Von Willebrand Disease Cases Research Articles

Usefulness of Emicizumab Associated with Immune Tolerance Induction in Patient with Hemophilia a and Inhibitors: Experience in Cuenca-Ecuador

Background: Referring to the World Federation of Hemophilia (WFH) 2020 Annual Global Survey Report published in October 2021: In Ecuador, with a population of 17,643,060 inhabitants, there are 1,708 cases of hemophilia, 99 cases of Von Willebrand disease, and 7 cases of other coagulation disorders. Within the hemophilia A group, 21 patients have active inhibitors, and there is a record of 2 new cases of inhibitors in relation to the previous notification. Emicizumab is a bispecific, humanized monoclonal antibody that binds activated FIX and factor X (FX) resulting in the generation of activated FX (FXa) which then catalyzes the formation of thrombin from prothrombin. Based on the HAVEN 1-4 clinical trials, the FDA and EMA approved the use of Emicizumab as prophylaxis in Hemophilia A (with and without inhibitors) in both adults/adolescents (>12 years) and pediatrics (<12 years). In both the primary analyzes and long-term follow-up, emicizumab produced statistically and clinically significant reductions in annual bleeding rates compared with Factor VIII prophylaxis (in patients without inhibitors); and with bypassing agents (in patients with inhibitors). These trials excluded patients in immune tolerance (ITI). Keywords: emicizumab, immune tolerance, hemophilia. Objectives: -Assess the usefulness of Emicizumab in immune tolerance in terms of bleeding control, osteoarticular health and functional activity Materials and Methods: 1) The evaluation was carried out in a 9-year-old patient (boy) with severe Hemophilia A and high titer inhibitors who, prior to the start of ITI, had predictive factors of high risk and poor prognosis (historical peak 234 UB, 5 years since inhibitor screening) with 4-8 joint bleeds per year. The ITI scheme used was with plasmatic Factor VIII 100 IU/Kg 3 times a week with management with bypass agents on demand (ITI duration: 3 years) and inclusion of emicizumab 2 years after starting the strategy 2) The analysis was determined based on periodic clinical evaluations, osteoarticular status was assessed through the Hemophilia Joint Health Score 2.1 (HJHS), Disease Activity Score (DAS28); and functional activity through Functional Independence Score in Hemophilia (FISH), and Health Assessment Questionnaire (HAQ). An analysis was made prior to the start of immune tolerance and after reaching immunological tolerance. Results: 1) This strategy contributed to better control of joint bleeding, and therefore to the inhibitor eradication process. 2) Improved the evolutionary course of his osteoarticular state: - Prior to ITI: DAS28: 4.26 (moderate activity), HJHS 33. Target joints: left knee and ankle. - After immunological tolerance: DAS28: 1.87 (clinical remission), HJHS 12. 3) Favorable progression of his functional status, despite slight limitation of his left knee in flexion (sequel to recurrent episodes of hemarthrosis): - Prior to the start of ITI: FISH 14, HAQ: 1.50 (severely affected functional capacity), functional scale IV (use of a wheelchair). - After immunological tolerance: FISH 27, HAQ: 1.00, functional scale II (able to carry out activities of daily living with slight difficulty). Conclusions: 1) Larger-scale studies and accumulated evidence are needed that allow us to establish the usefulness of Emicizumab in ITI and therefore corroborate these results. 2) We must establish the best clinical application profile and the economic impact of these therapies; especially in health systems like ours, in which accessibility to drugs is complex and optimization of resources is the norm. Bibliography: 1. Alvarez Roman M: Guías Españolas para el manejo de la hemophilia. 2022, 1-190. 2. Callaghan M, Negrier C, Paz-Priel I, Chang T, Chebon S y col: Long-term outcomes with emicizumab prophylaxis for hemophilia A with or without FVIII inhibitors from the HAVEN 1-4 studies. 2021;137(16):2231-2242 3. Carcao M, Escurriola C, Santagostina E, Oldenburg J, Liesner R y col: The changing face of immune tolerance induction 3. Hematology Am Soc Hematol Educ Program. 2021, Dec 10;2021(1):219-225. 4. Young G: Management of children with hemophilia A: How emicizumab has changed the landscape. Journal of Thrombosis and Haemostasis. 2021 Jul;19(7):1629-1637 Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Von Willebrand disease: a report of 3 cases diagnosed with different contexts and review of literature

