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Semin Thromb Hemost 2025; 51(01): 081-090
DOI: 10.1055/s-0044-1787841
Review Article

Current Diagnosis of von Willebrand Disease in Italy: 3 Years Following the Release of the International Guidelines

Augusto B. Federici
1   Hematology and Transfusion Medicine, School of Medicine of the University of Milan, L. Sacco University Hospital, Milan, Italy
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Abstract

The American Society of Hematology–International Society on Thrombosis and Haemostasis–National Hemophilia Foundation–World Federation of Hemophilia 2021 International Guidelines (IGL) on von Willebrand disease (VWD) have pointed out many challenges, mainly in the diagnostic approach of VWD patients. To determine the impact of these IGL on the current clinical and laboratory diagnosis of Italian VWD patients, we have recently conducted a survey among 43 centers affiliated with the Italian Association of Hemophilia Centers (AICE). Directors and colleagues responsible for the management of VWD patients were invited to report in a detailed questionnaire how IGL recommendations about the assessment of the specific activities of von Willebrand Factor (VWF) could be applied at their local sites. Results from such a survey showed that bleeding assessment tools, VWF antigen, and factor VIII procoagulant are currently in use in all centers. The automated assays for platelet-dependent VWF activity with or without ristocetin described in IGL have been used since 2021 in 37/43 (86%) centers. Among other laboratory tests, VWF collagen binding, ristocetin-induced platelet agglutination, multimeric analysis, VWF propeptide, VWF:FVIII binding assay were available in 49, 63, 26, 7, and 28% of AICE, respectively. Analyses of VWF gene defects are available only at 3/43 (7%) centers. Desmopressin (DDAVP) infusion trials at diagnosis, with measurements of VWF activities at 1 and 4 hours post-DDAVP, is currently performed at 38/43 (88%) centers. Based on this information, a simplified clinical diagnosis using a few automated tests before and after DDAVP has been proposed. Such a diagnostic approach will be validated prospectively in a large cohort of Italian VWD patients.


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Keywords

von Willebrand factor - bleeding assessment tools - VWF activities - laboratory diagnosis of VWD - biological response to DDAVP

von Willebrand disease (VWD) is due to quantitative and/or qualitative defects of von Willebrand factor (VWF), the multimeric glycoprotein synthesized by endothelial cells and megakaryocytes that mediates platelet adhesion/aggregation and stabilizes factor VIII (FVIII) in the circulation.[1] VWD has always been considered the most common inherited bleeding disorder, even though its prevalence varies considerably according to the setting of diagnosis.[1] In population-based studies, prevalence was estimated to be as high as 0.6 to 1.3%,[2] [3] about two orders of magnitude higher than in specialized centers (0.005–0.01%) to which symptomatic patients with VWD are usually referred, as reported in many national registries.[4] [5] [6] [7] [8] [9] [10] In VWD, bleeding events are caused not only by impaired platelet-VWF interactions, usually assessed in plasma by platelet-dependent VWF activity (PD-VWFact) in the presence or absence of ristocetin and by VWF collagen binding (VWF:CB), but also by reduced FVIII levels that often accompany the VWF defect.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10]

The current classification of VWD has proposed six different types: VWD1, VWD3, VWD2A, VWD2B, VWD2M, and VWD2N.[1] A partial quantitative defect marks VWD1, whereas VWD3 is characterized by the nearly total absence of VWF in plasma and platelets. VWD2A and VWD2B are marked by the absence of high molecular weight (HMW) VWF multimers assessed in plasma using VWF multimeric analyses (VWF:MA). In VWD2B, there is also an increased affinity of VWF for its platelet receptor, glycoprotein Ibα (GpIbα). The identification of qualitatively abnormal variants with decreased PD-VWFact and a normal multimeric structure marks VWD2M. VWD2N shows a full array of VWF multimers, the defect being in the N-terminal region of the VWF where the binding domain for FVIII is located. The pathophysiology, inheritance, and VWF gene defects of the six different VWD types described previously [1] are summarized in [Table 1]. Correct classification of different types by clinical and laboratory parameters is important for the management of patients with VWD.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10]

Table 1

Classification and characterization of VWD types

Type

Pathogenetic mechanisms

Inheritance

Most frequent VWF gene defects

VWD1

Partial quantitative

deficiency of VWF

Autosomal dominant

Missense mutations (85%),

null alleles (15%),

variable penetrance.

VWD2A

Decreased VWF Platelet-dependent adhesion due to a

loss of HMW–VWF multimers

Autosomal dominant

Autosomal recessive

Missense mutations,

mainly in D3, A2, and CK domains.

Missense mutations in pro-peptide.

