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VWD
Kinds of VWD Terms modified by VWD Selected AbstractsPerioperative Management of von Willebrand Disease in Dermatologic SurgeryDERMATOLOGIC SURGERY, Issue 4 2007AIMEE L. LEONARD MD BACKGROUND Von Willebrand disease (VWD) is the most common inherited bleeding disorder, affecting an estimated 0.1% to 1% of the population. It is caused by a qualitative or quantitative defect of von Willebrand factor. Primary manifestations include intractable mucocutaneous bleeding after surgery or trauma. OBJECTIVE The objective was to review the pathophysiology and clinical features of VWD and to propose a perioperative management strategy for patients with this condition undergoing dermatologic surgery. METHODS AND MATERIALS Literature is reviewed. RESULTS The various types and clinical manifestations of this condition are reviewed, and a perioperative strategy is presented for managing patients with VWD who undergo cutaneous oncologic or cosmetic surgical procedures. CONCLUSIONS In most cases, dermatologic surgery can be safely performed in patients with VWD. The use of appropriate therapeutic prophylaxis in conjunction with a hematologist is indicated in high-risk, nonelective procedures. [source] The role of prophylaxis in bleeding disordersHAEMOPHILIA, Issue 2010E. BERNTORP Summary., The rationale for long-term prophylaxis in more severe forms of von Willebrand's disease (VWD) is obvious, as mucosal bleeding and haemophilia-like joint bleeds resulting in chronic morbidity may occur. However, the experience with prophylactic treatment in this group is scanty. An international VWD Prophylaxis Network (VWD PN) was established in 2006. The VWD PN will investigate prophylaxis with retrospective and prospective studies. Eighteen centres in Europe and North America are recruiting patients and an additional 40 centres are preparing for or evaluating participation. In the absence of randomized prospective studies for most rare bleeding disorders, guidelines for prophylaxis are a subject of controversy. In situations where there is a strong family history of bleeding, long-term prophylaxis is administered in selected cases. Short intervals of prophylaxis can also be given before some surgeries or during pregnancy. The benefits of prophylaxis must be balanced by the risk of side effects. Therefore, it is essential to delineate its management in a specialized comprehensive care environment. In haemophilia, decades of clinical experience and numerous retrospective and, recently, prospective studies clearly demonstrate that prophylactic treatment is superior to on-demand treatment, regardless of whether the outcome is the number of joint- or life-threatening bleeds, arthropathy evaluated by X-ray or MRI, or quality of life measured by generic or haemophilia-specific instruments. Optimal prophylactic treatment should be started early in life (primary prophylaxis) but various options exist for the dose and dose interval. These depend on the objective of treatment in the individual patient, which, in turn, is dependent on resources in the health care system. [source] Factor VIII and von Willebrand factor interaction: biological, clinical and therapeutic importanceHAEMOPHILIA, Issue 1 2010V. TERRAUBE Summary., The interaction of factor VIII (FVIII) with von Willebrand Factor (VWF) is of direct clinical significance in the diagnosis and treatment of patients with haemophilia A and von Willebrand disease (VWD). A normal haemostatic response to vascular injury requires both FVIII and VWF. It is well-established that in addition to its role in mediating platelet to platelet and platelet to matrix binding, VWF has a direct role in thrombin and fibrin generation by acting as a carrier molecule for the cofactor FVIII. Recent studies show that the interaction affects not only the biology of both FVIII and VWF, and the pathology of haemophilia and VWD, but also presents opportunities in the treatment of haemophilia. This review details the mechanisms and the molecular determinants of FVIII interaction with VWF, and the role of FVIII,VWF interaction in modulating FVIII interactions with other proteases, cell types and cellular receptors. The effect of defective interaction of FVIII with VWF as a result of mutations in either protein is discussed. [source] Complications of hysterectomy in women with von Willebrand diseaseHAEMOPHILIA, Issue 4 2009A. H. JAMES Summary., Case reports and small case series suggest that women with von Willebrand disease (VWD) are at a very high risk of bleeding complications with hysterectomy. As the procedure may be beneficial to women who suffer from heavy menstrual bleeding and have completed childbearing, an understanding of the true risks involved is essential for appropriate decision making. To estimate the incidence of bleeding and other complications in women with VWD who undergo hysterectomy. The United States Nationwide Inpatient Sample (NIS) from the Healthcare Cost and Utilization Project of the Agency for Healthcare Research and Quality for the years 1988,2004 was queried for all hysterectomies for non-malignant conditions. Data were analysed based on the NIS sampling design. Bivariate analyses were used to examine the differences between women with and without VWD. Multivariate analysis was used to adjust for potential confounders among women who underwent hysterectomy for heavy menstrual bleeding. 