Background: Von Willebrand disease is the most common human inherited bleeding disorder. A major challenge for affected patients is achieving an accurate and timely diagnosis. We reported 3 cases of von Willebrand disease diagnosed with different contexts. Case report: Case 1: male, 2.5 months old, whose grandfather and aunt have a bleeding disorder. Hospitalized with purpura and ecchymosis. Was diagnosed with VWD type 1 and monitored at home when bleeding. Case 2: male, 13 years old, diagnosed with Hemophilia A from 2 years old. Unresponsive to treatment, bleeding of the skin and mucosa. Diagnosis of VWD type 1. Treating with cryoprecipitate and oral minirin, the frequency of hospitalization is reduced and well-response. Case 3: female, 9 years old, hospitalized because of a centipede bite. After 4 days, the skin was bleeding with purpura and ecchymosis, and the laboratory showed prolonged APTT and decreased VWF antigen. Diagnosis of acquired VWD after a centipede bite. After 1 month of follow-up, the child did not bleed, and the test returned to normal. Conclusion: The cases described above help to generalize the different diagnostic contexts. The suggestion of VWD is raised when there is a mismatch between clinical and general coagulation tests. A definitive diagnosis of VWD requires a VWF test. Key words: von Willebrand disease, Bleeding disorder, von Willebrand factor

Rhinoplasty on Patients with von Willebrand's Disease

Von Willebrand's disease (VWD) is the most common hereditary bleeding disorder. Due to its frequency, occasionally, patients with this disease apply for rhinoplasty. Classically, desmopressin is used in emergent cases, and it is highly effective. However, the lack of long-term treatment and possible side effects limit the desmopressin treatment. Because the fibrinolytic activity in the nasal mucosa is high, antifibrinolytics such as tranexamic acid are beneficial in all types of VWD. An 18-year-old patient with Type 1 VWD who was operated without facing any complications is presented. Treatment involved 4 days of treatment starting the day before the surgery and healing process was uneventful. Patients with a diagnosis of VWD can be operated successfully with preoperative tranexamic acid treatment and using vasoconstrictor agents and avascular surgery planes. In Type 1 VWD or low von Willebrand's factor cases, tranexamic acid is a safe and successful treatment alternative due to its long-term use, local and systemic applicability, and regional affinity.

Multiple Sclerosis Diagnosed in a Woman With Von-Willebrand Disease: A Case Report

Background: Von-Willebrand Disease (VWD) is the most common inherited bleeding disorder with an autosomal inheritance pattern. Multiple Sclerosis (MS) is a neurological disease, causing neurodegeneration and demyelination of the central nervous system through autoimmune mechanisms, and is a major cause of non-traumatic disabilities in youths. Some studies have shown the higher plasma activity of Von-Willebrand Factor in the active phase of MS. However, we could not find any study reporting co-occurrence of VWD and MS. Case Presentation and Intervention: In this case report, we present a woman with VWD who had optic neuritis 8 years ago and a new onset right-side hemiparesis. She was finally diagnosed as a new case of MS. Conclusion: There is a case of both VWD and MS; however, further investigation is needed regarding the association of VWD and MS

Dispatch and delivery at the ER-Golgi interface: how endothelial cells tune their hemostatic response.

