BACKGROUND:Pregnant hemophilia carriers receive prophylactic factor [F]VIII or FIX concentrate based on third trimester FVIII/FIX activity to reduce the risk of severe postpartum hemorrhage (PPH, ≥ 1000 mL). Due to persistently 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 hemophilia carriers were prospectively enrolled (2018-2024) in Dutch hemophilia treatment centers to assess the severe PPH incidence after implementation of the revised guideline. FVIII/FIX activity and hematologic and obstetric outcomes were recorded and compared with a historical cohort (2012-2017). Statistics included descriptives and logistic regression to correct for confounders. RESULTS:Severe PPH occurred in 12.4% of 170 deliveries. No thrombosis was recorded. Prophylaxis in the subgroup with third trimester levels of < 80 IU/dL led to similar PPH rates to those with spontaneous rises of > 80 IU/dL. Compared with the historic cohort with the third trimester cutoff of < 50 IU/dL, the severe PPH incidence did not decrease (n = 170 vs n = 197; odds ratio, 1.16; 95% CI, 0.46-2.93), neither in the third trimester of the 50- to 80-IU/dL subgroup (n = 28/170 vs n = 21/197; odds ratio, 1.0; 95% CI, 0.20-2.90). CONCLUSION:Increasing the third trimester cutoff to < 80 IU/dL and aiming for ≥ 150 IU/dL at delivery did not decrease the risk for severe PPH in hemophilia carriers. More research is needed on optimal clotting factor levels during delivery to prevent severe PPH.

A State-of-the-Art lecture entitled "Allele-selective von Willebrand Factor (VWF) silencing" was presented at the International Society on Thrombosis and Haemostasis (ISTH) congress in 2025. The concept, potential applications, and feasibility of alleleselective VWF inhibition will be discussed in detail in this review. VWF plays a crucial role in supporting hemostasis, which is important in bleeding as well as thrombotic disorders. Decreased or functionally defective VWF results in von Willebrand disease (VWD), whereas high VWF levels have been associated with thrombotic risk. By silencing the synthesis of VWF from the mutant VWF gene in VWD, one might eliminate the production of mutant VWF and thereby normalize multimer composition and increase the levels of functional VWF. This would lead to phenotypic improvement in VWD. In the context of high plasma VWF levels and thrombotic disorders, silencing of one VWF allele will lower VWF in the circulation and endothelial cells, but at the same time, allele-selective silencing prevents an excessive reduction in VWF levels. Limited VWF reduction will reduce thrombosis risk without inducing bleeding. Selectively silencing the expression of one VWF allele, based on a single nucleotide difference between the 2 alleles, using small interfering RNAs has proven to be successful. This approach resulted in phenotypic improvement for VWD in vitro as well as in vivo. Preliminary data in the context of thrombotic risk indicated that silencing one VWF allele reduced thrombosis development without increasing bleeding. Finally, we summarize relevant new data on other new treatments for VWD presented during the 2025 ISTH Congress.

Cofactor-independent activity of FIX has previously been achieved in FIX-IDAV and FIX-FIAV variants containing L6F, V181I, E185D, K265A, and I383V substitutions. Cofactor-dependent FIX hyperactivity was attained through the V10K, R338L, and S377W (KLW) modifications. We evaluated whether combining IDAV/FIAV and KLW substitutions could enhance cofactor-independent activity and elucidated the biochemical mechanisms underlying FVIII-independent FIX-FIAV function. Recombinant FIX variants, expressed in HEK293 cells, were analyzed for FIX-specific and FVIII-equivalent clotting activities. Highly purified FIX-FIAV was characterized using purified component assays and FXIa-triggered thrombin generation in FVIII-deficient plasma. FIX-IDAV-KLW and FIX-FIAV-KLW exhibited 20-28-fold higher FIX-specific activity and a modest twofold increase in FVIII-equivalent clotting activity. Owing to thrombotic safety concerns, KLW combinations were not further pursued. FIX-FIAV displayed normal FIX-specific activity and fourfold enhanced FVIII-equivalent clotting activity. The FIAV substitutions did not alter activation by the extrinsic (TF-FVIIa) or intrinsic (FXIa) pathways, nor cofactor-dependent FX activation, but conferred FVIII-independent FX conversion. Kinetic analyses revealed a modified active site conformation with a trend toward reduced antithrombin inhibition. In FVIII-deficient plasma, FIX-FIAV dose-dependently increased FXIa-triggered thrombin generation by shortening the lag time and time to peak and shifted coagulation phenotype categories based on FVIII-equivalent thrombin generation (TG) activity from severe toward moderate/mild ranges in plasma-based models, without exceeding normal FVIII-equivalent TG activity. FIX-FIAV represents a FIX variant with FVIII-independent activity, normal FIX-specific activity, and reduced inactivation by antithrombin. Targeted modification of regions surrounding the FIXa active site enables allosteric activation, providing a potential foundation for novel bypassing strategies in hemophilia A therapy.

