scholarly journals THE ROLE OF BLEEDING HISTORY AND CLINICAL MARKERS FOR THE CORRECT DIAGNOSIS OF VWD

2013 ◽  
Vol 5 (1) ◽  
pp. e2013051 ◽  
Author(s):  
Alberto Tosetto
Keyword(s):  
Correct Diagnosis ◽  
Von Willebrand Disease ◽  
Assessment Tools ◽  
Bleeding Tendency ◽  
Clinical Markers ◽  
Web Based ◽  
Bleeding Score ◽  
Bleeding History ◽  
Von Willebrand ◽  
Willebrand Factor

Quantification of the bleeding severity by use of bleeding assessment tools (BAT) and bleeding score (BS) has been consistently shown to improve the clinical diagnosis of von Willebrand disease (VWD) while helping researchers establish phenotype/genotype correlations.  Subjects with a BS equal or higher than 3 may be consider having a bleeding tendency, and should be referred for a laboratory investigation, particularly for VWD. In the diagnosis of type 1 VWD, the use of the BS has been shown to be highly specific (>95%) with reported sensitivities ranging from 40 to 100%. The BS is related to all available measurements of von Willebrand factor activity, including the PFA-100 closure time. Therefore, in clinical practice the use of BAT should always be the first step to standardize the assessment of patients with suspected VWD. The use of the recent ISTH consensus BAT is suggested to harmonize the collection of bleeding symptoms in patients with a suspected or confirmed hemostatic disorder, particularly VWD. The ISTH BAT is also coupled with a Web-based repository of bleeding symptoms, therefore providing an integrated framework for collaboration in the field of clinical evaluation of VWD and mild bleeding disorders.

How I treat von Willebrand disease

Blood ◽  
2009 ◽  
Vol 114 (6) ◽  
pp. 1158-1165 ◽  
Author(s):  
Francesco Rodeghiero ◽  
Giancarlo Castaman ◽  
Alberto Tosetto
Keyword(s):  
Molecular Basis ◽  
Normal Subjects ◽  
Von Willebrand Disease ◽  
Optimal Management ◽  
Multicenter Studies ◽  
Bleeding Score ◽  
Bleeding History ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Ristocetin Cofactor

Abstract Recent multicenter studies have clarified the molecular basis underlying the different von Willebrand disease (VWD) types, all of which are caused by the deficiency and/or abnormality of von Willebrand factor (VWF). These studies have suggested a unifying pathophysiologic concept. The diagnosis of VWD, remains difficult because its clinical and laboratory phenotype is very heterogeneous and may overlap with normal subjects. Stringent criteria are therefore required for a clinically useful diagnosis. In this paper, we delineate a practical approach to the diagnosis and treatment of VWD. Our approach is based on the critical importance of a standardized bleeding history that has been condensed into a final bleeding score and a few widely available laboratory tests, such as VWF ristocetin cofactor activity, VWF antigen and factor VIII. This approach would help identify those subjects who will probably benefit from a diagnosis of VWD. The next step involves performing a trial infusion with desmopressin in all patients who fail to exhibit an enhanced responsiveness to ristocetin. On the basis of these results and through a series of illustrative examples, the clinician will be able to select the best approach for the optimal management of VWD, according to the patient's characteristics and clinical circumstances.

scholarly journals Bleeding scores: are they really useful?

Hematology ◽  
2012 ◽  
Vol 2012 (1) ◽  
pp. 152-156 ◽  
Author(s):  
Sarah H. O'Brien
Keyword(s):  
Laboratory Testing ◽  
Clinical Applications ◽  
Von Willebrand Disease ◽  
Assessment Tools ◽  
Bleeding Disorders ◽  
Clinical Markers ◽  
Precise Quantification ◽  
Bleeding Score ◽  
Von Willebrand