545 of the 1 358 133 hysterectomies were to women with VWD. Women with VWD were significantly more likely to experience intraoperative and postoperative bleeding (2.75% vs. 0.89%, P < 0.001) and require transfusion (7.34% vs. 2.13%, P < 0.001) than women without VWD. One woman with VWD died. While the risk of bleeding complications from hysterectomy in women with VWD is smaller than previously reported, women with VWD did experience significantly more bleeding complications than women without VWD. Nonetheless, for women who have completed childbearing, the risks of hysterectomy may be acceptable. [source] Haemate® P von Willebrand factor/factor VIII concentrate: 25 years of clinical experienceHAEMOPHILIA, Issue 2008W. SCHRAMM Summary., Although von Willebrand disease (VWD) has a very long history, our understanding and treatment of the bleeding disorder has only evolved during the past 50 years or so. It was not until the 1920s that VWD was first recognized as a disease separate from that of classical haemophilia. It then took another 30 years before the first effective treatment was developed. Since then, the medical management of VWD has evolved considerably, but not without its ups and downs. One of the key milestones in the evolution of the treatment of VWD was the development of Haemate® P/Humate-P® (CSL Behring) , the first virus-inactivated factor VIII plasma product. For 25 years, this concentrate has demonstrated excellent clinical efficacy and safety for patients with VWD and for those with haemophilia. This article provides an historical overview of the early landmark efforts to ensure a safe plasma-derived replacement product and outlines the clinical evolution in the use of Haemate® P. [source] Intracranial haemorrhage in patients with congenital haemostatic defectsHAEMOPHILIA, Issue 5 2008P. MISHRA Summary., We investigated 52 of 457 patients with congenital factor deficiencies with 57 episodes of intracranial haemorrhage (ICH) between 1998 and 2007. There were 38 severe haemophiliacs, 6 with factor XIII deficiency, 5 with factor X deficiency, 2 factor V-deficient patients, and 1 with type 3 von Willebrand disease (VWD). The median age was 8 years (range 1 month,22 years). Most patients were below 15 years of age (86.5%). All patients with factor X deficiency were between 1 and 5 months of age. ICH was the primary bleeding episode leading to detection of factor deficiency in 19.2% (five patients with severe haemophilia and all patients with factor X deficiency). Trauma caused bleeding in 66%. None of the patients with factor X deficiency had history of prior trauma. Surgery was performed in five patients with subdural haematomas, all of whom survived. Conservative factor replacement with 100% correction for 3 days followed by 50,60% correction for 7 days was possible in 60% patients. Seizures requiring prolonged therapy were noted in eight patients. Death was recorded in 15 patients (29%). Inadequate therapy in the form of delay or insufficient replacement was noted in 7/15 deaths. ICH was seen in 11.3% of all patients with coagulation factor deficiencies. Factor X deficiency presented with ICH at an earlier age. Inadequate replacement therapy including delayed treatment caused nearly 50% of all deaths. Most patients can be managed satisfactorily with adequate replacement therapy alone, with surgery being reserved for those with worsening neurological conditions. [source] The molecular analysis of von Willebrand disease: a guideline from the UK Haemophilia Centre Doctors' Organisation Haemophilia Genetics Laboratory NetworkHAEMOPHILIA, Issue 5 2008S. KEENEY Summary., 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. [source] Type 1 von Willebrand disease: application of emerging data to clinical practiceHAEMOPHILIA, Issue 4 2008P. W. COLLINS Summary., There has been much recent data published on type 1 von Willebrand disease (VWD) predominantly from three multi-centre cohort studies. These data have influenced a revision of the classification of type 1 VWD and have important implications for the management of this disorder. Patients with low von Willebrand factor (VWF) levels tend to have VWF mutations and VWD is transmitted predictably within families. In patients with VWF levels close to the lower end of the normal range, candidate mutations are found less often, ABO blood group is a more important factor and the disease has variable heritability within families. The importance of bleeding symptoms, in addition to VWF levels, in the diagnosis of type 1 VWD has been highlighted. [source] Domiciliary application of CryoCuff in severe haemophilia: qualitative questionnaire and clinical auditHAEMOPHILIA, Issue 4 2008A. I. D'YOUNG Abstract., The acute management of haemophilic bleeding episodesin the home setting is based on the concept of immediate factor replacement therapy and the PRICE regime , an acronym representing the concepts of Protection, Rest, Ice, Compression and Elevation [1,2]. Integral to this regime is the application of cold therapy, and yet little is known regarding the safe periods of application, or