VWD, 167 hemophilia A, and 30 hemophilia B carriers) were included. The severe primary PPH incidence was 10% (36/ 348) and remained stable over time, whereas this incidence has increased in the general population (to 8%), leading to a similar risk (P = .17). Severe primary PPH risk was comparable between women with coagulation activity levels <50 and >= 50 IU/dL (11% [7/66] vs 10% [29/279]; odds ratio, 1.02; 95% CI, 0.43-2.44) and comparable between those with and those without prophylaxis (12% [11/91] vs 10% [25/254]; odds ratio, 1.26; 95% CI, 0.59-2.68). Conclusion: Severe primary PPH in women with VWD and HCs remained stable and is comparable with the increasing prevalence in the general population. More research is needed to find the optimal pregnancy management strategy for safe delivery in VWD and HC.

Background: While hemophilia mostly affects males through X-linked inheritance, female hemophilia carriers (HCs) can experience extensive bleeding, such as postpartum hemorrhage (PPH, ≥ 500 mL). To reduce the risk of severe PPH (≥ 1000 mL), pregnant HCs in the Netherlands receive clotting factor suppletion based on their third trimester Factor (F) VIII or FIX levels. Prior research showed a higher prevalence of severe PPH in HCs compared to the general Dutch population (12.5% vs. 7.7%), leading to a revision of the Dutch guideline in 2018. The third trimester cut-off value for clotting factor suppletion was changed from < 50 IU/dL to < 80 IU/dL, and peak target FVIII/FIX levels at delivery were increased from > 100 IU/dL to > 150 IU/dL. The change in the cut-off value and target peak clotting factor levels was initiated to aim for similar physiological VWF activity and FVIII levels as in the general population during childbirth, with the goal to reduce the incidence of (severe) PPH in women with VWD. Aim: to assess the incidence of (severe) PPH in HCs, after the implementation of the novel Dutch Hemophilia guideline in 2018. Methods: The study is a multicenter, observational cohort study in all six Dutch hemophilia treatment centers. All ongoing HCs pregnancies > 10 weeks of gestation were eligible. Prophylactic FVIII or FIX suppletion was indicated during delivery for pregnancies with third trimester FVIII/FIX levels < 80 IU/dL. Baseline parameters, FVIII/FIX activity levels, blood count parameters, total vaginal blood loss < 24 hours postpartum, and obstetric risk factors were recorded. Statistical analysis: we used descriptive statistics for baseline parameters, obstetric risk factors and delivery outcomes, including PPH incidence. Logistic regression was used for multivariate analysis with primiparity, cesarean section and a history of PPH as possible confounders. Subgroup analysis was performed in those with and without indication for prophylactic clotting factor suppletion (third trimester levels < 80 IU/dL and ≥ 80 IU/dL. Results: between September 2018 and March 2024, 170 deliveries were recorded, 88.3% (n=150/170) in hemophilia A carriers. Overall, 47.6% (n=81/170) were primipara HCs. History of PPH occurred in 14.2% (n=24/170). Cesarean section occurred in 24.1% (n=41/170). The incidence of PPH and severe PPH was 33.5% (n=57/170) and 12.4% (n=21/170), respectively. Median blood loss was 300 mL (IQR 200-540). 20% (n=34/170) of the deliveries had third trimester levels < 80 IU/dL and 73.5% (n=25/34) received prophylactic clotting factor suppletion during delivery. The ≥ 80 IU/dL group received prophylaxis in 2.2% (n=3/136). There were less cesarean sections in the < 80 IU/dL group, however this was not significantly lower (14.7%, n=5/34 vs. 26.5%, n=36/136, p-value 0.18). Overall, 44.1% (n=15/34) in the < 80 IU/dL group and 48.5% (n=66/136) in the ≥ 80 IU/dL group were primipara. The < 80 IU/dL group had a lower incidence of a history of PPH (8.8%, n=3/34 vs. 15.4%, n=21/136), but this was not significant (p-value 0.32). In the < 80 IU/dL group, the PPH incidence was 29.4% (n=10/34) compared to 34.6% (n=47/136) in the ≥ 80 IU/dL group (p-value 0.57). Multivariate analyses showed no difference in PPH incidence when adjusted for cesarean section, a history of PPH, and primiparity (adjusted OR 1.11, 95% CI 0.48-2.71). The incidence of severe PPH was similar in the < 80 IU/dL group (11.8%, n= 4/34) vs. the ≥ 80 IU/dL group (12.5%, n= 17/136, p-value 0.91, adjusted OR of 1.07, 95% CI 0.36-0.93). Median blood loss was 300 mL (IQR 200-500, < 80 IU/dL group) vs. 365 mL (IQR 200-580, ≥ 80 IU/dL group, p-value 0.27). Conclusion: Prophylactic clotting factor suppletion in HCs with third trimester FVIII or FIX levels < 80 IU/dL results in similar (severe) PPH incidence as in deliveries of HCs with third trimester levels ≥ 80 IU/dL who do not receive prophylaxis, after adjustment for obstetric risk factors. The overall incidence of PPH in HCs remains high. Future analysis: Upcoming analysis focusses on comparing the subgroups with third trimester levels < 50 IU/dL and between 50-80 IU/dL who received more intensive clotting factor supplementation with data from a cohort study on PPH in HCs during the six years prior to the guideline revision. In addition, the incidence of PPH and obstetric risks factors in the general Dutch population during the same period as the PRIDES study will be compared.

