Laboratory Diagnosis of von Willebrand Disease

2009 ◽  
Vol 03 (01) ◽  
pp. 33 ◽  
Author(s):  
Muriel Meiring ◽  
Philip N Badenhorst ◽  
Mareli Kelderman ◽  
◽  
◽  
...  
Keyword(s):  
Factor Viii ◽  
Correct Diagnosis ◽  
Laboratory Diagnosis ◽  
Binding Activity ◽  
Von Willebrand Disease ◽  
Coagulant Activity ◽  
Low Sensitivity ◽  
Von Willebrand ◽  
Willebrand Factor

von Willebrand disease (VWD) is a bleeding disorder caused by either quantitative (type 1 and 3) or qualitative (type 2) defects of von Willebrand factor (VWF). No single available test provides appropriate information about the various functions of VWF, and the laboratory diagnosis of VWD is based on a panel of tests, including the measurement of factor VIII coagulant activity (FVIIIC), VWF antigen levels (VWF:Ag), VWF activity as measured by the ristocetin co-factor activity (VWF:RCo), the collagen-binding activity of VWF (VWF:CB), VWF multimer analysis, ristocetininduced platelet agglutination (RIPA), the factor-VIII-binding assay of plasma VWF and VWF propeptide levels. Due to the heterogeneity of VWF defects and the variables that interfere with VWF levels, a correct diagnosis of types and subtypes may sometimes be difficult, but is very important for therapy. Furthermore, the RCo assay and the RIPA test are based on platelet agglutination in reaction with the non-physiological antibiotic ristocetin. These tests also have low sensitivity and are difficult to standardise. Therefore, several analyses (tests) are required to diagnose VWD and it is important to be aware of the pitfalls to which these tests are subjected in terms of the diagnosis. In this article, the laboratory diagnosis of patients with type 1, 2A, 2B, 2M, 2N and 3 VWD will be explained by using a modified algorithm that was first proposed by the guidelines for diagnosis and treatment of VWD in Italy.

Managing Patients with von Willebrand Disease Type 1, 2 and 3 with Desmopressin and von Willebrand Factor-Factor VIII Concentrate in Surgical Settings

2009 ◽  
Vol 121 (2-3) ◽  
pp. 167-176 ◽  
Author(s):  
Jan Jacques Michiels ◽  
Huub H.D.M. van Vliet ◽  
Zwi Berneman ◽  
Wilfried Schroyens ◽  
Alain Gadisseur
Keyword(s):  
Factor Viii ◽  
Von Willebrand Factor ◽  
Disease Type ◽  
Von Willebrand Disease ◽  
Von Willebrand ◽  
Willebrand Factor

Von Willebrand Factor Levels Do Not Increase with Age in Patients with Type 1 Von Willebrand Disease.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4028-4028
Author(s):  
Hong I. Tarng ◽  
Lynne Taylor ◽  
Barbara A. Konkle
Keyword(s):  
Factor Viii ◽  
Von Willebrand Factor ◽  
Von Willebrand Disease ◽  
Test Results ◽  
Age Related ◽  
One Year ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Over Time

Abstract A number of inherited and acquired factors modulate von Willebrand factor antigen (VWF:Ag) levels, including blood type, race, activity and stress level, thyroid hormone status, and, in women, time in menstrual cycle. In reported studies a positive correlation between VWF:Ag and/or factor VIII levels and age has been demonstrated, with an increase of 5 – 6 IU/dL per decade (Conlan MG et al, 1993; Kamphuisen PW et al, 1998). Those studies have primarily assessed VWF and factor VIII as risk factors for ischemic heart disease, cerebrovascular disease, and venous thromboembolism. None of the subjects had von Willebrand disease (VWD). Their VWF:Ag levels were in the higher normal or elevated range. The purpose of this study was to determine whether there is a relationship between age and VWF:Ag level in patients with Type 1 VWD. We collected the data from 36 patients who were diagnosed with type 1 VWD and followed at the Penn Comprehensive Hemophilia and Thrombosis Program up to a period of 13 years (See Table 1 below). For each patient, date of birth, VWF:Ag levels with corresponding test dates were collected by reviewing the medical histories and the lab results. Test results obtained during pregnancy, DDAVP testing, or during prophylaxis or therapy for bleeding control were excluded. One year was set as the observation period, so the adjacent VWF:Ag levels that were tested less than one year were excluded from the dataset. When two test results were available on a patient within a one-year period, the lower test result was used. To investigate whether there was a relationship between VWF:Ag levels and age, cross-sectional analyses (across each visit) and longitudinal analyses were performed using scatter plots, Spearman and Pearson correlations, and regression analysis. No significant increase in VWF:Ag levels with age was demonstrated. The fact that we did not find an increase in VWF:Ag levels over time in our patients could be due to the relatively small number of patients studied or could reflect a subtype of VWD, due to our selection criteria. Only patients with abnormal values were included. Some patients have a prior diagnosis of VWD and bleeding symptoms, but have normal values when tested. Since these patients are adults, this may be due, at least in part, to an age-related increase. Type 1 VWD may occur secondary to decreased VWF synthesis and/or clearance. It is possible that age-related effects on VWF levels will differ depending on the underlying factor(s) resulting in a lower VWF level. Further studies correlating a patient’s values longitudinally with the underlying pathophysiology of their disease would aid in our understanding of their bleeding risks over time. Patient # Age at Last Visit, range (mean) Females (%) Race % (Cauc/AA/Other) VWF:Ag mean 36 17–70 (34) 89 78/19/3 49%