the relative safety of cryotherapy devices such as the CryoCuffÔ when used in the home setting by patients suffering from severe haemophilia and related bleeding disorders. This study examines the subjective patient response to the application of the CryoCuffÔ device in the home setting in terms of the effect on pain, joint swelling and the return to ,pre-bleed status' of the knee, ankle or elbow in patients with severe haemophilia A/B or type III von Willebrand's disease (VWD) immediately following haemarthrosis, and any potential adverse effects related to the device or recommended duration of application as stated in the PRICE guideline (Fig. 1). Twelve patients, either with severe haemophilia A/B or with VWD were recruited and asked to use the CryoCuffÔ device as part of the PRICE regime immediately following the onset of knee-, ankle- or elbow bleeds for the next one year. Each subject was then sent a qualitative questionnaire to determine subjective responses to the device. All patients reported that the application protocol was easy to follow, they were able to apply the device as per the PRICE regime and they were able to tolerate it for the recommended period. Whereas, all the patients felt that the device had a significant impact on alleviation of pain and return to pre-bleed status, 78% of the patients felt that the device led to a significant reduction in swelling around the affected joint. There was no conclusive evidence that the device resulted in any reduction in the amount of factor used to treat the acute bleeding episode, however, no patients reported any perceived delay in achieving haemostasis or required extra factor replacement therapy consequent to the usage of the device. No other adverse effects were reported by participants in this study. Figure 1. ,The qualitative participant questionnaire, given following 1 year of unsupervised use in the home setting immediately following the onset of the symptoms of haemarthroses. [source] The 80th anniversary of von Willebrand's disease: history, management and researchHAEMOPHILIA, Issue 6 2006A. B. FEDERICI Summary., The history of von Willebrand's disease (VWD) is fascinating because it demonstrates how good clinical observations, genetic studies and biochemical skills can improve basic understanding of a disease and its management. The continuous efforts of scientists and clinicians during the last 80 years have significantly improved the knowledge of von Willebrand factor (VWF) structure and function and the management of VWD. Diagnosis of phenotype and genotype is now available in many countries and treatment is becoming more specific according to the VWD type. Any therapeutic agents must correct the dual defect of haemostasis, i.e. the abnormal platelet adhesion due to reduced and/or dysfunctional and low levels of factor VIII (FVIII) associated with VWF defects. Desmopressin (DDAVP) is the treatment of choice for type 1 VWD because it induces release of VWF from cellular compartments. Plasma virally inactivated VWF concentrates containing FVIII are effective and safe in patients unresponsive to DDAVP. There are advanced plans to develop a recombinant VWF but this product will require the concomitant administration of FVIII for the control of acute bleeds. Basic research studies on cellular biology, biochemistry and immunology have confirmed the role of VWF as a crucial participant in both haemostasis and thrombosis as its main biological activity is to support platelet adhesion,aggregation in the circulation. Retrospective and prospective clinical research studies, including bleeding history and laboratory markers for diagnosis as well as the use of DDAVP and VWF concentrates to manage or prevent bleeds in patients with VWD have been essential to provide general guidelines for VWD management. The large number of publications quoting VWD and VWF emphasizes the important role of VWF in medicine. [source] Identification and management of women with inherited bleeding disorders: a survey of obstetricians and gynaecologists in the United KingdomHAEMOPHILIA, Issue 4 2006C. CHI Summary., A mail survey of members and fellows of Royal College of Obstetricians and Gynaecologists was carried out to determine current practices of obstetricians and gynaecologists in the United Kingdom in the management of women with inherited bleeding disorders. In total, 3929 questionnaires were sent, 707 returned and analysis was limited to 545 valid questionnaires. In the past 5 years, 91% have managed women with inherited bleeding disorders. The majority (83%) considered inherited bleeding disorders to be under diagnosed in obstetrics and gynaecology. More than 80% considered the prevalence of von Willebrand's disease (VWD) to be <0.2% in the general population and <1% in women with menorrhagia and no gynaecological pathology, although the reported prevalence is 1% and 5,25% respectively. Twelve percent of the respondents would arrange testing for VWD when reviewing an 18-year-old with menorrhagia and no pelvic pathology, while only 2% would do the same for a 35-year-old with the same presentation. Twenty-one percent thought elective caesarean section is indicated in all fetuses known to be at risk of being affected by haemophilia. Eighty-four percent