To evaluate the clinical impact of a dedicated multidisciplinary spontaneous coronary artery dissection (SCAD) care pathway compared with standard acute coronary syndrome management, focusing on safety, treatment patterns, clinical outcomes, and recurrence rates in patients with SCAD. In this retrospective observational cohort study, 117 SCAD patients were included: 63 managed within a SCAD-specific care pathway and 54 receiving standard care prior to or independent of its implementation. The SCAD pathway included protocolized angiographic diagnosis, conservative management when feasible, individualized medical therapy, screening for fibromuscular dysplasia (FMD) and systemic disorders, and SCAD-specific rehabilitation with structured follow-up. The primary endpoint was major adverse cardiovascular events (MACE) at 1‑year follow-up. Patients in the SCAD pathway group were more often managed conservatively in the acute setting (76

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: Hemophilia carriers (HCs) and women with von Willebrand disease (VWD) receive specialized obstetric care because of a higher chance for postpartum bleeding and potential bleeding in the neonates. It is unknown what their postpartum quality of life (QoL), childbirth satisfaction, and experience are and how this differs from the general population. Objectives: This study assessed QoL, childbirth satisfaction and experience in HCs and women with VWD at week 1 and 6 postpartum. These outcomes are compared with those from retrospective studies of the general population. Methods: Participants completed 3 patient-reported outcome measures postpartum: the Short Form-36 at week 1 and 6 measuring QoL, the Mackey Childbirth Satisfaction Rate Scale at week 1 for childbirth satisfaction, and the Labor and Delivery Index at week 6 for childbirth experience. Descriptive statistics were used. Results: In total, 85 HCs and 81 women with VWD completed ≥1 questionnaire. Pain and physical functioning improved over time (both moderate to fairly well; P < .001). Six weeks postpartum, QoL was lower in both groups than those in the general population. Over 88% of both cohorts reported “at least satisfied” on the Mackey Childbirth Satisfaction Rate Scale, significantly higher than the general population (>61%; P < .001). Mean Labor and Delivery Index scores (1.3-1.9 points) indicated an adequate childbirth experience. HCs reported more child-related worries than the general population (37.3% vs 72.2%; P < .001). Conclusion: HCs and women with VWD recover less between week 1 and 6 postpartum than the general population. HCs report more worries about their child during childbirth than women with VWD and the general population.

