A novel deletion mutation is recurrent in von Willebrand disease types 1 and 3

Blood ◽  
2009 ◽  
Vol 114 (5) ◽  
pp. 1091-1098 ◽  
Author(s):  
Megan S. Sutherland ◽  
Anthony M. Cumming ◽  
Mackenzie Bowman ◽  
Paula H. B. Bolton-Maggs ◽  
Derrick J. Bowen ◽  
...  
Keyword(s):  
Genomic Dna ◽  
Direct Sequencing ◽  
Von Willebrand Disease ◽  
Compound Heterozygous ◽  
Asian Origin ◽  
Expression Studies ◽  
Autosomal Dominant Fashion ◽  
Type 3 ◽  
Von Willebrand

Direct sequencing of VWF genomic DNA in 21 patients with type 3 von Willebrand disease (VWD) failed to reveal a causative homozygous or compound heterozygous VWF genotype in 5 cases. Subsequent analysis of VWF mRNA led to the discovery of a deletion (c.221-977_532 + 7059del [p.Asp75_Gly178del]) of VWF in 7 of 12 white type 3 VWD patients from 6 unrelated families. This deletion of VWF exons 4 and 5 was absent in 9 patients of Asian origin. We developed a genomic DNA-based assay for the deletion, which also revealed its presence in 2 of 34 type 1 VWD families, segregating with VWD in an autosomal dominant fashion. The deletion was associated with a specific VWF haplotype, indicating a possible founder origin. Expression studies indicated markedly decreased secretion and defective multimerization of the mutant VWF protein. Further studies have found the mutation in additional type 1 VWD patients and in a family expressing both type 3 and type 1 VWD. The c.221-977_532 + 7059del mutation represents a previously unreported cause of both types 1 and 3 VWD. Screening for this mutation in other type 1 and type 3 VWD patient populations is required to elucidate further its overall contribution to VWD arising from quantitative deficiencies of VWF.

Characterisation of Type 2N von Willebrand Disease Using Phenotypic and Molecular Techniques

1996 ◽  
Vol 75 (06) ◽  
pp. 959-964 ◽  
Author(s):  
I M Nesbitt ◽  
A C Goodeve ◽  
A M Guilliatt ◽  
M Makris ◽  
F E Preston ◽  
...  
Keyword(s):  
Direct Sequencing ◽  
Von Willebrand Disease ◽  
Molecular Techniques ◽  
Haemophilia A ◽  
Binding Region ◽  
Gene Encoding ◽  
Covalently Linked ◽  
Von Willebrand ◽  
Willebrand Factor

Summaryvon Willebrand factor (vWF) is a multimeric glycoprotein found in plasma non covalently linked to factor VIII (FVIII). Type 2N von Willebrand disease (vWD) is caused by a mutation in the vWF gene that results in vWF with a normal multimeric pattern, but with reduced binding to FVIII.We have utilised methods for the phenotypic and genotypic detection of type 2N vWD. The binding of FVIII to vWF in 69 patients, 36 with type 1 vWD, 32 with mild haemophilia A and one possible haemophilia A carrier with low FVIII levels was studied. Of these, six were found to have reduced binding (five type 1 vWD, one possible haemophilia A carrier), DNA was extracted from these patients and exons 18-23 of the vWF gene encoding the FVIII binding region of vWF were analysed. After direct sequencing and chemical cleavage mismatch detection, a Thr28Met mutation was detected in two unrelated individuals, one of whom appears to be a compound heterozygote for the mutation and a null allele. No mutations were found in the region of the vWF gene encoding the FVIII binding region of vWF in the other four patients

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

2021 ◽  
Vol 47 (02) ◽  
pp. 192-200
Author(s):  
James S. O'Donnell
Keyword(s):  
Von Willebrand Factor ◽  
Bleeding Risk ◽  
Von Willebrand Disease ◽  
Personalized Treatment ◽  
Treatment Plans ◽  
Type 3 ◽  
Von Willebrand ◽  
Willebrand Factor