considered vacuum extraction unsafe in these cases, but 76% would consider the use of low forceps. In conclusion, obstetricians and gynaecologists underestimate inherited bleeding disorders as an underlying cause for menorrhagia. Increased awareness and management guidelines are essential in minimizing haemorrhagic complications and improving quality of care of these women. [source] Management of von Willebrand disease: a guideline from the UK Haemophilia Centre Doctors' OrganizationHAEMOPHILIA, Issue 3 2004K. J. Pasi Summary., von Willebrand disease (VWD) is the commonest inherited bleeding disorder. The aim of therapy for VWD is to correct the two defects of haemostasis in this disorder, impaired primary haemostasis because of defective platelet adhesion and aggregation and impaired coagulation as a result of low levels of factor VIII. The objective of this guideline is to inform individuals making choices about the treatment and management of VWD including the use of therapeutic products. This is the second edition of this UK Haemophilia Centre Doctors' Organization (UKHCDO) guideline and supersedes the previous edition which was published in 1994. [source] The role of the platelet function analyser (PFA-100TM) in the characterization of patients with von Willebrand's disease and its relationships with von Willebrand factor and the ABO blood groupHAEMOPHILIA, Issue 3 2003I. C. Nitu-Whalley Summary. Determination of the closure time (CT) with the platelet function analyser (PFA-100TM) is a useful screening test for von Willebrand's disease (VWD) but its role in the characterization of VWD is not well established. We studied the relationship between the prolongation of the CT with adenosine diphosphate (ADP) (CT-ADP) and epinephrine (CT-EPI) cartridges and the von Willebrand factor (VWF) in 53 patients with VWD. We found that a relatively small percentage of the prolongation of the CT-ADR and CT-ADP (16 and 29%, respectively) was determined by a reduction in VWF levels. The CT-ADP was significantly more prolonged in the presence of qualitative defects in VWF but could not discriminate between the VWD subtypes. The ABO blood group had no effect on the prolongation of the CT or the bleeding time. In conclusion, the PFA-100TM appears of little use in the characterization of severity and subtype of VWD. [source] Clinical, laboratory and therapeutic aspects of platelet-type von Willebrand diseaseINTERNATIONAL JOURNAL OF LABORATORY HEMATOLOGY, Issue 2 2008M. FRANCHINI Summary Platelet-type von Willebrand disease (PT-VWD), or pseudo-VWD, is a rare inherited platelet disorder characterized by an increased affinity of the platelet membrane glycoprotein Ib, receptor for normal von Willebrand factor leading to characteristic platelet hyperaggregability. As PT-VWD shares most of the clinical and laboratory features of subtype 2B VWD, the differential diagnosis between these two inherited bleeding disorders requires either platelet-mixing or molecular genetic studies. In this review, the main clinical, laboratory and therapeutic characteristics of PT-VWD are concisely reported. [source] Evaluation of an automated screening assay for von Willebrand Disease Type 2NINTERNATIONAL JOURNAL OF LABORATORY HEMATOLOGY, Issue 6 2002S. L. Taylor Summary Evaluating the factor VIII (FVIII) binding activity of von Willebrand factor (VWF) is an important step in the diagnostic work-up of families affected by apparent mild haemophilia A. In von Willebrand's disease (VWD) type 2N (Normandy), mutations at the N-terminal end of the mature VWF subunit gene prevent the binding of FVIII. Individuals heterozygous for type 2N VWD are generally asymptomatic. Homozygotes and compound heterozygotes present with a clinical picture which mimics haemophilia A, with a markedly reduced FVIII : C activity and VWF within the normal range, but instead of exhibiting X-linked inheritance they show an autosomal recessive inheritance pattern. The distinction between haemophilia A and VWD type 2N has important implications for therapy and genetic counselling. We present a highly specific enzyme-linked immunosorbent assay screening method for the Normandy variant, which measures VWF : FVIII binding activity in parallel with VWF antigen, using monoclonal capture and detection antibodies. The assay is fully automated using a robotic microtitre plate processor, requiring minimal user intervention and providing the capacity to screen large numbers of patients. [source] Improved performance characteristics of the von Willebrand factor ristocetin cofactor activity assay using a novel automated assay protocolJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 10 2010A. HILLARP Summary.,Background, objectives and methods:,An accurate, sensitive and precise assay for reliable determination of the ristocetin cofactor activity of von Willebrand factor (VWF:RCo) in plasma and von Willebrand Factor (VWF)-containing concentrates has been evaluated. The assay is based on a commercially available automated protocol with modifications including a combination of adding additional ristocetin and the use of two calibration curves for the high and low measuring ranges. Results:,Addition of extra ristocetin resulted in improved measurement of VWF recoveries from