The Clinical Utility of the 1-Deamino-8-D-Arginine Vasopressin (DDAVP) Trial in the Management of Patients with Von Willebrand Disease: A Retrospective Study.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1033-1033
Author(s):  
Stephen S. Opat ◽  
Jake Shortt ◽  
Malgorzata B. Gorniak ◽  
Heather A. Aumann ◽  
Margaret F. Collecutt ◽  
...  
Keyword(s):  
Factor Viii ◽  
Complete Response ◽  
Binding Activity ◽  
Von Willebrand Disease ◽  
Therapeutic Trial ◽  
Normal Range ◽  
Suboptimal Responder ◽  
Post Infusion ◽  
Von Willebrand

Abstract DDAVP has been shown to be effective in securing hemostasis in certain patients with mild and moderate von Willebrand disease (vWD) undergoing hemostatic challenge. However as the response to this agent is heterogeneous, it is currently recommended that patients with vWD undergo a therapeutic trial of this agent prior to any elective invasive procedures. We performed a retrospective review of DDAVP response in patients with vWD in order to determine which patient groups most benefit from a DDAVP trial, and the optimum testing protocol, particularly examining the need to recall the patient for testing at 24 hours. Between 1990–2006 we identified 129 patients undergoing DDAVP trial for a historical diagnosis of vWD based on a previous low von Willebrand factor antigen (vWF:Ag), ristocetin cofactor activity (vWF:RiCoF) or collagen-binding activity (vWF:CBA), and a bleeding history. Twenty-one patients were excluded from analysis having normal vWD parameters prior to DDAVP infusion. The median age of patients was 25 years, (range 4–64), with 60% being female. The distribution of vWD subtypes was as follows: 94 type 1, eight type 2A, and six with a bleeding phenotype and no abnormality other than mildly reduced vWF:RiCoF. DDAVP was administered by IV infusion with samples taken for testing pre-infusion and between 1–2 hours post infusion. Additional testing at 24 hours was performed in the majority after 2003. A complete response (CR) was defined as an increase in all vWD parameters to within the normal range (vWF:Ag [50–200%], vWF:RiCoF [50–150%], vWF:CBA [50–200%]); a partial response (PR), an increase to between 30% and lower limit of normal. Results: In the type 1 vWD cohort, at one hour post infusion 75/94 experienced CR, 15/94 PR and 4/94 no response (NR). All patients with baseline vWF:Ag >15% and vWF:CBA >9% responded. Virtually all patients with a baseline vWF:Ag >25%, vWF:RiCoF >25% and a vWF:CBA >27% had a CR at one hour. Factor VIII levels reached normal levels in all cases regardless of vWF responses. No patient with type 2A responded, and all patients with mildly reduced RiCoF in isolation achieved CR. Nineteen patients with type 1 disease underwent testing at 24 hours. 13/15 with type 1 and a CR at one hour had adequate (>30%) levels at 24 hours. None of four patients with a PR at one hour had adequate levels at 24 hours. Median vWF:Ag and vWF:CBA levels were approximately 20% above initial levels at 24 hours in the responders. Conclusions: Patients with type 2A, and type 1 vWD with baseline vWF:Ag ≤15% and vWF:CBA ≤9% should not undergo DDAVP trial as they are unlikely to respond. Patients with type 1 vWD and baseline vWF:Ag >25%, vWF:RiCoF >25% and vWF:CBA >27%, or others with isolated low vWF:RiCoF and bleeding phenotype, need not undergo a DDAVP trial to establish efficacy. However, these patients may still require a DDAVP trial for assessment of safety and tolerability. It is not essential to measure factor VIII levels in patients who are undergoing a DDAVP trial. All patients with vWD parameters in the normal range one hour following DDAVP should be considered for further testing at 24 hours to identify the occasional suboptimal responder. Implementation of this testing strategy would reduce the requirement for DDAVP trials by approximately 35%, based upon our series.

scholarly journals Type 2M:Milwaukee-1 von Willebrand disease: an in-frame deletion in the Cys509-Cys695 loop of the von Willebrand factor A1 domain causes deficient binding of von Willebrand factor to platelets