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

Novel Large Deletion Is the Most Frequent Cause of Type 3 von Willebrand Disease in Hungary.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1013-1013
Author(s):  
Adrien Mohl ◽  
Tamás Masszi ◽  
Eszter Nagy ◽  
Tobias Obser ◽  
Florian Oyen ◽  
...  
Keyword(s):  
Direct Sequencing ◽  
Large Deletion ◽  
Severe Form ◽  
Von Willebrand Disease ◽  
Rational Approach ◽  
Molecular Testing ◽  
Spontaneous Bleeding ◽  
Virtual Absence ◽  
Type 3 ◽  
Von Willebrand

Abstract Background: Type 3 is the most severe form of von Willebrand disease (VWD) caused by the virtual absence of von Willebrand factor (VWF) in affected patients. The prevalence of type 3 VWD in Hungary is 2.6 per million. Capitalizing on a nationwide National Bleeding Disorder Registry, we designed a study to characterize the genetic background of the entire Hungarian type 3 VWD population. The current report focuses on the molecular characterization of a novel large deletion. Methods: 24 patients from 23 unrelated families were studied by direct sequencing of the 52 exons of the VWF gene. The breakpoints of a large deletion were characterized by standard gene mapping. Breakpoint-specific PCR was used to confirm the presence of the deletion, and to screen for identical deletions in other populations from Germany, Russia, and Poland. Results: A large partial deletion (delExon1-3) of the 5′-region of the VWF gene was detected in 10 alleles (19 percent of all type 3 mutations). Five patients from 4 unrelated families were homozygous, and 2 patients were heterozygous for the deletion. Consanguinity was known in one of the families. In comparison, 2435 delC in exon 18, a common cause of type 3 VWD in some European populations, was found on 6 alleles (12 percent; one patient homozygous). The large deletion resulted in the loss of a 35 kb fragment, incorporating exons 1, 2 and 3. The 5′ breakpoint is located in the 5′ untranslated region, while the 3′ breakpoint is in intron 3 of VWF. No other known gene is lost with the deletion. Clinically, all homozygous patients had serious bleeding episodes from infancy requiring frequent VWF substitutions. However, bleeding became much milder in all patients with no significant spontaneous bleeding after the age of 3-5 years. No inhibitor to VWF was detected. delExon1-3 was not detected in any of the other screened populations. Conclusion: We report a large novel deletion including exons 1, 2 and 3 of VWF commonly causing type 3 VWD in the Hungarian population. This mutation, which is most probably due to a founder effect, seems to be unique to Hungarian patients with a high allele frequency. Together, delExon1-3 and 2435delC make up 31 % of genetic defects in Hungarian patients with VWD type 3. This offers a rational approach to molecular testing of respective families in Hungary.

Incidence and Determinants of Bleeding in Different Types of von Willebrand Disease: Results of the First Prospective Multicenter Study on 814 Italian Patients.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 713-713 ◽  
Author(s):  
Augusto B. Federici ◽  
Paolo Bucciarelli ◽  
Giancarlo Castaman ◽  
Maria G. Mazzucconi ◽  
Massimo Morfini ◽  
...  
Keyword(s):  
Prospective Study ◽  
Von Willebrand Disease ◽  
Free Survival ◽  
Risk Of Bleeding ◽  
Bleeding Episodes ◽  
Mucosal Bleeding ◽  
One Year ◽  
Type 3 ◽  
Von Willebrand