various VWF-containing concentrates that were underestimated using the standard automated protocol. The modifications resulted in improved assay performance over an extended measuring range (2.00,0.03 IU mL,1). Accuracy was tested using VWF deficiency plasma spiked with the 1st international standard (IS) for VWF concentrate. Seven dilutions, ranging from 1.80 to 0.05 IU mL,1, were analyzed and resulted in measured concentrations between 80% and 100% of the assigned potency of the standard. Linearity was determined from the regression plot of the same concentrate dilutions and resulted in a correlation coefficient of 0.998. The repeatability, expressed as coefficient of variation, was 2% in the normal range (0.90 IU mL,1) and 8% at the level of 0.05 IU mL,1. The corresponding reproducibility results were 2% and 15% at the normal and low measuring ranges, respectively. Conclusions:,Analysis of patients with von Willebrand disease (VWD) indicates that the modified automated BCS® protocol has a superior discrimination power compared with the standard protocol. This is especially true in samples with low VWF, as in patients with type 3 VWD. [source] Homozygous type 2N R854W von Willebrand factor is poorly secreted and causes a severe von Willebrand disease phenotypeJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 9 2010G. CASTAMAN Summary.,Background:,von Willebrand disease (VWD) type Normandy (VWD 2N) is caused by mutations at the factor (F)VIII-binding site of von Willebrand factor (VWF), located in the D,and D3 domains on the N-terminus of mature VWF. The R854Q mutation is the most frequent cause of this phenotype. Objectives:,We report the characterization of a homozygous VWD 2N mutation, R854W, detected in a patient with a severe VWD phenotype. Methods:,The plasma VWF phenotype was studied, transient expression of recombinant mutant full-length VWF in 293 EBNA cells was performed, and the results were compared with those obtained with wild-type (WT) VWF. Furthermore, expression was also examined in HEK293 cells, which form Weibel,Palade body-like granules when transfected with WT VWF. Results:,The multimer analysis of plasma VWF showed the lack of the typical triplet structure, with the presence of the central band only, and a relative decrease in the high molecular mass multimers. Homozygous expression of recombinant R854W VWF resulted in normal amounts of cellular VWF, but with a severe reduction in secretion into the medium. Severe reductions in FVIII binding to R854W VWF, glycoprotein Ib binding activity and collagen binding of secreted W854 VWF was observed, and reproduced the phenotypic parameters of plasma VWF. In HEK293 cells, homozygous R854W VWF failed to form Weibel,Palade body-like granules. Conclusions:,Our results demonstrate that a homozygous R854W mutation in the D, domain of VWF induces impaired secretion and activity of the protein, thereby explaining the severe phenotype of the patient. [source] Health-related quality of life among adult patients with moderate and severe von Willebrand diseaseJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 7 2010E. M. DE WEE Summary.,Background:,von Willebrand Disease (VWD) is the most frequent inherited bleeding disorder. It is unknown how this disorder affects quality of life. Objectives:,This nationwide multicenter cross-sectional study determined health-related quality of life (HR-QoL) in adult patients with moderate or severe VWD, and assessed whether bleeding severity and type of VWD are associated with HR-QoL. Methods:,HR-QoL was assessed using the Short Form (SF)-36, and bleeding severity was measured using the Bleeding Score (BS). Results:,Five hundred and nine patients participated; 192 males and 317 females, median age and range 45 (16,87) and 47 (16,84) years, respectively. Compared with the general population, HR-QoL in VWD patients was lower in the vitality domain (61 vs. 66 P < 0.001 for females, 67 vs. 72 P < 0.001 for males). Patients with the most severe bleeding phenotype (highest quartile BS, BS > 17) had a lower HR-QoL in eight domains than patients with a less severe bleeding type (lowest quartile BS, BS < 7) in the univariate analysis. After adjustment for age, gender, co-morbidity and employment/educational status, a more severe bleeding phenotype was associated with lower scores on the domains of physical functioning, role limitations due to physical functioning, bodily pain, general health, social functioning and physical component summary. Conclusions:,HR-QoL is lower in VWD patients compared with the general population. HR-QoL is strongly associated with bleeding phenotype. [source] Generation and validation of the Condensed MCMDM-1VWD Bleeding Questionnaire for von Willebrand diseaseJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 12 2008M. BOWMAN Summary.,Background:,Given the challenges involved in obtaining accurate bleeding histories, attempts at standardization have occurred and the value of quantifying hemorrhagic symptoms has been recognized. Patients/methods:,An extensive validated bleeding questionnaire (MCMDM-1VWD) was condensed by eliminating all details that did not directly affect the bleeding score (BS) and the correlation between the two versions was tested. Additionally, the diagnostic