No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Inconsistency of Association between Type 1 von Willebrand Disease Phenotype and Genotype in Families Identified in an Epidemiological Investigation
Abstract
In a previous epidemiological investigation among schoolchildren of Northern Italy, a conservative 1% prevalence of type 1 von Willebrand disease (VWD) was found. Diagnosis was based on a positive family history and low von Willebrand factor (VWF) ristocetin cofactor activity. To investigate whether the type 1 VWD phenotype as detected by our original methodology cosegregates with one or more specific alleles of the VWF gene, we have performed genotype analysis in affected subjects and their family members.
Eleven of the 14 subjects previously identified as having VWD, all with mild personal bleeding symptoms, agreed to participate in the genetic study. Remarkably, the laboratory measurements of the previous investigation were completely confirmed in 10 of the 11 subjects. Clear cosegregation of the VWD type 1 and a specific VWF allele was observed in one family and was likely in the family of two other pro-bands. In three additional propositi and their families a possible association of the phenotype with a VWF allele was found. No association was observed in the remaining five subjects and their families. During 13-year follow-up few additional bleeding episodes were recorded among investigated subjects, most often occurring in the one family manifesting clear cosegregation.
The results of this study illustrate that a personal and family bleeding history and persistently low VWF ristocetin cofactor activity, fitting the usual criteria for type 1 VWD, may not cosegregate with genetic markers at the VWF gene locus. Thus the prevalence of VWD defined as a disorder involving the VWF locus might be overestimated in population study. However, phenotypic diagnosis still remains fundamental to identify patients at risk of bleeding. Further research should clarify whether in families with more severe clinical and laboratory phenotype a clear association with markers of VWF is found.
... [2][3][4][5][6] The World Federation of Hemophilia (WFH) show a continuous increase in the number of VWD patients reported via the WFH global survey which collects data in specific practise and reporting sites across the world. 7 VWD is an autosomal dominant (or recessive, depending on subtype) bleeding disorder caused by quantitative or qualitative deficiency of the complex multimeric glycoprotein von Willebrand factor (VWF). 8 The reduction in available VWF reduces platelet adhesion, platelet aggregation, and factor VIII (FVIII) availability, which gives rise to an increased frequency and length of bleeds (particularly mucosal bleeding) especially in the skin, gastrointestinal tract, and uterus, as well as bleeding in joints, leading to deterioration in severe or poorly managed patients; 9 in the event of progressive, extensive joint damage due to bleeds, orthopaedic surgery may be carried out. 10 Female VWD patients may experience heavy menstrual bleeding so severe as to require regular hospitalisation. ...
... Each of the aforementioned present mild, moderate, and severe symptoms, respectively. 8,17,18 However, symptoms may vary depending on phenotypic expression. 19 While in 2021 the international guidelines on the management of VWD (as developed by the American Society of Hematology, International Society on Thrombosis and Haemostasis, National Hemophilia Foundation, and World Federation of Hemophilia) were released, 20 prior to this there were limited formal guidelines for standard of care of VWD across Europe. ...
Background
Von Willebrand disease (VWD) is one of the most common inherited bleeding disorders, imposing a substantial health impact and financial burden. The Cost of von Willebrand disease in Europe: A Socioeconomic Study (CVESS) characterises the socio-economic cost of VWD across Germany, Spain, Italy, France, and the UK.
Methods
A retrospective, cross-sectional design captured 12 months of patient disease management, collected from August-December 2018, for 974 patients. This enabled estimation of direct medical, direct non-medical and indirect costs, utilising prevalence estimates to extrapolate to population level.
Results
Total annual direct medical cost (including/excluding von Willebrand factor [VWF]) across all countries was the highest cost (€2 845 510 345/€444 446 023), followed by indirect costs (€367 330 271) and direct non-medical costs (€60 223 234). Differences were seen between countries: the UK had the highest direct medical costs excluding VWF (€159 791 064), Italy the highest direct-non medical (€26 564 496), and Germany the highest indirect cost burden (€197 036 052). Total direct medical costs per adult patient increased across VWD types with Type 1 having the lowest cost (€23 287) and Type 3 having the highest cost (€133 518).
Conclusion
A substantial financial burden arises from the prevalence of VWD for the European healthcare systems considered.
... 56 Interestingly, in a follow-up study by these workers published in 1999, most cases identified in the 1987 study were confirmed to yield consistent (low) VWF-related phenotypic data but conversely showed that most patients did not show evidence of cosegregation to the VWF gene in a genotype analysis. 57 Similar data on high prevalence rates for VWD have been obtained in other epidemiological/population screening studies. For example, a French study identified 5 cases (of type 1 VWD) from a pool of 832 investigated cases, yielding a prevalence of 0.6% (or $6000 cases per million population), and a U.S. study identified 8 cases of VWD in 600 investigated cases, yielding a prevalence of 1.3% (or $13,000 cases per million population) 58,59 ( Table 2). ...
... 60,61 As previously mentioned, most individuals with so-called VWD identified by these epidemiological/ population screening studies are identified as having mild type 1 VWD without any evident VWF genetic basis. 57 Such cases are now more often recognized as representing individuals with low VWF levels, or possible type 1 VWD, rather than reflecting true (VWF genetic basis) VWD. 40 It is important to recognize that most individuals with identifiable borderline low levels of VWF (as, for example, those identified by the previously mentioned epidemiological/population screening studies) would not otherwise actively present themselves to hemostasis centers for investigation of any evident bleeding issues, and hence prevalence data collected by the more usual approach (case referral or bleeding disorder registry data) would reflect much lower prevalence rates, as well as likely identifying cases representing more significant bleeding disorders. ...
von Willebrand disease (VWD) is the most common inherited bleeding disorder and arises from deficiencies and/or defects in the plasma protein von Willebrand factor (VWF). The current report overviews the diagnosis and management of VWD as reflected by differential processes applied within centers around the world. The prevalence of VWD, as well as the frequency of different VWD types, is also reported. VWD prevalence data varies according to methodology used, with epidemiological/population screening estimates approximating 1% of the population (or 10,000 cases per million population), several orders of magnitude higher than estimates from bleeding disorders registry data or regional/center analysis (which instead range from <1 to ~450 cases per million population). Frequency of different VWD types also varies according to source and analysis, with type 1 VWD identified as the clear dominant type in most developed countries (ranging from 40% to 90% of all VWD cases), whereas type 3 VWD predominates in developing countries such as India and Iran. The frequency of qualitative (i.e., type 2) VWD also varies considerably among different reports, ranging from 3% to >50% of all VWD cases, as does the frequency of specific qualitative VWD types (i.e., 2A, 2B, 2M, and 2N). Although type 2A VWD is considered the most common form of type 2 VWD, in some reports workers consider type 2M VWD to be as, or more, common. Although not considered to be a "true" VWD, given its platelet origin, platelet-type VWD is only rarely identified. Finally, management of VWD also differs according to geographic region. Most developed countries use standard therapy, employing desmopressin (DDAVP) wherever possible, factor concentrate in other situations, and antifibrinolytic therapy as required. In contrast, the relative high cost and unavailability of factor concentrates in developing countries, and sometimes the unavailability of DDAVP, requires different management strategies to be applied.
... VWD prevalence estimates range from ;1 in 100 to 1 in 10 000. 13,[15][16][17] At the level of primary care, ;1 in 1000 individuals are affected and require medical attention for bleeding. 18,19 The current International Society on Thrombosis and Haemostasis (ISTH) classification recognizes 3 types: type 1 is a partial quantitative deficiency of VWF, type 2 is caused by qualitative abnormalities of VWF, and type 3 is a virtual absence of the VWF protein with associated very low FVIII levels. ...
Background
von Willebrand disease (VWD) is the most common inherited bleeding disorder known in humans. Accurate and timely diagnosis presents numerous challenges.