Blood ◽  
1996 ◽  
Vol 88 (7) ◽  
pp. 2559-2568 ◽  
Author(s):  
DJ Mancuso ◽  
PA Kroner ◽  
PA Christopherson ◽  
EA Vokac ◽  
JC Gill ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Genetic Defect ◽  
Binding Activity ◽  
Von Willebrand Disease ◽  
Variant Form ◽  
New Variant ◽  
A1 Domain ◽  
Von Willebrand ◽  
Willebrand Factor

This report examines the genetic basis of a variant form of moderately severe von Willebrand disease (vWD) characterized by low plasma von Willebrand factor antigen (vWF:Ag) levels and normal multimerization, typical of type 1 vWD, but disproportionately-low agonist-mediated platelet-binding activity. We identified an in-frame deletion in vWF exon 28 in three generations of affected family members, who are heterozygous for this mutation. The deletion of nucleotides 4,173–4,205 results in the loss of amino acids Arg629-Gln639 in the Cys509-Cys695 loop of the A1 domain in mature vWF. The secreted mutant vWF showed a normal multimeric profile but did not bind to platelets in the presence of optimal concentrations of either ristocetin or botrocetin. The mutant vWF also failed to interact with heparin, and with vWF monoclonal antibody AvW3, which blocks the binding of vWF to GPlb. In addition, mutant vWF showed reduced secretion from transfected cells concomitant with increased intracellular levels. These results confirm that the deletion is the genetic defect responsible for the reduced interaction of vWF with platelets. We have designated this new variant type 2M:Milwaukee-1 vWD. Our analysis suggests that the potential frequency of this phenotype in individuals diagnosed with type 1 vWD is about 0.5%.

2B or not 2B? Disparate discrimination of functional VWF discordance using different assay panels or methodologies may lead to success or failure in the early identification of type 2B VWD

2007 ◽  
Vol 98 (08) ◽  
pp. 346-358 ◽  
Author(s):  
Roslyn Bonar ◽  
Muriel Meiring ◽  
Alison Street ◽  
Katherine Marsden ◽  
Emmanuel Favaloro ◽  
...  
Keyword(s):  
Early Identification ◽  
Correct Diagnosis ◽  
Diagnostic Errors ◽  
Von Willebrand Disease ◽  
External Quality ◽  
Platelet Aggregometry ◽  
Von Willebrand ◽  
Willebrand Factor

SummaryLaboratory proficiency in the identification of functional von Willebrand factor (VWF) discordance in type 2B von Willebrand disease (VWD) was assessed by external quality assurance surveys conducted by the RCPA Haematology QAP, and using six different type 2B VWD plasma samples (three historical and three previously unpublished) tested by up to 52 laboratories. For the three most recent samples, functional VWF discordance was either not identified in testing or by interpretation with misidentification as ‘normal’ or ‘type 1 VWD’, on average for 25.7% of test occasions when laboratories performed VWF:Ag and VWF:RCo as their primary VWF test panel, but somewhat fewer occasions (10.9%) for laboratories that incorporated VWF:CB as an additional functional VWF assay. VWF assay sub-methodologies also influenced the appropriate identification of samples as potentially type 2 VWD, and VWF functional discordance was more consistently identified when laboratories used (i) automated platelet agglutination for VWF:RCo compared to classical platelet aggregometry, (ii) inhouse VWF:CB assays compared to commercial kit methods, and (iii) automated LIA-based ‘VWF:Activity’ assays compared to ELISA based assays.We conclude that:(i) laboratories are generally proficient in tests for VWD but interpretative diagnostic errors do occur; (ii) correct diagnosis is more likely when test panels are more comprehensive and include the VWF:CB; (iii) sub-methodology influences the appropriate identification of VWF functional discordance. On the basis of these findings, we provide a series of recommendations to enable the appropriate laboratory identification of VWD, in particular type 2B VWD.

Laboratory diagnosis of von Willebrand disease

2010 ◽  
Vol 30 (04) ◽  
pp. 203-206 ◽  
Author(s):  
R. Schneppenheim ◽  
J. Patzke
Keyword(s):  
Laboratory Diagnosis ◽  
Binding Activity ◽  
Von Willebrand Disease ◽  
Activity Assay ◽  
Binding Assays ◽  
New Type ◽  
Von Willebrand ◽  
Made In