Background: In the Netherlands, pregnant hemophilia carriers (HCs) receive prophylactic clotting factor suppletion when third trimester Factor VIII or IX activity 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: to assess patient reported outcomes (PROMs) at week 1 and week 6 postpartum and compare results between HCs with and without (severe) PPH. Method: Pregnant HCs (age ≥ 18 years) with an ongoing pregnancy who visited a Dutch hemophilia treatment center were eligible. PROMs data were combined with PPH and clotting factor prophylaxis data 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 birth 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, week 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 2024,87 HCs, mostly hemophilia A (83.9%, n=73/87), completed at least one questionnaire. Vaginal deliveries occurred in 81.2% (n=69/87). The incidences of PPH and severe PPH in this cohort were 37.6% (n=32/87) and 17.6% (n=15/87), respectively. In total, 23.0% (n=20/87) completed the SF-36 at both week 1 and week 6 postpartum. Of these women, 50% (n=10/20) had PPH ≥ 500 mL, and 20% (n=4/20) severe PPH. Week 1 was completed by 80.0% (n=68/87), 38.2% (n=26/68) with PPH and 19.1% (n=13/68) with severe PPH. Week 6 was completed by 51.2% (n=43/87), with 39.5% (n=17/43) experiencing PPH and 20.9% (n=9/43)severe PPH. QoL scores did not differ between women with and without a (severe) PPH at week 1 and week 6 postpartum. At week 6, HCs with either PPH or severe PPH had lower scores on emotional wellbeing as compared to week 1 postpartum (p-values < 0.05). Compared to the general population, HCs had lower scores on ‘Role limitation due to emotional problems’ (mean difference -41.8, p-value <0.001) at week 1. At week 6, HCs had lower QoL scores on 7/8 domains (p-values < 0.05). The MCSRS was completed by 71 HCs, 37% (n=26/71) with PPH There were no differences in MCSRS scores between HCs with and without PPH. HCs with severe PPH (18.8%, n=13/71) reported lower MCSRS scores on the domains ‘Baby’ (beta -1.55, 95% CI -2.82 - -0.27), and ‘General’ (beta -2.70, 95% CI -4.85 - -0.55). Compared to the general population, HCs reported more frequently ‘satisfied’ and ‘very satisfied’ on all MCSRS domains (all p-values < 0.001). The LADY-X was completed by 59 HCs. 41.4% (n=24/59) had PPH and 24.1% (n=14/59) severe PPH. No significant differences in LADY-X scores were found between HCs with and without (severe) PPH. HCs reported more concerns about their newborn as compared to the general population (OR 0.27, 95% CI 0.15-0.48). Conclusions: HCs with PPH reported similar QoL scores at week 1 and week 6 postpartum compared to those without PPH. However, HCs with (severe) PPH had lower emotional wellbeing scores at week 6. HCs with severe PPH have lower satisfaction with general wellbeing and interaction with their newborn during labor. Childbirth experience was similar between HCs with and without (severe) PPH. Compared to the general population, HCs reported lower QoL at 6 weeks postpartum and more concerns about their newborn. However, HCs experienced higher childbirth satisfaction on the MCSRS. The results should be interpreted cautiously due to comparisons with a historical cohort.

