Standardization of definition and management for bleeding disorder of unknown cause: communication from the SSC of the ISTH.

In many patients referred with significant bleeding phenotype, laboratory testing fails to define any hemostatic abnormalities. Clinical practice with respect to diagnosis and management of this patient cohort poses significant clinical challenges. We recommend that bleeding history in these patients should be objectively assessed using the International Society on Thrombosis and Haemostasis (ISTH) bleeding assessment tool. Patients with increased bleeding assessment tool scores should progress to hemostasis laboratory testing. To diagnose bleeding disorder of unknown cause (BDUC), normal complete blood count, prothrombin time, activated partial thromboplastin time, thrombin time, von Willebrand factor antigen, von Willebrand factor function, coagulation factors VIII, IX, and XI, and platelet light transmission aggregometry should be the minimum laboratory assessment. In some laboratories, additional specialized hemostasis testing may be performed to identify other rare causes of bleeding. We recommend that patients with a significant bleeding phenotype but normal laboratory investigations should be registered with a diagnosis of BDUC in preference to other terminology. Global hemostatic tests and markers of fibrinolysis demonstrate variable abnormalities, and their clinical significance remains uncertain. Targeted genomic sequencing examining candidate hemostatic genes has a low diagnostic yield. Underlying BDUC should be considered in patients with heavy menstrual bleeding since delays in diagnosis often extend to many years and negatively impact quality of life. Treatment options for BDUC patients include tranexamic acid, desmopressin, and platelet transfusions.

Diagnosis and treatment of von Willebrand disease in 2024 and beyond.

MANUSCRIPT BACKGROUND AND AIM: The diagnosis and clinical care of patients with von Willebrand disease (VWD) has continued to evolve since the characterization of the von Willebrand factor (VWF) gene in 1985. This condition is almost certainly the most common inherited bleeding disorder, and the major symptomatic burden of the disease is experienced by females during their reproductive years. Diagnosis relies on the identification of a personal and family history of excessive mucocutaneous bleeding, and laboratory features consistent with quantitative and/or qualitative abnormalities of VWF. This review focuses on three aspects of VWD management, with current updates and a look into the future. MANUSCRIPT THEMES: First, we will address the role of genetics in the diagnosis and possible therapies for VWD. With current technologies, VWD genetic diagnosis is usually confined to the confirmation of type 2 subtypes of the disease and type 3 VWD analysis for family planning. While type 3 VWD is a potential candidate for the application of gene therapy, no treatments are currently close to entering the clinic. Second, the peri-procedural management of patients with VWD remains an important element of care. The choice of product, its dose and schedule all require careful consideration depending upon the type and disruptive nature of the planned procedure. Lastly, in addition to gene therapy, several other novel therapeutic interventions are also being developed for bleeding and prophylaxis in VWD. These include a VWF aptamer interfering with VWF clearance and bioengineered forms of VWF.

What do we know about why women bleed and what do we not know?

Women or people with a uterus are vulnerable to both normal and abnormal bleeding. During the reproductive years, the uterus is prepared physiologically to accept an embryo and support its growth and development during pregnancy, or in the absence of implantation of an embryo, recycle through the process of menstruation and accept an embryo a month or so later. If fertilization takes place and an embryo or embryos implant in the uterus, the fetal trophoblast, or outer cell layer of the embryo, invades and dilates the maternal spiral arteries and forms the placenta. No matter when in gestation a pregnancy ends, at the conclusion of pregnancy, the placenta should separate from the wall of the uterus and be expelled. Abnormal bleeding occurs during pregnancy or after delivery when the normal uteroplacental interface has not been established or is interrupted; during miscarriage; during ectopic pregnancy; during premature separation of the placenta; or during postpartum hemorrhage. Heavy menstrual bleeding, a subset of abnormal menstrual bleeding, can be quantitatively defined as >80 mL of blood loss per cycle. Unlike postpartum hemorrhage, heavy menstrual bleeding is significantly associated with an underlying bleeding disorder. While there is other reproductive tract bleeding in women, notably bleeding at the time of ovulation or with a life-threatening ruptured ectopic pregnancy, the unique bleeding that women experience is predominantly uterine in origin. Many of the unique aspects of uterine hemostasis, however, remain unknown.