Spontaneous coronary artery dissection (SCAD) is often overlooked as a cause of acute coronary syndrome (ACS), particularly in young women. SCAD requires distinct management, underscoring the importance of its timely and accurate diagnosis for effective treatment. This study aims to evaluate the frequency of SCAD underdiagnosis in young women with ACS and pinpoints potential SCAD indicators. All consecutive women ≤55 years with ACS who underwent coronary angiography (CAG) at our tertiary center from 2012 to 2024, were included. Clinical data at baseline and follow-up were retrospectively collected. All coronary angiography's (CAGs) were reviewed for SCAD-signs using the Yip-Saw criteria. Accurately diagnosed SCAD patients were compared to those with initially unrecognized SCAD and patients with other ACS causes. Of 394 patients (mean age 48.4 ± 5.8 years) evaluated, 23% (n = 92) had SCAD, but 41% (n = 38) were not initially correctly diagnosed. SCAD type 3 was most often missed. SCAD patients were younger and more frequently lacked traditional cardiovascular risk factors. They also showed higher coronary tortuosity scores, which were significantly associated with SCAD in multivariate analysis. Invasively treated SCAD patients received more stents than non-SCAD patients, largely due to hematoma extension. Follow-up revealed fewer atherosclerotic ACS in SCAD patients, with recurrent SCAD occurring only in undiagnosed cases. In conclusion, underdiagnosis of SCAD in young women with ACS is common and leads to inappropriate treatment, highlighting the need for increased awareness and improved diagnostic approaches. Young ACS patients with minimal cardiovascular risk factors and high coronary tortuosity scores should be carefully evaluated for SCAD.

Treatment options for the bleeding disorder von Willebrand disease type 2B (VWD2B) are insufficient and fail to address the negative effects of circulating mutant von Willebrand factor (VWF). The dominant-negative nature of VWD2B makes functionally defective VWF an interesting therapeutic target. Previous in vitro studies have demonstrated the feasibility of allele-selective silencing of mutant VWF using small interfering RNAs (siRNAs) targeting common single nucleotide polymorphisms (SNPs) in the human VWF gene, an approach that can be applied irrespective of the disease-causing VWF mutation. This study aims to extend this concept to a heterozygous VWD2B mouse model (c.3946G>A; p.Val1316Met) here using mouse strain-specific genetic differences as proxy for human SNPs. Homozygous VWD2B C57BL/6J (2B-B6) mice were crossed with homozygous wild-type 129S1/SvImJ (129S) mice to create heterozygous 2B-B6.129S F1 offspring. These 2B-B6.129S mice were intravenously injected with endothelial-specific lipid nanoparticles loaded with the alleleselective siVwf.B6 or control and 96 hours later, lung Vwf messenger RNA, plasma VWF levels, and phenotypic characteristics were evaluated. Treatment with siVwf.B6 reduced total VWF levels by 50%, with an expected selective reduction in mutant VWF protein. This coincided with normalization of multimeric structure, improved VWF collagen binding/ VWF antigen ratio, and normalized bleeding times in two-thirds of heterozygous 2B-B6.129S mice. Being a novel approach in the field of hemostasis, we proved, for VWD, in mice, the concept of selectively inhibiting a mutant dominant-negative allele with siRNAs targeting a single nucleotide variation rather than the disease-causing mutation. For dominantnegative VWD, this offers potential for a customized therapeutic strategy.

Desmopressin (DDAVP) can be used to prevent or stop bleeding. However, large inter-individual variability is observed in DDAVP response and determinants are largely unknown. In this systematic review and meta-analysis we aim to identify the response to DDAVP, and the factors that determine DDAVP response in patients. We included studies with patients with any bleeding disorder receiving DDAVP. First and second screening round and risk of bias assessment were performed by independent reviewers. The main outcome was proportion of patients with complete (factor level > 50 U/dL), or partial (30-50 U/dL) response to DDAVP. Determinants of response including disease type, age, sex, Von Willebrand factor (VWF) and factor VIII (FVIII) mutations, and baseline factor levels were investigated. In total, 591 articles were found and 103 were included. Of these, 71 articles (1772 patients) were suitable for the study's definition of response. Meta-analysis showed a pooled response proportion of 0·71 [0·64;0·78] and a significant difference in response between disease subtypes. For hemophilia A, baseline FVIII:C was a borderline significant determinant of response. In von Willebrand disease (VWD) type 1 patients, VWF:Ag, VWF:Act and FVIII:C were significant determinants. A large variation in response was observed for specific mutations in VWF and F8. Response to DDAVP varied between disease subtypes, and was largely determined by the baseline levels of FVIII:C for hemophilia A and VWF:Ag for VWD. Our findings highlight the significant differences in response and emphasize the need for a standardized response definition and further research into response mechanisms.

