FIGURE 1 - uploaded by Pierre Boisseau
Content may be subject to copyright.
Distribution of von Willebrand disease (VWD) types in the global cohort (n ¼ 1167 patients) and in the index cases (n ¼ 670 cases). The proportion of each VWD type (1, 2A, 2B, 2M, 2N, and 3) is represented with blue histograms for the global cohort of 1167 patients and with red histograms for the 670 index cases (IC). These proportions are similar for both groups of patients within each VWD type. IC ¼ index cases, VWD ¼ von Willebrand disease.
Source publication
von Willebrand disease (VWD) is a genetic bleeding disease due to a defect of von Willebrand factor (VWF), a glycoprotein crucial for platelet adhesion to the subendothelium after vascular injury. VWD include quantitative defects of VWF, either partial (type 1 with VWF levels <50 IU/dL) or virtually total (type 3 with undetectable VWF levels) and a...
Contexts in source publication
Context 1
... suppl. Figure 1, http://links.lww.com/MD/A761). Patients genomic DNA was screened for sequence variations by direct sequencing of VWF gene and in some cases, by multiplex ligation-depen- dent probe amplification (MLPA). ...
Context 2
... proportions of the miscellaneous VWD types and subtypes were similar between the 670 IC and the global cohort of 1167 subjects (Figure 1). Among 670 IC, after second-level phenotypic assays and direct sequencing of VWF gene, 648 patients exhibited a genotype supporting their phenotype (1 mutation of VWF gene in 87% of cases, several mutations in 13% of cases) (Figure 2). ...
Similar publications
Force-dependent binding of platelet glycoprotein Ib (GPIb) receptors to plasma von Willebrand factor (VWF) plays a key role in hemostasis and thrombosis. Previous studies have suggested that VWF activation requires force-induced exposure of the GPIb binding site in the A1 domain that is autoinhibited by the neighboring A2 domain. However, the bioch...
Citations
... 14) and c.4943C>G (p.Pro1648Arg; patient no. 15), which locate closely to ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) cleavage site (p.Tyr1605-Met1606) found in patients with type 2A VWD, were frequently observed, 12 Four (67%) of the six patients with type 2U VWD could be reclassified as type 2A VWD (patients no. 5 and 13-15) based on type 2A VWD-specific variants or variants supportive against type 2B VWD, whereas the other two (patients no. 4 and 10) remained unclassified since data on VWF multimer analysis were lacking and the identified VWF variants could lead to pleiotropic or uncertain phenotype. 13 27 28 30-32 In total, 10 (83%) of the 12 patients with type 2 VWD had a bleeding history in the first-degree relatives. ...
Aims
Von Willebrand disease (VWD) is an inherited haemostatic disorder with a wide range of bleeding phenotypes based on von Willebrand factor (VWF) levels. Multiple assays including VWF gene analysis are employed to correctly diagnose VWD and its subtypes. However, data on VWF mutations among Southeast Asian populations are lacking. We, therefore, aimed to explore genetic variations in Thai patients with type 2 and type 3 VWD by whole exome sequencing (WES).
Methods
In this multicentre study, Thai patients with type 2 and type 3 VWD, according to the definitions and VWF levels recommended by the international guidelines, were recruited. WES was performed using DNA extracted from peripheral blood in all cases. The novel variants were verified by Sanger sequencing.
Results
Fifteen patients (73% females; median age at diagnosis 3.0 years) with type 2 (n=12) and type 3 VWD (n=3) from 14 families were enrolled. All patients harboured at least one VWF variant. Six missense (p.Arg1374Cys, p.Arg1374His, p.Arg1399Cys, p.Arg1597Trp, p.Ser1613Pro, p.Pro1648Arg) and one splice-site (c.3379+1G>A) variants in the VWF gene were formerly described. Notably, six VWF variants, including three missense (p.Met814Ile, p.Trp856Cys, p.Pro2032Leu), one deletion (c.2251delG) and two splice-site (c.7729+4A>C, c.8115+2delT) mutations were novelly identified. Compound heterozygosity contributed to type 2 and type 3 VWD phenotypes in two and one patients, respectively.
Conclusions
Type 2 and type 3 VWD in Thailand demonstrate the mutational variations among VWF exons/introns with several unique variants. The WES-based approach potentially provides helpful information to verify VWD diagnosis and facilitate genetic counselling in clinical practice.