Objective
These evidence-based guidelines of the American Society of Hematology (ASH), the International Society on Thrombosis and Haemostasis (ISTH), the National Hemophilia Foundation (NHF), and the World Federation of Hemophilia (WFH) are intended to support patients, clinicians, and other health care professionals in their decisions about VWD diagnosis.
Methods
ASH, ISTH, NHF, and WFH established a multidisciplinary guideline panel that included 4 patient representatives and was balanced to minimize potential bias from conflicts of interest. The Outcomes and Implementation Research Unit at the University of Kansas Medical Center (KUMC) supported the guideline-development process, including performing or updating systematic evidence reviews up to 8 January 2020. The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, including GRADE Evidence-to-Decision frameworks, to assess evidence and make recommendations, which were subsequently subject to public comment.
Results
The panel agreed on 11 recommendations.
Conclusions
Key recommendations of these guidelines include the role of bleeding-assessment tools in the assessment of patients suspected of VWD, diagnostic assays and laboratory cutoffs for type 1 and type 2 VWD, how to approach a type 1 VWD patient with normalized levels over time, and the role of genetic testing vs phenotypic assays for types 2B and 2N. Future critical research priorities are also identified.
... 23 It is the most common inherited bleeding disorder in humans, with prevalence estimates ranging from ∼1 in 100 to 1 in 10 000. [23][24][25][26] At the level of primary care, ∼1 in 1000 individuals is affected and requires medical attention for bleeding. 9,27 Although VWD is autosomally inherited, only women suffer from the gynecologic and obstetrical manifestations. ...
Women with bleeding disorders suffer from multiple bleeding symptoms, including easy bruising, epistaxis, bleeding from minor wounds and the oral cavity, and bleeding after dental work or surgery. However, women with bleeding disorders especially suffer from gynecologic and obstetrical bleeding. These symptoms often are not recognized as abnormal, and many women are left undiagnosed and without access to appropriate medical care. Additional challenges to diagnosing women with bleeding disorders include lack of access to appropriate laboratory testing and issues around disease classification and nomenclature. Efforts have been undertaken to address these challenges, including the development and validation of bleeding assessment tools and strategies to clarify diagnostic thresholds and algorithms for von Willebrand disease (VWD) and platelet function disorders. Efforts to improve communication with the nomenclature used for hemophilia carriers are also underway.
... 3,4 Furthermore, linkage studies have demonstrated that in many families with low VWF, inheritance is independent of the VWF locus on chromosome 12. [6][7][8] Together, these data support the hypothesis that as yet unidentified modifier loci contribute to the pathobiology underlying low VWF levels. ...
Glycan determinants on von Willebrand factor (VWF) play critical roles in regulating its susceptibility to proteolysis and clearance. Abnormal glycosylation has been shown to cause von Willebrand disease (VWD) in a number of different mouse models. However, because of the significant technical challenges associated with accurate assessment of VWF glycan composition, the importance of carbohydrates in human VWD pathogenesis remains largely unexplored. To address this, we developed a novel lectin-binding panel to enable human VWF glycan characterization. This methodology was then used to study glycan expression in a cohort of 110 patients with low VWF compared with O blood group-matched healthy controls. Interestingly, significant interindividual heterogeneity in VWF glycan expression was seen in the healthy control population. This variation included terminal sialylation and ABO(H) blood group expression on VWF. Importantly, we also observed evidence of aberrant glycosylation in a subgroup of patients with low VWF. In particular, terminal α(2-6)-linked sialylation was reduced in patients with low VWF, with a secondary increase in galactose (Gal) exposure. Furthermore, an inverse correlation between Gal exposure and estimated VWF half-life was observed in those patients with enhanced VWF clearance. Together, these findings support the hypothesis that loss of terminal sialylation contributes to the pathophysiology underpinning low VWF in at least a subgroup of patients by promoting enhanced clearance. In addition, alterations in VWF carbohydrate expression are likely to contribute to quantitative and qualitative variations in VWF levels in the normal population. This trial was registered at www.clinicaltrials.gov as #NCT03167320.
... Von Willebrand's disease (VWD) is the most common inherited bleeding disorder worldwide, with a prevalence varying within 0.1-1% of the general population depending on the method of diagnosis (1)(2)(3)(4). The disorder is caused by a quantitative or qualitative deficiency in the von Willebrand factor (VWF). ...
Women with the inherited bleeding disorder von Willebrand's disease (VWD) face gender‐speci c hemo- static challenges during menstruation. Heavy menstrual bleeding (HMB) can negatively affect their overall life activi- ties and the health-associated quality of life. The purpose of the present study was to investigate whether women with VWD experienced HMB and an impaired health-associated quality of life. The study subjects were recruited from the Coagulation Unit of Karolinska University Hospital. Information was retrieved from various self-administered forms and medical records. Of the 30 women (18-52 years) that were included in the present study, 50% suffered from HMB, although the majority received treatment for HMB. In addition, almost all the included women perceived limitations in the overall life activities due to menstruation. The health-associated quality of life for women with HMB was signi cantly lower (P<0.10) with regards to ‘bodily pain’ compared with Swedish women of the general population. In conclusion, women with VWD experienced reduced health-associated quality of life as a result of HMB. Therefore, preventing limitations in overall life activities and improving their health-associated quality of life thorough counseling on menstrual bleeding is important for women with VWD.
... Su prevalencia varía dependiendo del enfoque que se tome para definir el diagnóstico. En por lo menos 2 grandes estudios prospectivos se ha encontrado que hasta el 1% de la población predominantemente pediátrica presenta síntomas y signos de laboratorio de enfermedad de von Willebrand 19,20 . Se cree que la prevalencia de la enfermedad de von Willebrand con síntomas hemorrágicos es de aproximadamente 1 por ...
Von Willebrand disease is the most common inherited disorder of the coagulation proteins in humans. There are three types: 1, 2A, 2B, 2N, 2M and 3. It is associated with mutations on chromosome 12 in the region p13.2, encoding the von Willebrand factor (VWF), which is synthesized in endothelial cells and megakaryocytes.
The VWF gene has been characterised using molecular biology techniques, which have acquired an important role in diagnosis von Willebrand disease, as well as in the investigation of alterations in other genes, which may be involved in regulating the synthesis, processing, and secretion of VWF. However, there are still no strategies to integrate the molecular biology diagnostic tests available. Analysis of VWF multimers is a methodology that meets the characteristics for diagnosis, but it is not easy to standardise. Considering that even in tertiary centres in our country, von Willebrand patients do not have a definitive diagnosis, it is necessary to implement these methodologies to study and improve diagnosis.
Von Willebrand disease is highly heterogeneous due to the molecular mechanisms that produce the various clinical and laboratory phenotypes. In Mexico there are few studies related to this disease; therefore it is essential to conduct a comprehensive study including clinical, basic, and special testing laboratory tests, in order to establish a correct diagnosis, develop new therapeutic approaches, and offer the appropriate medical care and genetic counselling.
Copyright © 2015 Academia Mexicana de Cirugía A.C. Published by Masson Doyma México S.A. All rights reserved.
... 9 Families with VWF levels < 15 IU/dL had the highest probability of co-segregation, unlike families with VWF levels > 45 IU/dL, as previously suggested in families enrolled in an epidemiological investigation. 10 These results were further reinforced by the observation that 50% of patients with VWF > 45 IU/dL had mutations in VWF, whereas 96% of those with VWF levels < 15 IU/dL had mutations. This also emphasizes the view of considering mildly reduced VWF as a risk factor for bleeding rather than a true genetic disorder. ...