Abstract Background. von Willebrand disease (VWD) is the most common inherited bleeding disorder and is due to quantitative and/or qualitative defects of von Willebrand factor (VWF). Despite the improved knowledge of the disorder, no data on the incidence and determinants of bleedings requiring specific treatments have been available thus far. Aims and design of the study: to determine the incidence and determinants of bleedings requiring therapy with DDAVP and/or VWF concentrates in VWD, a national registry was organized by using a database devised to collect detailed retrospective information. Patients included in the registry were followed up for one year and prospective data on number, type and management of bleeding episodes were analyzed. Methods: all patients were diagnosed following recommendations of the ISTH-SSC-SC on VWF with bleeding severity score (BSS) calculated at enrollment. Diagnoses of VWD were confirmed by the coordinating center using also multimeric analysis in plasma and mutations of VWF gene in all types 2 and 3. For different risk categories the incidence of bleeding (mucosal and non-mucosal bleeding) was calculated. Bleeding-free survival was computed with the Kaplan-Meier method and a Cox’s proportional hazard model was used to calculate the risk of bleeding (hazard ratio = HR) Results: In the retrospective study, 1,234/1,529 (81%) cases satisfied the inclusion criteria and were enrolled in the registry as types 1 (54%), 2 (40%) and 3 (6%).VWD diagnosis occurs in young adults (83%), mainly in women (57%). Mucosal bleeding (64%) are more frequent than hematomas or hemarthrosis (15%) but 73% of patients did not require transfusions. In the prospective study based on 814/1,234 (66%) cases of the registry (type 1=47%, 2=47%, 3=6%) 147/815 (18%) were treated in a year for 318 bleeding episodes and 87 minor or major surgeries. BSS >10 (6.8, 3.8–12.3), bleeding time >20 min (BT = 5.5, 3.1–9.8), VWF:RCo <10 U/dL (3.2, 1.7–5.9) and FVIII:C <20 U/dL (4.1, 2.4–7) were significantly associated with high risk of bleeding. By multivariate model including all the variables, BSS (5.5, 2.8–10.8) was the most significant determinant of bleeding. The bleeding-free survival at one year was significantly different in type 3 (52%) versus types 1 (96%) and 2 (91%) VWD. On the other hands, patients with VWF.RCo >30 U/dL and FVIII:C > 40 U/dL showed always BSS <5 with the lowest incidence of bleeding. A total of 292 DDAVP injections were used to manage bleeding and surgeries in types 1 (65%) and 2 (35%) VWD and 452 injections of VWF concentrates were used to treat bleeding and surgeries in type 3 (75%), type 2 (34%) and type 1 (15%) VWD. Conclusions: This prospective study confirms that BSS is an important predictive factor for clinical bleeding and the need for treatment. In cases with VWF.RCo >30 U/dL and FVIII:C >40 U/dL bleeding episodes are very rare, in agreement with their relatively low BSS.

Usefulness of Whole Blood Thromboelastography for the Diagnosis and Characterisation of Von Willebrand Disease.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2274-2274
Author(s):  
Catherine Lambert ◽  
Cedric R. Hermans
Keyword(s):  
Factor Viii ◽  
Whole Blood ◽  
Alpha Angle ◽  
Von Willebrand Disease ◽  
Factor Viii Deficiency ◽  
Closure Time ◽  
Significant Prolongation ◽  
Type 3 ◽  
Von Willebrand