Abstract Given the commonality of bleeding symptoms in the general population and the diagnostic limitations of available laboratory testing for mild bleeding disorders, there has been increasing interest in a more precise quantification of bleeding symptoms. The Vicenza bleeding score (and its successor, Molecular and Clinical Markers for the Diagnosis and Management of Type 1 von Willebrand disease [MCMDM-1 VWD]) and its pediatric counterpart, the Pediatric Bleeding Questionnaire, are validated research tools that have demonstrated their ability to discriminate between healthy subjects and those with VWD. These instruments collect data regarding both the presence and severity of a variety of bleeding symptoms and generate a bleeding score by summing the severity of all symptoms reported by a subject. More recent work demonstrates the promise of these tools as a diagnostic aid in the evaluation of patients with a suspected inherited mild bleeding disorder, as well as the development of a condensed score with increased clinical applicability. This review focuses on the development of these bleeding assessment tools, recent publications applying and refining these instruments, and current limitations of bleeding scores. Needed research studies and potential clinical applications of bleeding scores are also discussed. The ultimate goal would be for bleeding scores to be integrated with the results of standardized laboratory testing to allow for a universal diagnostic approach to patients with suspected bleeding disorders.

scholarly journals PATIENTS REFERRED FOR BLEEDING SYMPTOMS OF UNKNOWN CAUSE: DOES EVALUATION OF THROMBIN GENERATION CONTRIBUTE TO DIAGNOSIS?

2016 ◽  
Vol 8 ◽  
pp. 2016014 ◽  
Author(s):  
Elena Holm ◽  
Eva Zetterberg ◽  
Susanna Lövdahl ◽  
Erik Berntorp
Keyword(s):  
Thrombin Generation ◽  
Assessment Tool ◽  
Correlation Coefficients ◽  
Von Willebrand Disease ◽  
Assessment Tools ◽  
Clotting Factors ◽  
Viii And Ix ◽  
Bleeding Score ◽  
Von Willebrand ◽  
Willebrand Factor

IntroductionPatients with mild to moderate bleeding symptoms referred for coagulation investigation sometimes never receive a definitive diagnosis. Bleed assessment tools have been developed and validated to assess the severity of symptoms. Global coagulation assays, e.g., the thrombin generation test (thrombogram) have a potential to identify hemostatic defects that are not detected in specific assays.Material and MethodsOne hundred and eighty-five patients referred to our centre because of bleeding symptoms were evaluated using  the bleeding assessment tool (BAT) described by Tosetto and colleagues in 2006.  Blood samples were investigated for thrombin generation (TG) capacity (Technoclone) , in platelet poor (PPP)  plasma , and specific clotting factors, i.e, von Willebrand factor, factor VIII and IX, as well as INR, APTT, platelet count, and platelet adhesion.ResultsOf the 185 patients, five women were diagnosed with mild von Willebrand disease and one male with mild hemophilia A. The remaining 179 subjects (76% females and 24% males with average ages of 33 and 28 years, respectively) were evaluated further. In the total cohort and among women, peak TG, and lag time   correlated with bleeding score (p=0.01 and p=0.04, respectively with correlation coefficients).  No such correlations were found among males. Discussion and conclusion Although our study showed some correlation between TG and bleeding score, results are generally consistent with a previous report which failed to demonstrate the value of TG measurement in a similar setting. In conclusion, the complexity of the mechanisms underlying clinical bleeding complicates the ability to use TG tests as reliable predictors of bleeding. Mild congenital bleeding disorders, especially VWD, should be specifically screened for in patients with mild/moderate symtoms.

The Genetic Defect of Type I von Willebrand Disease “Vicenza” Is Linked to the von Willebrand Factor Gene

1993 ◽  
Vol 69 (02) ◽  
pp. 173-176 ◽  
Author(s):  
Anna M Randi ◽  
Elisabetta Sacchi ◽  
Gian Carlo Castaman ◽  
Francesco Rodeghiero ◽  
Pier Mannuccio Mannucci
Keyword(s):  
Von Willebrand Factor ◽  
Autosomal Dominant ◽  
Genetic Defect ◽  
Von Willebrand Disease ◽  
Type I ◽  
Bleeding Tendency ◽  
Factor Gene ◽  
Low Levels ◽  
Von Willebrand ◽  
Willebrand Factor

SummaryType I von Willebrand disease (vWD) Vicenza is a rare variant with autosomal dominant transmission, characterized by the presence of supranormal von Willebrand factor (vWF) multimers in plasma, similar to those normally found in endothelial cells and megakaryocytes. The patients have very low levels of plasma vWF contrasting with a mild bleeding tendency. The pathophysiology of this subtype is still unknown. The presence of supranormal multimers in the patients’ plasma could be due to a mutation in the vWF molecule which affects post-translational processing, or to a defect in the cells’ processing machinery, independent of the vWF molecule. In order to determne if type I vWD Vicenza is linked to the vWF gene, we studied six polymorphic systems identified within the vWF gene in two apparently unrelated families with type I vWD Vicenza. The results of this study indicate a linkage between vWF gene and the type I vWD Vicenza trait. This strongly suggests that type I vWD Vicenza is due to a mutation in one of the vWF alleles, which results in an abnormal vWF molecule that is processed to a lesser extent than normal vWF.