Von Willebrand factor (VWF) is a glycoprotein that is secreted into the circulation and controls bleeding by promoting adhesion and aggregation of blood platelets at sites of vascular injury. Substantial inter-individual variation in VWF plasma levels exists among the healthy population. Prior to secretion, VWF polymers are assembled and condensed into helical tubules, which are packaged into Weibel-Palade bodies (WPBs), a highly specialized post-Golgi storage compartment in vascular endothelial cells. In the inherited bleeding disorder Von Willebrand disease (VWD), mutations in the VWF gene can cause qualitative or quantitative defects, limiting protein function, secretion, or plasma survival. However, pathogenic VWF mutations cannot be found in all VWD cases. Although an increasing number of genetic modifiers have been identified, even more rare genetic variants that impact VWF plasma levels likely remain to be discovered. Here, we summarize recent evidence that modulation of the early secretory pathway has great impact on the biogenesis and release of WPBs. Based on these findings, we propose that rare, as yet unidentified quantitative trait loci influencing intracellular VWF transport contribute to highly variable VWF levels in the population. These may underlie the thrombotic complications linked to high VWF levels, as well as the bleeding tendency in individuals with low VWF levels.

Von Willebrand disease combined with coagulation defects in Iran.

Although Von Willebrand disease (VWD) is the most common inherited bleeding disorder, few cases of VWD combined with coagulation defects have been reported. This study sought to determine the clinical and laboratory features of VWD combined with other coagulation defects and to evaluate the prevalence of this combination in Iran. A total of 3,120 cases were evaluated to confirm a suspected diagnosis of VWD. Clinical and laboratory phenotypes, including bleeding scores (BS), were also obtained. A diagnosis of VWD was established for 130 patients. Following their further characterisation, a subgroup of 25 patients with a dual or triple combination of VWD with coagulation defects (FXII, FXI, FIX, FVII, FV, and lupus anticoagulant) was identified. Their laboratory and clinical data were compared with those of healthy controls (n=25) and VWD-only patients (n=25). No differences were observed for VWF-related laboratory measurements between the combined deficient cases and those with VWD only, results being expectedly lower than in healthy controls. The median BS of combined patients was 4, higher than for VWD-only and control groups (median BS 3 and 1; p=0.55 and p<0.001, respectively). The prevalence of combined coagulation defects was 19.2% among all the VWD cases. The co-occurrence of VWD with clotting factor deficiencies may lead to more severe clinical presentations. To ensure adequate treatment, combined defects should be considered in VWD patients presenting with a more severe bleeding phenotype than expected or with a poor response to treatment.

Toward Personalized Treatment for Patients with Low von Willebrand Factor and Quantitative von Willebrand Disease.

The biological mechanisms involved in the pathogenesis of type 2 and type 3 von Willebrand disease (VWD) have been studied extensively. In contrast, although accounting for the majority of VWD cases, the pathobiology underlying partial quantitative VWD has remained somewhat elusive. However, important insights have been attained following several recent cohort studies that have investigated mechanisms in patients with type 1 VWD and low von Willebrand factor (VWF), respectively. These studies have demonstrated that reduced plasma VWF levels may result from either (1) decreased VWF biosynthesis and/or secretion in endothelial cells and (2) pathological increased VWF clearance. In addition, it has become clear that some patients with only mild to moderate reductions in plasma VWF levels in the 30 to 50 IU/dL range may have significant bleeding phenotypes. Importantly in these low VWF patients, bleeding risk fails to correlate with plasma VWF levels and inheritance is typically independent of the VWF gene. Although plasma VWF levels may increase to > 50 IU/dL with progressive aging or pregnancy in these subjects, emerging data suggest that this apparent normalization in VWF levels does not necessarily equate to a complete correction in bleeding phenotype in patients with partial quantitative VWD. In this review, these recent advances in our understanding of quantitative VWD pathogenesis are discussed. Furthermore, the translational implications of these emerging findings are considered, particularly with respect to designing personalized treatment plans for VWD patients undergoing elective procedures.

Diagnosis and management of von Willebrand disease: A community-wide effort to deliver evidence-based clinical practice guidelines.