The common VWF variant p.Y1584C: detailed pathogenic examination of an enigmatic sequence change.

BACKGROUND: As knowledge of the human genome has advanced, so too has the recognition that interpretation of the pathogenic nature of sequence variants can be challenging. The von Willebrand factor (VWF) gene exhibits a significant degree of sequence variability, and the first VWF variant associated with type 1 von Willebrand disease (VWD), c.4751 A>G, p.Y1584C, was described in 2003. However, since that time, the pathogenic nature of this variant has remained unclear, being assigned properties ranging from a risk factor to a pathogenic variant. OBJECTIVES: To provide additional evaluation on the interpretation of pathogenicity for this common VWF variant. METHODS: Fifty-eight subjects with only the p.Y1584C variant were recruited from 2 cohort studies (the Zimmerman Program and the Canadian type 1 VWD study). Clinical and laboratory phenotypes were assessed. RESULTS: The prevalence of the p.Y1584C variant in our cohorts was 23- to 27-fold higher than that in large normal population databases. Significantly more p.Y1584C subjects had an abnormal bleeding score when compared to Y1584 individuals. In comparison with a group of 35 subjects without the p.Y1584C variant, subjects with the variant had lower mean VWF:antigen and VWF:ristocetin cofactor values and significantly higher VWF propeptide/VWF:antigen ratios suggestive of enhanced clearance. CONCLUSION: Collectively, the results of this analysis suggest that p.Y1584C is likely pathogenic, however, due to influences such as incomplete penetrance, variable expressivity, and other genetic modifiers like ABO blood group, the straightforward assignment of pathogenicity to this variant is inevitably challenging.

Type 1 VWD classification revisited: novel insights from combined analysis of the LoVIC and WiN studies.

ABSTRACT: There is significant ongoing debate regarding type 1 von Willebrand disease (VWD) defintion. Previous guidelines recommended patients with von Willebrand factor (VWF) levels <30 IU/dL be diagnosed type 1 VWD, whereas patients with significant 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 (ß = 0.00; 95% confidence 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 findings 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 classification criteria.

New and emerging therapies for women, girls, and people with the potential to menstruate with VWD.

Innovation in therapies for patients with von Willebrand disease (VWD) has lagged far behind that for hemophilia, creating inequity in the bleeding disorder community. Although currently existing treatments of antifibrinolytics, desmopressin, and plasma-derived von Willebrand factor replacement are considered effective, multiple studies report poor quality of life in patients with VWD, especially those with heavy menstrual bleeding (HMB). This disconnect underscores the need for novel therapies that are safe and effective and that consider a patient's specific contraceptive and reproductive needs. Recombinant von Willebrand factor is the most recent new therapy for VWD; the data specific to women are reviewed. We also present emerging data on emicizumab for the treatment of VWD, BT200 (rondoraptivon pegol), generalized hemostatic therapies (VGA039 and HMB-011), as well as treatments based on nanotechnology (platelet-inspired nanoparticles and KB-V13A12). We are optimistic as we move toward pivotal clinical trials for these elegant and innovative treatments.

Patient-centered care in von Willebrand disease: are we there yet?