Abstract Whole blood coagulation tests such as thromboelastography and platelet function analyser (PFA-100) are increasingly used for the investigation of haemostatic disorders. These global tests offer the advantages of a simple use and fast results. Although PFA-100 using the ADP cartridge has been validated as a useful tool to assess primary haemostatic disturbancies and has a high sensitivity to detect Von Willebrand disease (VWD), this test is neither specific for, nor predicitve of, any particular disorder of primary haemostasis. On the other hand, the potential usefulness of thromboelastography for the evaluation of VWD has so far not been investigated. The present study was undertaken in order to determine alterations of the thromboelastogram tracing in patients with VWD and evaluate its usefulness in adjunction to PFA-100 for the diagnosis and characterisation of VWD. Thromboelastographic analysis (Pentafarm RoTEM® ) was performed, as previously described by Sorensen et al. (J Thromb Haemost. 2003 Mar;1(3):551–8), over a 36 months period on all consecutive patients referred for bleeding work-up to the Haemostasis and Thrombosis Unit of the Cliniques universitaires Saint-Luc, Brussels, Belgium. Ninety-three patients fulfilling the diagnosis criteria of VWD were analysed (38 ± 18 year, 29 males-64 females). The distribution of VWD types was as follows: type 1 (59), type 2 (31) with subtypes 2A (12), 2M (17), 2B (2) and type 3 (3). The control population included 43 healthy individuals (24 females, 19 males, mean age: 38 ± 10 yr). For each patient, the following tests were performed: closure time measured by PFA-100 using the ADP cartridge, Von Willlebrand factor antigen (VWF:Ag) and activity (VWF:Ac) (collagen binding assay), factor VIII level (one-stage assay) and RoTEM®. The following parameters of the RoTEM® tracing were analysed: clotting time (CT), clot formation time (CFT), maximum clot firmness (MCF), alpha angle and maximum clot lysis (ML). VWD was associated with a significant prolongation of the CT and the CFT. By contrast, the MCF, the alpha angle and the ML were not significantly different between patients and controls. By multiple regression analysis, the CT and CFT prolongation was found to be influenced only by the reduction of the factor VIII levels. The most important prolongations of the CT and the CFT were found in type 3 VWD reflecting the severe factor VIII deficiency. No significant differences of the RoTEM® parameters were found between type 1, subtypes 2A and 2M, which altogether represent the majority (94%) of the VWD population. CT and CFT prolongation was not correlated with other parameters (closure time, VWF:Ag and VWF:Ac). As expected, the closure time was determined by the level of VWF activity. In conclusion, although we observed a significant prolongation of the CT and the CFT in patients with VWD, RoTEM® appears to be of limited value for the diagnosis and characterization of VWD. Nevertheless, RoTEM® could be used as a screening tool to identify factor VIII deficiency present in a subset of patients with VWD.

Founder von Willebrand factor haplotype associated with type 1 von Willebrand disease

Blood ◽  
2003 ◽  
Vol 102 (2) ◽  
pp. 549-557 ◽  
Author(s):  
Lee A. O'Brien ◽  
Paula D. James ◽  
Maha Othman ◽  
Ergul Berber ◽  
Cherie Cameron ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Structural Changes ◽  
Significant Proportion ◽  
Thiol Group ◽  
Homology Model ◽  
Von Willebrand Disease ◽  
Expression Studies ◽  
Von Willebrand ◽  
Willebrand Factor

AbstractTo date, no dominant mutation has been identified in a significant proportion of patients with type 1 von Willebrand disease (VWD). In this study, we examined 70 families as part of the Canadian Type 1 VWD Study. The entire VWF gene was sequenced for 1 index case, revealing 2 sequence variations: intron 30 (5312—19A&gt;C) and exon 28 at Tyr1584Cys (4751A&gt;G). The Tyr1584Cys variation was identified in 14.3% (10 of 70) of the families and was in phase with the 5312—19A&gt;C variation in 7 (10.0%) families. Both variants were observed in 2 of 10 UK families with type 1 VWD, but neither variant was found in 200 and 100 healthy, unrelated persons, respectively. Mean von Willebrand factor antigen (VWF:Ag), VWF ristocetin cofactor (VWF:RCo), and factor VIII coagulant activity (FVIII:C) for the index cases in these families are 0.4 U/mL, 0.36 U/mL, and 0.54 U/mL, respectively, and VWF multimer patterns show no qualitative abnormalities. Aberrant VWF splicing was not observed in these patients, and both alleles of the VWF gene are expressed as RNA. Molecular dynamic simulation was performed on a homology model of the VWF-A2 domain containing the Tyr1584Cys mutation. This showed that no significant structural changes occur as a result of the substitution but that a new solvent-exposed reactive thiol group is apparent. Expression studies revealed that the Tyr1584Cys mutation results in increased intracellular retention of the VWF protein. We demonstrate that all the families with the Tyr1584Cys mutation share a common, evolved VWF haplotype, suggesting that this mutation is ancient. This is the first report of a mutation that segregates in a significant proportion of patients with type 1 VWD.

scholarly journals Prophylaxis in von Willebrand Disease: Coming of Age?