Background:Von Willebrand disease (VWD) type 3 is characterized by a complete deficiency of von Willebrand factor (VWF), resulting in a severe bleeding phenotype. Treatment often requires administration of VWF concentrates/factor (F)VIII. However, the development of alloantibodies is a rare complication, resulting in ineffective recovery and allergic reactions. Emicizumab, a bispecific antibody mimicking FVIII function, has emerged as a potential alternative, with promising results reported in several case reports.Key Clinical Question:Description of multiple approaches to control highly severe postpartum hemorrhage in type 3 VWD with alloantibodies, including off-label use of emicizumab.Clinical Approach:Here we present a 28-year-old patient with type 3 VWD and alloantibodies, known to have arthropathy of the right elbow. Previous immune tolerance induction was unsuccessful. Despite receiving negative pregnancy advice during preconception counseling, the patient became pregnant. Delivery was induced at 38 4/7 weeks with prostaglandin, and recombinant FVIIa (rFVIIa) was administered every 2 hours. Despite administration of rFVIIa, bleeding persisted, requiring manual placental removal and insertion of a Bakri balloon. Since bleeding persisted, plasma-derived VWF was administered with an initial excellent recovery and successful embolization of the uterine artery. Twelve days postpartum, she developed endometritis and recurrent vaginal bleeding treated with antibiotics, rFVIIa every 2 hours, and multiple erythrocyte transfusions. Plasma-derived VWF was administered but was complicated by anaphylaxis and no recovery. Due to persistent vaginal bleeding, reembolization of uterine arteries was performed and off-label emicizumab was initiated. Twenty-nine days postpartum, she developed septic shock requiring an abdominal hysterectomy, again complicated by severe bleeding necessitating direct intraabdominal packing after rFVIIa. A computed tomography scan 9 days postsurgery revealed thrombosis in the left iliac vein and asymptomatic pulmonary embolisms. rFVIIa was stopped and prophylactic low-molecular-weight heparin was started. The patient was discharged 2 months after delivery on low-dose low-molecular-weight heparin, emicizumab, and antibiotics for an intra-abdominal abscess. During 2.5 years of emicizumab prophylaxis, she has had no rebleeding in her arthropathic right elbow.Conclusion:The current case emphasizes the postpartum clinical challenges of patients with type 3 VWD and alloantibodies. It underscores the potential role of emicizumab in maintaining hemostatic control.

INTRODUCTION:The severity of Von Willebrand disease (VWD) is currently based on laboratory phenotype. However, little is known about the severity of the patient's experience with the disease. The most recent VWD guidelines highlight the need for patient-reported outcomes (PROs) in VWD. AIM:The study aimed to investigate the patient-perspective on VWD severity and to identify key factors that determine the severity of disease experienced by patients. MATERIALS AND METHODS:Patients participated in a nationwide cross-sectional study on VWD in the Netherlands (WiN-study). Patients filled in a questionnaire containing questions on the experienced severity of VWD (4-point scale), bleeding score (BS) and quality of life (QoL). RESULTS:We included 736 patients, median age of 41.0 years (IQR 23.0-55.0) and 59.5% were women. A total of 443 had type 1, 269 type 2 and 24 type 3 VWD. Self-reported severity of VWD was categorized as severe (n = 52), moderate (n = 171), mild (n = 393) or negligible (n = 120). Classification by historically lowest FVIII:C levels < 0.20 IU/mL as a proxy for severe VWD aligned with patient-reported severity classification with a 72% accuracy. Type 3 VWD (OR = 4.02, 95%CI: 1.72-9.45), higher BS (OR = 1.09, 95%CI: 1.06-1.11), female sex (OR = 1.36, 95%CI: 1.01-1.83), haemostatic treatment in the year preceding study inclusion (OR = 1.53, 95%CI: 1.10-2.13) and historically lowest VWF:Act levels (OR = 0.26, 95%CI: 0.07-1.00) were independent determinants of patient-reported severity. CONCLUSION:This study shows that patient-reported data provide novel insights into the determinants of experienced disease severity. Our findings highlight the need for studies on PROs with validated questionnaires to assess the burden of VWD.

There is signi fi cant ongoing debate regarding type 1 von Willebrand disease (VWD) de fi ntion. Previous guidelines recommended patients with von Willebrand factor (VWF) levels <30 IU/dL be diagnosed type 1 VWD, whereas patients with signi fi cant bleeding and VWF levels from 30 to 50 IU/dL be diagnosed with low VWF. To elucidate the relationship between type 1 VWD and low VWF in the context of age-induced increases in VWF levels, we combined data sets from 2 national cohort studies: 162 patients with low VWF from the Low VWF in Ireland Cohort (LoVIC) and 403 patients with type 1 VWD from the Willebrand in The Netherlands (WiN) studies. In 47% of type 1 VWD participants, VWF levels remained <30 IU/dL despite increasing age. Conversely, VWF levels increased to the low VWF range (30-50 IU/dL) in 30% and normalized (>50 IU/dL) in 23% of type 1 VWD cases. Crucially, absolute VWF antigen (VWF:Ag) levels and increase of VWF:Ag per year overlapped between low VWF and normalized type 1 VWD participants. Moreover, multiple regression analysis demonstrated that VWF:Ag levels in low VWF and normalized type 1 VWD patients would not have been different had they been diagnosed at the same age ( beta = 0.00; 95% con fi dence interval, -0.03 to 0.04). Consistently, no difference was found in the prevalence of VWF sequence variants; factor VIII activity/VWF:Ag or VWF propeptide/VWF:Ag ratios; or desmopressin responses between low VWF and normalized type 1 VWD patients. In conclusion, our fi ndings demonstrate that low VWF does not constitute a discrete clinical or pathological entity. Rather, it is part of an age-dependent type 1 VWD evolving phenotype. Collectively, these data have important implications for future VWD classi fi cation criteria.