VWD2B

Increased affinity of VWF

for platelet GP-Ibα

Autosomal dominant

Missense mutations

in A1 domain.

VWD2M

Decreased VWF Platelet-dependent adhesion without a

loss of HMW–VWF multimers

Autosomal dominant

Missense mutations

in A1 domain.

VWD2N

Decreased binding VWF affinity for factor VIII

Autosomal recessive

Missense mutations in D′

and D3 domains.

VWD3

Virtually complete

deficiency of VWF

Autosomal recessive

Mainly null alleles,

Large-small deletions.

Abbreviations: HMW, high molecular weight multimers; VWD, von Willebrand disease; VWF, von Willebrand factor.


Despite many attempts by experts on VWF pathophysiology who have tried for the past 20 years to improve the clinical and laboratory assessments of this inherited bleeding disorder, VWD awareness remains poor not only at low- but also in medium- income countries (MIC) because laboratory testing is complex and costly.[11] [12] Thus, complex diagnostic approaches for VWD using an all test repertoire for phenotypic and genotypic assessments of inherited and acquired VWF defects as recommended in various guidelines are only available in a few hemophilia centers, located at high-income countries, where all these tests can be reimbursed by insurance companies (e.g., in United States: Blue Cross Shield at different U.S. States, Centene Corp, Humana) or can be performed thanks to private or public research grants. The American Society of Hematology–International Society on Thrombosis and Haemostasis (ISTH)–National Hemophilia Foundation–World Federation of Hemophilia-2021 International Guidelines (IGL) on VWD have summarized the most recent recommendations for the diagnosis of VWD patients.[13] On behalf of the Italian Association of Hemophilia Centers (AICE), we have recently conducted a survey among the 43 affiliated centers. Directors and colleagues who are responsible for the management of VWD patients were invited to report in a detailed questionnaire how the different diagnostic recommendations of IGL could be applied at their local sites. Since the results of this survey confirmed that only a few centers could perform all the tests recommended for phenotypic and genotypic assessment of VWF defects, we have identified the minimal test requirements for the clinical and laboratory diagnosis of different VWD types and proposed a simplified diagnostic approach to be used at all AICE.

Recommendations for Clinical Assessment of von Willebrand Disease

The IGL confirmed that three main criteria are required for correct VWD diagnosis: (1) positive bleeding history since childhood; (2) reduced VWF activity in plasma; and (3) history of bleeding in the family with autosomal dominant or recessive inheritance. The list of different clinical and laboratory assessments for VWD diagnosis is summarized in [Table 2]. As far as clinical assessment of VWD is concerned, both personal and family history of bleeding must be considered, because the presence of other affected members within the family is important to determine whether the inheritance is autosomal dominant or recessive. Most common clinical manifestations are excessive mucosal and cutaneous bleeding with prolonged oozing after surgical procedures. In women, menorrhagia may be the only clinical manifestation. Soft tissue and joint bleeding are rare, except in patients with VWD3, characterized by undetectable levels of VWF and very low concentrations (<10 U/dL in most cases) of FVIII. The bleeding phenotype of the disease is usually mild in most patients with VWD1 and VWD2N, whereas severity increases in VWD2M, VWD2B, VWD2A, and particularly in VWD3. While in classical hemophilia there is an excellent relationship between plasma levels of FVIII and frequency/severity of clinical bleeding, such a relationship is less clear and straightforward in VWD. Members of IGL confirmed that the threshold level to distinguish patients with a bleeding tendency from healthy subjects with low-borderline plasma levels of VWF plasma must be considered at 30 IU/dL, especially in case of the normal structure of VWF as in VWD1.[13] Members of IGL have also discussed the issue of individuals with levels of VWF activities ranging between 30 and 50 U/dL and suggested how to distinguish cases with very mild VWD from normal subject with low VWF, essentially based on clinical/family histories.[13] Usually, the bleeding history is an essential criterion for the diagnosis of inherited bleeding disorders, including VWD.[14] [15] A bleeding score (BS) based upon bleeding symptoms and calculated using the questionnaire proposed by Tosetto et al [16] was used to confirm the diagnosis in a large cohort of European families with VWD1 [17]; it was subsequently applied with some modifications to other clinical studies on VWD1.[18] More recently, in a limited number of patients with some VWD types (1, 2A, 2B, 2M), attempts were made to use the BS, not only for diagnostic purposes but also to evaluate the patients' tendency to bleed.[19] [20] [21] It has been suggested that BS > 3 and BS > 5 in males and females, respectively, constitute useful cut-offs to identify individuals for whom measuring VWF activities is worthwhile. Pediatric cases should be evaluated using less stringent criteria.[22] [23] However, since a young child may have had no hemostatic challenges at all, the correct diagnosis of VWD requires in most cases repeated assessment of VWF activities and an accurate family history. The IGL suggested to use the more comprehensive bleeding assessment tool (ISTH-BATs), as proposed by the International Society on Thrombosis and Haemostasis.[24]

Table 2

Clinical and laboratory assessments including molecular parameters for VWD diagnosis

 • Clinical parameters for VWD

 – Clinical history: lifelong mucosal, cutaneous, and postoperative bleeding, to be collected with appropriate questionnaires to calculate the bleeding score.