In 1926 Erik von Willebrand decribed a novel bleeding disorder in a large family from Foglo on the islands of Aland in the Gulf of Bothnia. At variance with the well known X-linked inheritance of Hemophilia, the epitome of inherited bleeding disorders, both sexes were equally affected, suggesting an autosomal pattern of inheritance, Mucosal bleeding was the dominant symptom, while hemarthrosis and muscle hematoma were rare. The latter finding, together with the observation of a prolonged bleeding time with normal platelet count, led von Willebrand to surmise a functional disorder of the platelets, associated with systemic lesion of the vessel wall, as the possible cause of the disorder. Only in the 50s, was it demonstrated that in these patients the prolonged bleeding time was associated with reduced FVIII, but we had to wait until the 70s to clarify that the deficiency of a new factor, called von Willebrand factor (VWF) and different from FVIII, was responsible for von Willebrand disease (VWD). Surprisingly, the reduction of this factor caused low FVIII, pointing to the strict relationships between the two factors. The cloning in the 80s of VWF gene has settled the basis to unravel the molecular causes of the disorder. In his paper, Federici summarizes the milestones in the history of von Willebrand disease. Despite the fact that the history of the disorder dates back to 1926,1 several questions about molecular genetics, diagnostic criteria, laboratory methodology and clinical history remained and only recently important insights have been provided by relevant publications about these issues.
... An important question not addressed here, however, is whether reducing or eliminating the DDAVP challenge may result in increased bleeding and associated health effects and treatment costs. Other studies have reported a very low risk of bleeding and lack of correlation between risk of bleeding and DDAVP challenge response, which would suggest that current practice to perform the DDAVP challenge test among this group of patients may not be a good use of limited health care resources (Castaman et al, 1999;Rodriguez et al, 2010). Nevertheless, further prospective studies should evaluate that trade-off between savings and increased risks, if any, within this group. ...
Low von Willebrand factor (VWF), defined as either VWF antigen (VWF:Ag) or Ristocetin cofactor (VWF:RCo) level ≥ 30 and < 50 iu/dl, is a common finding in paediatric patients tested for von Willebrand Disease (VWD), the most common inherited bleeding disorder. DDAVP (1-deamino-8-D-arginine vasopressin, desmopressin), a synthetic derivative of vasopressin that promotes the release of VWF multimers from Weibel-Palade bodies in the vascular endothelium, is safe and effective in preventing and treating bleeding in children with VWF levels < 50 iu/dl (Gilly, et al 2002, Khair, et al 2007, Leissinger, et al 2001). In our paediatric population, children are often tested for VWD due to a family history of VWD, personal bleeding history or prolonged partial thromboplastin time, as well as, but not limited to, part of a pre-operative evaluation. If found to have VWF:Ag or VWF:RCo <50 iu/dl, patients automatically undergo a DDAVP challenge test to assess laboratory response prior to the administration of DDAVP for the prevention or treatment of bleeding.
... von Willebrand Disease (VWD) is the most common inherited bleeding disorder, with a prevalence of approximately 1% according to population studies, 1 but clinically relevant cases have a tenfold lower prevalence. 2 The 2011Registro Nazionale delle Coagulopatie Congenite [National Registry of Congenital Coagulopathy], 3 which reports data relative to 51 of 54 hemophilia centers in Italy, indicated that a total of 8,411 subjects are affected by coagulation disorders -25% by VWD; 43% by hemophilia A; 9% by hemophilia B; 14% by disorders of other coagulation factors; and 9% by platelet disorders, carrier hemophilia A/B, or other disorders. ...
Prophylaxis with von Willebrand factor (VWF)/factor VIII (FVIII) concentrates is a potential approach for patients with severe von Willebrand disease (VWD). As far as we are aware, to date there have been no pharmacoeconomic analyses in order to assess the economic impact of treatments for severe VWD. The analysis presented here estimates the cost-benefit ratio of VWF with a low FVIII content when compared with VWF/FVIII concentrates currently used in Italy for long-term prophylaxis in patients with severe VWD.
A cost-consequence analysis was undertaken to assess the economic impact of the treatment of severe VWD from the perspective both of the Italian National Health Service and society. The analysis was based on four case reports of long-term prophylaxis with VWD with VWF/FVIII concentrates and VWF with a low FVIII content. The costs per patient included direct and indirect costs for each treatment.
Considering the four case reports, health care costs (without cost of treatment) and indirect costs per patient per year were lower with VWF with a low FVIII content than VWF/FVIII concentrates. The total health care costs (without cost of treatment) and indirect costs avoided with VWF with a low FVIII content per patient per year ranged from €2,295 to €17,530 and from €1,867 to €4,978, respectively.
VWF with a low FVIII content seems to be a cost-effective treatment option for patients with severe VWD. Although the drug cost per se is higher, the use of VWF with a low FVIII content is associated with decreased consumption of hospital resources and fewer lost working days due to bleedings and consequently with an improvement of the quality of life of the patients.
... Von Willebrand disease (VWD) is the most common inherited bleeding disorder, with a prevalence of approximately 1-2% according to population studies, 1 but clinically relevant cases have a 10-fold lower prevalence. 2 The disorder is mainly transmitted in an autosomal dominant manner and is caused by the deficiency or abnormality of VWF, which is required for platelet adhesion to subendothelium to occur and serves as carrier of FVIII, protecting it from early inactivation by the activated protein C (APC) system. 3 The recommended nomenclature for the two proteins and their activities is reported in Table 1. ...
Von Willebrand disease is a common autosomal inherited bleeding disorder caused by quantitative or qualitative defects of von Willebrand factor, a multi-adhesive protein that binds platelets to exposed subendothelium and carries factor VIII in circulation. As a result of von Willebrand factor deficiency or abnormality, levels of factor VIII, the protein deficient in hemophilia A, may be variably reduced. Clinical manifestations are mainly represented by mucous membrane and of soft tissue bleeding. Their severity is variable depending on the degree of von Willebrand factor and factor VIII reduction. While a clear-cut diagnosis is easy in severe von Willebrand factor reductions, the advantage of pursuing a definite diagnosis in mild or dubious cases should be weighed against the risk of over-medicalization. The aim of treatment is to correct the dual defect of hemostasis caused by the abnormal/ reduced von Willebrand factor and the concomitant deficiency of factor VIII. Desmopressin is the treatment of choice for type 1 von Willebrand disease patients with factor VIII and von Willebrand factor levels of 10 U/dL or over who have proved responsive to a test-infusion with the compound. Von Willebrand factor/factor VIII concentrates are needed when desmopressin is ineffective (mainly type 2 and 3 von Willebrand disease).
... 8 A more reliable diagnostic pathway for type 1 VWD is required to prevent false positive diagnoses, which may lead to stigmatization and unnecessary treatment with potentially dangerous plasma-derived factor concentrates, and to prevent false negative diagnoses with the risk of unnecessary bleeding complications. 9 To systematically study the value of clinical, phenotypic, and molecular markers for the diagnosis of type 1 VWD, a multicenter European study was initiated entitled Molecular and Clinical Markers for the Diagnosis and Management of Type 1 von Willebrand Disease (MCMDM-1VWD). 10 Previous reports from this study have focused on bleeding symptoms in type 1 VWD 11 and on linkage with the VWF gene. ...
... Well-controlled epidemiological criteria considering the combination of bleeding symptoms and reduced VWF values in more than one family member could produce a diagnosis of VWD in up to 1% of a screened population of school children [7]. As a matter of fact, only one of the 10 patients identified in this investigation has sought medical assistance for bleeding during the past 15 years, indicating that diagnosing very mild cases may not be helpful [8]. Clearly, we need different criteria in order to make clinically meaningful diagnoses. ...
... The enthusiasm for our findings prompted us to include VWF measurement in the first-level screening of all subjects referred for hemostasis evaluation. However, we had to temper our enthusiasm on the basis of a later reinvestigation of the cases previously labeled as affected and of their families [7]. Of the original 14 subjects, 11 were available, and VWD was reconfirmed in 10 with a reference range that is now established for adults. ...
It is a physicians' privileged activity to meet people presenting with different clusters of symptoms and signs in order to offer them medical assistance. Thanks to an increasing knowledge and with the aid of phenotypic and molecular analysis, they have become able to classify patient's illnesses into distinct diagnostic categories that correspond to specific diseases which pathophysiology could be more or less known, such as, in our case, type 1 von Willebrand disease (VWD). However, once a definite diagnosis has been made, at least two additional critical requirements should be met. This article is protected by copyright. All rights reserved.