SummaryOver the last decade, considerable progress has been made in the laboratory diagnosis of VWD. Precise, sensitive and automated VWF : Ag assays became widely available. The VWF : RCo performance was improved to a certain degree. However, the sensitivity, precision and general availability of automated applications is not yet optimal. Nevertheless, this type of assay is still recognized as superior to other activity assays, e. g. VWF : CBA assays and antibody-binding “activity” assays, for the detection of defects in VWF function.A decision limit of either 30 or 40 IU dl-1 VWF (VWF:RCo or VWF:Ag) is recommended for a diagnosis of type 1 VWD. Type 2 VWD can be differentiated from type 1 by calculating the VWF:RCo/VWF:Ag ratio.Improved and easier to perform multimer analysis and genetic testing are beginning to facilitate the diagnosis of the VWD type 1, 2A, 2B, 2N, 2M or 3. Within type 1 or 2, a decreased VWF survival can be detected by the VWFpp assay and its ratio to VWF : Ag.A new type of VWF activity assay, based on the binding of VWF to a GPIb〈-fragment, has been developed. One assay variant does not need ristocetin as a cofactor anymore. The performance investigations presented so far are very promising. It is probable that these GPIb〈-binding assays will detect functional VWF defects as the VWF : RCo assay, but are much more sensitive and precise. Fully automated applications on routine analyzers are expected to be commercialized soon.

scholarly journals Bleeding Symptoms and von Willebrand Factor Levels: 30-Year Experience in a Tertiary Care Center

2019 ◽  
Vol 25 ◽  
pp. 107602961986691
Author(s):  
Chatphatai Moonla ◽  
Benjaporn Akkawat ◽  
Yaowaree Kittikalayawong ◽  
Autcharaporn Sukperm ◽  
Mukmanee Meesanun ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Care Center ◽  
Tertiary Care ◽  
Bleeding Risk ◽  
Binding Activity ◽  
Von Willebrand Disease ◽  
Von Willebrand ◽  
Willebrand Factor

Correlations between bleeding symptoms and von Willebrand factor (VWF) levels may help to predict hemorrhagic severity in the Westerners with von Willebrand disease (VWD), but data in Asians are lacking. In this study, Thai patients with VWF levels <50 IU/dL without any secondary causes were enrolled from 1988 to 2018 to determine the relationship between VWF levels and hemorrhagic manifestations. According to the current concept, we reclassified VWD and low VWF by VWF levels ≤30 and 30 to 50 IU/dL, respectively. Type 2 VWD was diagnosed if VWF activity to antigen ratio was ≤0.6. Bleeding severity was determined by the condensed MCMDM-1VWD bleeding score (BS). Among 83 patients, VWF activities showed negative correlations with BS ( P = .001), which were higher in type 2 (median: 7, interquartile range [IQR]: 5-11) compared with type 1 VWD (median: 3, IQR: 2-4) and low VWF (median: 4, IQR: 2-8). Bleeding symptoms were indistinguishable between type 1 VWD and low VWF using the 30 IU/dL cutoff point. However, VWF ristocetin cofactor activity or gain-of-function mutant glycoprotein Ib binding activity <36.5 IU/dL and VWF collagen binding activity <34.5 IU/dL could predict increased bleeding risk (BS ≥3) by 92.3% specificity and 70.0% sensitivity ( P < .0001).

scholarly journals New advances in the diagnosis of von Willebrand disease

Hematology ◽  
2019 ◽  
Vol 2019 (1) ◽  
pp. 596-600
Author(s):  
Ruchika Sharma ◽  
Sandra L. Haberichter
Keyword(s):  
Diagnostic Algorithm ◽  
Laboratory Diagnosis ◽  
Binding Activity ◽  
Von Willebrand Disease ◽  
Assessment Tools ◽  
Molecular Testing ◽  
Platelet Binding ◽  
History Of ◽  
Von Willebrand

Abstract von Willebrand disease (VWD) is the most common autosomal inherited bleeding disorder, with an estimated prevalence of 1 in 1000 individuals. VWD is classified into quantitative and qualitative forms. Diagnosis of VWD is complex and requires (1) a personal history of bleeding symptoms, (2) family history of bleeding or VWD, and (3) confirmatory laboratory testing. There are certain bleeding assessment tools to objectively measure bleeding symptoms in patients that have been shown to correlate with the diagnosis as well as the severity of VWD. Laboratory diagnosis requires at least initially a measurement of von Willebrand factor (VWF) antigen levels, VWF platelet binding activity (VWF:RCo, VWF:GPIbM, and VWF:GPIbR), and factor VIII (FVIII) activity. Additional testing to confirm the specific subtype may include VWF collagen binding activity, low-dose ristocetin VWF-platelet binding, FVIII-VWF binding, VWF multimer analysis, and VWF propeptide antigen. Recent advances have been made regarding some of these assays. Molecular testing in VWD is not found to be useful in “low VWF” or most type 1 VWD cases but may be informative in patients with severe type 1 VWD, type 1C VWD, type 2 VWD, or type 3 VWD for accurate diagnosis, genetic counseling, and appropriate treatment. The diagnostic algorithm for VWD is complex, but advances continue to be made in improving VWF functional assays and diagnostic pathways.

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