Background: Pregnant women with von Willebrand Disease (VWD) are at a high risk for postpartum hemorrhage (PPH, ≥ 500 mL). To reduce the risk of severe PPH (≥ 1000 mL), pregnant women in the Netherlands with VWD receive prophylactic clotting factor suppletion based on their third trimester von Willebrand factor (VWF) activity and factor (F) VIII activity levels. Prior research showed a higher prevalence of severe PPH in women with VWD compared to the general Dutch population (13.3% versus 7.7%), leading to a revision of the Dutch guideline in 2018. The third trimester cut-off value for clotting factor suppletion was changed from < 50 IU/dL to < 80 IU/dL, and peak target VWF activity and FVIII levels during childbirth were increased from > 100 IU/dL to > 150 IU/dL. The change in the cut-off value and target peak clotting factor levels was initiated to aim for similar physiological VWF activity and FVIII levels as in the general population during childbirth, with the goal to reduce the incidence of (severe) PPH in women with VWD. Aim: Assess the incidence of (severe) PPH in pregnant women with VWD, after implementation of the novel Dutch Hemophilia guideline in 2018. Methods: The study design is a multicenter, observational cohort study in all six Dutch hemophilia treatment centers. All ongoing pregnancies > 10 weeks of gestation of women with VWD were eligible. Prophylactic VWF or VWF/FVIII concentrate was indicated during delivery for pregnancies with third trimester VWF or FVIII activity levels < 80 IU/dL. Baseline parameters, VWF activity/FVIII levels, blood count parameters, total vaginal blood loss < 24 hours postpartum, and obstetric risk factors were recorded. Statistical analysis: we used descriptive statistics for baseline parameters, obstetric risk factors and delivery outcomes, including PPH incidence. Logistic regression was used for multivariate analysis, with primiparity, cesarean section and a history of PPH as possible confounders. Subgroup analysis was performed in those with and without indication for prophylactic clotting factor suppletion (third trimester levels < 80 IU/dL and ≥ 80 IU/dL). Results: between September 2018 and March 2024, 160 deliveries in women with VWD were recorded, most from women with VWD type 1 (74.4%, n=119/160). Overall, 37.5% (n=60/160) were primipara. History of PPH was present in 28.7% (n=46/160). Cesarean section occurred in 23.1% (n=37/160). The incidences of PPH and severe PPH were 38.1% (n=61/160) and 18.1% (n=29/160), respectively. Median blood loss was 385 mL (IQR 200-700). 58.8% (n=94/160) deliveries had third trimester levels < 80 IU/dL and 93.6% (n=88/94) received prophylactic clotting factor suppletion during delivery. The ≥ 80 IU/dL group (n=66) received prophylaxis in 7.6% (n=5/66). Both groups had similar occurrences of a cesarean section (23.4%, n=22/94 and n=15/66, p-value 0.92) and primiparity (37.2%, n=35/94 and 37.9%, n=25/66, respectively). The < 80 IU/dL group had a lower incidence of a history of PPH (22.5%, n=24/94 vs. 33.3%, n=22/66), but this was not significant (p-value 0.26). In the < 80 IU/dL group, the PPH incidence was 41.5% (n=39/94) compared to 33.3% (n=22/66) in the ≥ 80 IU/dL group (p-value 0.30). Multivariate analysis showed no difference in PPH incidence when adjusted for cesarean section, a history of PPH, and primiparity (adjusted OR 0.69, 95% CI 0.35-1.36). The incidence of severe PPH was similar in the < 80 IU/dL group (19.1%, n= 18/94) vs. the ≥ 80 IU/dL group (16.7%, n=11/66, p-value 0.69), with an adjusted OR of 0.84 (95% CI 0.36-1.91). Median blood loss was 360 mL (IQR 200-700, < 80 IU/dL) vs. 400 mL(IQR 250-685, ≥ 80 IU/dL group, p-value 0.97). Conclusion: prophylactic clotting factor suppletion in women with VWD with third trimester VWF activity or FVIII levels < 80 IU/dL resulted in similar PPH and severe PPH incidences as in deliveries of women with VWD with ≥ 80 IU/dL without prophylaxis, when adjusted for obstetric risk factors. The overall incidence of PPH in women with VWD remains high. Future analysis: Upcoming analysis focusses on comparing the subgroups with third trimester levels < 50 IU/dL and between 50-80 IU/dL who received more intensive clotting factor supplementation with data from a cohort study on PPH in women with VWD during the six years prior to the guideline revision. In addition, the incidence of PPH and obstetric risks factors in the general Dutch population during the same period as the PRIDES study will be compared.