utility of the condensed version was prospectively tested. Results:,Data on 259 individuals who were administered the questionnaire are presented here; 217 being prospectively investigated for von Willebrand disease (VWD) (group 1) and 42 previously known to have type 1, 2 or 3 VWD (group 2). Of the 217 prospectively investigated, 35 had positive BS (,4) and 182 had negative scores. Seven individuals (all with positive BS) had laboratory results consistent with type 1 VWD. This results in a sensitivity of 100% and a specificity of 87%. The positive predictive value is 0.20 and the negative predictive value is 1. The correlation between the full MCMDM-1VWD and condensed versions is excellent (Spearman's 0.97, P < 0.001, linear regression r2 = 96.4). Inter-observer reliability for the condensed version is reasonable (Spearman's 0.72, P < 0.001 and intra-class correlation coefficient 0.805, P < 0.001). There was a significant difference in BS between subtypes of VWD, with type 3 >> type 2 >> type 1 VWD (anovaP < 0.001). There is a strong inverse relationship between VWF:Ag level and BS (Spearman's ,0.411, P < 0.001). Conclusions:,The Condensed MCMDM-1VWD Bleeding Questionnaire is an efficient, effective tool in the evaluation of patients for VWD. [source] Expression studies on a novel type 2B variant of the von Willebrand factor gene (R1308L) characterized by defective collagen bindingJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 12 2005L. BARONCIANI Summary., A novel mutation, R1308L (3923G > T) was present in the heterozygous state in five members of a family with type 2B von Willebrand disease (VWD) characterized by a full set of von Willebrand factor (VWF) multimers in plasma and by the absence of thrombocytopenia before and after desmopressin (DDAVP). The defect (R1308L) was located at the same amino acid position of one of the most common mutations associated with type 2B VWD (R1308C), which is characterized by the loss of high molecular weight VWF multimers (HMWM) in plasma and the occurrence of thrombocytopenia. To understand the mechanisms of this defect, the novel (R1308L) and ,common' (R1308C) mutations were expressed in COS-7 cells, either alone or, to mimic the patients' heterozygous state, together with wild-type VWF. R1308L recombinant VWF (rVWF) had a higher affinity for the platelet glycoprotein Ib, (GPIb,) receptor than wild-type rVWF, R1308C rVWF showing an even higher affinity. A novel finding was that both mutant rVWFs showed a similarly reduced binding to collagen type I and type III in comparison with wild-type rVWF. The latter finding suggests a more important role than recognized so far for the VWF A1 domain in VWF binding to collagen, which may contribute to the in vivo hemostatic defect associated with type 2B VWD. [source] Cysteine-mutations in von Willebrand factor associated with increased clearanceJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 10 2005C. J. VAN SCHOOTEN Summary.,Background:,von Willebrand disease (VWD) is a bleeding disorder caused by the decrease of functional von Willebrand factor (VWF). Low levels of VWF can result from decreased synthesis, impaired secretion, increased clearance or combinations thereof. Several mutations lead to impaired synthesis or secretion of VWF, however, little is known about the survival of VWF in the circulation. Objectives:,To evaluate the effect of several VWF mutations on VWF clearance. Patients/methods:,The effect of three cysteine-mutations (C1130F, C1149R or C2671Y) on the in vivo survival of VWF was studied in patients carrying these mutations and in a VWF-deficient mice model. Results:,In patients carrying these mutations, we observed increased propeptide/mature VWF ratios and rapid disappearance of VWF from the circulation after desmopressin treatment. Detailed analysis of in vivo clearance of recombinant VWF in a VWF-deficient mice model revealed a fourfold increased clearance rate of the mutants. The mutations C1130F, C1149R and C2671Y are each associated with reduced survival of VWF in the circulation. Detailed analysis of the recombinant mutant VWF demonstrated that increased clearance was not due to increased proteolysis by ADAMTS-13. We did not identify functional or structural characteristics that the mutant proteins have in common and could be associated with the phenomenon of increased clearance. Conclusions:,Cysteine-mutations in VWF may result in reduced in vivo survival. The observation that various mutations are associated with increased in vivo clearance may have major implications for the therapeutic strategies that rely on the rise of endogenous VWF after desmopressin administration. [source] Clinical and laboratory diagnosis of von Willebrand disease: A synopsis of the 2008 NHLBI/NIH guidelines,AMERICAN JOURNAL OF HEMATOLOGY, Issue 6 2009William L. Nichols Von Willebrand factor (VWF) mediates blood platelet adhesion and accumulation at sites of blood vessel injury, and also carries coagulation factor VIII (FVIII) that is important for generating procoagulant activity. Von Willebrand disease (VWD), the most common inherited bleeding disorder, affects males and females, and reflects deficiency or defects of VWF that may also cause decreased FVIII. It may also occur less commonly as an acquired disorder (acquired von Willebrand syndrome). This article briefly summarizes selected features of the March 2008 evidence-based clinical and laboratory diagnostic recommendations from the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel for assessment for VWD or other bleeding disorders or risks. Management of VWD is also addressed in the NHLBI guidelines, but is not summarized here. The VWD guidelines are available at the NHLBI Web site (http://www.nhlbi.nih.gov/guidelines/vwd). Am. J. Hematol. 