Autoantibody Selectively Inhibits Binding of von Willebrand Factor to Glycoprotein Ib. Recognition Site Is Located in the A1 Loop of von Willebrand Factor

1997 ◽  
Vol 77 (04) ◽  
pp. 760-766 ◽  
Author(s):  
Hiroshi Mohri ◽  
Etsuko Yamazaki ◽  
Zekou Suzuki ◽  
Toshikuni Takano ◽  
Shumpei Yokota ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Significant Inhibition ◽  
Von Willebrand Disease ◽  
Recognition Site ◽  
Severe Bleeding ◽  
Bleeding Tendency ◽  
Virtual Absence ◽  
Heavy Chains ◽  
Von Willebrand ◽  
Willebrand Factor

SummaryA 20-year-old man with severe von Willebrand disease recently presented a progressive bleeding tendency, characterized recurrent subcutaneous hemorrhages and cerebral hemorrhage. Mixing and infusion studies suggested the presence of an inhibitor directed against vWF:RCo activity of von Willebrand factor (vWF) without significant inhibition of the FVIII:C. The inhibitor was identified as an antibody of IgG class. The inhibitor inhibited the interaction of vWF in the presence of ristocetin and that of asialo-vWF with GPIb while it partially blocked botrocetin-mediated interaction of vWF to GPIb. The inhibitor reacted with native vWF, the 39/34kDa fragment (amino acids [aa] 480/ 481-718) and the recombinant vWF fragment (MalE-rvWF508-704), but not with Fragment III-T2 (heavy chains, aa 273-511; light chains, aa 674-728). A synthetic peptide (aa 514-542) did not inhibit vWF-inhibitor complex formation. We conclude that this is the first autoantibody of class IgG from human origin that recognizes the sequence in the A1 loop of vWF, resulting in a virtual absence of functional vWF and a concomitant severe bleeding tendency although recognition site is different from the residues 514-542 which is crucial for vWF-GPIb interaction.

scholarly journals Acquired von Willebrand disease caused by an autoantibody selectively inhibiting the binding of von Willebrand factor to collagen

Blood ◽  
1994 ◽  
Vol 84 (10) ◽  
pp. 3378-3384 ◽  
Author(s):  
PJ van Genderen ◽  
T Vink ◽  
JJ Michiels ◽  
MB van 't Veer ◽  
JJ Sixma ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Binding Activity ◽  
Von Willebrand Disease ◽  
Low Grade ◽  
Bleeding Tendency ◽  
Glycoprotein Ib ◽  
Acquired Von Willebrand Disease ◽  
Recurrent Epistaxis ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract An 82-year-old man with a low-grade malignant non-Hodgkin lymphoma and an IgG3 lambda monoclonal gammopathy presented a recently acquired bleeding tendency, characterized by recurrent epistaxis, easy bruising, and episodes of melena, requiring packed red blood cell transfusions. Coagulation studies showed a von Willebrand factor (vWF) defect (Ivy bleeding time, > 15 minutes; vWF antigen [vWF:Ag], 0.08 U/mL; ristocetin cofactor activity [vWF:RCoF], < 0.05 U/mL; collagen binding activity [vWF:CBA], 0.01 U/mL; absence of the high molecular weight multimers of vWF on multimeric analysis). Mixing experiments suggested the presence of an inhibitor directed against the vWF:CBA activity of vWF without significantly inhibiting the FVIII:C, vWF:Ag, and vWF:RCoF activities. The inhibitor was identified as an antibody of the IgM class by immunoabsorption of vWF and inhibitor-vWF complexes from the plasma of the patient. Subsequent immunoprecipitation experiments using recombinant fragments of vWF showed that the inhibitor reacted with both the glycoprotein Ib binding domain (amino acids [aa] 422–826) and the A3 (aa 909–1112) domain of vWF, but not with the A2 (aa 716–908) or D4 (aa 1183–1535) domains. We conclude that the IgM autoantibody inhibits the vWF:CBA activity by reacting with an epitope present on both the glycoprotein Ib and A3 domains of vWF.