Diagnosis and management of von Willebrand disease: A community-wide effort to deliver evidence-based clinical practice guidelines.

First Case of Von Willebrand Disease in Niger

Von Willebrand’s disease was first described in 1926 by Erik Von Willebrand. It is a genetic, constitutional defect of hemostasis that is different from hemophilia. It is classified among the rare diseases whose clinical manifestations are dominated by a hemorrhagic profile, which varies from patient to patient. It is an easily diagnosed disease based on a quantitative and qualitative bioassay of VWF. Treatment is multidisciplinary and is based on well-structured prevention. We report the first case of von Willebrand disease in Niger, diagnosed in the Hematology Department of Niamey’s National Hospital.

Клинический случай болезни Виллебранда после операции тонзиллотомии и аденотомии у ребенка

The authors present a clinical case of von Willebrand disease detected after tonsillotomy and adenotomy in a child. The peculiarity of this observation lies in the rare occurrence of von Willebrand disease in clinical practice, as well as the manifestation of the clinical manifestations of this pathology against the background of surgical treatment in a child.

Correcting dominant‐negative von Willebrand disease

Correcting dominant‐negative von Willebrand disease

Von Willebrand Disease, A Rare Cause of Massive Upper GI Bleeding: A Case Report

von Willebrand Disease (VWD) is the most common inherited bleeding disorder. It occurs due to either qualitative or quantitative defect of von Willebrand Factor (VWF). VWF is a large multimeric glycoprotein necessary for platelet aggregation and adhesion to the subendothelium following any vascular injury. Typical presentation of VWD patient include mucosal bleeding, easy bruising and bleeding following minor trauma. Rarely, these patients may present with gastro intestinal bleeding. The treatment of choice in mild forms of VWD is the synthetic agent desmopressin. In patients with severe form or in children who do not response to desmopressin, the appropriate treatment is a VWF rich factor VIII concentrate. There are few case reports of VWD with upper gastrointestinal (UGI) bleeding. So, we report a case of 9 years old female child who was admitted at Bangabandhu Sheikh Mujib Medical University in Paediatric Gastroenterology Department with the complaints of recurrent UGI bleeding for 3 years. She also had history of spontaneous gum bleeding, easy bruising, echymosis, prolong bleeding following minor trauma since early age. After appropriate evaluation of the patient including history and relevant investigation, she was diagnosed as a case of VWD with GI bleeding. We report this as it is a rare presentation of VWD.&#x0D; Bangladesh J Child Health 2019; VOL 43 (3) :188-191

Establishment and Clinical Application of Flow Cytometric Immunobead Array in Detecting Plasma von Willebrand Factor Antigen

To establish a novel flow cytometric immunobead array (FCIA) for detecting plasma von Willebrand factor antigen (vWF:Ag), and to analyze the clinical value of FCIA in predicting the prognosis of patients with ischemic stroke (IS). Anti-human vWF monoclonal antibody SZ29 IgG was coated on microspheres overnight, the diluted plasma was added after blocking, then incubated with FITC-conjugated sheep-anti-human vWF IgG polyclonal antibody, and finally detected by flow cytometry. The plasma vWF in 21 case of von Willebrand disease (vWD) and 105 controls (CTL) were detected by FCIA and ELISA, so as to carry out methodological assessment. Plasma vWF:Ag of 61 IS patients was detected by FCIA and the data of prognosis followed-up for 2-year were collected. The linear fitting of FCIA was good (R2=0.99) without significant difference between FCIA and ELISA. The Bland-Altman bias was 1.12% with 95% limits of agreement that spanned from -45.06% to 47.30%, and the slope of the linear regression was 0.97 (r=0.86, P＜0.01). Importantly, the FCIA method was faster than ELISA, and superior to the ELISA in the detection of low levels of vWF:Ag. The levels of vWF:Ag, vWF:GPIbR and vWF:CB in IS patients were significantly higher than those in healthy controls (Z=8.36, 8.71, 6.22, respectively, P＜0.01). The FCIA for detecting plasma vWF:Ag is not only an effective supplement to ELISA, but also the efficiency is faster and more sensitive, thus improves the diagnosis of type 3 vWD. Elevated levels of vWF: Ag in IS patients indicate the poor recovery of daily activities and prognosis.