... Linkage analysis was performed in both the EU [16] and Canadian [17] studies. Previous studies have suggested variable linkage within type 1 families [18,19]. The EU study concluded that in the complete cohort, type 1 VWD co-segregated completely with the VWF gene in about 70% of families. ...
Since its first description in 1926, the precise nature and indeed significance of von Willebrand factor (VWD) in the area of human bleeding has been unsure and often controversial. The recognition of VWD as a distinct entity in blood and the cloning of the von Willebrand factor (VWF) gene in the 1980s encouraged both phenotypic and genotypic studies, culminating in 1994 with the recognition, by the VWF subcommittee of the Scientific and Standardization Committee (SSC) of International Society of Thrombosis and Haemostasy (ISTH), of three types of VWD, characterized by severe plasma VWF deficiency (type 3), functionally deficient plasma VWF (type 2) and reduced (below normal) levels of plasma VWF, which is functionally essentially normal (type 1; 70% of all cases). Since then, whereas gene analysis has recognized VWF gene (VWF) mutations in most individuals with type 3 and type 2 disease, the latter mutations correlating well with recognized functional domains within the VWF protein, few mutations have been reported in cases with type 1 VWD. This led to speculation that other factors, particularly ABO blood group, may be primarily responsible for the majority of such patients, perhaps combined with a generic bleeding tendency throughout the normal population. Recent large studies in Europe and Canada have considerably clarified this situation, revealing that the majority of type 1 VWD is associated with mutations within VWF. The role of these mutations in the aetiology of the disease opens up new approaches to the study of the diagnosis and treatment of the condition. Conversely, the lack of a change in the VWF gene in many recruited families will lead to enhanced efforts to identify non-VWF gene causes both at the genetic and epigenetic level.
... In contrast, patients with borderline low levels in the range 35-50 % may have no bleeding symptoms, and rarely have genetic mutations [20]. Diagnosis of type 1 VWD is not useful for such patients, and an assignment of ''risk of mild bleeding'' may be more appropriate [21,22]. The exact level of reduction below which a diagnosis of type 1 VWD can be made has been the subject of much debate and continues to be a problem [22,23]. ...
Von Willebrand disease is the most common autosomal inherited bleeding disorder. It is caused by quantitative or qualitative defects of the von Willebrand factor. The International Society of Thrombosis and Hemostasis recognizes three types of Von Willebrand disease, with four qualitative subtypes, i.e. six different groups in total. All variants present with mucocutaneous bleeding of variable severity depending on the penetrance of the disease, the level of von Willebrand factor (VWF), and the specific abnormality of the defect, resulting in altered VWF interactions between either platelets and collagen or factor VIII. Diagnosis is difficult because the clinical and laboratory phenotypes are very heterogeneous and may overlap for normal subjects. The molecular pathology of the condition corresponds to the specific variants but has a wide range of genetic mechanisms. Accurate diagnosis of the disorder is of critical importance to establish appropriate treatment options for individual patients. This review covers the pathophysiology and genetics of the condition, the diagnostic classification, testing, and the available treatments, specifically highlighting the population.
... Von Willebrand disease (VWD) is the most common inherited bleeding disorder, with a prevalence of approximately 1-2% according to population studies, 1 but clinically relevant cases have a 10-fold lower prevalence. 2 The disorder is mainly transmitted in an autosomal dominant manner and is caused by the deficiency or abnormality of VWF, which is required for platelet adhesion to subendothelium to occur and serves as carrier of FVIII, protecting it from early inactivation by the activated protein C (APC) system. 3 The recommended nomenclature for the two proteins and their activities is reported in Table 1. ...
... Through different laboratory criteria it is possible to identify three primary types of the disease [5]. Alterations on the plasma levels of VWF are associated with VWD types 1 and 3, whereas structural and functional defects of VWF result in VWD type 2 [3,[6][7][8][9][10][11]. VWD types 1 and 3 reflect, respectively, partial and complete deficiency of the VWF. ...
Von Willebrand disease (VWD) is an inherited hemorrhagic disorder promoted by either quantitative or qualitative defects of the von Willebrand factor (VWF). The disease represents the most common human coagulopathy afflicting 1.3% of the population. Qualitative defects are subdivided into four subtypes and classified according to the molecular dysfunction of the VWF. The differential diagnosis of the VWD is a difficult task, relying on a panel of tests aimed to assess the plasma levels and function of the VWF. Here, we propose biochemical approaches for the identification of structural variants of the VWF. A bioinformatic analysis was conducted to design seven peptides among which three were representatives of specific amino acid sequences belonging to normal VWF and four encompassed sequences found in the most common VWD subtype 2B. These peptides were used to immunize mice, after which, peptide-specific immunoglobulins were purified. This resulted in four Ig preparations capable of detecting alterations in the subtype 2B VWD plus additional three antibody fractions targeting the normal VWF. The panel of antibodies could serve many applications among them (1) assessment of VWF: antigen interaction, (2) VWF multimer analysis, and (3) production of monoclonal antibodies against VWF for therapeutic purposes as in thrombotic thrombocytopenic purpura.
... type II and type III [now termed type 2 and 3]), which had ABO blood group frequencies that did not differ from the expected distribution, the authors concluded that the type I VWD diagnosis could be influenced by the patient's ABO status. In epidemiological studies of VWD, in which a high frequency of type 1 VWD is typically identified 68 , a relative predominance of O-blood group individuals has been reported 69,70 . ...
The antigens of the ABO system (A, B, and H determinants, respectively) consist of complex carbohydrate molecules. It has been known for nearly half a century that the ABO blood group exerts a major influence on plasma levels of the von Willebrand factor (VWF)-factor VIII (FVIII) complex and that normal group O individuals have significantly lower levels of VWF and FVIII than do non-O individuals. As a consequence, several investigators have studied the association between ABO blood group and the risk of developing bleeding or thrombotic events. A number of epidemiological studies have also analyzed the biologic relevance of this interaction by assessing whether the ABO blood group could influence human longevity through the regulation of VWF-FVIII plasma levels. In this review, the molecular mechanisms by which the ABO blood group determines plasma VWF and consequently, FVIII levels, the possible clinical implications, and the current knowledge on the association between the ABO blood group and the risk of developing certain cancers will be reviewed.
... In many cases, therefore, the condition may be considered to be a complex multi-factorial disorder, with inter-relating genetic and environmental components. Up to 50% of cases diagnosed to have type 1 VWD may not have an identifiable mutation within the essential regions of VWF and the phenotype is not always linked to the gene [39,40,41,42,43,44]. At the present time there is limited diagnostic utility for genetic analysis in type 1 VWD, either by direct mutation detection or linkage studies. ...
von Willebrand disease (VWD) is a common autosomally inherited bleeding disorder associated with mucosal or trauma-related bleeding in affected individuals. VWD results from a quantitative or qualitative deficiency of von Willebrand factor (VWF), a glycoprotein that is essential for primary haemostasis and that carries and protects coagulation factor VIII (FVIII) in the circulation. Through characterization of the phenotype and identification of mutations in the VWF gene in patients with VWD, understanding of the genetics and biochemistry of VWF and VWD has advanced considerably. The importance of specific regions of VWF for its interaction with other components of the vasculature has been revealed, and this has facilitated the formal classification of VWD into three subtypes based upon quantitative (types 1 and 3) and qualitative (type 2) deficiency of VWF. The underlying genetic lesions and associated molecular pathology have been identified in many cases of the qualitative type 2 VWD variants (2A, 2B, 2M, 2N) and in the severe quantitative deficiency, type 3 VWD. However in the partial quantitative deficiency, type 1 VWD, the picture is less clear: there is a variable relationship between plasma levels of VWF and bleeding, there is incomplete penetrance and variable expressivity within affected families, the causative molecular defect is unknown in a substantial number of cases, and even in those cases where the causative mutation is known, the associated molecular pathology is not necessarily understood. This guideline aims to provide a framework for best laboratory practice for the genetic diagnosis of VWD, based upon current knowledge and understanding.