... It has also been suggested that type 1 VWD should be diagnosed only in patients with significantly decreased VWF levels and frequent bleeding, to reduce the risk of diagnosing with an inherited hemorrhagic disease a number of healthy people. 18 Following this criterion, several large genetic studies on VWD type 1 showed that pathogenic VWF variants are often identified in patients with VWF levels <30 IU/dL, [19][20][21][22] whereas only approximately 40 to 50% of those with levels of 30 to 50 IU/dL have a pathogenic VWF variant. 8,9 Despite these comprehensive investigations of type 1 VWD, cases with low VWF received less attention. ...
Background Low von Willebrand factor (VWF) refers to subjects with plasma levels of 30 to 50 IU/dL. The mechanism of low VWF is poorly understood. We chose to determine the clinical presentation, laboratory phenotype, and underlying mechanisms of low VWF.
Material and Methods We included 250 patients characterized with low VWF. The International Society on Thrombosis and Haemostasis Bleeding Assessment Tool (ISTH-BAT) was used to assess clinical symptoms. To determine the underlying mechanisms of low VWF, we used as markers the VWF propeptide (VWFpp) assay and FVIII:C/VWF:Ag ratio for VWF synthesis and the VWFpp/VWF:Ag ratio for VWF clearance. Results were compared with those of 120 healthy controls. Cases with abnormal screening tests were further evaluated for coagulation factor levels and platelet disorders.
Results The median age of the cohort was 35 years (range 3–85), 21% were children (n = 53), 34% were adult males (n = 85), and 45% (n = 112) were adult females. According to the ISTH-BAT, abnormal bleeding was found in 35% of children, 47% of males, and 49% of females. No association was found between VWF activity levels and ISTH-BAT. Patients showed an overall decreased VWF synthesis/secretion and an enhanced VWF clearance was identified in 33% of them. In 89 patients (36%), there were other hemostasis-related defects, but there was no difference in the ISTH-BAT between the two groups.
Conclusion Our findings indicate that reduced VWF synthesis/secretion and enhanced VWF clearance are major mechanisms of low VWF levels. Patients with low VWF have significant bleeding manifestations. While other hemostasis defects occurred together with low VWF, this combination did not exacerbate clinical symptoms.
... They found that this patient had a mild reduction in VWF:Ag and a reduction in high-molecular-weight VWF, but expressed pseudo-Weibel-Palade bodies similar to wild type in appearance and localization. This deletion has also previously been reported in a patient with VWD type 1 [16] and a patient with type 2A VWD, hemophilia, and a mutation in the F8 gene [17,18]. As expected, the patients with type 1C VWD had a higher VWFpp-to-VWF:Ag ratio than the patients with type 1 VWD (P = 1.43 × 10 −8 ). ...
Background
Genetic analysis for von Willebrand disease (VWD) commonly utilizes DNA sequencing to identify variants in the von Willebrand factor (VWF) gene; however, this technique cannot always detect copy-number variants (CNVs). Additional mapping of CNVs in patients with VWD is needed.
Objectives
This study aimed to characterize CNVs in a large sample of VWF mutation-negative VWD patients.
Methods
To determine the role of CNVs in VWD, a VWF high-resolution comparative genomic hybridization array was custom-designed to avoid multiple sequence variations, repeated sequences, and the VWF pseudogene. This was performed on 204 mutation-negative subjects for whom clinical variables were also available.
Results
Among the 204 patients, 7 unique CNVs were found, with a total of 24 CNVs (12%). Of the 7 unique CNVs, 1 was novel, 1 was found in a VWF database, and 5 were previously reported. All patients with type 1C VWD and a CNV had the same exon 33 and 34 in-frame deletion. Certain clinical variables were also significantly different between those with and without CNVs.
Conclusion
The in-frame deletion in patients with type 1C VWD exactly matches the D4N module of the D4 domain, a region where mutations and deletions are known to affect clearance. We observed significantly higher VWF–to–ristocetin cofactor levels in patients with type 1C VWD and a CNV than in patients without a CNV, suggesting a relationship between CNVs and the increased clearance observed in patients with type 1C VWD. Glycoprotein IbM activity was significantly lower in patients with type 1 VWD and a CNV than in patients without a CNV, suggesting that platelet binding is more affected by CNVs than single base pair mutations. This work elucidates some of the underlying genetic mechanisms of CNVs in these patients.
... Whilst in the overall VWD patient population the frequency of quantitative defects is higher, in the severe VW disease subpopulation, qualitative defects are more prevalent. For example, in a cohort study of 1167 people from 670 families, studied in a hematology reference center in France, the corresponding prevalences were 25% Type 1, 8% Type 3, 66% Type 2 (2A: 18%, 2B: 17%, 2M: 19%, 2N: 12%), and 1% undetermined type [22]. ...