Establishment and Clinical Application of Flow Cytometric Immunobead Array in Detecting Plasma von Willebrand Factor Antigen

To establish a novel flow cytometric immunobead array (FCIA) for detecting plasma von Willebrand factor antigen (vWF:Ag), and to analyze the clinical value of FCIA in predicting the prognosis of patients with ischemic stroke (IS). Anti-human vWF monoclonal antibody SZ29 IgG was coated on microspheres overnight, the diluted plasma was added after blocking, then incubated with FITC-conjugated sheep-anti-human vWF IgG polyclonal antibody, and finally detected by flow cytometry. The plasma vWF in 21 case of von Willebrand disease (vWD) and 105 controls (CTL) were detected by FCIA and ELISA, so as to carry out methodological assessment. Plasma vWF:Ag of 61 IS patients was detected by FCIA and the data of prognosis followed-up for 2-year were collected. The linear fitting of FCIA was good (R2=0.99) without significant difference between FCIA and ELISA. The Bland-Altman bias was 1.12% with 95% limits of agreement that spanned from -45.06% to 47.30%, and the slope of the linear regression was 0.97 (r=0.86, P＜0.01). Importantly, the FCIA method was faster than ELISA, and superior to the ELISA in the detection of low levels of vWF:Ag. The levels of vWF:Ag, vWF:GPIbR and vWF:CB in IS patients were significantly higher than those in healthy controls (Z=8.36, 8.71, 6.22, respectively, P＜0.01). The FCIA for detecting plasma vWF:Ag is not only an effective supplement to ELISA, but also the efficiency is faster and more sensitive, thus improves the diagnosis of type 3 vWD. Elevated levels of vWF: Ag in IS patients indicate the poor recovery of daily activities and prognosis.

Potential Undiagnosed VWD Or Other Mucocutaneous Bleeding Disorder Cases Estimated From Private Medical Insurance Claims.

IntroductionVon Willebrand disease (VWD) is a common inherited bleeding disorder, but awareness among health care professionals is low. We estimated the number of cases of undiagnosed VWD or other mucocutaneous bleeding disorders among commercially insured patients in the United States with a recent history of bleeding events.MethodsPatients with a VWD diagnosis who were users of or candidates for von Willebrand factor replacement were identified from the IMS PharMetrics Plus Database (2006–2015). We constructed a unary patient-finding model based on 12 prediagnosis variables that best defined this population, and applied this to undiagnosed patients with recent bleeding events from the same database. Cases of symptomatic undiagnosed VWD or other mucocutaneous bleeding disorders in the commercially insured population were estimated from the “best fit” (positive predictive value [PPV] 83%) and “good fit” (PPV 75%) patients thus identified.ResultsOverall, 507,668 undiagnosed patients with recent bleeding events were identified (86% female, 14% male). Application of the VWD model identified 3318 best-fit and 37,163 good-fit patients; 91% of best-fit patients were females aged <46 years, with heavy menstrual bleeding as the most common claim. Projection to the full commercially insured US population suggested that 35,000–387,000 patients may have symptomatic, undiagnosed VWD or other mucocutaneous bleeding disorders.DiscussionComputer modeling suggests there may be a significant number of patients with symptomatic, undiagnosed VWD or other mucocutaneous bleeding disorder in the commercially insured population. Enhanced awareness of VWD symptoms and their impact, and of screening and testing procedures, may improve the diagnosis of VWD and reduce disease burden.