 – Family history positive for bleeding and/or other affected VWD (not always).

 • Laboratory parameters for correct diagnosis of VWD types

First level:

 – Platelet-dependent VWF activity (PD-VWFact) with different methods[a]

 – VWF binding activity to collagen binding (VWF:CB)

 – VWF antigen (VWF:Ag)

 – Factor VIII procoagulant (FVIII:C)

 – PD-VWFact/Ag, VWF:CB/Ag, and FVIII:C/VWF:Ag

Second level:

 – Ristocetin-induced platelet agglutination

 – VWF multimeric analyses on low–high-resolution gels

 – VWF propeptide measured as ratio with VWF antigen (VWFpp/VWF:Ag)

 – Infusion test with desmopressin (DDAVP)

 – Factor VIII binding assay (VWF:FVIIIB)

 • Molecular parameters for confirmation of VWD

 – Search for large deletion in VWD3

 – Search for mutations clustered within specific VWF domains: D2-D3-C2-A2-CK (VWD2A); D3 (VWD1C/2M Vicenza); D′–D3 (VWD2N); A1 (VWD2B and VWD2M)

Abbreviations: CK, C-terminal cystine knot domain of VWF; HMW, high molecular weight multimers; VWD, von Willebrand disease; VWF, von Willebrand factor.


a See [Table 3].



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Tests of von Willebrand Factor Activities Useful for Diagnosis of von Willebrand disease Types

In contrast to hemophilia A, which requires only two parameters for diagnosis, namely the prolonged activated partial thromboplastin time with low levels of FVIII:C, several (from 5 to 8) laboratory tests are always necessary to appropriately diagnose all VWD types ([Table 2]). The first and most appropriate tests of VWF activity to identify VWD patients are those assessing in plasma the interaction between VWFA1 domain and its specific platelet receptor, GPIbα. Such platelet-VWF interactions occur in circulation always before the adhesion of VWF to subendothelial matrices, as typically observed in VWF variants of VWD2B characterized by enhanced VWFA1–GPIb binding.[25] In IGL, these assays are indicated as PD-VWFact according to previous recommendations of the subcommittee on VWF for the Scientific Standardization Committees of the ISTH.[26] Since there are many assays currently available for assessing this VWFA1–GPIbα interaction, a panel of experts in 2015 updated the correct nomenclature to be used to identify the type of assay ([Table 3]). The detailed description of the methods used for assessing the specific VWF activities recommended in IGL have been reported previously in another review article [27] and more recently have been updated by Favaloro and Pasalic.[28] In their review article, Favaloro and Pasalic pointed out the advantages of the PD-VWFact versus the old VWF:RCo and discussed the potency of the automated assays commercially available that were previously described.[29] [30] [31] [32] [33] [34] Favaloro and Pasalic agreed with IGL members who recommended to avoid the old VWF:RCo assay and to use the most recent PD-VWFact tests. They also agreed with IGL members to compare the results of PD-VWFact with VWF:Ag levels because the PD-VWFact/Ag ratio >0.7 can identify VWD1, while VWD2A, VWD2B and VWD2M are characterized by PD-VWFact/Ag ratio <0.7.[13] Another important recommendation reported in IGL is the role of the VWF:CB assay in the laboratory diagnosis of VWD. This assay is sensitive to variants characterized by the absence of the larger VWF multimers.[35] [36] [37] Therefore, VWF:CB has been proposed in IGL as an alternative to VWF multimeric analysis (VWF:MA). Also in this case, VWF:CB/Ag ratios must be calculated and compared with those of PD-VWFact/Ag ratio >0.7 because both parameters are useful in distinguishing VWD2A from VWD2M.[13] The methods and role of the other laboratory assays useful in the VWD diagnosis have been described in detail previously.[27] [28] The procoagulant activity of factor VIII (FVIII:C) is usually very low in VWD3 patients, who are also characterized by undetectable levels of VWF, while FVIII:C is normal in most cases with VWD2A, VWD2B, and VWD2M. The FVIII:C/VWF:Ag ratio is a useful parameter for the identification of VWD types because values >1 suggest VWD1 and <1 VWD2N. To confirm VWD2B, members of IGL recommended to use VWF:FVIIIB assay or molecular diagnosis since VWD2N defects are all located at D′–D3 domains of VWF.[13] Ristocetin-induced platelet agglutination (RIPA) is recommended for VWD2B diagnosis because these patients are characterized by enhanced RIPA. A similar enhanced RIPA can be also found in platelet-type VWD (PT-VWD). Most importantly, both VWD2B and PT-VWD can be associated with thrombocytopenia.[1] To exclude PT-VWD, IGL members suggested molecular diagnosis since VWD2B defects are all located at A1 domain of VWF.[13] VWF:MA is useful to determine the presence of an intact structure of VWF as in normal plasma: the loss of HMW multimers is typical of VWD2A and VWD2B.[1] When VWF:MA is not available, VWF:CB/Ag ratio <0.7, with PD-VWFact/Ag ratio also <0.7, can be used as the surrogate marker of loss of HMW multimers.[13]

