Repair of type II paraesophageal hernia with Nissen fundoplication in a patient with von Willebrand disease and spondylolisthesis - a clinical case report.

Hiatal hernias continue to be fairly common in clinical practice. However, the variety of different symptoms presented by patients may hinder establishing the ultimate diagnosis. Nevertheless, currently, the diagnosis of hiatal hernia can be easily established, based on barium swallow radiography. We would like to present a clinical case report of a patient with complex medical history, including von Willebrand disease, degenerative spinal disease, and chronic sinusitis, who was finally diagnosed with hiatal hernia and treated with a standard laparoscopic Nissen fundoplication. Our case focuses on the significance of comorbidities on patients' symptoms, which sometimes may mislead the therapeutic process.

Early diagnosis of persons with von Willebrand disease using a machine learning algorithm and real-world data.

BACKGROUND: Von Willebrand disease (VWD) is underdiagnosed, often delaying treatment. VWD claims coding is limited and includes no severity qualifiers; improved identification methods for VWD are needed. The aim of this study is to identify and characterize undiagnosed symptomatic persons with VWD in the US from medical insurance claims using predictive machine learning (ML) models. RESEARCH DESIGN AND METHODS: Diagnosed and potentially undiagnosed VWD cohorts were defined using Komodo longitudinal US claims data (January 2015-March 2020). ML models were built using key characteristics predictive of VWD diagnosis from the diagnosed cohort. Two ML models predicted VWD diagnosis with the highest accuracy in females (random forest; 84%) and males (gradient boosting machine; 85%). Undiagnosed persons suspected to have VWD were identified using an 80% cutoff probability; profiles of key characteristics were constructed. RESULTS: The trained ML models were applied to the undiagnosed cohort (28,463 females; 20,439 males) with suspected VWD. Fifty-two percent of undiagnosed females had heavy menstrual bleeding, a key pre-diagnosis symptom. Undiagnosed males tended to have more frequent medical procedures, hospitalizations, and emergency room visits compared with undiagnosed females. CONCLUSIONS: ML algorithms successfully identified potentially undiagnosed symptomatic people with VWD, although many may remain undiagnosed and undertreated. External validation of the algorithms is recommended.

The Utility of Thromboelastography in Monitoring Von Willebrand Disease: A Case Report.

Von Willebrand disease (VWD) is the most common inherited bleeding disorder. It is primarily attributed to malfunctioning or deficient Von Willebrand factor (VWF). Thromboelastography (TEG) has emerged as a valuable tool for assessing coagulation dynamics and guiding transfusion therapy in bleeding patients. Given this, we present a case study of a 23-year-old pregnant female with a past medical history of type 2B VWD, wherein TEG was employed to optimize disease screening and therapy monitoring while minimizing costs and preventing complications associated with low platelet counts. This case underscores the potential utility of TEG in enhancing the care of VWD patients, particularly in unique critical settings such as pregnancy.

[Factor XI deficiency: actuality and review of the literature]. / Déficit en facteur XI : actualités et revue de littérature.

Although two clusters have been identified in France, constitutional factor XI deficiency is a rare disorder. Acquired factor XI deficiency is extremely rare. The management of factor XI deficiency is not staightforward because of the unpredictable bleeding tendency that does not clearly relate to the factor XI level. Other haemostastis parameters have to be taken into account to evaluate the bleeding tendency. We report the cases of a congenital factor XI deficiency, an acquired factor XI deficiency and a von Willebrand disease associated to a factor XI deficiency. On the other hand, some interferences can lead to underestimation of factor XI and we report the case of an interference by lupus anticoagulant. The objective of this review is to better understand how to manage a reduced factor XI level.

ST-segment elevation myocardial infarction (STEMI) caused by spontaneous coronary artery dissection (SCAD) in a patient with von Willebrand disease.