2016 ◽  
Vol 42 (05) ◽  
pp. 498-506 ◽  
Author(s):  
Giorgia Saccullo ◽  
Mike Makris
Keyword(s):  
Coming Of Age ◽  
Severe Disease ◽  
Standard Of Care ◽  
Von Willebrand Disease ◽  
The Past ◽  
Patients Experience ◽  
Type 3 ◽  
Von Willebrand ◽  
Willebrand Factor

Although in most cases von Willebrand disease (VWD) is a mild disorder, a subgroup of patients experience frequent bleeding. In contrast to severe hemophilia in which prophylaxis is the accepted standard of care, this is less frequently used in VWD. Most type 1 VWD patients can be adequately managed with episodic desmopressin and tranexamic acid. In patients with more severe disease, especially those with type 3 VWD, joint bleeds, epistaxis, menorrhagia, and gastrointestinal bleeding are problematic and usually require treatment with von Willebrand factor/factor VIII (VWF/FVIII) concentrate. While in the past these patients were managed with on-demand VWF/FVIII concentrate, several recent reports have demonstrated the value of prophylactic treatment. Despite some uncertainties about the economic impact of treatment of severe VWD, prophylaxis with VWF concentrate should now be considered as the standard of care for the more severe end of the spectrum of affected individuals. The recent introduction of recombinant VWF concentrate is likely to improve the acceptability of prophylaxis in VWD.

scholarly journals Wish-Qol Study - Assessment of Health-Related Quality of Life (HRQoL) and Health-Economic Aspects in Patients with Von Willebrand Disease (VWD) in France: Results of the Women Cohort

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1395-1395
Author(s):  
Annie Borel-Derlon ◽  
Jenny Goudemand ◽  
Dominique Desprez ◽  
Fabienne Volot ◽  
Yves Gruel ◽  
...  
Keyword(s):  
Interim Analysis ◽  
Research Funding ◽  
Von Willebrand Disease ◽  
Female Group ◽  
Bleeding Score ◽  
Type 3 ◽  
Von Willebrand

Abstract Background: Von Willebrand disease (VWD) is the most common inherited bleeding disorder with a prevalence of 1% in the general population. VWD results from a deficiency in or a dysfunction of von Willebrand factor which is a protein that is necessary for normal platelet adhesion and protection of factor VIII from proteolysis in the circulation. Nevertheless, prevalence of the most symptomatic forms such as bleeds requiring replacement treatment and /or hospitalization is about 0.01%. Although VWD affects both genders, there is a higher proportion in females than in males.VWD seems to be more symptomatic in women because of their reproductive life. Women with VWD have an increased bleeding risk in numerous situations including anemia, menorrhagia, bleeding during pregnancy, postpartum hemorrhage and impairments in their quality of life (QoL).The prevalence of menorrhagia in women with VWD is 74-92%. According to the Francecoag Network, the referral-based prevalence of moderate-to-severe VWD patients is about 1,750 cases in France. Aim: Since the disease and its treatment can affect every-day life of patients and their families, a French HRQoL Study (WiSH-QoL) exploring this impact started 22 months ago. Methods: This non-interventional 5-year study evaluates patients HRQoL and costs of care in France. At least 350 patients will be followed for 24 months in minimum 30 centers. HRQoL is assessed with the generic SF-36 and the disease-specific VWD-QoL questionnaires. Bleeding severity was measured using the Tosetto Bleeding Score (BS). Results: Since October 2014, 245 patients have been included. We present here the first interim analysis with a focus on the female group. At the first interim analysis, data from 140 patients were documented: 91 adults with a median age of 40.0 years [18.3-78.0] and 49 children with a median age of 10.1 years [2.9-17.5]. VWD Types were already identified for 122 (87%) of these patients: 33 with VWD type 1 (27%) including 5 type 1 Vicenza; 76 type 2 (62%) and 13 type 3 (11%). The median Tosetto bleeding score reported for 124 patients (males and females) was +7 ranging from -1 to +28. From the 95 female patients, 70 were aged ≥18 years, 21 were adolescents between 8-17 years and 4 were girls below 4 years of age. Median age was 29.4 (range 4.3-78.0) years. A total of 25 women had type 1 VWD (31%), 49 had type 2 VWD (60%), and 7 had type 3 VWD (9%), for 14 patients VWD type is undetermined. The median Tosetto bleeding score of the female group was +8 ranging from -1 to +28. Out of 95 patients, 45 patients (47.4%) have received a concomitant treatment due to menorrhagia, such as iron therapy, oral contraceptive, levonorgestrel intrauterin system: 5/21 patients in the group between 8 and 17 years and 40/70 in the group ≥18 years. Out of the 60 women of childbearing potential defined as age between 15-50 years, 6 women were pregnant at time of inclusion. A total of 46 patients, aged 18 years or more have had obstetrical history prior to study inclusion. The mean number of childbirth was more than 2 i.e 2.39 range (1-8) per woman, 75% of these deliveries were natural delivery and 25% were caesarean section. Out of 108 deliveries, 28 (26%) were experienced with post-partum hemorrhages. Conclusions: With the results of the WiSH-QoL study, the first prospective study of von Willebrand disease conducted in France, especially the VWD-specific evaluation of HRQoL and treatment satisfaction a deeper insight will be gathered into the patients' daily life, their perception of well-being and their specific health care needs. With the additional domain 'pregnancy' included in the French version of the VWD-QoL questionnaire for female adult patients, it will possible to better understand how women may be affected by VWD during childbearing years. Disclosures Borel-Derlon: LFB: Other: Reference expert and national coordinator for VWD; Octapharma: Research Funding; NovoNordisk: Other: Expert for scientific committee; Shire - Baxalta: Research Funding. Chatelanaz:LFB Biomedicaments: Employment. Doriat-Robin:LFB Biomedicaments: Employment. von Mackensen:SOBI: Research Funding; Shire: Research Funding.