2009. © 2009 Wiley-Liss, Inc. [source] Inherited and de novo von Willebrand disease ,Vicenza' in UK families with the R1205H mutation: diagnostic pitfalls and new insightsBRITISH JOURNAL OF HAEMATOLOGY, Issue 1 2006William A. Lester Summary von Willebrand disease (VWD) caused by the R1205H mutation has distinct and reproducible clinical and laboratory features. This report describes the phenotypic and molecular investigation of seven kindreds with VWD Vicenza R1205H. All affected individuals have historically been diagnosed with moderate to severe type 1 VWD. Amongst all families with highly penetrant type 1 VWD investigated at our centre, heterozygosity for the R1205H mutation was found to be the most common underlying molecular defect. A severe laboratory phenotype associated with a bleeding history that was milder than expected was commonly observed, consistent with previous published case reports; however, abnormal ultralarge high molecular weight multimers were not detected in resting plasma samples. We also provide evidence that the R1205H mutation may arise de novo, evidence that a common genetic origin for this mutation is unlikely. [source] Measurement of von Willebrand factor binding to a recombinant fragment of glycoprotein Ib, in an enzyme-linked immunosorbent assay-based method: performances in patients with type 2B von Willebrand diseaseBRITISH JOURNAL OF HAEMATOLOGY, Issue 6 2006Claudine Caron Summary Type 2B von Willebrand disease (VWD) is characterised by an increased affinity of von Willebrand factor (VWF) for its platelet receptor glycoprotein Ib (GPIb). This feature is usually studied in vitro by a ristocetin-dependent VWF platelet-binding assay, which has some limitations as it requires [e.g. (radio)-labelled anti-VWF antibodies and normal formaldehyde-fixed platelets]. We, here, extended the applicability of an enzyme-linked immunosorbent assay-based method previously described for the measurement of ristocetin co-factor activity that used a recombinant fragment of GPIb (rfGPIb,) and horseradish peroxidase-labelled rabbit anti-human VWF antibodies for measuring the captured ristocetin-VWF complexes on the rfGPIb,. Thirty-one type 2B VWD patients from 15 families with eight different known mutations were studied. VWF in plasma from 28 of these patients bound better than normal VWF at 0·2 mg/ml ristocetin, with the ratio, optical density (OD) patient/OD normal pool plasma, higher than 1·8. For two of the three other patients with no enhanced response of plasma VWF, the platelet lysate VWF showed an enhanced binding capacity; for the last patient, the results in other members of the family are unequivocal. We conclude that, this new method for measurement of plasma or platelet VWF-binding capacity offers great advantages for correct type 2B VWD diagnosis. [source] Distinguishing between type 2B and pseudo-von Willebrand disease and its clinical importanceBRITISH JOURNAL OF HAEMATOLOGY, Issue 6 2006Mohammad S. Enayat Summary Pseudo-von Willebrand disease (p-VWD) and type 2B von Willebrand disease (VWD) have similar phenotypic parameters and clinical symptoms, but different aetiologies. Fourteen individuals from five families with a historical diagnosis of type 2B VWD but with no mutation in the von Willebrand factor gene were re-investigated for the possibility of p-VWD, using platelet aggregation in the presence of cryoprecipitate. p-VWD was confirmed by targeted DNA sequencing of the glycoprotein Ib, gene, identifying a heterozygous Glycine 233 Valine substitution. This study suggests that p-VWD may be under diagnosed, and that platelet aggregation in the presence of cryoprecipitate is useful in differentiating this disorder from type 2B VWD. [source] Gene conversions are a common cause of von Willebrand diseaseBRITISH JOURNAL OF HAEMATOLOGY, Issue 5 2005P. K. Gupta Summary von Willebrand disease (VWD), the most common inherited bleeding disorder, is very heterogeneous, both in its phenotype and genotype. One particular molecular mechanism of VWD is due to recombination events between the true gene and its pseudogene on chromosome 22. We assessed the frequency and extension of such events in 50 multi-ethnic index patients with severe VWD type 3 and in five index patients with VWD type 2M Vicenza. One additional unclassified patient had been diagnosed with possible VWD in Russia solely on a clinical basis. Gene conversions, previously thought to be rare events, were identified in >10% of our study population: in six multi-ethnic patients with severe VWD type 3, in one patient with VWD type 2M Vicenza and the Russian patient was finally diagnosed with VWD type 2B New York/Malmoe. Our results suggest a significant contribution of this particular molecular mechanism to