Introduction:
Rare Bleeding Disorders have a low population prevalence and may not be recognized by most clinicians. In addition, knowledge gaps of the indicated laboratory tests and their availability add to the potential for delayed diagnosis or misdiagnosis. The lack of widely available commercial, regulatory body approved esoteric tests limit them to reference laboratories, thus limiting easy access for patients.
Areas covered:
A literature search of Pubmed, Medline, Embase and review of international society guidelines was performed. Additional references from published articles were reviewed. A patient-centered approach to recognition and evaluation of RBD is discussed.
Expert opinion:
Recognition of RBD relies on obtaining a detailed patient personal and family hemostatic history. Inquiry into a history of involvement of other organ systems is important and if present should lead to suspicion of an inherited platelet disorder or a variant of Ehlers Danlos Syndrome. Multiple factors contribute to the complexity of development of efficient algorithms for diagnostic testing. Limitations in diagnostic sensitivity and specificity of screening tests, diagnostic tests, and esoteric tests further compound the complexity of establishing a diagnosis. Educational efforts focusing on clinician awareness of RBDs and available testing options are vital for optimal management of such patients.
Von Willebrand disease (VWD) is the most common inherited bleeding disorder. It is defined by a deficiency or dysfunction of plasma von Willebrand factor (VWF), a glycoprotein with a multifaceted role in haemostasis. The majority of circulating VWF is synthesised and released by endothelial cells (ECs). VWD is caused by rare DNA sequence variants in the VWF gene. However, coupling genotype with phenotype is complicated by factors including incomplete penetrance and the trans-acting effect of the ABO histo-group. High throughput sequencing (HTS) is becoming the standard of care for the diagnosis of inherited bleeding disorders, including VWD. This raises several challenges. First, how should candidate VWF variants be searched for and their pathogenicity assessed? Second, if a pathogenic variant (PV) for VWD is identified how does this influence bleeding risk? Third, if the mechanism of the identified PV is unknown, how can its effect be elucidated? These questions are sequentially addressed in this thesis. I curated 1,455 unique VWF variants into a single repository called VWDbase. Variants were only included if they had been previously linked to VWD. Two thirds of VWDbase variants had previously been deemed causal of VWD and were termed Putatively Aetiological VWD Variants (PAVVs). Of these, 194 PAVVs were identified in the whole exome sequencing data of 140,327 participants in UK Biobank (UKB). These data were used to accurately determine the minor allele frequency (MAF) of these PAVVs. The pathogenicity of each PAVV was then scrutinised using published data. Seventy three of 194 PAVVs were rejected as being pathogenic for VWD. In over half of cases this was because the PAVV occurred too frequently to be compatible with VWD prevalence. The PAVVs that were accepted as being pathogenic for VWD were identified in 401 UKB participants (the ‘genetically accepted VWD’ [ga] group). Hospital inpatient data were analysed for UKB participants from 1997 to 2020. These were used to create the ICD-bleeding assessment tool (ICD-BAT) to assess the presence or absence of bleeding episodes across 16 different domains and the time over which UKB participants lived without experiencing an episode (bleeding free survival). There was no difference in the ICD-BAT score or bleeding-free survival when the gaVWD group was compared to the rest of the UKB population. However, blood group O predicted for both an increased ICD-BAT score and a reduced risk of bleeding-free survival over the observation period. VWDbase was then utilised to analyse 10 patients with VWD in whom no molecular diagnosis had previously been identified. The patient with the most severe (type 3) VWD phenotype was homozygous for a rare PAVV, c.8155+6T>A, situated in the donor splice site of the penultimate exon-intron junction. Analysis of platelet mRNA demonstrated that c.8155+6T>A results in a transcript with a frameshift and premature termination codon (PTC). Evaluation of patient-derived endothelial colony forming cells (ECFCs) revealed that c.8155+6T>A resulted in VWF that was mostly retained in a perinuclear position as opposed to being packed into Weibel-Palade bodies (WPBs). In order to overcome the finite supply of ECFCs and assess the effect of c.8155+6T>A in a different genetic context, a new cellular model of VWD was created. Human induced pluripotent stem cells (hiPSCs) were edited using CRISPR/Cas9 to contain a PTC in exon 50, positioned 10 nucleotides 5’ of c.8155+6T>A. They were then differentiated to ECs and the findings in the patient ECFCs were replicated. The effect of c.8155+6T>A is likely to be due to the truncation of VWF prior to the C-terminal cysteine knot (CK), the domain which is crucial for VWF dimerisation and exit from the endoplasmic reticulum. In summary, this thesis highlights the utility of large reference populations and hiPSC-derived ECs (iECs) in the critical appraisal of PAVVs.
Introduction
In the network of U.S. comprehensive haemophilia treatment centres (HTCs), von Willebrand disease (VWD) is the most common bleeding disorder other than haemophilia. Estimates of the size and characteristics of the VWD population receiving treatment are useful for healthcare planning.
Aim
Estimate the prevalence and incidence of VWD among males and females receiving care at U.S. HTCs (HTC‐treated prevalence and incidence).
Methods
During the period 2012–2019, de‐identified surveillance data were collected on all VWD patients who visited an HTC including year of birth, sex, race, Hispanic ethnicity, VWD type, and laboratory findings and used to calculate period HTC‐treated prevalence by VWD type and sex. Data from patients born 1995–1999 were used to estimate HTC‐treated incidence rates.
Results
During the period, 24,238 patients with a diagnosis of VWD attended HTCs; for 23,479 (96.9%), VWD type was reported or could be assigned. Age‐adjusted HTC‐treated prevalence was 8.6 cases/100,000 (7.2/100,000 for Type 1, 1.2/100,000 for Type 2 and 1.7/million for Type 3) and was twice as high in women as men (4.8 vs. 2.4 cases/100,000) for Type 1 and similar by sex for Type 2 and Type 3. HTC‐treated Type 1 incidence increased over the period, averaging nearly threefold higher for women than men (26.2 vs. 9.9/100,000 live births). Sex differences were less for Type 2 (2.2 vs. 1.4 cases/100,000 births) and slight in Type 3.
Conclusion
Prevalence and incidence of HTC‐treated VWD differ by sex and type and are likely strongly influenced by differences in rates of diagnosis.
The deficiency or abnormal activity of von Willebrand factor, a multi-adhesive protein which binds platelets to exposed subendothelium and carries factor VIII in circulation, is responsible for von Willebrand disease, the most frequent inherited bleeding disorder. Clinical symptoms are characterized by mucous membrane and soft tissue bleeding, bleeding after surgery and rarely joint and gastrointestinal bleeding. Intriguingly, also factor VIII, the protein deficient in hemophilia A, may be variably reduced because VWF stabilizes it into circulation. Treatment strategies are well designed for patients with levels of VWF activity <30 U/dL, while the diagnosis and the magnitude of risk may be difficult to be assessed accurately for subjects with levels between 30 and 50 U/dL. Three types of the disorder have been identified according to partial (type 1) or severe VWF quantitative deficiency (type 3) while patients who present variable abnormality of VWF structure are categorized as type 2. The aim of treatment is to correct either the abnormal/reduced von Willebrand factor and the associated deficiency of factor VIII, when present. Desmopressin is able to transiently correct the deficiency of FVIII and VWF for up to 8–12 h in a significant proportion of patients with type 1 von Willebrand disease and factor VIII and von Willebrand factor levels ≥10 U/dL. When desmopressin is not usual (mainly in patients with type 2 and 3 VWD) or correction is required cannot be used for an extended time (e.g., major surgery), von Willebrand factor-containing concentrates, with or without FVIII, must be used.