Table 3

Nomenclature of platelet-dependent VWF activity

Assay

Activator

Description of activity

VWF:RCo

Ristocetin

Ristocetin-induced VWF binding to GPIbα on platelets

VWF:GPIbR

Ristocetin

Ristocetin-induced VWF binding to

recombinant wild-type GPIbα fragment

VWF:GPIbM

–

Spontaneous VWF binding to recombinant

gain-of-function mutant GPIbα fragment

VWF:Ab

–

Binding of monoclonal antibody to the GPIbα

binding site in VWF (A1 domain epitope)

Abbreviation: VWF, von Willebrand factor.


Source: Bodó et al.[26]


The VWF propeptide (VWFpp) and mature VWF proteins remain noncovalently associated and stored in α-granules of megakaryocytes/platelets or Weibel–Palade bodies in endothelial cells for regulated release. VWFpp circulates in plasma as a homodimer with a half-life of 2 to 3 hours, while mature VWF circulates with a half-life of 8 to 12 hours.[1] For these reasons, the ratio between VWFpp and VWF:Ag has been proposed to identify VWD1C patients with reduced VWF survival.[38] [39] An increased VWFpp/VWF:Ag ratio can be observed also in patients with acquired von Willebrand Syndrome (AVWS), as originally reported.[40] Since the VWFpp assay is not commercially available in most countries, members of IGL suggested to use instead the Desmopressin (1-deamino-8-D-arginine vasopressin, DDAVP) trial with VWF activities measured after 1 and 4 hours to determine the shorter half-life of VWF as typically observed in VWD1C and AVWS patients. DDAVP is a synthetic analog of vasopressin. When administered intravenously or subcutaneously, this drug usually increases plasma VWF and FVIII 3 to 5 times above baseline levels within 1 hour and can induce VWF activities higher than baseline for 6 to 8 hours following DDAVP administration.[41] [42] A DDAVP challenge test is an important tool for VWD management, because VWD patients can be divided according to their biological response into three different groups: short half-life, responsive, and not responsive.[41] The use of DDAVP challenge test at the time of diagnosis with the assessment before and after DDAVP administration of platelet counts and all the four main VWF parameters (VWF:Ag, PD-VWFact, VWF:CB, and FVIII:C) may allow the clinical identification of VWD types (see later). Molecular diagnosis can be useful to confirm specific VWF defects in VWD families, especially those with VWD2A, VWD2B, VWD2M, and VWD2N since mutations are clustered in specific exons of VWF gene.[1] In VWD3 patients, no specific mutations can be used as molecular markers for the disease since gene defects are spread throughout the entire VWF gene. However, large deletions should be sought because they can be associated with the appearance of allo-antibodies against VWF. In VWD1, the probability of finding mutations within the entire VWF gene is high only when VWF levels are below 30 U/dL. It is still not clear whether most mild VWD1 patients really have a mutation in the VWF locus and the possibility of external modifiers of VWF levels should be considered.[1]


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Current Diagnosis of von Willebrand Disease in Italy Following International Guidelines