scholarly journals Rare Occurrence of Inhibitors in Von Willebrand Disease: A Case Report

2022 ◽  
Vol 8 ◽  
Author(s):  
Bipin P. Kulkarni ◽  
Kirti Ghargi ◽  
Chandrakala Shanmukhaiah ◽  
Shrimati D. Shetty
Keyword(s):  
Correct Diagnosis ◽  
Severe Form ◽  
Von Willebrand Disease ◽  
Rare Occurrence ◽  
Standard Assay ◽  
Type 3 ◽  
Von Willebrand ◽  
High Degree ◽  
Willebrand Factor ◽  
Inhibitor Titer

Introduction: Type 3 Von Willebrand Disease (VWD) is the least common but the most severe form of a disease, with a prevalence of about 0. 5 to 1 per million in Western countries. The prevalence of type 3 VWD in the developing countries, with a high degree of consanguinity, is about 6 per million. Moreover, due to underdiagnosis of the milder cases, the prevalence of type 3 VWD is about 50% of the cases. Rarely, some patients develop the Von Willebrand Factor (VWF) inhibitors, which may subsequently develop severe anaphylactic reactions on further exposure to the VWF containing factor replacement therapy. The prevalence of inhibitor development in patients with type 3 VWD has been shown to be in the range of 5.8 to 9.5%. In the absence of a gold standard assay for the quantitation of VWF inhibitors, a correct diagnosis and management of these patients are often challenging.Objectives: The objective of this study is to standardize the Bethesda assay for the VWF inhibitors and to estimate the VWD inhibitor titer in two cases of congenital type 3 VWD, which developed the VWF inhibitors.Results and Conclusions: We could successfully standardize the Bethesda assay for the quantitation of VWF inhibitors in two patients with congenital type 3 VWD with inhibitors.

Reduced von Willebrand factor survival in type Vicenza von Willebrand disease

Blood ◽  
2002 ◽  
Vol 99 (1) ◽  
pp. 180-184 ◽  
Author(s):  
Alessandra Casonato ◽  
Elena Pontara ◽  
Francesca Sartorello ◽  
Maria Grazia Cattini ◽  
Maria Teresa Sartori ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Von Willebrand Disease ◽  
Bleeding Tendency ◽  
Normal Platelet ◽  
Cofactor Activity ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Ristocetin Cofactor ◽  
Ristocetin Cofactor Activity ◽  
Original Type

Type Vicenza variant of von Willebrand disease (VWD) is characterized by a low plasma von Willebrand factor (VWF) level and supranormal VWF multimers. Two candidate mutations, G2470A and G3864A at exons 17 and 27, respectively, of the VWF gene were recently reported to be present in this disorder. Four additional families, originating from northeast Italy, with both mutations of type Vicenza VWD are now described. Like the original type Vicenza subjects, they showed a mild bleeding tendency and a significant decrease in plasma VWF antigen level and ristocetin cofactor activity but normal platelet VWF content. Unlike the original patients, ristocetin-induced platelet aggregation was found to be normal. Larger than normal VWF multimers were also demonstrated in the plasma. Desmopressin (DDAVP) administration increased factor VIII (FVIII) and VWF plasma levels, with the appearance of even larger multimers. However, these forms, and all VWF oligomers, disappeared rapidly from the circulation. The half-life of VWF antigen release and of elimination was significantly shorter than that in healthy counterparts, so that at 4 hours after DDAVP administration, VWF antigen levels were close to baseline. Similar behavior was demonstrated by VWF ristocetin cofactor activity and FVIII. According to these findings, it is presumed that the low plasma VWF levels of type Vicenza VWD are mainly attributed to reduced survival of the VWF molecule, which, on the other hand, is normally synthesized. In addition, because normal VWF-platelet GPIb interaction was observed before or after DDAVP administration, it is proposed that type Vicenza VWD not be considered a 2M subtype.

scholarly journals Impact of Two Immobilized GPIbα Assays in the Diagnosis of Von Willebrand Disease