Abstract: Heavy menstrual bleeding (HMB) is a common clinical condition affecting adolescent and adult women and compromising their quality of life. Primary hemostasis disorders, affecting platelet plug formation, can be the underlying cause of HMB. They comprise a heterogeneous group of diseases with Von Willebrand disease (VWD) being the most commonly diagnosed; other disorders in this group that have been linked to HMB include (a) Glanzmann thrombasthenia, (b) Bernard-Soulier syndrome, (c) Hermansky-Pudlak syndrome, (d) immune thrombocytopenia (ITP), and (e) Ehlers-Danlos syndromes (EDS) and hypermobility spectrum disorders (HSD). Diagnosing these diseases can be challenging, as the basic laboratory investigations can be within the normal range. Thus, identification of specific clinical features and a thorough hematologic workup can be very important, providing the correct diagnosis. Proper diagnosis of the underlying disorder is important, as management may vary accordingly. Although disease-specific management guidelines exist for some of these disorders such as VWD and ITP, due to the rarity of most primary hemostasis disorders, the best approach for the management of HMB in these women remains elusive. The goal of this study was to create an informative, comprehensive review of the primary hemostasis disorders that have been linked to HMB. This study provides a summary of the basic published information regarding epidemiology, pathophysiology, clinical phenotype, diagnosis, and treatment of HMB in those diseases and serves as a reference guide for further reading.
... The multimeric analysis was normal, and it caused enhanced platelet aggregation. The bleeding score is lower in patients with this variant [16][17][18]. Additionally, the variant (c.3835G>A) was identified in one AFM in family 9 in this study. ...
... Additionally, the variant (c.3835G>A) was identified in one AFM in family 9 in this study. This missense variant causes an amino acid change from Valine to Isoleucine and has been reported in many studies in many patients with type 1, 2, and 3 VWD, although its clinical significance is still uncertain [18,19]. While the pathogenic variants found in exon 28 may explain the mutational cause of the disease in some participants, the causative disease mutation in most participants was not identified. ...
Von Willebrand factor (VWF) is a plasma glycoprotein that plays a key role in hemostasis. Mutations in this protein can result in von Willebrand disease (VWD), the most common form of bleeding disorder in humans. Patients with type 1 VWD have a quantitative plasmatic deficiency of normal structural and functional VWF. Our study aimed to investigate the phenotypic and genotypic characteristics of VWD type 1 patients in eastern Saudi Arabia, focusing on exon 28. We included patients previously diagnosed with WWD type 1 at the King Fahad teaching hospital in Al Khobar and their family members. The correlations between various phenotypic data and genotypic (exon 28) were analyzed using statistical software (SPSS) version 21. While these variants were generally considered benign with minor clinical effects, our analysis did identify two pathogenic variants that could lead to severe VWD symptoms. Specifically, we found these two pathogenic variants in three VWD patients from Saudi Arabia, providing essential insights into pathogenic VWD mutations in this population. Our study, therefore, sheds light on the prevalence of VWF variants in the eastern province of the Kingdom and highlights the need for continued research into the genetic causes of VWD in this region.
... Of the 29 variants evaluated, only 3 were reported to be associated with different VWD types (p.Arg1315Leu, p.Arg1374Cys, and p.Arg1374His). Each of these variants was mainly associated with either type 2M [20,21,22], 2A [23,24,25], or even as type 2A/2M (p.Arg1374Cys) [25]. In our center, these variants were classified as type 2M/2A [26]. ...
Background:
Several assays are now available to evaluate platelet-dependent von Willebrand factor (VWF) activity.
Objective:
To report the results obtained using 4 different assays in patients with von Willebrand disease (VWD) carrying variants mainly in the A1 domain, which is critical for VWF binding to glycoprotein Ib (GPIb) and ristocetin.
Methods:
We evaluated 4 different assays, 2 gain-of-function mutant GPIb binding (VWF:GPIbM) and 2 ristocetin cofactor (VWF:RCo) assays, in 76 patients with type 2 VWD. Patients and healthy controls were tested using VWF:GPIbM enzyme-linked immunosorbent assay (ELISA), VWF:GPIbM automated, VWF:RCo aggregometric, and VWF:RCo automated assays.