A postpartum woman in her early 40s, with a history of pre-eclampsia and von Willebrand disease (VWD), presented to the emergency room with chest pain suggestive of an acute coronary syndrome. Initial workup revealed an evolving anterior wall ST-segment elevation myocardial infarction on ECG and elevated cardiac biomarkers, confirming myocardial damage. Point-of-care ultrasound showed apical hypokinesis and coronary angiography revealed a distal dissection of the left anterior descending coronary artery. There was TIMI 3 flow and no evidence of plaque rupture. No percutaneous coronary intervention was performed and the patient was managed conservatively.Fibromuscular dysplasia was ruled out on screening CT angiography. Dual antiplatelet therapy was initiated for an amended course of 3 months given the history of VWD. Our patient had an uncomplicated course in the hospital with a downward trend in their cardiac biomarkers, resolving anterior ST elevation on serial ECGs, and no bleeding complications.

Acquired bleeding disorders.

Acquired bleeding disorders can develop in previously healthy people irrespective of age or gender but are particularly common in patients with certain underlying conditions. Here, we review recent advances in the management of acquired haemophilia A (AHA), acquired von Willebrand syndrome (AVWS), and patients with hemostatic abnormalities due to chronic liver disease (CLD). Patients with AHA can now benefit from prophylaxis with emicizumab, a therapeutic antibody that mimics the function of activated coagulation factor VIII. The treatment of AVWS remains challenging in many situations and requires careful consideration of the underlying condition. Haemostatic abnormalities in CLD are often compensated by proportional reduction in pro and anti-haemostatic factors resulting in sustained or even increased thrombin generation. Consequently, bleeding in CLD is rarely caused by haemostatic failure and infusion of plasma or coagulation factor concentrates may not be effective.

Cost-effectiveness of prophylaxis with recombinant vs plasma-derived VWF in severe von Willebrand disease in the United States.

ABSTRACT: We evaluated the cost-effectiveness of prophylaxis with recombinant von Willebrand factor (rVWF) vs with plasma-derived von Willebrand factor (pdVWF) for patients with severe Von Willebrand disease. We found that rVWF is a cost-saving factor replacement compared with pdVWF across all willingness-to-pay thresholds in the United States.

Heyde's syndrome: a challenging case of severe aortic stenosis and gastrointestinal bleeding.

We present the case of an elderly man with a history of diastolic congestive heart failure, severe aortic stenosis and atrial fibrillation, who presented with fatigue, weakness, coffee ground emesis and black tarry stool. Haemoglobin was 68 g/L. Lactate dehydrogenase was elevated at 1038. Evaluation by cardiology and gastroenterology specialists revealed reflux oesophagitis and a mild hiatal hernia on oesophagogastroduodenoscopy, normal colonoscopy and small bowel series without obstruction. Capsule endoscopy identified angiodysplasia in the small intestine.The patient was diagnosed with Heyde's syndrome based on the triad of severe aortic stenosis, gastrointestinal bleeding from angiodysplasia and acquired von Willebrand syndrome. The patient underwent transcatheter aortic valve replacement, resulting in the resolution of symptoms.Heyde's syndrome represents a challenging clinical entity requiring a multidisciplinary approach for accurate diagnosis and management. Early recognition, prompt intervention and interdisciplinary collaboration are crucial in optimising patient outcomes.

Diagnosis and treatment challenges in lower resource countries: State-of-the-art.

The 2022 World Federation of Haemophilia Annual Global Survey (AGS) reports that 454,690 patients with inherited bleeding disorders (IBD) have been identified globally. While this represents noteworthy progress, haemophilia epidemiology data indicate that 75% of people with inherited bleeding disorders living in low-income and low-to-middle-income countries have yet to be diagnosed. The AGS also revealed that 11 billion clotting factor units are available to treat haemophilia A and B globally. Due to a lack of finance, these treatments are unavailable to haemophilia in low-income countries with a consequence lack of access equity for haemophilia treatment in these communities. This sobering reality is not limited to haemophilia but applies to von Willebrand Disease (VWD). While VWD is the most prevalent IBD, only 103,844 people living with this condition have been diagnosed globally. Of the diagnosed patients, only a fraction live in low- or middle-income countries. Moreover, the majority of VWD patients are still treated sub-optimally without replacement therapies or prophylaxis, both of which are now accepted as global standards of care. In this state-of-the-art review, the authors reflect on three issues. First, the minimum elements required to diagnose haemophilia in a resource-constrained setting are identified. Second, this review points to the critical stakeholders and outlines their roles in removing access to haemophilia treatment barriers. Finally, the authors examine von Willebrand disease's ongoing diagnostic and treatment challenges and compare these to haemophilia. With the rapidly evolving novel therapies, the therapeutic landscape of all IBD will likely change for the better.

