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Background: Ε‐Aminocaproic acid oral solution (EACA OS) is the only commercially available antifibrinolytic for patients who cannot swallow tablets. Insurance denials and high costs remain barriers to its use. Objectives: To determine the safety and efficacy of crushed tranexamic acid tablets in water (cTXAw) for children with bleeding disorders. Methods: We retrospectively reviewed records of children (<10 years) with bleeding disorders who received cTXAw or EACA OS from 1 December 2018, through 31 July 2022, at Mayo Clinic (Rochester, Minnesota). Bleeding outcomes were defined according to ISTH criteria. Results: Thirty‐two patients were included (median age, 3 years; male, n = 23). Diagnoses were VWD (n = 17), haemophilia (n = 5), FVII deficiency (n = 3), inherited platelet disorder (n = 4), ITP (n = 2), and combined FV and FVII deficiencies (n = 1). Thirty‐two courses of cTXAw (monotherapy 24/32; mean duration 6 days) and fifteen courses of EACA (monotherapy 12/15; mean duration 5 days) were administered. No surgical procedures (n = 28) were complicated by bleeding. Of the 19 bleeding events, 16 had effective haemostasis, two had no reported outcome, and one had no response. cTXAw and EACA were equally effective in preventing and treating bleeding (p value >.1). No patients had adverse effects. Eight of 19 patients (42%) who were initially prescribed EACA OS did not receive it because of cost or insurance denial. The estimated average wholesale price of one treatment was $94 for cTXAw and $905 for EACA OS. Conclusions: CTXAw appears to be an effective, safe, and low‐cost alternative option to EACA OS for young children with bleeding disorders. [ABSTRACT FROM AUTHOR]

A novel variant involving noncanonical splicing acceptor site (c.875-5 T > G) in propeptide coding region of von Willebrand factor (VWF) was identified in a patient with type 2A von Willebrand disease (VWD), who co-inherited with a null variant (p.Tyr271*) and presented characteristic discrepancy of plasma level of VWF antigen and activity, and a selective reduction of both intermediate-molecular-weight (IMWMs) and high-molecular-weight VWF multimers (HMWMs). VWF mRNA transcripts obtained from peripheral leukocytes and platelets of the patients were investigated to analyze the consequence of c.875-5 T > G on splicing. The impact of the variant on expression and multimer assembly was further analyzed by in vitro expression studies in AtT-20 cells. The intracellular processing of VWF mutant and the Weibel-Palade bodies (WPBs) formation was evaluated by immunofluorescence staining and electron microscopy. The mRNA transcript analysis revealed that c.875-5 T > G variant led to exon 8 skipping and an in-frame deletion of 41 amino acids in the D1 domain of VWF (p.Ser292_Glu333delinsLys), yielding a truncated propeptide. Consistent with the patient's laboratory manifestations, the AtT-20 cells transfected with mutant secreted less VWF, with the VWF antigen level in conditioned medium 47 % of wild-type. A slight retention in the endoplasmic reticulum was observed for the mutant. Almost complete loss of IMWMs and HMWMs in the medium and impaired WPBs formation in the cell, indicating truncated VWF propeptide lost its chaperon-like function for VWF multimerization and tubular storage. The VWF splicing site variant (c.875-5 T > G) causes propeptide truncation, severely compromising VWF multimer assembly and tubular storage. [Display omitted] • The regions in VWF propeptide that are critical for VWF multimerization and granular storage are not completely clear. • This study provides a functional characterization of a naturally occurring type 2A-related splicing variant (c.875-5 T > G). • The variant led to exon 8 skipping and an in-frame deletion of 41 amino acids in the D1 domain of VWF propeptide. • The truncation moderately affects the synthesis or secretion of VWF, but severely affects its multimerization and storage. [ABSTRACT FROM AUTHOR]

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

Background: Patient-reported outcomes measurement information system (PROMIS) measures can be used to measure patient-reported outcomes. PROMIS measures, including computer adaptive tests (CATs) and short forms, have demonstrated the ability to adequately assess outcomes in patients with hemophilia. It is, however, unclear if PROMIS measures are suitable for patients with von Willebrand disease (VWD), inherited platelet function disorders (IPFDs), and rare bleeding disorders (RBDs). Objectives: To evaluate the feasibility, measurement properties, and relevance of PROMIS measures in adults with VWD, IPFDs, and RBDs. Methods: In this cross-sectional multicenter study, adults with VWD, IPFDs, and RBDs completed 9 PROMIS measures and the Short Form-36 version 2 (SF-36v2) electronically. Feasibility was determined by the number of completed items and floor/ceiling effects. Measurement properties included construct validity based on a multitrait–multimethod analysis and reliability using the reliability coefficient and greatest lower bound. Relevance was evaluated based on comparison with the Dutch general population. Results: In total, 111 patients (median age, 57 years [IQR, 44-67]; 60% VWD, 16% IPFD, 24% RBD) participated. Mean number of items answered varied from 5.3 to 8.7 (range, 4-12) per PROMIS CAT in patients with VWD. Construct validity was supported for all CATs and all instruments had a good reliability (≥0.70). The PROMIS measures had less ceiling effects than the SF-36v2. Conclusion: The PROMIS measures are a feasible, valid, and reliable alternative for the SF-36v2 in patients with primarily nonsevere forms of VWD. The relevance of the selected measures was limited. Additional research is necessary to evaluate the PROMIS measures in adults with IPFDs and RBDs.