scholarly journals Profile of Mutations Identified in the 3WINTERS-IPS Project on European & Iranian Patients with Previously Diagnosed Type 3 Von Willebrand Disease.

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1184-1184
Author(s):  
Luciano Baronciani ◽  
Flora Peyvandi ◽  
Anne Goodeve ◽  
Reinhard Schneppenheim ◽  
Zahra Badiee ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Advisory Board ◽  
Von Willebrand Disease ◽  
Compound Heterozygous ◽  
Advisory Committees ◽  
Type 3 ◽  
Von Willebrand ◽  
Two Populations ◽  
Iranian Patients

Abstract Background: The type 3 Von Willebrand International RegistrieSInhibitor Prospective Study (3WINTERS-IPS) is a no-profit, investigator initiated, multicenter, European-Iranian observational, retrospective and prospective study on patients with diagnosis of type 3 VWD. Patients with type 3 von Willebrand Disease (VWD3) have markedly reduced levels of von Willebrand factor (VWF) and very severe bleeding phenotype. Due to the recessive inheritance pattern, VWD3 is by definition a rare bleeding disorder (1:Million) but its prevalence may increase in countries like Iran with consanguineous marriages. Aim: To identify the VWF genetic defects in a cohort of European and Iranian patients with previously diagnosed VWD3 enrolled into the 3WINTERS-IPS project. Methods: Patients classified locally as VWD3 were enrolled in the study following informed consent. 141 patients were from 9 different European countries and 119 patients were from the Islamic Republic of Iran. Plasma/buffy-coat samples were sent to expert labs to confirm patient's laboratory phenotype and to perform molecular analysis. PCR and Sanger sequencing/ next generation sequencing and multiplex-ligation dependent probe amplification were used in Hamburg, Sheffield and Milan to confirm previously identified variants or to seek previously unidentified variants. Results: DNA samples from 122 patients from Europe and 114 patients from Iran were analyzed at the molecular level. Of the 236 VWD3 patients under evaluation 24 are still in progress. Of the 212 fully evaluated patients 139 were homozygous (EU/IR=46/93) and 43 were compound heterozygous (EU/IR=36/7). In the remaining 30 patients no variants were identified in 19 samples (EU/IR=6/13) and only one variant was found in the remaining 11 cases (EU/IR=10/1). 135 (EU/IR=82/53) different gene defects were identified among the 375 (EU/IR=174/201) alleles found in this study. Of these 135 variants identified 51(EU/IR=22/29) were not reported on the www.ensembl.org database. The distribution of the different type of variants identified in the two populations is shown in the Figure. The two charts are showing quite similar percentages of the variants identified, with a main exception for the Small deletions and Small insertions. Only five variants are shared among the two populations. Three of these are the "hotspot" variants at the Arg codon, p.Arg1659* (EU/IR=9/8), p.Arg1853* (EU/IR=2/3) and p.Arg2535* (EU/IR=1/2). However, a missense variant , p.Cys275Ser (EU/IR=1/2) and a large deletion, delEx1_Ex5 (EU/IR=1/2) were also found in both populations. Fifteen variants were recurrent and were found in 154 alleles, whereas 49 variants were found only once in the heterozygous state (EU/IR=40/9) and 50 variants were found only twice, mainly in the homozygous state (EU/IR=25/25). Six large deletions were identified (delEx1_Ex3, delEx1_Ex5, delEx14_Ex15, delEx17, delEx35_Ex52 and delEx1_Ex52) and a duplication (dupEx1_Ex28), nevertheless 52 alleles with missense variants were identified (EU/IR=20/32). Discussion: As expected, the majority of the Iranian patients were found to be homozygous (Homozygous/Compound Heterozygous=93/7) reflecting a high rate of consanguinity, nevertheless half of the European patients were found to be homozygous (Homozygous/Compound Heterozygous=46/36). The European populations demonstrated a higher heterogeneity of variants with 82 different variants among the 175 mutated alleles vs 53 different variants among the 201 mutated alleles identified in the Iranian population. Nevertheless, a higher number of previously unreported variants was found in the Iranian population (29) vs the European one (22), probably due to bias of previous investigations performed in European patients. Figure Figure. Disclosures Peyvandi: Ablynx: Other: Member of Advisory Board, Speakers Bureau; Shire: Speakers Bureau; Roche: Speakers Bureau; Grifols: Speakers Bureau; Grifols: Speakers Bureau; Novo Nordisk: Speakers Bureau; Sobi: Speakers Bureau; Sobi: Speakers Bureau; Novo Nordisk: Speakers Bureau; Kedrion: Consultancy; Novo Nordisk: Speakers Bureau; Octapharma US: Honoraria; Novo Nordisk: Speakers Bureau; Sobi: Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Kedrion: Consultancy; Novo Nordisk: Speakers Bureau; Kedrion: Consultancy; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Octapharma US: Honoraria; Shire: Speakers Bureau; Roche: Speakers Bureau; Kedrion: Consultancy; Kedrion: Consultancy; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Octapharma US: Honoraria; Octapharma US: Honoraria; Sobi: Speakers Bureau; Roche: Speakers Bureau; Octapharma US: Honoraria; Shire: Speakers Bureau; Sobi: Speakers Bureau; Roche: Speakers Bureau; Roche: Speakers Bureau; Shire: Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Grifols: Speakers Bureau; Grifols: Speakers Bureau; Grifols: Speakers Bureau; Shire: Speakers Bureau. Schneppenheim:CSL Behring: Consultancy; SHIRE: Consultancy. Berntorp:Octapharma: Consultancy; CSL Behring: Consultancy; Shire: Consultancy, Other: honoraria for lecturing . Eikenboom:CSL: Research Funding. Mannucci:Bayer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kedrion: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Grifols: Speakers Bureau; Alexion: Speakers Bureau; Baxalta/Shire: Speakers Bureau; Novo Nordisk: Speakers Bureau. Mazzucconi:Baxalta-Shire: Consultancy, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Novartis,: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Novo Nordisk: Consultancy, Speakers Bureau; CSL Behring: Consultancy, Speakers Bureau. Oldenburg:Swedish Orphan Biovitrum: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Grifols: Honoraria, Membership on an entity's Board of Directors or advisory committees; Biogen Idec: Honoraria, Membership on an entity's Board of Directors or advisory committees; Chugai: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Biotest: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Clinical Study to Investigate the Efficacy and Safety of Wilate during Prophylaxis in Previously Treated Patients with Von Willebrand Disease (VWD)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4931-4931
Author(s):  
Robert F. Sidonio ◽  
Bruce A. Schwartz
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Prophylactic Treatment ◽  
Von Willebrand Disease ◽  
Advisory Committees ◽  
Previously Treated Patients ◽  
Previously Treated ◽  
Type 3 ◽  
Von Willebrand