Results:
There was a good correlation (Pearson's r>0.82) and agreement (Bland-Altman plots assessment) between the 4 assays, although several outliers existed among the type 2B without high-molecular-weight multimers (HMWM). The VWF activity/VWF:antigen ratios, calculated for each assay, were used to establish the percentage of a correct diagnosis of type 2 (ratio<0.60) in these patients: VWF:RCo aggregometric, 2A(100%), 2M(78%), 2M/2A(100%), 2B(68%); VWF:RCo automated, 2A(88%), 2M(89%), 2M/2A(100%), 2B(63%); VWF:GPIbM ELISA, 2A(96%), 2M(67%), 2M/2A(67%), 2B(0%); VWF:GPIbM automated, 2A(73%), 2M(44%), 2M/2A(75%), 2B(84%). In type 2B patients with HMWM, all assays gave a ratio ≥0.60.
Conclusion:
The VWF:GPIbM-automated assay is the most effective to diagnose as type 2 the 2B variants, whereas the VWF:RCo assays are the most effective in detecting 2M and 2M/2A variants. The VWF:GPIbM ELISA greatly overestimates the activity of the type 2B patients lacking HMWM. In this study, the use of a VWF activity/VWF:antigen ratio cut-off of 0.70 halved the number of misdiagnosed patients.
... Patients with VWD were selected from the French cohort multicentric database of VWD (Centre Reference Maladie Willebrand). 19 The database and biobank of this cohort are declared to and approved by the ...
... We then analyzed plasma samples obtained from controls (n = 31) and VWD patients included in the French reference center for VWD (n = 101). 19 The cohort consisted of patients To determine the amount of intact VWF, the amount of antigen obtained using KB-VWF-D3.1 (= intact VWF) was divided by the amount of total VWF antigen, using normal pooled plasma as a calibrator. In doing so, we found that the ratio of intact VWF to total antigen for controls was 1.0 ± 0.2 ( Figure 5B). ...
Von Willebrand factor (VWF) is a multimeric protein, the size of which is regulated via ADAMTS13-mediated proteolysis within the A2-domain. We aimed to isolate nanobodies distinguishing between proteolyzed and non-proteolyzed VWF, leading to the identification of a nanobody (designated KB-VWF-D3.1) targeting the A3-domain, the epitope of which overlaps the collagen-binding site. While KB-VWF-D3.1 binds with similar efficiency to dimeric and multimeric derivatives of VWF, binding to VWF was lost upon proteolysis by ADAMTS13, suggesting that proteolysis in the A2-domain modulates exposure of its epitope in the A3-domain. We therefore used KB-VWF-D3.1 to monitor VWF degradation in plasma samples. Spiking experiments showed that a loss of 10% intact-VWF could be detected using this nanobody. By comparing plasma from volunteers to that of congenital VWD-patients, intact-VWF levels were significantly reduced for all VWD-types, and most severely in VWD-type 2A-group 2 in which mutations promote ADAMTS13-mediated proteolysis. Unexpectedly, we also observed increased proteolysis in some patients with VWD-type 1 and VWD-type 2M. A significant correlation (r=0.51, p<0.0001) between the relative amount of high molecular weight-multimers and levels of intact-VWF was observed. Reduced levels of intact-VWF were further found in plasmas from patients with severe aortic stenosis and patients receiving mechanical circulatory support. KB-VWF-D3.1 is thus a nanobody that detects changes in the exposure of its epitope within the collagen-binding site of the A3-domain. In view of its unique characteristics, it has the potential to be used as a diagnostic tool to investigate whether a loss of larger multimers is due to ADAMTS13-mediated proteolysis.
... According to the current ISTH-SSC classification, 6 A total of 191 patients were confirmed as having VWD and around half of them could be classified as type 1 VWD, type 2A (2A/IIA and 2A/IIE) as the second largest group, and with type 2B (typical), 2M-GPIb, and 2N as less frequent types. This distribution has been reported before [15][16][17]45 and is in line with our own previous reported findings. 18 In addition, 50% of type 3 patients were found within type 1 VWD families. ...
... 15 The Åland mutation (p.Pro812Argfs à 31, type1) continues to be the most frequent mutation (15%) in all VWD cases, which has also been reported in other European countries. [15][16][17] Twenty-three novel VWF gene variations were identified with 19 confirming the laboratory phenotype and multimeric pattern. MLPA identified large deletions of exon 1-3 46 in 15 VWD patients (7 type 3 and 8 type 1), where no underlying mutation had been found by direct DNA sequencing, accounting for a linkage of 92% of all VWD patients, overall, and 83% of all type 1 patients, a figure which has also been reported in other population studies. ...