INTRODUCTION: Von Willebrand Disease is the most common inherited bleeding disorder. Paradoxically, affected individuals are often misdiagnosed and experience substantial diagnostic delay. There are sex-specific health disparities in VWD rooted in the stigmatization of vaginal bleeding, which leads to symptom dismissal, lack of timely access to care and lower health-related quality of life. AREAS COVERED: Following the core elements of patient-centered care - respect for patient preferences, values, and needs, we describe the current state of VWD care. Challenges of diagnostic delay, serial misrecognition of abnormal bleeding, and symptom dismissal are barriers that disproportionately affect women with VWD. These negative effects are further amplified in individuals living in low- and middle-income countries. We describe the importance of coordinated multidisciplinary care, as well as the need for patient education and empowered self-advocacy. EXPERT OPINION: While tremendous work has been done to improve the diagnosis and management of VWD, timely and high-quality research is urgently needed to address care gaps. Systemic changes such as resource investment, dedicated research funding for novel treatment modalities, and effective knowledge translation strategies to address structural barriers are needed to facilitate effective patient-centered care for VWD.

Impact of transcatheter aortic valve implantation on circulating von Willebrand factor in patients with severe aortic stenosis.

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.

Gastrointestinal bleeding in von Willebrand patients: special diagnostic and management considerations.

INTRODUCTION: Severe and recurrent gastrointestinal (GI) bleeding caused by angiodysplasia is a significant problem in patients with von Willebrand disease (VWD) and in those with acquired von Willebrand syndrome (AVWS). At present, angiodysplasia-related GI bleeding is often refractory to standard treatment including replacement therapy with von Willebrand factor (VWF) concentrates and continues to remain a major challenge and cause of significant morbidity in patients despite advances in diagnostics and therapeutics. AREAS COVERED: This paper reviews the available literature on GI bleeding in VWD patients, examines the molecular mechanisms implicated in angiodysplasia-related GI bleeding, and summarizes existing strategies in the management of bleeding GI angiodysplasia in patients with VWF abnormalities. Suggestions are made for further research directions. EXPERT OPINION: Bleeding from angiodysplasia poses a significant challenge for individuals with abnormal VWF. Diagnosis remains a challenge and may require multiple radiologic and endoscopic investigations. Additionally, there is a need for enhanced understanding at a molecular level to identify effective therapies. Future studies of VWF replacement therapies using newer formulations as well as other adjunctive treatments to prevent and treat bleeding will hopefully improve care.

Von Willebrand disease (VWD) is the most common inherited bleeding disorder. It is caused by problems with von Willebrand factor (VWF), a protein in blood that helps stop bleeding. People with VWD either have low levels of VWF or VWF that does not work properly. The disease causes bleeding symptoms in 1 in 1000 individuals. Three main types of VWD exist. Depending on the type, people can have minimal symptoms or serious bleeding that needs hospital care.Patients with severe VWD may often experience repeated bleeding from the gastrointestinal tract. This is usually due to the formation of abnormal fragile vessels (malformations) called angiodysplasia, which have been linked to the absence or abnormal function of VWF. These fragile vessels are very difficult to find and diagnose. At present, available treatments for angiodysplasia, including long-term VWF replacement therapy, are not very effective. As a result, VWD patients with angiodysplasia have a poor quality of life.More research is needed to better evaluate current treatments and explore the contribution of abnormal VWF in the development of angiogenesis and angiodysplasia in VWD which may reveal new targets for treatment.

Von Willebrand Disease: Gaining a global perspective.