Correction of a dominant‐negative von Willebrand factor multimerization defect by small interfering RNA‐mediated allele‐specific inhibition of mutant von Willebrand factor

Background Treatment of the bleeding disorder von Willebrand disease (VWD) focuses on increasing von Willebrand factor (VWF) levels by administration of desmopressin or VWF-containing concentrates. Both therapies leave the production of mutant VWF unhindered, which may have additional consequences, such as thrombocytopenia in patients with VWD type 2B, competition between mutant and normal VWF for platelet receptors, and the potential development of intestinal angiodysplasia. Most cases of VWD are caused by dominant-negative mutations in VWF, and we hypothesize that diminishing expression of mutant VWF positively affects VWD phenotypes. Objectives To investigate allele-specific inhibition of VWF by applying small interfering RNAs (siRNAs) targeting common single-nucleotide polymorphisms (SNPs) in VWF. This approach allows allele-specific knockdown irrespective of the mutations causing VWD. Methods Four SNPs with a high predicted heterozygosity within VWF were selected, and siRNAs were designed against both alleles of the four SNPs. siRNA efficiency, allele specificity and siRNA-mediated phenotypic improvements were determined in VWF-expressing HEK293 cells. Results Twelve siRNAs were able to efficiently inhibit single VWF alleles in HEK293 cells that stably produce VWF. Transient cotransfections of these siRNAs with two VWF alleles resulted in a clear preference for the targeted allele over the untargeted allele for 11 siRNAs. We also demonstrated siRNA-mediated phenotypic improvement of the VWF multimerization pattern of the VWD type 2A mutation VWF p.Cys2773Ser. Conclusions Allele-specific siRNAs are able to distinguish VWF alleles on the basis of one nucleotide variation, and are able to improve a severe multimerization defect caused by VWF p.Cys2773Ser. This holds promise for the therapeutic application of allele-specific siRNAs in dominant-negative VWD.

Evaluation of the Utility of von Willebrand Factor Propeptide in the Differential Diagnosis of von Willebrand Disease and Acquired von Willebrand Syndrome.

An increased von Willebrand factor propeptide (VWFpp) to VWF antigen (VWF:Ag) ratio (VWFpp/VWF:Ag) indicates an enhanced clearance of VWF. This finding has been described in von Willebrand disease (VWD) and in acquired von Willebrand syndrome (AVWS). A distinction between these two diseases, one congenital and the other acquired, is primarily based on family and personal history of bleeding. However, if this information is scanty, the diagnosis might be challenging due to the lack of an effective diagnostic biomarker. In this cross-sectional study, we assessed the ability of VWFpp/VWF:Ag for the differential diagnosis between VWD and AVWS. VWFpp/VWF:Ag was measured in a group of 153 patients (125 with VWD and 28 with AVWS). Most patients with AVWS and VWD showed an increased VWFpp/VWF:Ag, although to variable degrees. A marked increase of VWFpp/VWF:Ag was mainly associated with the diagnosis of AVWS and VWD type 1 Vicenza. A receiver operating characteristic curve was used to identify the optimal cutoff of VWFpp/VWF:Ag for discrimination of patients with a modestly increased (most VWD cases) versus those with a markedly increased clearance (AVWS and VWD type 1 Vicenza), and this cutoff was identified at the value of 3.9 (sensitivity: 0.70, specificity: 0.97). The ROC curve sorting from a logistic model containing VWFpp/VWF:Ag, age, and sex had an area under the curve (AUC) of 0.88 (95% confidence interval: 0.80-0.95). A subsequent molecular evaluation discriminated VWD type 1 Vicenza from AVWS. In conclusion, VWFpp/VWF:Ag appears helpful to discriminate patients with a markedly increase VWF clearance (AVWS or VWD type 1 Vicenza) from those with a modestly increased clearance (most VWD patients).

Relevance of Abusive Head Trauma to Intracranial Hemorrhages and Bleeding Disorders.