Over the last several decades, the increasing focus on women with inherited bleeding disorders (WBD) has brought more patients into Haemophilia Treatment Centres (HTC) around the world. These women present with unique challenges including a significant risk of heavy menstrual bleeding (HMB). The influx of a new patient group has necessitated expansion of the services provided by the multi‐disciplinary team in HTCs. Nurses already play a central role in patient and family education within the HTC. As such, they are well positioned to participate in the development of adaptations within the HTC infrastructure to provide clinical care and education specifically for WBD. The nursing experts in HTCs should play an active role in outreach as well as providing education to WBD. Despite this supposition, review of the growing body of literature surrounding the topic of WBD is notable for a paucity of literature highlighting the role of the HTC nurse and potential impact on this, relatively new, but steadily increasing, patient population.
Partial quantitative deficiency of plasma von Willebrand factor (VWF) is responsible for the majority of cases of von Willebrand disease (VWD), the most common inherited human bleeding disorder. International consensus guidelines recommend that patients with reduced plasma VWF antigen (VWF:Ag) levels and bleeding phenotypes be considered in 2 distinct subsets. First, patients with marked reductions in plasma VWF levels (<30 IU/dL) usually have significant bleeding phenotypes and should be classified with "type 1 VWD." In contrast, patients with intermediate reduced plasma VWF levels (in the range of 30-50 IU/dL) should be considered in a separate category labeled "low VWF levels." These patients with low VWF commonly display variable bleeding phenotypes and often do not have VWF gene sequence variations. Because the pathophysiology underlying low VWF levels remains largely undefined, diagnosis and management of these patients continue to pose significant difficulties. In this article, we present a number of clinical case studies to highlight these common clinical challenges. In addition, we detail our approach to establishing a diagnosis in low VWF patients and discuss strategies for the management of these patients in the context of elective surgery and pregnancy.
Epidemiologic studies carried out in the 1980s have demonstrated that the prevalence of von Willebrand disease (VWD) is around 1%. This figure has been obtained by using conservative clinical and laboratory criteria. However, many of these individuals will experience only minor or trivial bleedings during their lifetime and most of them will probably never be referred for medical assistance. Reasonably, the prevalence of cases referred to specialized centers for the treatment of bleeding can be estimated to be around one case for every 10,000 individuals, which is similar to the cumulative prevalence of hemophilia A and B. Severe VWD is a rare disorder with a prevalence around one case for 1 million individuals, depending on the ethnic background. Even though about 1% of the normal population could satisfy quite conservative epidemiologic criteria sufficient to diagnose VWD in ad hoc cross-sectional investigations, a diagnosis of VWD in clinical practice should be pursued through standardized clinical tools (e.g., bleeding score), when a clear benefit for the patient and his or her family will derive in terms of prophylaxis and treatment.
Von Willebrand disease (VWD) is a common autosomal inherited bleeding disorder caused by quantitative or qualitative defects of von Willebrand factor (VWF), a multiadhesive protein which binds platelets to exposed subendothelium and carries factor VIII (FVIII) in circulation. Clinical manifestations are mainly represented by mucous membrane and soft tissue bleeding and their severity and frequency usually correlate with the degree of VWF and FVIII reduction. The diagnosis requires an array of tests, but in mild cases the advantage of pursuing a definite diagnosis is not always straightforward. The correction of the dual defect of hemostasis (abnormal/ reduced VWF and the concomitant deficiency of FVIII) is required for an appropriate treatment. Desmopressin is the treatment of choice for type 1 VWD patients with FVIIII and VWF levels ≥ 10 U/dL responsive to a test infusion with the compound. VWF/FVIII concentrates are needed when desmopressin is ineffective (mainly type 2 and 3 VWD).
Giancarlo Castaman, Silvia Linari Department of Oncology, Center for Bleeding Disorders, Careggi University Hospital, Florence, ItalyAbstract: Several plasma-derived intermediate and high-purity concentrates containing von Willebrand factor (VWF) and factor VIII (FVIII) are currently available. The main role of these products in the management of pediatric the population is represented by the replacement therapy in patients with severe or intermediate forms of von Willebrand disease, in whom other treatments are ineffective or contraindicated. Another important role of VWF/FVIII concentrates in children may be their use in immune tolerance induction (ITI) protocols. ITI is particularly recommended for hemophilia A children who have developed an inhibitor against FVIII, currently the most serious complication of substitutive treatment in hemophilia. Although recombinant concentrates may represent the preferred option in children with hemophilia A, VWF/FVIII concentrates may offer an advantage in rescuing patients who failed previous ITI.Keywords: von Willebrand factor, factor VIII, plasma-derived concentrates, children, von Willebrand disease, hemophilia A
von Willebrand disease (VWD) is caused by quantitative or qualitative defects of von Willebrand factor (VWF), associated with mucocutaneous bleeding symptoms. VWD is classified into three major groups and four subcategories. The classification is intended to be simple, to rely on widely available laboratory tests, and to correlate with important clinical characteristics. It is meant to facilitate the diagnosis, treatment, and counseling of patients with VWD. The International Society on Thrombosis and Haemostasis/Scientific and Standardization Committee (ISTH/SSC) reviewed the classification and published update information on the diagnosis and treatment of VWD in 2006 based on the most recent pathophysiology data for VWF. Notably, Vicenza type has been classified into type 1 from type 2M. In epidemiology, there may be small differences of frequency in VWD subcategories (type 2) between Europe and lapan. For treatment, factor VIII/VWF concentrate is commonly employed in Japan, although DDAVP has been the first choice for VWD in Europe.
Key Points
A novel ELISA-based VWF multiplex activity assay assigns VWD phenotype among a cohort of type 1 and 2 VWD with an overall accuracy of >88%. This assay shows correlation with traditional quantitative clinical VWF assays and may provide a rapid diagnostic method for variant VWD.
Type 1 von Willebrand disease (VWD) is the most common form of this highly prevalent inherited bleeding disease. The condition represents a partial quantitative deficiency of von Willebrand factor (VWF), in which the protein has normal function and shows only subtle structural abnormalities. The clinical manifestations of type 1 VWD are extremely variable. At one extreme, women with a moderately severe VWF deficiency state (plasma VWF levels < 0.25 IU/dL) may experience significant menorrhagia, while in contrast, men with a mild deficiency state may remain asymptomatic throughout life. The key element to the laboratory diagnosis of type 1 VWD is the demonstration of reduced plasma levels of VWF. The VWF antigen and ristocetin cofactor levels (as a measure of VWF function) will usually be reduced proportionately between 0.05 and 0.50 IU/dL, and the factor VIII (FVIII) coagulant level will also often be low. Preliminary genetic analysis of type 1 VWD indicates that the disease is the consequence of many different mutations both within the VWF gene and at other genetic loci.
GeneticsProteomicsPhysiologyClassification of von Willebrand diseaseClinical manifestationsLaboratory diagnosis of von Willebrand diseaseManagement of patients with von Willebrand diseaseConclusions
Further reading
Ascertainment and validity of epidemiologic data on von Willebrand diseasePrevalence of severe VWD (group A VWD)Prevalence of intermediate VWD (group B VWD)Prevalence of mild VWDFrequency of VWD subtypesPrevalence of VWD in developing countriesPractical implicationsAcknowledgment
von Willebrand disease (VWD), which is the most common inherited bleeding disorder, arises from deficiencies and/or defects in the plasma protein von Willebrand factor (VWF). VWD is classified into six types, with type 1 identifying a (partial) quantitative deficiency of VWF, type 3 defining a (virtual) total deficiency of VWF, and type 2 identifying four types (2A, 2B, 2M, and 2N) that are characterized by qualitative defects. The classification of VWD is based on phenotypic testing that includes factor VIII, VWF level, and VWF activity determined by ristocetin cofactor and/or collagen binding. Phenotypic testing may be supplemented by multimer analysis, ristocetin-induced platelet agglutination, and VWF:factor VIII binding. Although not required to diagnose VWD or for its classification, genetic analysis may be useful in discrete situations. The current review briefly covers this diagnostic process, with a focus on the newer approaches that include extended test panels and data from desmopressin challenges as a diagnostic tool.