Introduction: Severe aortic stenosis (AS) can lead to degradation of high molecular weight (HMW) von Willebrand factor (VWF) which can result in haemostatic abnormalities. While studies have explored changes in VWF profiles before and after surgical aortic valve replacement (SAVR), the longer‐term changes in VWF profiles pre‐ and post‐transcatheter aortic valve implantation (TAVI) are less understood. Aim: Our primary objective was to identify differences in VWF multimer profiles and VWF function pre‐TAVI and 1‐month post‐TAVI. Our secondary objective was to correlate VWF markers with measures of AS severity. Methods: Adult patients with severe AS referred for TAVI at our institution were prospectively enrolled in this cohort study. Blood samples were collected for plasma analysis at three time points for all patients: 1 day pre‐TAVI, 3 days post‐TAVI, and 1‐month post‐TAVI. VWF antigen, activity, propeptide, collagen binding, multimers, and factor VIII coagulant activity were determined at each time point. Correlations between VWF parameters and severity of AS were assessed. Results: Twenty participants (15 males, five females) with severe AS were recruited for the study. There was a significant increase in HMW VWF between pre‐procedure and 1‐month post‐TAVI (p <.05). There was a transient increase in VWF antigen levels and activity at 3‐days post TAVI that decreased to pre‐TAVI levels at 1‐month. There were no statistically significant correlations between VWF markers and AS severity. Conclusions: This is the first study to elucidate longer‐term (>1 week) improvements in HMW VWF after a TAVI procedure in severe AS patients. [ABSTRACT FROM AUTHOR]

Introduction: Von Willebrand disease (VWD) is the most widespread congenital bleeding disorder. Caregivers are highly involved in its treatment, and from the time of the child's bleeding diagnosis, they face new demands such as recognition of bleeds and treatment options. Aim: The aim of this study was to assess Health related quality of life (HRQoL) in caregivers of children with moderate and severe VWD in Sweden, and to describe the impact of psychosocial aspects on the burden. Methods: A multicentre, cross‐sectional study. The Short Form 36 Health Survey (SF‐36) was used to assess HRQoL. Caregiver burden was measured using The HEMOphilia associated Caregiver Burden scale (HEMOCAB). Children´s clinical data were collected from the Swedish national registry for bleeding disorders. Results: Seventy caregivers of children with moderate or severe VWD were included. Caregivers of children with moderate VWD scored significantly lower in the mental health domains on SF‐36, compared to matched normative data. Psychosocial aspects that significantly impacted the caregiver burden negatively measured by HEMOCAB total score were: if the caregiver reported that VWD affected their life in general (p =.001), if the child was absent from preschool/school ≥2 day/12 months due to VWD (p =.002) or that VWD had a financial impact on the family (p =.001). Conclusion: This study contributes to knowledge about caregivers' HRQoL and highlights the situation of caregivers of children with moderate VWD. Furthermore, the caregiver burden was negatively affected by psychosocial aspects. Clinical follow‐ups should include assessment of psychosocial aspects to identify caregivers that are at risk of high burden. [ABSTRACT FROM AUTHOR]

Introduction: Peri‐procedural management of von Willebrand disease (VWD) utilizes von Willebrand factor (VWF) concentrates or desmopressin (DDAVP) to increase VWF levels. DDAVP is safe, easily administered, and inexpensive. Currently, a consensus definition for adequate DDAVP response is lacking, and outcomes of peri‐procedural DDAVP use in VWD patients are seldom reported. Aim: This single‐centre retrospective review aims to characterize DDAVP‐responsiveness and assess clinical outcomes of peri‐procedural DDAVP use in VWD. Patients and Methods: We reviewed records for all our adult VWD patients (age ≥18 years) who underwent DDAVP challenge testing between January 2007 and January 2022. DDAVP‐responsiveness was assessed using six definitions. Bleeding outcomes following procedures covered by DDAVP were classified as excessive or expected bleeding. Results: Eighty‐four of 94 (89.4%) patients were DDAVP‐responsive by our definition (1‐h VWF Activity/Factor VIII ≥0.50 IU/mL). However, the proportion of DDAVP‐responders varied from 53.2% to 91.5%, depending on the literature definition used. Ninety‐nine procedures pre‐treated with DDAVP were performed during the study period. Eighty‐six (86.7%) procedures (31 major; 55 minor) were covered with only DDAVP ± tranexamic acid (TXA). Excessive bleeding occurred following 4/31 major procedures and 2/55 minor procedures (both performed in a single patient with a bleeding score of 16). When covered with DDAVP+Factor ± TXA, one each of 10 major and 3 minor procedures (performed in 2 patients with bleeding scores 15–16) resulted in post‐procedural bleeding. Conclusions: Peri‐procedural DDAVP prophylaxis appears to be effective among individuals with VWD. Beyond DDAVP‐responsiveness, patient bleeding history and procedure invasiveness should be considered in determining suitability for DDAVP prophylaxis. [ABSTRACT FROM AUTHOR]

Data on infants and toddlers (ITs) with von Willebrand disease (VWD) are lacking. We used data collected in the US Hemophilia Treatment Center Network (USHTCN) to describe birth characteristics, bleeding episodes, and complications experienced by 105 patients with VWD who were