... 12,14 It shows that an extensive panel of all VWD assays with all available techniques, including VWF multimer analysis and a full genetic analysis (DNA sequencing and MLPA), is required for a complete VWD diagnosis and classification, as it was done in other VWD population studies. [15][16][17] It provides unique information on the laboratory phenotype-genotype relationship in VWD, including the pitfalls in diagnosis of the disease, but adds the data of a large geographical region into the ISTH/EAHAD database on VWF mutations. This study and several other population studies [15][16][17] in VWD invite comparisons between the different mutations identified in different regions. ...
Background von Willebrand disease (VWD) is a genetic bleeding disorder caused by defects of von Willebrand factor (VWF), quantitative (type 1 and 3) or qualitative (type 2). The laboratory phenotyping is heterogenic making diagnosis difficult.
Objectives Complete laboratory analysis of VWD as an expansion of the previously reported cross-sectional family-based VWD study in the Czech Republic (BRNO-VWD) and Slovakia (BRA-VWD) under the name “Heart of Europe,” in order to improve the understanding of laboratory phenotype/genotype correlation.
Patients and Methods In total, 227 suspected VWD patients were identified from historical records. Complete laboratory analysis was established using all available assays, including VWF multimers and genetic analysis.
Results A total of 191 patients (from 119 families) were confirmed as having VWD. The majority was characterized as a type 1 VWD, followed by type 2. Multimeric patterns concordant with laboratory phenotypes were found in approximately 83% of all cases. A phenotype/genotype correlation was present in 84% (77% type 1, 99% type 2, and 61% type 3) of all patients. Another 45 candidate mutations (23 novel variations), not found in the initial study, could be identified (missense 75% and truncating 24%). An exon 1–3 gene deletion was identified in 14 patients where no mutation was found by direct DNA sequencing, increasing the linkage up to 92%, overall.
Conclusion This study provides a cross-sectional overview of the VWD population in a part of Central Europe. It is an addition to the previously published BRNO-VWD study, and provides important data to the International Society of Thrombosis and Haemostasis/European Association for Haemophilia and Allied Disorders VWD mutation database with identification of novel causal mutations.
... Furthermore, c.658-3C>A was listed as a VWD1 variant in a French cohort study which included individuals with VWD1 if they had "VWF levels < 0.30 IU/ml [and] VWF:RCo/VWF:Ag > 0.6", but the levels of the affected individual was not provided (Veyradier et al., 2016). However, as previously illustrated there is variable expression of a laboratory phenotype in pLoF heterozygotes (Figure 3.7, pages 120-121). ...
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.
... Similar prevalence has been reported by Nicholas et al, and Veyradier et al, in their studies. 17,18 Menorrhagia (overall 22.7%), was found in 100% of females of reproductive age group in our study sample. Balkan et al, conducted a study in turkey and concluded that 55% of the females affected with vWD, had menorrhagia. ...
Armed Forces Med J 2022; 72 (Suppl-2): S107 C Cl li in ni ic ca al l S Sp pe ec ct tr ru um m a an nd d L La ab bo or ra at to or ry y S St tu ud dy y o of f V Vo on n W Wi il ll le eb br ra an nd d D Di is se ea as se e-E Ex xp pe er ri ie en nc ce e f fr ro om m T Te er rt ti ia ar ry y C Ca ar re e H Ho os sp pi it ta al l i in n P Pa ak ki is st ta an n ABSTRACT Objective: To determine the clinical features and laboratory parameters of patients of von Willebrand disease (vWD) in our population. Study Design: Cross-sectional study. Place and Duration of Study: Department of Hematology, Armed Forces Institute of Pathology (AFIP), Rawalpindi Pakistan, from Jan to Jul 2019. Methodology: All patients newly diagnosed von Willebrand disease patients were assessed clinically. Complete blood counts, bleeding time, coagulation profile, von Willebrand antigen levels and FVIII levels were determined. Results: A total of 66diagnosed patients of von Willebrand disease were included in the study. Out of these 15 (22.7%) were male while 51 (77.2%) were females. The most common clinical symptom was pallor, seen in 49 (74.2%) patients, followed by epistaxis in 36 (54.5%) and gum bleeding in 28 (42.4%) patients. Consanguineous marriages were found in 40 cases (60.6%) and family history was positive in 23 (34.8%). Patients mean vWF Ag level was4.29 ± 7.7 IU/dL while mean FVIII levels was 5.18 ± 7.8 1 U/mL. Conclusion: Von Willebr and disease is among the most common inherited bleeding disorder which presents with a classical pattern of mucocutaneous/soft tissue bleed, with pallor epistaxis and gum bleed being the most common presenting complaints.