Patients with known coagulation deficiencies, either congenital or acquired, may bleed spontaneously with trauma or with surgical intervention. In contrast, however, are the unchallenged patients who bleed in a variety of clinical settings that demand rapid diagnosis so that appropriate therapy can be instituted.
In the first section Dr. Louis M. Aledort demonstrates a series of vignettes of actual cases who presented with unexpected bleeding or a screening laboratory abnormality prior to a needed surgical intervention. Settings include dental, oral surgical, obstetrical, surgical and gynecological. The differential diagnoses of these cases are discussed.
In the second section Dr. David Green also uses vignettes to demonstrate how the laboratory is used to differentiate the various clinical entities. The choice and priority of required tests indicated by the settings, history, site and type of bleeding, and the syllogisms used to define the abnormality are stressed.
In the third section, Dr. Jerome Teitel reviews in detail the therapeutic armamentarium available to the clinician and presents algorithms for the management of these bleeding disorders.
Objective
To study the prevalence of hemostatic abnormalities, including bleeding disorders and risk factors, in young females referred to a multidisciplinary clinic for evaluation of heavy menstrual bleeding (HMB).
Methods
Retrospective chart review was undertaken for 131 post-menarchal girls with HMB, 7 to 17 years of age, enrolled in the institutional ‘Menorrhagia Data Registry’ protocol. The diagnostic approach included: (1) complete blood count, prothrombin time, partial thromboplastin time, fibrinogen, von Willebrand panel (2) platelet aggregometry, specific clotting factor assay, fibrinolytic pathway analysis, and factor XIII level as needed. The prevalence of hemostatic abnormalities and the prognostic significance of clinical variables associated with hemostatic abnormalities in young girls with HMB were evaluated.
Results
A hemostatic abnormality was identified in 69 (53%) young girls with HMB. Of these, 27 (21%) had an underlying bleeding disorder and 42 (32%) had a risk factor for bleeding, namely low von Willebrand factor activity. A larger number of girls with underlying bleeding disorder had personal history of other bleeding symptoms (48% vs 31%) and bleeding after surgical or dental procedure (25% vs 8%) when compared to females without hemostatic abnormality. Furthermore, girls with risk factor for bleeding (low vWF activity) were more likely to have bleeding after surgical or dental procedure (15% vs 8%) and family history of bleeding (79% vs 60%) than patients without hemostatic abnormality.
Conclusions
There is high prevalence of hemostatic abnormalities, including bleeding disorders and risk factors, in young girls with HMB. These findings support comprehensive and systematic hemostatic evaluation in this group of patients.
Inherited bleeding disorders pose a particular challenge for pregnancy and the puerperium, due to both the inheritance risk to the fetus and the bleeding risk to the mother. Women at risk require counselling to address the following questions 1 Will I bleed?
2 What treatment do I need?
3 Can I pass it on to my children?
In 1926, Dr Erik von Willebrand first described the autosomal bleeding disorder that we now call von Willebrand disease (VWD). Since then, the protein responsible – eponomously named von Willebrand factor (VWF) – has been identified, the gene encoding the protein has been localized , the gene sequence has been determined and many mutations within the gene that lead to a deficiency or dysfunction of VWF and cause VWD have been characterized. Through the concerted efforts of scientists and clinicians, there is now considerable understanding of the molecular genetics of VWD and, through studies done both in vitro and in vivo , the mechanism of disease has been revealed for many of the characterized gene defects. Despite the complexities of both the VWF protein and its gene, we have a detailed picture of the molecular genetics of VWD. This review aims to provide an informative summary of current knowledge.
Key concepts
von Willebrand factor (VWF) is a polymeric (multimeric) blood protein that is essential for the initial stages of blood clot formation.
VWF has several biological activities that are important for its role in haemostasis, including binding to platelet glycoprotein Ib, coagulation factor VIII, collagen.
VWF has a complex biochemistry that is influenced by independent modifiers such as ABO blood group and the metalloprotease ADAMTS13.
von Willebrand disease (VWD) is classified into three types according to the quantity and functional activity of VWF: type 1, type 2 and type 3. Type 2 VWD is further subdivided according the functional defect present: type 2A, 2B, 2M and 2N.
The genetic basis for VWD is highly heterogeneous; the disease shows dominant inheritance for some mutations and recessive inheritance for others.
Mutations that cause milder forms of the disease show variable penetrance and this, in part relates to other modifying factors such as ABO blood group and possibly ADAMTS13.
The relationship between cause and effect is understood for some mutations but not for all.
von Willebrand disease (VWD) is the most common inherited bleeding disorder and is due to a deficiency and/or abnormality of von Willebrand factor (VWF), the high-molecular-weight glycoprotein that plays a major role in the early phases of hemostasis. VWD is inherited by autosomal dominant or recessive pattern, but women with milder VWD forms are apparently more symptomatic. VWD is also very heterogeneous disorder and therefore patients with mild VWD forms are sometimes under- and misdiagnosed, due to physiologic changes of VWF within the same individual and to the relative high variability of diagnostic tests. Three main criteria are required for correct diagnoses of VWD: (1) positive bleeding history since childhood; (2) reduced VWF activity in plasma; and (3) history of bleeding in the family. The bleeding score (BS) calculated following a detailed questionnaire devised to quantify symptoms was useful to confirm the diagnosis of VWD1. BS together with baseline VWF levels and family history have been proposed as more evidence-based criteria for VWD1. More recently, the use of BS and threshold levels of VWF activity have been investigated in a prospective study to predict clinical outcome and the need of therapy with desmopressin and/or VWF concentrates in a large cohort of patients with different VWD types.
von Willebrand disease is a highly heterogeneous inherited bleeding disorder producing a wide spectrum of clinical and laboratory phenotypes. This peculiarity sometimes affects the possibility of a clear-cut diagnosis in several mild cases and thus of a reliable estimate of its true prevalence in the general population. While for most severe cases, the prevalence could approach that of hemophilia A, mild cases could range from 1/1000 to 1/10 000 inhabitants. Clinically, the accurate evaluation of the bleeding history represents the cornerstone on which to discriminate subjects requiring diagnosis and appropriate treatment from those having minimal bleeding symptoms not influencing their quality of life.
von Willebrand disease (VWD) is the most frequent inherited bleeding disorder and is caused by quantitative (Types 1 and 3) or qualitative (Type 2) defects of von Willebrand factor (VWF). VWD is inherited by autosomal dominant or recessive pattern, but women with milder VWD forms seem to be more symptomatic than men. Mild VWD forms are both under- and misdiagnosed. The clinical expression of VWD is usually mild in Type 1, increasing in severity in Types 2 and 3. Mucocutaneous bleeding (epistaxis, menorrhagia) is a typical manifestation of the disease, and bleeding after dental extraction is the most frequent postoperative bleeding type. Because FVIII levels are usually only slightly reduced in most VWD types, spontaneous haemarthroses or haematomas are rare in VWD Types 1, 2A and 2B, whereas in Type 3 the severity of bleeding may resemble haemophilia. In Type 1 VWD, bleeding after delivery is rare because FVIII/VWF levels become normal at the end of pregnancy. Post-operative bleeding may not occur in Type 1 VWD patients, but in Type 3 VWD, prophylaxis is always required. Only a few retrospective studies on clinical diagnosis of VWD are available. In the 1234 cases enrolled by an Italian retrospective study, diagnosis of Types 1, 2 and 3 VWD occurred in young adults (83%), mainly in women (57%). Mucosal bleeding (64%) was more frequent than haematomas or haemarthrosis (15%), and 63% of patients did not require transfusions. In a more recent Italian prospective study (815/1234 cases observed for 1 year in 6/16 Italian centres), only 147 (18%) VWD patients showed bleeding episodes (n = 318) and minor or major surgeries (n = 87).