the manifestation of VWD. The location of the gene conversions, their extension and their occurrence as homozygous, compound heterozygous or heterozygous mutations determines the resulting phenotype. [source] Efficacy and safety of a factor VIII,von Willebrand factor concentrate 8Y: stability, bacteriological safety, pharmacokinetic analysis and clinical experienceHAEMOPHILIA, Issue 5 2002A. Lubetsky Summary., The present study was undertaken to evaluate stability, pharmacokinetic profile and efficacy of continuous infusion of 8Y in patients with different types of von Willebrand disease (vWD). Following reconstitution, 8Y levels of von Willebrand factor ristocetin cofactor (vWF:Rco), vWF antigen and factor VIII coagulant activity (FVIII:C) decreased to about 80% of the baseline levels; addition of low molecular weight heparin decreased the level of FVIII:C even further. Reconstituted 8Y was found to be sterile for up to 6 days postreconstitution. Ten vWD patients (four with type 2A, three with type 3, two with type 1 and one with 2N) underwent pharmacokinetic analysis. The recovery of vWF: RCo was significantly lower in patients with type 3 vWD (1.4 ± 0.05% U,1 kg,1) compared withthat of the patients with types 1 (2.3 ± 0.52% U,1 kg,1) or 2A (2.0 ± 0.06% U,1 kg,1) vWD (P = 0.015). Type 3 vWD patients exhibited significantly higher vWF:RCo clearance (5.1 ± 1.1 mL kg,1 h,1) compared with that of patients with type 2A (2.8 ± 0.7 mL kg,1 h,1) and type 1 (2.6 ± 1.0 mL kg,1 h,1) vWD (P = 0.028). Accordingly, terminal half-life was lower in patients with type 3 vWD (8.0 ± 0.6 h,1) compared with type 2A (12.7 ± 5.9 h,1) or type 1 (14 ± 1.2 h,1) vWD patients. Multimeric pattern of vWF from patients' plasma was similar to that of 8Y. In two patients treated with 8Y by continuous infusion for prevention or treatment of bleeding haemostasis was achieved. Thus, 8Y is suitable and haemostatically effective for continuous infusion treatment in patients with vWD. [source] Use of ristocetin cofactor activity in the management of von Willebrand diseaseHAEMOPHILIA, Issue 2001B.M. Ewenstein von Willebrand disease (vWD), the most common of the hereditary bleeding disorders, arises from quantitative or qualitative defects in von Willebrand factor (vWF). vWF is a multimeric plasma protein that plays a key role in primary and secondary haemostasis. In the current classification scheme, vWD is divided into six subtypes that are based on the nature of the vWF defect. Therapeutic strategies depend on the accurate identification of these subtypes. In most clinical situations, desmopressin is effective treatment for the great majority of patients with mild (type 1) disease, while replacement therapy with factor VIII/vWF concentrates that contain high levels of vWF activity is required for most type 2 and nearly all type 3 vWD patients. Several factor VIII/vWF replacement products are available, one of which (Humate P) has been approved for the treatment of vWD by the US Food and Drug Administration. Preliminary results of recent studies support the hypothesis that treatment with factor VIII/vWF concentrates based upon the content of vWF activity as reflected in the ristocetin cofactor assay is practicable, safe and efficacious. The establishment of optimal treatment regimens with respect to dose intensity and duration will require further study. [source] vWD, Diagnosis and manifestationsHAEMOPHILIA, Issue 4 2000Article first published online: 9 OCT 200 [source] Adverse events during use of intranasal desmopressin acetate for haemophilia A and von Willebrand disease: a case report and review of 40 patientsHAEMOPHILIA, Issue 1 2000Dunn We report our experience with the incidence of adverse events during the use of Stimate® brand intranasal desmopressin acetate (IN DDAVP) for patients with haemophilia A (HA) or von Willebrand disease (vWD) after noting two severe adverse events in one adult patient. All patients with documented vWD (type 1 or 2 A) or haemophilia A (mild, moderate or symptomatic carrier) from the Emory Comprehensive Hemophilia Center who had IN DDAVP challenge testing or were using Stimate® for treatment of bleeding were evaluated for adverse events by patient report or nursing observation of clinical signs and symptoms. Forty patients were studied. Sixty-eight per cent (27/40) experienced clinical signs and/or symptoms. The majority of these symptoms were mild, however several patients reported moderate to severe side-effects and one adult patient required medical intervention for symptomatic hyponatraemia. In our experience, two-thirds of patients tested experienced adverse signs and/or symptoms with the use of Stimate®; considerably higher than that reported from preliminary results in the literature. Young age did not correlate positively with adverse reactions. Severe adverse events requiring medical intervention were rare, however symptoms such as moderate to severe headache, nausea, vomiting and weakness may necessitate evaluation for hyponatraemia. This is the first report of symptomatic hyponatraemia in an adult patient with recommended dosing of Stimate®. Side-effects may be minimized if patients adhere to instructions regarding fluid intake and composition while using IN DDAVP. [source] | ||||||||||