Background:Immune tolerance induction (ITI) is the only treatment to eradicate inhibitors in people with severe hemophilia A (SHA). Successful ITI restores factor VIII (FVIII) tolerance. ITI is demanding and successful in approximately 70% of people. Objectives:Identifying predictors of ITI outcome is essential to guide clinical decision making. We aimed to identify genetic predictors of ITI success in people with SHA and inhibitors who underwent ITI. Methods:This observational multicenter study included people with SHA who underwent ITI, between 2015 and 2023. Clinical and patient data, including FVIII gene (F8) mutation type, and DNA samples were collected. Successful ITI was defined by a negative inhibitor titer and an adequate response to FVIII concentrates. By employing a global screening array, the associations between ITI success and F8 genotype and 216 candidate predictors, including single nucleotide polymorphisms and human leukocyte antigen variants, CA dinucleotide short tandem repeat polymorphisms in the IL10 promoter region, and FCGR2/3 gene locus variations, were analyzed. Results:Of 204 participants, 147 (72.1%) achieved ITI success. The majority (52.0%) of participants had F8 intron 22 inversion. None of the candidate single nucleotide polymorphisms/human leukocyte antigen variants, IL10 CA dinucleotide short tandem repeats, or FCGR2/3 gene locus variations were associated with ITI success. F8 large deletions were negatively associated with ITI success (odds ratio, 0.15; 95% CI, 0.04-0.51; P = .002). Conclusion:Our study of 204 people with SHA identified F8 large deletions as a predictor of ITI failure. Pooling cohorts may allow the identification of additional genetic predictors of ITI success in the future.

von Willebrand disease (VWD) is a hereditary bleeding disorder first described by Erik von Willebrand in 1926. The disease is characterized by frequent bruising, bleeding from minor wounds, nosebleeds, heavy menstrual bleeding, bleeding after tooth extraction, gastrointestinal bleeding, and joint bleeds. The underlying cause of VWD was identified 45 years later as a deficiency of von Willebrand factor (VWF), a high-molecular-weight protein that circulates with factor VIII in plasma. The clinical diagnosis of VWD involves the presence of bleeding symptoms, detection of at least one abnormality of VWF function in laboratory tests, and demonstration of familial inheritance. VWD presents a broad spectrum of clinical and laboratory abnormalities, making the diagnostic process complex. Integrating clinical and laboratory data into the diagnostic pathway using a Bayesian approach can help build evidence for a diagnosis. Over the years, several diagnostic assays have been developed to measure the quantitative and qualitative properties of VWF. Automated laboratory assays for measuring VWF have been implemented in recent decades, and assessment tools for clinical evaluation of bleeding severity have been developed. Laboratory diagnosis involves screening and first-level diagnostic tests to measure VWF antigen, VWF-platelet binding activity, and factor VIII coagulant activity. Second-level subtyping tests are required to characterize the phenotypic defects of the type 2 variants and classify the patients. Proper diagnosis and classification of VWD are essential in order to recognize patients who may benefit from treatment, determine the optimal treatment modality, and prevent overdiagnosis.