The first Italian guidelines for the management of VWD were published on behalf of AICE in 2002, mainly as recommendations of experts and reported data of a previous retrospective registry collected from >40 AICE.[4] Since then, clinical and laboratory information about VWD Italian patients has been obtained by two Italian registries. The first retrospective Registry of National von Willebrand disease (RENAWI-1) with more detailed data collected from 16/43 AICE on 1,236 cases was published in 2011.[8] Results of RENAWI-1 obtained in these 1,236 VWD patients were compared versus those reported annually (2010) in the Registry on Hemophilia and Allied Disorders of the AICE. Selective criteria for VWD diagnosis were introduced by coordinators of RENAWI-1 at enrolment and 246 cases were not included in RENAWI-1 because they did not meet minimal criteria for VWD diagnosis. The second registry on Italian VWD (RENAWI-2) was the continuation of RENAWI-1 but included only 796 patients who were followed up at six comprehensive hemophilia centers.[9] The aim of RENAWI-2 was to evaluate the incidence, type, and spontaneous bleeding episodes requiring treatment with DDAVP and/or VWF/FVIII concentrates. Both registries at that time confirmed the difficulties of many AICE to make correct diagnosis at their local sites because they could not count on appropriate laboratory tests for VWF activities. The most recent data about Italian VWD patients were published in 2018.[10] We have compared absolute number of Italian VWD patients versus cases stratified according to levels of VWF and FVIII activities in both VWD and HA ([Fig. 1]). In the most recent update of the Italian National Registry published in 2018,[10] absolute numbers of VWD cases are lower than those with HA: 3,245 versus 4,109, respectively. More importantly, a striking difference is present when we consider the severity of VWD versus HA characterized by baseline levels of their VWF and FVIII activities. To be compared with HA, VWD were arbitrarily classified as mild, moderate, severe when VWD patients were diagnosed at AICE as VWD1, VWD2, and VWD3 types. This observation confirms that mild VWD1 are the most frequent cases (77%) of VWD registered in Italy with a minority of cases with severe–moderate patients. As far as severe cases, VWD3 can be easily diagnosed in all AICE because of their very low (<3 U/dL) levels of VWF:Ag and the autosomal recessive inheritance. As far as moderate–mild cases shown in [Fig. 1] correct classification as VWD1, VWD2A, VWD2B, VWD2M, and VWD2N require BAT and measuring at least the four main VWF parameters (VWF:Ag, PD-VWFact, VWF:CB, and FVIII:C), possibly before and after DDAVP trial, as recommended by IGL members.[13] Previous experiences obtained from retrospective and prospective VWD registries unfortunately showed that the assays for VWF activities were not present in all AICE.[8] [9]

Zoom Image
Fig. 1 Distribution of severe, moderate, and mild cases of the Italian patients with HA versus VWD. This figure has been prepared ex novo by Federici et al using data reported in reference [10]. The different percent distribution of VWD versus HA is shown in three types of gray according to the severity of both diseases: severe (dark gray), moderate (intermediate gray), and mild (light gray). Classification of VWD clinical severity is based on baseline levels of VWF activity following the definition of HA according to FVIII:C levels. Note the different percent distribution of mild cases in HA (42%) versus those in VWD (77%) (Report of ISTISAN 2018).

To overcome these difficulties about availability of VWF assays that still exist in most AICE, a working group on VWD diagnosis (WG-VWDIAG) was organized in October 2022 to explore the current levels of assessing VWD types and to propose more simplified clinical approach that might allow correct identification and management of Italian patients with inherited and acquired defects of VWF. Members of this WG-VWDIAG shared among all the 43 AICE a detailed questionnaire that proposed the most important recommendations published in the IGL in 2021.[13] The results of this survey were analyzed by the members of this WG-VWDIAG and are briefly summarized in [Fig. 2]. BATs as well as VWF antigen (VWF:Ag) and FVIII:C are currently in use in all AICE. The assays for PD-VWFact described in the IGL have been used since 2021 in 37/43 (86%) centers but 17/43 (39%) rely on the old VWF:RCo, against the recommendations of IGL. More importantly, 6/43 (14%) centers declared that no tests for PD-VWFact was available locally and that VWD diagnosis was performed only by BAT as clinical assessment and by VWF:Ag and FVIII:C before and after DDAVP trial as laboratory diagnosis. These findings confirmed previous information that minimal criteria for VWD diagnosis as proposed by IGL cannot be met. Among other laboratory tests, VWF:CB, ristocetin-induced platelet agglutination (RIPA), VWF:MA, VWFpp, and VWF:FVIII binding assay (VWF:FVIIIB) were available in 49, 63, 26, 7, and 28% of AICE, respectively. Analyses of VWF gene defects are available only at 3/43 (7%) centers. DDAVP infusion trial at diagnosis with measurements of VWF activities at 1 and 4 hours post-DDAVP is currently performed at 38/43 (88%) centers.

Zoom Image
Fig. 2 Percent of diagnostic tools available at the Italian center in 2023. In this figure, the percent of the 11 diagnostic tools that were available locally at the 43 Italian centers are shown, as retrieved from the survey organized in 2023 by AICE. Note that only three tools (BAT, VWF:Ag, and Factor VIII) are available in all centers, while five tools (VWF:CB, VWF multimers, VWF pro-peptide, VWF:FVIIIB, and VWF gene analyses) can be performed only in <50% of centers.