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.

Impact of allele-selective silencing of von Willebrand factor in mice based on a single nucleotide allelic difference in von Willebrand factor.

INTRODUCTION: Von Willebrand factor (VWF) plays a pathophysiological role in hemostatic disorders. Partial inhibition of the VWF gene through small interfering RNA (siRNA)-mediated allele-selective silencing could be a promising therapeutic strategy. For von Willebrand disease, allele-selectively inhibiting dominant-negative VWF-alleles might ameliorate the phenotype. For thrombotic disorders, partial VWF reduction can lower thrombotic risk, while avoiding bleeding. Previously, we demonstrated the feasibility of Vwf-silencing in homozygous C57BL/6J (B6) or 129S1/SvImJ (129S) mice. The present study investigated allele-selective Vwf-silencing in a complex heterozygous setting of crossed B6 and 129S mice and its subsequent hemostatic impact. MATERIALS AND METHODS: Heterozygous B6.129S mice were treated with siRNAs targeting Vwf expressed from either B6- (siVwf.B6) or 129S-alleles (siVwf.129S). Plasma VWF and lung Vwf mRNA were determined. siVwf.B6-treated B6.129S mice were subjected to ferric chloride-induced mesenteric vessel thrombosis and tail-bleeding. RESULTS: In B6.129S mice, siVwf.B6 reduced Vwf mRNA of the targeted B6-allele by 72% vs. only 12% of the non-targeted 129S-allele (41% total mRNA reduction), lowering plasma VWF by 46%. Oppositely, siVwf.129S reduced Vwf mRNA by 45%, now selectively inhibiting the 129S-allele over the B6-allele (58% vs. 9%), decreasing plasma VWF by 43%. The allele-selective VWF reduction by siVwf.B6 coincided with decreased thrombus formation in mesenteric arterioles, without prolonging tail-bleeding times. CONCLUSIONS: This study demonstrates the feasibility of allele-selective Vwf-silencing in a heterozygous setting, achieving a controlled close to 50% reduction of plasma VWF. The observed thromboprotection and absence of prolonged bleeding times underline the potential of allele-selective Vwf-silencing as a therapeutic strategy in hemostatic disorders.

Mental health in persons with von Willebrand disease in the United States - a large national database study.

BACKGROUND: There are very few large population-based studies studying mental health in persons with von Willebrand disease (PwVWD). OBJECTIVES: We aim to assess prevalence of depression and anxiety in PwVWD over a period of 20 years and identify bleeding symptoms that may be more likely associated with depression and anxiety in PwVWD. METHODS: This is a retrospective cohort study using a deidentified national dataset from 1118 hospitals with 176 million patients. Cases were defined as patients aged 0-110 years, both male and female, with von Willebrand disease (VWD), without hemophilia. Controls were defined as patients aged 0-110 years, both male and female, without VWD or hemophilia. We compared rates of depression and anxiety in cases and controls and by type of bleeding symptoms. RESULTS: We identified 66 367 PwVWD and 183 890 766 controls. The prevalence of depression (23.12% vs 8.62%; p ≤ .00093; relative risk = 2.68) and anxiety (32.90% vs 12.29%; p ≤ .00093; relative risk = 2.68) was higher in PwVWD. Most of the bleeding symptoms were associated with higher rates of depression and anxiety in PwVWD with the highest rates with abnormal uterine bleeding, hematemesis, hemoptysis, hematuria, and melena. CONCLUSION: Our study shows that mental health disorders in PwVWD are a significant health burden, and that burden is increased with documented bleeding symptoms. It is important that primary care physicians and hematologists caring for this population recognize this increased risk and appropriately screen and refer to mental health professionals.

Frequency, clinical, and laboratory findings of platelet secretion disorders in patients referred to the specialized coagulation laboratory of the Iranian Blood Transfusion Organization.