Background: Inherited von Willebrand disease (VWD) is the most common inherited hemorrhagic disorder, with an estimated prevalence of 1 in every 100 individuals. Type 1 and type 3 (the most severe form) are characterized by a quantitative deficiency of von Willebrand factor (VWF) and type 2 arises from a qualitative deficiency of VWF. Treatment of VWD depends on the type and severity of the disease. Severe bleeding is reported in patients with all subtypes, leading to progressive joint disease as well as diminished quality of life (QoL). VWF/factor VIII (FVIII) concentrates have become the mainstay of VWD treatment for these patients with severe disease or for those patients in whom other treatments (e.g., desmopressin) are ineffective or contraindicated but this is broadly applicable only for on demand treatment. Aims: The primary objective of this study is to determine the efficacy of VWF/FVIIII concentrate in the prophylactic treatment of previously treated patients with type 3, type 2 (except 2N), or severe type 1 VWD. Secondary objectives of this study will be to collect data to 1) Assess the VWF:Ac and VWF:Ag incremental IVR of VWF/FVIIII concentrate over time and, 2) Assess the safety and tolerability of VWF/FVIIII concentrate in this indication. The study will also examine, the efficacy of VWF/FVIIII concentratein the treatment of breakthrough bleeding episodes (BEs), and in surgical prophylaxis, as well as the QoL during prophylaxis with VWF/FVIIII concentrate. Methods: The study is planned to enroll 28 patients aged ≥6 years and with VWD type 1, 2A, 2B, 2M, or 3. Eligible patients must be receiving on-demand treatment with a VWF-containing product, with at least 1, and an average of ≥2, documented spontaneous BEs per month in the preceding 6 months requiring treatment with a VWF-containing product. This will be assessed as part of a run-in observational study to collect the bleeding profile prior to the start of prophylaxis. From the beginning of the study, patients will receive prophylactic treatment with VWF/FVIIII concentrate for 12 months and record all BEs in a patient diary. Based on these data, the frequency of BEs and the annualized bleeding rate (ABR) under prophylactic treatment will be calculated. Treatment efficacy of BEs will be assessed by the patient (together with the investigator in case of on-site treatment) using a 4-point scale (excellent, good, moderate, none) In patients that undergo surgeries, efficacy of VWF/FVIIII concentratewill be assessed at the end of surgery by the surgeon and at the end of the postoperative period by the haematologist. In both cases, predefined assessment criteria will be used. In addition, an overall assessment of efficacy will be made at the end of the postoperative period by the investigator. Results: Data will be monitored on an ongoing basis and the study is expected to end Q2 2021. Conclusions: Prophylactic treatment in other congenital bleeding disorders is widely accepted as the standard of care to prevent bleeding and preserve QoL in patients but to date, this form of treatment in VWD is not well characterized. This study will provide data on the efficacy of prophylactic treatment in reducing the rate of bleeding and on the impact of prophylaxis on the QoL in VWD patients. Disclosures Sidonio: Genetech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda-Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding; Biomarin: Membership on an entity's Board of Directors or advisory committees; Octapharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioverativ: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Grifols: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kedrion: Research Funding; Uniqure: Membership on an entity's Board of Directors or advisory committees. Schwartz:Octapharma: Employment.

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