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1524-1524
Author(s):  
Silmara Lima Montalvão ◽  
Sandra Martins Silva Soares ◽  
Marina P Colella ◽  
Joyce M Annichino-Bizzacchi ◽  
Samuel de Souza Medina ◽  
...  
Keyword(s):  
Sensitivity And Specificity ◽  
False Positive ◽  
New Technologies ◽  
Von Willebrand Disease ◽  
The Other ◽  
Bleeding Score ◽  
Bleeding History ◽  
Von Willebrand ◽  
Positive Results

Abstract The diagnosis of von Willebrand Disease (VWD) remains a challenge of daily hematology practice. Ristocetin cofactor activity (VWF:RCo) is an important parameter for the diagnosis of VWD and is also essential for its management. However, reproducibility of the available tests for VWF:RCo is still a major issue, as evidenced by coefficient of variations (CV) as high as 30%, 45% and 27% in the ECAT, NEQAS and PALQ external quality assessment program. Classical methods to measure VWF:RCo include light-transmission platelet agregometry (LPA) and visual agglutination with formaldehyde fixed human platelet (VA), and more recently, VWF activity based on automated latex immunoassay (LIA). The glycoprotein (GP) Ibα is the main receptor for von Willebrand factor (VWF) in the platelet membrane. Currently, two automated methods with immobilized GPIbα have been developed to improve the sensitivity and specificity of VWF:RCo. One of them is performed with ristocetin while the other one uses a mutant GPIbα with gain of function and does not require ristocetin. This study aims to compare the two assays using immobilized GPIbα with other four assays for VWF functional determination, in patients with confirmed and under investigation for VWD. We evaluated six different VWF functional assays: VWF:RCo LPA (Chrono-Log); VA (Siemens); VA in house (with ristocetin from Chrono-Log); automated-LIA (Hemosil); in comparison to two assays using immobilized GPIbα with or without ristocetin, the GPIbα-ristocetin (Hemosil), and GPIbα-mutant (Siemens Innovance). Reference ranges for each method were established in 20 healthy adults. Plasma samples collected at the same time from 40 individuals were used in this comparative study, with 25 type 1 VWD, 2 type 3 VWD, and 13 under investigation. Diagnosis of VWD was based on bleeding history (evaluated by MCMDM-1VWD Bleeding Score), historical levels of VWF antigen (VWF:Ag) by ELISA, and VWF:RCo (assayed by LTA or VA) obtained from medical records. Statistical analysis were performed based on linear regression (Spearman correlation), agreement test (Altman Bland), and chi-square test using Prism 6.0. When all 40 patients were evaluated for both methods, GPIbα-ristocetin and GPIbα-mutant, we observed a good coefficient of correlation (r = 0.8954; p<0.0001). However, when 7 type 1 VWD patients, and 1 under investigation case were evaluated for the six methods, the two using immobilized GPIbα showed lower median (16.78 ± 4.62 with GPIbα-ristocetin, and 16.28 ± 4.29 with GPIbα-mutant), when compared with the other four assays (LTA: 22.38 ± 5.5; VA in house: 21.45 ± 4.87; VA Siemens: 22.65 ± 4.9; and LIA: 24.19 ± 9.0). In this group, when the bleeding score (BS) were ≥ 5, the VWF functional results were lower than 25 IU/dL, using all six methods (figure). Among 13 individuals under VWD investigation, GPIbα-ristocetin and GPIbα-mutant showed good agreement with the LTA/VA results and clinical history, and we could concluded that 4 have VWD, and for 4 individuals VWD was excluded. However, 2 individuals with no history of bleeding presented abnormal results for GPIbα-ristocetin and GPIbα-mutant, showing probably false positive results. One patient with no bleeding history, and abnormal LTA/VA results had normal GPIbα-ristocetin and GPIbα-mutant results, demonstrating poor reproducibility and precisian of the classical methods. On the other hand, two patient with BS 6, the diagnosis of VWD was demonstrating only by immobilized GPIbα methods. The VWF:RCo is a cumbersome assay and can be affected by polymorphisms present in the ristocetin binding site of VWF. Recently, new technologies have been developed to improve the VWF functional evaluation. It is consensus that methodologies using platelets are more accurate than other methods. Therefore, immobilized GPIbα has the objective to improve the sensitivity and specificity. Besides good results of concordance between immobilized GPIbα in the group of VWD patients and for 62% individual under investigation, we also observed false positive results related with these methods. The presence or absence of ristocetin on the immobilized GPIbα setting appear not engender different results in this study. In general, this new technologies present better precision compared to VA and LTA. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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