INTRODUCTION: Recent guidelines for von Willebrand Disease (VWD) highlighted the challenges in diagnosis and management. Identifying the number of persons with VWD (PwVWD) internationally will help target support to aid diagnosis of PwVWD. AIM: To examine international registration rates of PwVWD, the influence of income status, geographical region and the age and sex profile. Cumulatively, these data will be used to inform future strategy from the World Federation of Haemophilia (WFH) to address unmet clinical and research needs. METHODS: Data from the 2018/2019 WFH Annual Global Survey (AGS) were analysed, providing a global perspective on VWD registration. RESULTS: Registration rates are lowest in South Asia (0.6/million population) and highest in Europe/Central Asia (50.9/million population, 0.005%), but below the expected prevalence rate (0.1%). National economic status impacted VWD registration rates, reflecting variation in access to optimal healthcare infrastructure. Females represented the majority of PwVWD globally, however, in low-income countries (LIC) males predominated. Age profile varied, with markedly higher rates of paediatric registrations in North America, Middle East and North Africa and South Asia. Rates of type 3 VWD registrations were significantly influenced by economic status (81% of VWD diagnoses in LIC), suggesting only the most severe VWD types are diagnosed in resource limited settings. CONCLUSION: Significant variation in registration rates of PwVWD exist internationally and is influenced by income status and the presence of HTC networks. Improved understanding of registration rates will enable targeting of advocacy to improve awareness, diagnosis and support for PwVWD internationally. KEY POINTS: Registration rates of People with Von Willebrand Disease (PwVWD) vary internationally and are influenced by national income status Although females represent the majority of PwVWD globally, in low income countries (LIC) males predominated, possibly related to stigma surrounding gynaecological bleeding. Rates of type 3 VWD registration were significantly influenced by economic status (81% of VWD diagnoses in LIC), suggesting only the most severe VWD types are diagnosed in resource limited settings.

Identifying the effect of inherited bleeding disorders on the development of postpartum hemorrhage: a population-based, retrospective cohort study.

Background: Women with inherited bleeding disorders (IBDs) are at an increased risk of postpartum hemorrhage (PPH). However, the impact of other maternal predelivery risk factors, including anemia, on the association between IBD and maternal bleeding remains poorly understood. Additionally, studies examining potential pathways linking IBD and PPH are limited. Objectives: We aimed to determine the risk of PPH associated with IBD. Methods: A retrospective cohort study was conducted using data held within ICES (formerly the Institute for Clinical Evaluative Sciences). Women with an in-hospital, live, or stillborn delivery between January 2014 and December 2019 were included. Poisson regression with robust error variance was used to determine the risk (RR) and 95% CIs of PPH among women with or without an IBD diagnosis. Models were stratified for primiparous and multiparous women. Results: Among the total population of 601,773 women, 29,661 (4.93%) experienced PPH. Multivariate models demonstrated that IBD was an independent risk factor for PPH among both the total cohort (adjusted RR [aRR] = 1.26; 95% CI: 1.08, 1.46) and primiparous women (aRR = 1.36; 95% CI: 1.12, 1.66). Among multiparous women, prior PPH was associated with an increased risk of PPH (aRR = 8.65; 95% CI: 8.32, 8.99), whereas IBD had no effect (aRR = 1.1; 95% CI: 0.86, 1.4). Predelivery anemia, placental conditions, multifetal gestation, and induction of labor were associated with increased PPH risk among all cohorts. Conclusions: IBD significantly increases the risk of PPH. The management of delivery should be based on individualized assessment of risk factors to ensure optimal maternal outcomes.

Management of heavy menstrual bleeding in women with bleeding disorders in a tertiary care center.

Background: Heavy menstrual bleeding (HMB) affects a significant number of women with bleeding disorders and has a negative impact on their quality of life. Objective: This retrospective study examined the management of patients with inherited bleeding disorders who used medical treatments, alone or in combination, for HMB. Methods: Chart review was performed on women attending the Women with Bleeding Disorders Clinic in Kingston, Ontario, between 2005 and 2017. Data collected included patient demographics, the reason for presentation and diagnosis, medical history, treatments, and patient satisfaction. Results: One hundred nine women were included in this cohort. Of these, only 74 (68%) were satisfied with medical management, and only 18 (17%) with first-line therapy. Treatments included combined contraceptives (oral pill, transdermal patch, and vaginal ring), progesterone-only pills, tranexamic acid, 52-mg levonorgestrel intrauterine system (LIUS), depomedroxyprogesterone acetate, and desmopressin, either alone or in combination. Satisfactory control of HMB occurred most often with the LIUS. Conclusion: In this cohort, managed in a tertiary care Women with Bleeding Disorders Clinic, only 68% of patients had successful control of HMB with medical treatment, and a minority were satisfied with first-line therapy. These data clearly highlight the need for additional research, including treatment approaches and novel therapies for this population.