OBJECTIVES: Platelet secretion disorders (PSDs) are a subgroup of platelet function disorders (PFDs) caused by defects in the content or release of platelet granules. These patients have a variable degree of mucocutaneous bleeding tendency. The diagnostic facilities of PSDs are imitated in Iran, even in specialized coagulation laboratories. The present study aims to estimate the frequency of PSDs among patients referred to the Iranian Blood Transfusion Organization (IBTO). METHODS: The research population includes all patients referred to the specialized coagulation laboratory of IBTO and requested platelet function and von Willebrand testing by their physicians. They were recruited between May 2022 and October 2022 if they were not diagnosed as having procoagulant defects, von Willebrand disease (VWD), Glanzmann thrombasthenia (GT), Bernard-Soulier syndrome (BSS), and platelet count <100 × 10 9 (except in the syndromic forms). Patients with a defect in response to at least two agonists in Light transmission aggregometry (LTA), one agonist in the ATP-secretion study, and/or impairment in the expression of CD62P are considered PSDs. RESULTS: Among 121 cases referred to our center over 6 months, 40 patients fulfilled the inclusion and exclusion criteria. Ten patients were diagnosed with PSDs. Six were classified as δ-platelet secretion disorders (δ-PSD), two α-platelet secretion disorders (α-PSD), and two αδ-platelet secretion disorders (αδ-PSD). CONCLUSIONS: The prevalence of PSDs in our population study was 25% (10/40), which seems highly prevalent. Therefore, expanding laboratory approaches to platelet function defects is necessary as a routine in our country.

Type 2M/2A von Willebrand disease: a shared phenotype between type 2M and 2A.

ABSTRACT: Four variants have been continuously subjected to debate and received different von Willebrand disease (VWD) classifications: p.R1315L, p.R1315C, p.R1374H, and p.R1374C. We chose to comprehensively investigate these variants with full set of VWD tests, protein-modeling predictions and applying structural biology. Patients with p.R1315L, p.R1315C, p.R1374H, and p.R1374C were included. A group with type 2A and 2M was included to better understand similarities and differences. Patients were investigated for phenotypic assays and underlying disease mechanisms. We applied deep protein modeling predictions and structural biology to elucidate the causative effects of variants. Forty-three patients with these variants and 70 with 2A (n = 35) or 2M (n = 35) were studied. Patients with p.R1315L, p.R1374H, or p.R1374C showed a common phenotype between 2M and 2A using von Willebrand factor (VWF):GPIbR/VWF:Ag and VWF:CB/VWF:Ag ratios and VWF multimeric profile, whereas p.R1315C represented a type 2M phenotype. There was an overall reduced VWF synthesis or secretion in 2M and cases with p.R1315L, p.R1374H, and p.R1374C, but not in 2A. Reduced VWF survival was observed in most 2A (77%), 2M (80%), and all 40 cases with p.R1315L, p.R1374H, and p.R1374C. These were the only variants that fall at the interface between the A1-A2 domains. p.R1315L/C mutants induce more compactness and internal mobility, whereas p.R1374H/C display a more extended overall geometry. We propose a new classification of type 2M/2A for p.R1315L, p.R1374H, and p.R1374C because they share a common phenotype with 2M and 2A. Our structural analysis shows the unique location of these variants on the A1-A2 domains and their distinctive effect on VWF.

A noncanonical splicing variant c.875-5 T > G in von Willebrand factor causes in-frame exon skipping and type 2A von Willebrand disease.

INTRODUCTION: 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). MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: The VWF splicing site variant (c.875-5 T > G) causes propeptide truncation, severely compromising VWF multimer assembly and tubular storage.

von Willebrand disease: A guide for the internist.

von Willebrand disease (VWD), the most common inherited bleeding disorder, results when patients either do not make enough von Willebrand factor (VWF) or make defective VWF. The pathophysiology of this disorder is complex but needs to be understood to interpret the diagnostic tests. Most patients have mild to moderate symptoms and can be adequately counseled and managed by a general internist, but some need to consult a hematologist. We review the pathophysiology of VWD, its subtypes, common presentations of each subtype, diagnostic testing, and management of mild as well as severe clinical manifestations of VWD.