The members of the WG-VWDIAG analyzed the results of the survey and have been working on the Italian adaptation of the recommendations reported in the original IGL considering the current availability of laboratory tests at AICE. The Italian adaptation of IGL for VWD diagnosis and therapy has been recently approved and published online by the Italian Institute of Health (ISS) and are currently available for consultation at ISS website. According to the results of the AICE survey shown in [Fig. 2], the members of the WG-VWDIAG were also invited to prepare a list of minimal requirements for the diagnosis of VWD types and to propose a more simplified diagnostic approach to be applied at all the AICE. Among the IGL recommendations to be transferred into the Italian version of VWD guidelines, members of WG-VWDIAG have approved the following statements. (1) BAT must be always applied to all suspected cases for VWD. (2) Identification of VWD patients must be performed using one of the recent automatic tests for PD-VWFact and not with VWF:RCo assay. (3) VWF:Ag and FVIII:C tests must be also assessed at first level together with PD-VWFact. (4) VWF:CB assay must be assayed as first-level test, especially in centers where the VWF:MA are not available. (5) RIPA is an essential assay for the identification VWD2B: as alternative, search for gene mutations within VWF-A1 domain can be used in centers where tests for molecular biology are available. (6) VWFpp can be useful for assessing the short half-life of VWF, as that observed in VWD1C and in AVWS: since VWFpp assay is not available in many centers, the half-life of VWF can be demonstrated by measuring VWF and FVIII activities 1 and 4 hours following DDAVP. (7) VWF:FVIIIB or genotype analysis for mutations located at D′–D3 domains of VWF can be used for VWD2N diagnosis. (8) Since a DDAVP infusion trial at diagnosis is essential to identify the biological response to this drug for the treatment of VWD patients, the use of DDAVP with the measurements of platelet counts and of the four main VWF parameters (VWF:Ag, PD-VWFact, VWF:CB, and FVIII:C) before, 1, and 4 hours post-DDAVP with calculated PD-VWFact/Ag, VWF:CB/Ag, FVIII/VWF:Ag ratios might be proposed as simplified diagnostic approach to identify patients with different types of VWD.

The minimal assessment tools for the diagnosis of VWD types are listed in [Table 4] and the simplified diagnostic approach is described in [Fig. 3]. The idea of using this algorithm for a simplified diagnosis of VWD types following DDAVP trial at diagnosis has been derived from several publications by Favaloro who could improve the algorithmic approach recommended in 2014 by United Kingdom Hemophilia Center Doctor Organization.[43] In 2016, we proposed in an invited editorial a more automatic and rapid VWD diagnosis to improve VWD awareness world-wide.[44] We acknowledge the great contribution of Favaloro et al in the field of VWD diagnosis: for the past 25 years, he has been working on the validation of novel methods for VWF:CB activity and has demonstrated how these assays can be useful in the diagnostic approaches of the different VWD types.[35] [45] [46] In particular, we have really appreciated Favaloro's proposal to use VWF:CB as first level test together with PD-VWFact, FVIII:C, and VWF:Ag (see [Fig. 3]) in his commentary on IGL.[47] Such a simplified diagnostic approach has been already assessed in a pilot study named Chinese Registry of von Willebrand disease with Instrumentation Laboratory approach using Automatic Tests designed by the Centers of Suzhou and of Milan. This study was discontinued during the coronavirus 2019 pandemic, and we could collect only partial data, recently published as abstract.[48] By using only baseline PD-VWFact/Ag, VWF:CB/Ag ratios VWD3 (n = 14), VWD1 (n = 39), VWD2A (n = 21), and VWD2M (n = 13) could be identified, while VWD1C (n = 6), VWD2B (n = 5), VWD2N (n = 4), and AVWS (n = 10) could be confirmed only after DDAVP trial when FVIII/VWF:Ag and platelet counts could be also assessed.[48] Members of the WG-VWDIAG affiliated with AICE and with Italian Society on Thrombosis and Hemostasis have decided to propose the continuation of this pilot study in a prospective clinical trial entitled as follows: Desmopressin Clinical Trial at Diagnosis for Management of Inherited and Acquired Defects of Von Willebrand Factor Defects: An Investigator-Driven Prospective Study (STADIAWIL-IPS). Major objective of STADIAWIL-IPS is to validate the simplified diagnostic approach using automatic tests before and after DDAVP trial at diagnosis in large cohort of patients with inherited and acquired VWF defects (at least 500) enrolled at AICE. Diagnosis of different VWD types will be confirmed in expert laboratories by second-level tests such as RIPA, VWFpp, VWF:MA, VWF:FVIIIB, and VWF gene mutations. Since biological response can be identified during DDAVP trial at diagnosis, VWD patients with positive response will be observed prospectively for 24 months for efficacy and safety of this drug in case of DDAVP therapy to manage spontaneous bleeding episodes or to prevent bleeding during minor or major surgery. Clinical efficacy, safety, and costs of the VWD group using DDAVP will be compared with those of the VWD patients nonresponsive to DDAVP who must be treated with VWF concentrates.