Bleeding disorders and abusive head trauma (AHT) are associated with intracranial hemorrhage (ICH), including subdural hemorrhage (SDH). Because both conditions often present in young children, the need to screen for bleeding disorders would be better informed by data that include trauma history and are specific to young children. The Universal Data Collection database contains information on ICH in subjects with bleeding disorders, including age and trauma history. Study objectives were to (1) characterize the prevalence and calculate the probabilities of any ICH, traumatic ICH, and nontraumatic ICH in children with congenital bleeding disorders; (2) characterize the prevalence of spontaneous SDH on the basis of bleeding disorder; and (3) identify cases of von Willebrand disease (vWD) that mimic AHT. We reviewed subjects <4 years of age in the Universal Data Collection database. ICH was categorized on the basis of association with trauma. Prevalence and probability of types of ICH were calculated for each bleeding disorder. Of 3717 subjects, 255 (6.9%) had any ICH and 206 (5.5%) had nontraumatic ICH. The highest prevalence of ICH was in severe hemophilia A (9.1%) and B (10.7%). Of the 1233 subjects <2 years of age in which the specific location of any ICH was known, 13 (1.1%) had spontaneous SDH (12 with severe hemophilia; 1 with type 1 vWD). The findings in the subject with vWD were not congruent with AHT. In congenital bleeding disorders, nontraumatic ICH occurs most commonly in severe hemophilia. In this study, vWD is not supported as a "mimic" of AHT.

Fifth Åland Island conference on von Willebrand disease.

The fifth Åland Island meeting on von Willebrand disease (VWD) was held on the Åland Islands, Finland, from 22 to 24 September 2016-90years after the first case of VWD was diagnosed in a patient from the Åland Islands in 1926. This meeting brought together experts in the field of VWD to share knowledge and expertise on current trends and challenges in VWD. Topics included the storage and release of von Willebrand factor (VWF), epidemiology and diagnostics in VWD, treatment of VWD, angiogenesis and VWF inhibitors.

Diagnosis and management of von willebrand disease in Spain

The correct diagnosis and classification of von Willebrand disease (VWD) is difficult because of the variability of its clinical expression and limitations of laboratory methods. However, correctly diagnosing VWD is important for therapy and genetic counselling. A survey related to the referred VWD patients in Spain revealed local diagnostic problems in at least one third of the cases of VWD. Consequently, a Spanish multicenter study was carried out in which a cohort of 556 patients from 330 families was analyzed centrally. VWD was confirmed in 480 patients. Next generation sequencing (NGS) of the whole coding von Willebrand factor gene ( VWF ) was carried out in all recruited patients, compared with the phenotype, and a final diagnosis was established. A total of 238 different VWF mutations were found: 154 were not included in the Leiden Open Variation Database (LOVD). Of the patients, 467 were found to have a VWF mutation/s. A good phenotype/genotype association was estimated in 94.6% of the cases. One hundred and eighty patients had two or more mutations. Occasionally a predominant phenotype masked the presence of a second abnormality. One hundred and sixteen patients presented with mutations that had previously been associated with an increased VWF clearance. Ristocetin induced platelet agglutination (RIPA) unavailability, central phenotypic results disagreement and difficult distinction between severe type 1 and type 3 VWD prevented a clear diagnosis in 74 patients. A local/central disagreement over diagnosis occurred in 42.3% of the whole cohort. The NGS study facilitated an appropriate classification in 60 of them. Based on these results, a proposal for a change in the VWD diagnostic paradigm, suggesting the inclusion of the analysis of VWF at the initial diagnostic process, has been made. An extension of this project to include 400 new VWD patients has begun. A diagnostic strategy has been developed, and a Spanish consensus guideline for optimal treatment of VWD was developed in Spain. Desmopressin (DDAVP) is the treatment of choice in responsive VWD patients. VWF concentrates (VWF/FVIII) are used in individuals unresponsive to DDAVP, when DDAVP is contraindicated, or in VWD types 2B and 3, and for long term management needs (e.g., post major surgery).