Background:Elevated von Willebrand factor (VWF) levels correlate with higher risk of atherosclerosis-related arterial thrombosis (atherothrombosis). Silencing the VWF gene via small-interfering RNAs (siRNAs) could mitigate this risk. Previous studies successfully delivered siRNA to the endothelium of healthy, wild-type (WT) mice using lipid nanoparticles (LNPs). Objectives:This study aimed to investigate whether the LNP-siRNA strategy could achieve endothelium-specific Vwf-silencing under diseased conditions of prolonged hypercholesterolemia and atherothrombosis-prone vasculature. Methods:Female transgenic mice expressing a variant of human APOE∗3 (ie, APOE∗3-Leiden) and human cholesteryl ester transfer protein (CETP), fed a cholesterol-enriched diet for 18 weeks, received an intravenous injection of LNP-encapsulated siRNA targeting Vwf (siVwf) or scrambled control siRNA at 1.5 mg siRNA/kg. For comparison, the same LNP-siRNAs were administered to young, chow-fed WT mice. Plasma VWF and Vwf mRNA levels were measured 96 hours after injection, with immunofluorescence analysis of lungs and heart aortic root to assess VWF protein expression. Results:APOE∗3-Leiden.CETP mice exhibited elevated plasma VWF levels compared with WT mice, alongside hypercholesterolemia and aortic atherosclerosis. siVwf administration led to over 85% reduction in plasma VWF in both strains, with a strong reduction in lung Vwf mRNA and VWF protein in the pulmonary endothelium. Similarly, siVwf treatment resulted in the virtual absence of VWF protein in the endothelial lining of the aortic root of both nondiseased (WT mice) and atherosclerotic (APOE∗3-Leiden.CETP mice) vessel walls. Conclusion:The LNP-siRNA targeting Vwf strongly reduced plasma and endothelial VWF in mice with hypercholesterolemia and advanced atherosclerosis, indicating feasibility to target endothelial VWF under proatherothrombotic conditions.

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.

Background: Endothelial cells are crucial for hemostasis as they produce von Willebrand factor (VWF). von Willebrand disease (VWD) results from a deficiency of, or defects in, VWF. Objectives: We analyzed the endothelial compartment of VWD patients with an unexplained decrease in VWF level or nonresponse to 1-8-deamino-D-arginine vasopressin (DDAVP) using endothelial colony-forming cells (ECFCs). Methods: Thirteen healthy controls and 10 VWD type 1 and 2 patients were included, and a total of 29 ECFC clones were obtained. Plasma was analyzed, and ECFCs were morphologically and functionally characterized by quantitative polymerase chain reaction, ELISA, imaging, migration assay, and mass spectrometry. Results: VWF plasma levels were reduced in all patients. ECFCs were categorized into 2 previously defined transcriptional clusters and matched between patients and controls. Four ECFC clones, all from DDAVP nonresponders, retained VWF in the endoplasmic reticulum. Cluster 1 ECFCs from DDAVP nonresponders closed more slowly in the migration assay and had lower basal release of VWF antigen than control ECFCs. Proteomic data of ECFC lysates showed overlap in clustering with RNA profiles, including ALDHA1, TGFB1, and other endothelial-to-mesenchymal/inflammatory markers. However, no patient group-specific phenotype was observed. Finally, regulated secretion of VWF and Weibel-Palade body count in ECFCs correlated with various secretory machinery components. Conclusion: Lower plasma VWF was linked to reduced production and secretion by ECFCs obtained from patients. Furthermore, nonresponse to DDAVP in some patients was explained by VWF retention in the endoplasmic reticulum. The correlation between functional aspects of ECFCs and their quantitative polymerase chain reaction and proteome profiles yielded potential targets for further research.

BACKGROUND:Managing older patients with acute pulmonary embolism (PE) is challenging due to their underrepresentation in clinical trials, comorbidities, and increased complication risk. OBJECTIVES:To evaluate risk assessment and management outcomes in older patients with PE focusing on home and reperfusion treatment. METHODS:A retrospective analysis was conducted on patients aged 70 years or older diagnosed with acute PE at an academic medical center (2015-2022). RESULTS:In total, 242 patients with a mean age of 77 years were included. All 59 patients with negative Hestia criteria were discharged ≤24 hours, and in total, 81 patients (35%) received home treatment. Among these 14-day mortality and recurrent venous thromboembolism were 0% and major bleeding occurred in 1.3% (1 patient, 95% CI: 0.11-6.1). European Society of Cardiology risk classification showed 9 low-risk (3.9%), 199 intermediate-risk (87%), and 20 high-risk (8.8) patients with PE. In 5 of the 20 high-risk patients, hypotension was mainly caused by another condition, that is, sepsis. Eight high-risk patients received reperfusion therapy. The 14-day mortality rate was 51% in high-risk patients (95% CI: 27-71); 5 of 8 patients receiving reperfusion treatment died within 5 days. Patients with an Acute Presenting Older Patient score of ≥45% had higher 14-day mortality (28%; 95% CI: 12-46) compared with <45% (3.2%; 95% CI: 0.85-8.3; hazard ratios: 10.2; 95% CI: 2.6-39). CONCLUSION:Selecting for home treatment using Hestia criteria was safe for older patients with PE in our cohort. Mortality in the high-risk group was high also when receiving reperfusion treatment. The European Society of Cardiology risk classification and Acute Presenting Older Patient score identified patients at higher mortality risk, suggesting their potential utility in clinical decision-making.