Challenges in the management of women with type 2B von Willebrand disease during pregnancy and the postpartum period: evidence from literature and data from an international registry and physicians' survey-communication from the Scientific and Standardization Committees of the International Society on Thrombosis and Haemostasis.

BACKGROUND: Management of women with type 2B von Willebrand disease (VWD) during pregnancy is challenging because of dysfunctional von Willebrand factor (VWF) and the complexity resulting from discrepant VWF/factor VIII (VWF/FVIII) levels, impaired platelet-dependent VWF activity, progressive thrombocytopenia, and risks associated with the use of desmopressin. There is a lack of high-quality evidence to support clinical decision making. OBJECTIVES: In this study, we examined the current diagnostic and management approaches and outcomes in women with VWD during pregnancy. METHODS: Data were collected via 3 avenues: literature review, an international registry, and an international survey on physicians' practices for the management of pregnancy in women with VWD. The registry and survey were supported by the International Society on Thrombosis and Haemostasis. RESULTS: Data on clinical and laboratory features, management and bleeding complications, and pregnancy outcomes of a total of 55 pregnancies from 49 women across the globe (literature: 35, registry: 20) and data reported by 112 physicians were analyzed. We describe the largest dataset on pregnancies in women with type 2B VWD available to date. The data highlight the following key issues: a) bleeding complications remain a concern in these patients, b) the target safe VWF level and the ideal monitoring approach are unknown, c) there is a wide range of hemostatic management practices in the type and timing of treatment, and d) physicians have diverse views on the mode of delivery and use of neuraxial anesthesia. CONCLUSION: We conclude that an international consensus and guidance are critically required for better care and improved outcomes in this patient cohort.

Beyond the guidelines: how we approach challenging scenarios in the diagnosis and management of von Willebrand disease.

Although von Willebrand disease (VWD) is the most common inherited bleeding disorder, its diagnosis and management are often challenging. Clinical practice guidelines, developed through systematic review of the medical literature and considering the best available evidence, provide guidance for common clinical scenarios. However, in the clinical setting, patients often present with characteristics and nuances that may fall outside the realm of available evidence and guidelines, and hence, shared decision-making will be essential in the evaluation and management of these patients. The challenges in the diagnosis of VWD are mainly attributable to the heterogeneity of the disorder, limitations of laboratory assays, and the significant impact of various physiologic processes on von Willebrand factor. The impact of physiologic normalization of von Willebrand factor, which may occur in various settings such as pregnancy, inflammation, or aging, remains uncertain, as is the optimal management in these scenarios. Multidisciplinary and individualized care, based on evolving evidence supported by clinicians, patients, caregivers, and stakeholders, will be needed to ensure the highest quality care for those who live with VWD.

Variability in International Society on Thrombosis and Haemostasis-Scientific and Standardization Committee endorsed Bleeding Assessment Tool (ISTH-BAT) score with normal aging in healthy females: contributory factors and clinical significance.

BACKGROUND: Bleeding assessment tools are key screening tests used in the evaluation of patients with suspected inherited bleeding disorders. The International Society on Thrombosis and Haemostasis-Scientific and Standardization Committee endorsed Bleeding Assessment Tool (ISTH-BAT) has differing reference ranges for adult males (0-3), adult females (0-5), and children (0-2), reflecting differing bleeding symptoms and exposure to hemostatic challenges in these healthy population subgroups. Age is known to markedly impact bleeding score in individuals with von Willebrand disease. However, the influence of age on bleeding score in healthy adult controls is poorly understood. OBJECTIVES: We aimed to assess variability in ISTH-BAT score with age among healthy control females. METHODS: We used the legacy "Merging Project" dataset of normal healthy controls upon which current ISTH-BAT normal ranges are based. We included women, totaling 646 individuals. The normal range (middle 95th percentile) of total ISTH-BAT and grouped subdomain scores between age quartiles was assessed. RESULTS: The normal range of ISTH-BAT scores increased with age, ranging from 0 to 4 in the youngest quartile (age range, 18-30) to 0 to 6 in the oldest (age range, 52-88). This increased variability with aging was related both to high menorrhagia domain scores in older women and an increase in postprocedural bleeding with accumulated exposure to hemostatic challenges. CONCLUSIONS: Cumulatively, our data highlight that normal aging leads to increased variability in bleeding scores in healthy adult females. Further refinement of the ISTH-BAT with age-adjusted reference ranges may improve the sensitivity and specificity of the tool among females.