Table 4

Minimal assessment tools required in Italy for the diagnosis of VWD types

VWD general

BAT, platelet count, PD-VWFact, and FVIII:C

VWD type 1 and 2

+ VWF:Ag with PD-VWFact/Ag ratio > or < 0.7

VWD type 2A and 2M

+ VWF:CB with VWF:CB/Ag or multimers

VWD type 2B

+ RIPA or genotype or platelet count post-DDAVP

VWD type 1C

+ VWF:pp or the three-main VWF parameters (VWF:Ag, PD-VWFact, and VWF:CB) post-DDAVP

VWD type 2N

+ VWF:FVIIIB or genotype or FVIII/VWF:Ag ratio post-DDAVP

Abbreviations: BAT, bleeding assessment tools; DDAVP, desmopressin; FVIII:C, factor VIII procoagulant; PD-VWFact, platelet-dependent VWF activity; RIPA, ristocetin-induced platelet agglutination; VWD, von Willebrand disease; VWF, von Willebrand factor; VWF:Ag, VWF antigen; VWF:CB, VWF binding activity to collagen binding.


Zoom Image
Fig. 3 Suggested flowchart for simplified diagnosis of VWD types in Italy. Flowchart proposed for a more rapid diagnosis and classification of different VWD types as modified from previous publication.[44] VWD3 can be diagnosed in the case of undetectable PD-VWFact. FVIII:C is always reduced in VWD3 and in VWD2N: it can be partially reduced or normal in all the other VWD types. After bleeding history of suspected patients with VWD is collected by BAT and the family history of bleeding investigated ([Table 2]), a reduced level of VWF activity should be measured as first parameter (1) using one of the PD-VWFact tests together with FVIII:C (2), VWF.Ag (3), and VWF.CB (4). The use of DDAVP challenge test at the time of diagnosis with the assessment before and after DDAVP of platelet counts and of all four tests, with calculated PD-VWFAct/Ag, VWF:CB/Ag and FVIII/VWF:Ag ratios, might allow the provisional identification of VWD types in most patients without performing additional tests, As examples, VWD2B can be identified without using RIPA, if platelet counts are reduced from baseline after DDAVP. Different PD-VWFAct/Ag and VWF:CB/Ag ratios may suggest VWD2A or VWD2M types. Moreover, VWD patients with circulating short half-life VWF to be assessed by the increased VWF:PP/Ag ratio and the VWD2N cases with abnormal VWF:FVIIIB can be identified by evaluating the behavior of the PD-VWFAct/Ag, VWF:CB/Ag, and FVIII/VWF:Ag ratios after 1 and 4 hours after DDAVP. Therefore, DDAVP trial can immediately identify the clinical diagnosis of patients with different VWD types and cases who can be treated with DDAVP or VWF concentrates.

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Conclusion

Despite the incredible knowledge of VWF pathophysiology obtained during the past 40 years, clinical diagnosis and classification of VWD patients are still difficult in many countries, 98 years after the first description of this bleeding disorder by Erik A. von Willebrand (1926). The likelihood of diagnosing VWD correctly improves when the clinical assessment of bleeding is correlated with appropriate laboratory studies. The IGL published in 2021 [13] have pointed out many challenges in VWD diagnosis, mainly related to the limited availability of the specific tests recommended for VWF activities, also in MIC. Molecular diagnosis can be useful to confirm specific VWF defects in VWD families, but it is not mandatory for choosing appropriate treatments with DDAVP or VWF concentrates in current clinical practice. Major efforts are still required to promote simplified and less expensive diagnostic approaches to improve awareness of VWD patients worldwide hopefully within 2026, when the 100th anniversary of VWD will be celebrated.


#
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Conflict of Interest

A.B.F. has been involved in advisory boards and received honoraria as a speaker at educational meetings organized by CSL-Behring, Grifols, Kedrion Biopharma, Octapharma, Takeda, Werfen-Instrumentation Laboratory.

Acknowledgments

We wish to thank all the members of the Italian Association of Hemophilia Centers (AICE) who participated in the previous Italian Registries of VWD (RENAWI-1 and RENAWI-2). Most data reported in this manuscript were discussed with the Members of the Working Group on VWD diagnosis (WG-VWDIAG) indicated by the Presidents of two Italian Scientific Societies: AICE and Italian Society for the Study of Hemostasis and Thrombosis (SISET). The WG-VWDIAG is composed by AB Federici (Chairman), P. Gresele (Co-chairman), and by the following Members: L. Contino, R. De Cristofaro, E. Grandone, S. Linari, AC Molinari, RC Santoro, P. Simioni, A. Tripodi, and B. Bianchi Bonomi. We acknowledge the work of Luigi Flaminio Ghilardini, who prepared the figures reported in this manuscript.