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.

BackgroundEndothelial cells generated from induced pluripotent stem cells (hiPSC-ECs) show the majority of endothelial cell characteristics and markers, such as cobblestone morphology and the expression of VEGF and VE-cadherin. However, these cells are failing to show a mature endothelial cell phenotype, which is represented by the low expression and production of von Willebrand Factor (VWF) leading to the round morphology of the Weibel Palade Bodies (WPBs). The aim of this study was to improve the maturation process of hiPSC-ECs and to increase the levels of VWF.MethodshiPSC-ECs were differentiated by a standard differentiation protocol from hiPSCs generated from healthy control donors. To induce maturation, the main focus was to increase the expression and/or production of VWF by the adjustment of potential parameters influencing differentiation and maturation. We also compared alternative differentiation protocols. Cells were analyzed for the expression of endothelial cell markers, WPB structure, and the production and secretion of VWF by flow cytometry, confocal microscopy and ELISA.ResultsThe generated hiPSC-ECs have typical endothelial cell surface expression profiles, with low expression levels of non-endothelial markers as expected. Co-culture with pericytes, varying concentrations and timing of differentiation factors, applying some level of flow, and the addition of HDAC inhibitors did not substantially improve maturation of hiPSC-ECs. Transfection with the transcription factor ETV2 to induce a faster hiPSC-EC differentiation process resulted in a limited increase in VWF production, secretion, and elongation of WPB structure. Alternative differentiation protocols had limited effect.ConclusionhiPSCs-ECs have the potential to show a more mature endothelial phenotype with elongated WPBs after >30 days in culture. However, this comes with limitations as there are very few cells detected, and cells are deteriorating after being in culture for extended periods of time.

BACKGROUND AND OBJECTIVES:Routine coagulation screens at birth are still standard in some European neonatal intensive care units (NICUs), although interpretation of these results is complex in preterm infants. It is unclear to what extent local coagulation assay results agree with published reference ranges when using different analysers and reagents. We aimed to assess coagulation assay results on day 1 of life in very preterm infants admitted to the NICU. MATERIALS AND METHODS:We included all preterm infants born below 32 weeks gestational age (GA) admitted to the Leiden University Medical Center between 2004 and 2020 in whom coagulation assays (prothrombin time [PT] and activated partial thromboplastin time [APTT]) were obtained during the first 24 h of life. Infants either diagnosed with major intraventricular haemorrhage or who received plasma transfusion before coagulation assay were excluded. We assessed coagulation assay results and compared the results between <28 weeks (extremely preterm) and 28-32 weeks (very preterm) GA groups. RESULTS:Coagulation assays were obtained at birth in 144 infants (144/2577; 5.5%) of whom 104 fulfilled the inclusion criteria. We found similar median PT and APTT values for extremely and very preterm infants (PT: 18.1 vs. 18.7 s [p-value = 0.400]; APTT: 44.2 vs. 47.7 s [p-value = 0.252], respectively). CONCLUSION:We found similar coagulation assay results at birth for extremely and very preterm infants; however, results deviated considerably from some of the published reference ranges. This may be due to differences between analysers and reagents, underlining the need for reference ranges calibrated to the equipment used per NICU.