Enhanced VWF clearance in low VWF pathogenesis: limitations of the VWFpp/VWF:Ag ratio and clinical significance.

Increased von Willebrand factor (VWF) clearance plays a key role in the pathogenesis of type 1 and type 2 von Willebrand disease (VWD). However, the pathological mechanisms involved in patients with mild to moderate reductions in plasma VWF:Ag (range, 30-50 IU/dL; low VWF) remain poorly understood. In this study, we investigated the hypothesis that enhanced VWF clearance may contribute to the pathobiology of low VWF. Patients with low VWF were recruited to the LoVIC study after ethics approval and receipt of informed consent. Desmopressin was administered IV in 75 patients, and blood samples were drawn at baseline and at the 1-hour and 4-hour time points. As defined by recent ASH/ISTH/NHF/WFH guidelines, 20% of our low-VWF cohort demonstrated significantly enhanced VWF clearance. Importantly, from a clinical perspective, this enhanced VWF clearance was seen after desmopressin infusion, but did not affect the steady-state VWF propeptide (VWFpp)-to-VWF antigen (VWF:Ag) ratio (VWFpp/VWF:Ag) in most cases. The discrepancy between the VWFpp/VWF:Ag ratio and desmopressin fall-off rates in patients with mild quantitative VWD may have reflected alteration in VWFpp clearance kinetics. Finally, bleeding scores were significantly lower in patients with low VWF with enhanced VWF clearance, compared with those in whom reduced VWF biosynthesis represented the principle pathogenic mechanism. This trial was registered at http://www.clinicaltrials.gov as #NCT03167320.

A transcriptome analysis of basal and stimulated VWF release from endothelial cells derived from patients with type 1 VWD.

Type 1 von Willebrand disease (VWD) is associated with a reduction in qualitatively normal von Willebrand factor (VWF). Current diagnostic guidelines only take into consideration the contribution of basal VWF levels, despite a lack of correlation with bleeding severity. Defects in stimulated VWF release, which occurs after hemostatic challenge, may contribute to bleeding in type 1 VWD, but the pathogenic mechanisms are poorly defined. In this study, a layered multiomic approach including messenger RNA (mRNA) and microRNA (miRNA) sequencing was used to evaluate transcriptome-wide differences between type 1 VWD- and control-derived endothelial colony forming cells (ECFCs) during basal and stimulated VWF release. ECFCs from 8 patients with type 1 VWD and 4 other patients were included in this study as controls. VWF protein analysis revealed heterogenous responses to stimulation among type 1 VWD and control ECFCs. During basal VWF release, 64 mRNAs and 7 miRNAs were differentially regulated between type 1 VWD and control ECFCs, and 65 putatively pathogenic miRNA-mRNA interactions were identified. During stimulated VWF release, 190 mRNAs and 5 mRNAs were differentially regulated between type 1 VWD and control ECFCs, and 110 putatively pathogenic miRNA-mRNA interactions were identified. Five gene ontology terms including coagulation, regulation of cell shape, and regulation of cell signaling were also differentially regulated in type 1 VWD ECFCs during stimulated release. To our knowledge, we have shown for the first time that transcriptome-wide differences exist between type 1 VWD and control ECFCs. These differences may contribute to bleeding in type 1 VWD, and further investigation may reveal novel biomarkers and therapeutic targets.