Von Willebrand disease (VWD) is an autosomally inherited bleeding disorder caused by a deficiency and/or abnormality of von Willebrand factor (VWF), a multimeric adhesive protein which plays an important role in primary hemostasis. VWF interacts with glycoprotein Ib on platelet surface thus promoting platelet adhesion to the subendothelium at sites of vascular injury and platelet-platelet interactions at high-shear rate conditions. Moreover, VWF is the carrier of factor VIII (FVIII), thus indirectly contributing to coagulation process. As a consequence, also FVIII is usually low in VWD. There are 3 types of VWD: most cases have a partial quantitative deficiency of VWF (Type 1 VWD) with variable bleeding tendency, while only a minority has a virtually complete reduction (Type 3), with moderate to severe bleeding tendency. Qualitative variants (type 2 VWD), due to a dysfunctional VWF, are clinically more homogeneous and account for about 20-30% of cases. The diagnosis of VWD may be difficult, especially in type 1, since the laboratory phenotype of the disorder is greatly heterogeneous and confounded by the influence on VWF levels by factors outside the VWF gene (e.g., blood group). The molecular bases of VWD are being unraveled in most cases and have provided useful information especially in those patients with partial or total gene deletion, associated with the occurrence of inhibitors and with allergic reactions upon treatement. The aim of treatment in VWD is to correct the dual defects of hemostasis (i.e. low levels of FVIII and low VWF-dependent platelet activities) Desmopressin (DDAVP) is the treatment of choice in patients with type 1 VWD because it corrects these abnormalities in the majority of cases. In type 3 and in severe forms of type 1 and 2 VWD, DDAVP is not effective and plasma virally-inactivated concentrates containing FVIII and VWF are the mainstay of treatment.
Special challenges exist in the management of patients with von Willebrand disease (VWD) because of limitations in diagnostic facilities and therapeutic options. However, even within these limitations, it is possible to establish comprehensive services for this condition. Our data show that among 202 patients with VWD, 107 were type 3, 62 were type 1, and the others different categories of type 2. Basic tests such as bleeding time and activated partial thromboplastin time with factor (F)VIII coagulant are able to diagnose most of those with severe disease. We have been able to adapt the specific tests such as von Willebrand factor (VWF) ristocetin cofactor and VWF antigen from the tedious batched manual methods to cost-effective automated methods on advanced coagulometers. Discriminatory tests such as VWF collagen binding, VWF:FVIIIB, ristocetin-induced platelet agglutination (RIPA) are done in batches. Therapeutic options and for the treatment of bleeding include desmopressin, cryoprecipitate, and intermediate purity VWF-containing clotting factor concentrates. Tranexamic acid is also widely used as well as hormonal therapy for menorrhagia. We have also shown that modest doses of intermediate purity FVIII (Koate DVI; Talecris Biotherapeutics, Raleigh, NC, USA) at 35 IU/kg preoperatively and 10 to 20 IU/kg after that are sufficient for surgical hemostasis in these patients.
Von Willebrand disease (VWD) is the most common bleeding disorder; it is believed to occur in approximately 1% to 2% of the population. Mucocutaneous and surgical hemorrhage in affected individuals is caused by quantitative and qualitative defects in von Willebrand factor (VWF), a large, multimeric protein that supports platelet adhesion and aggregation in the initiation of hemostasis at the time of vascular injury and functions as a carrier protein for factor VIII in the circulation. Advances in cellular and molecular biology have led to improved understanding of the pathophysiology of the disorder and development of a classification scheme that is based on quantitative and qualitative defects. Effective treatment is dependent on an accurate diagnosis using specific assays of VWF that define the various defects.
We describe a patient with a lifelong bleeding disorder previously classified as von Willebrand's disease (vWD) type I. The factor VIII (FVIII) level in this patient was disproportionately low and we showed that this was due to a decreased factor VIII binding capacity of her vWF. To characterize the molecular defect in this type of vWD, a cDNA-dependent polymerase chain reaction (PCR) amplification was performed using platelet RNA as a template. Direct sequencing of the amplified fragment, which encodes for the FVIII-binding domain, showed a single nucleotide change in exon 20 at codon 854, resulting in the substitution of CAG glutamine (Gln) for CGG arginine (Arg). At the level of the cDNA only the mutated sequence was found, whereas at genomic DNA level the patient was heterozygous for this mutation. This patient is therefore a compound heterozygote for a point mutation resulting in a FVIII-binding defect and a vWF allele with low transcript levels.
We have previously identified a microsatellite variable number tandem repeat region of the nucleotide sequence ATCT within intron 40 of the von Willebrand factor (vWF) gene. By polymerase chain reaction (PCR) amplification of this region, eight major alleles have been demonstrated in the South Wales population, with an overall heterozygosity rate of 75%. Direct sequencing has shown that the alleles correspond to lengths of between six and 14 ATCT repeats. In the present study we describe the use of this variable repeat sequence and previously reported restriction fragment length polymorphisms (RFLP) to study inheritance patterns in families with type I, IIA and severe type III von Willebrand's disease (vWD). The results confirm that analysis of this precisely localized intragenic locus provides a highly informative marker for gene tracking studies in the major forms of vWD.
Recently, in an epidemiological investigation involving 1,218 children aged 11-14, we demonstrated that the prevalence of von Willebrand’s disease, based on a low ristocetin cofactor activity (RiCof) in children with a personal and/or family history of hemorrhage, was at least 1% (Blood 1987; 69: 454). All the diagnosed cases had multimeric patterns typical of type I von Willebrand’s disease (vWd). Since standardization of RiCof is difficult and the test is not easily performed in a clinical laboratory, we measured von Willebrand factor antigen (vWf: Ag) in all available unthawed plasma samples of previously investigated children by ELISA, to assess the relative sensitivity of this more simple test for diagnosing vWd.
Separate normal ranges were calculated by non-parametric methods for 0 and non-0 subjects, and for children and adults, since values were higher in non-0 subjects and in children.
Taking into account the 90% confidence interval around the lower limit of the normal range, 7 (50%) of the 14 cases diagnosed by RiCof were detected by vWf: Ag. Furthermore, two new cases would have been diagnosed by vWf: Ag, leading to a relative Ag/ RiCof global sensitivity of 64%. A similar figure was obtained when the two tests were compared in the group of relatives of the affected children.
In conclusion, measurement of vWf: Ag seems to be definitely less sensitive than the RiCof assay for detecting patients with vWd, even in type I patients, and RiCof remains the test of choice for screening for vWd in hemorrhagic patients.
Blood samples were drawn from 129 randomly selected young adults. Intake of acetylsalicylic acid (ASA), contraceptive drugs, smoking habits and health state were registered. Males had significantly higher systolic blood pressure, shorter bleeding time and lower VIII:C. Smoking was only correlated to some variables assessed in the female group. Users of oral contraceptives smoked more, had a shorter bleeding time and higher fibrinogen levels. Factor VIIIR;Ag was elevated only in female smokers with blood group non-O. Non-secretors had shorter bleeding times and a tendency towards higher VIIIR:Ag.
We report the case of a family with type I von Willebrand disease (vWD), characterized by a quantitative defect in von Willebrand factor (vWF), associated with a defective binding of vWF to factor VIII (FVIII) also called the "Normandy" variant of vWD. PCR products from genomic DNA of the family members were analysed in the region coding for the binding domain of vWF to FVIII. It showed that the proposita and one of her sons were heterozygous for the Arg91Gln missense mutation, abolishing an MspI restriction enzyme site located in exon 20. The transcription of the normal and mutated alleles was tested by the amplification of cDNA after reverse transcription of platelet mRNA in this region. A total lack of expression of the normal allele was observed in the proposita, who appeared as a compound heterozygous with one allele mutated at Arg91 and a "silent" expression of the other one. The segregation of the "silent" allele was studied in the family with the exonic BstEII RFLP both at the DNA and mRNA levels. The proposita has transmitted her "silent" allele to her daughter and to another son. As this son was informative for this RFLP, the absence of expression of the allele could be demonstrated at the mRNA level, providing evidence that this defect was responsible for his type I vWD.