  • References

  • 1 Leebeek FWG, Eikenboom JCJ. Von Willebrand's Disease. N Engl J Med 2016; 375 (21) 2067-2080
    CrossrefPubMedSearch in Google Scholar
  • 2 Rodeghiero F, Castaman G, Dini E. Epidemiological investigation of the prevalence of von Willebrand's disease. Blood 1987; 69 (02) 454-459
    CrossrefPubMedSearch in Google Scholar
  • 3 Werner EJ, Broxson EH, Tucker EL, Giroux DS, Shults J, Abshire TC. Prevalence of von Willebrand disease in children: a multiethnic study. J Pediatr 1993; 123 (06) 893-898
    CrossrefPubMedSearch in Google Scholar
  • 4 Federici AB, Castaman G, Mannucci PM. Italian Association of Hemophilia Centers (AICE). Guidelines for the diagnosis and management of von Willebrand disease in Italy. Haemophilia 2002; 8 (05) 607-621
    CrossrefPubMedSearch in Google Scholar
  • 5 Laffan M, Brown SA, Collins PW. et al. The diagnosis of von Willebrand disease: a guideline from the UK Haemophilia Centre Doctors' Organization. Haemophilia 2004; 10 (03) 199-217
    CrossrefPubMedSearch in Google Scholar
  • 6 Pasi KJ, Collins PW, Keeling DM. et al. Management of von Willebrand disease: a guideline from the UK Haemophilia Centre Doctors' Organization. Haemophilia 2004; 10 (03) 218-231
    CrossrefPubMedSearch in Google Scholar
  • 7 Nichols WL, Hultin MB, James AH. et al. von Willebrand disease (VWD): evidence-based diagnosis and management guidelines, the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel report (USA). Haemophilia 2008; 14 (02) 171-232
    CrossrefPubMedSearch in Google Scholar
  • 8 Federici AB, Bucciarelli P, Castaman G. et al. Management of inherited von Willebrand disease in Italy: results from the retrospective study on 1234 patients. Semin Thromb Hemost 2011; 37 (05) 511-521
    Thieme ConnectPubMedSearch in Google Scholar
  • 9 Federici AB, Bucciarelli P, Castaman G. et al. The bleeding score predicts clinical outcomes and replacement therapy in adults with von Willebrand disease. Blood 2014; 123 (26) 4037-4044
    CrossrefPubMedSearch in Google Scholar
  • 10 Abbonizio F, Arcieri R. Associazione Italiana Centri Emofilia (AICE), Giampaolo A. Registro Nazionale delle Coagulopatie Congenite. Rapporto 2018; 20 (14) 1-18
    PubMedSearch in Google Scholar
  • 11 O'Sullivan JM, Tootoonchian E, Ziemele B. et al. Von Willebrand disease: gaining a global perspective. Haemophilia 2023; 29 (04) 1104-1112
    CrossrefPubMedSearch in Google Scholar
  • 12 Corrales-Medina FF, Federici AB, Srivastava A. et al. A need to increase von Willebrand disease awareness: vwdtest.com—a global initiative to help address this gap. Blood Rev 2023; 58: 101018
    CrossrefPubMedSearch in Google Scholar
  • 13 Connell NT, Flood VH, Brignardello-Petersen R. et al. ASH ISTH NHF WFH 2021 guidelines on the management of von Willebrand disease. Blood Adv 2021; 5 (01) 301-325
    CrossrefPubMedSearch in Google Scholar
  • 14 Rodeghiero F, Castaman G, Tosetto A. et al. The discriminant power of bleeding history for the diagnosis of type 1 von Willebrand disease: an international, multicenter study. J Thromb Haemost 2005; 3 (12) 2619-2626
    CrossrefPubMedSearch in Google Scholar
  • 15 Castaman G, Rodeghiero F, Tosetto A. et al. Hemorrhagic symptoms and bleeding risk in obligatory carriers of type 3 von Willebrand disease: an international, multicenter study. J Thromb Haemost 2006; 4 (10) 2164-2169
    CrossrefPubMedSearch in Google Scholar
  • 16 Tosetto A, Rodeghiero F, Castaman G. et al. A quantitative analysis of bleeding symptoms in type 1 von Willebrand disease: results from a multicenter European study (MCMDM-1 VWD). J Thromb Haemost 2006; 4 (04) 766-773
    CrossrefPubMedSearch in Google Scholar
  • 17 Goodeve A, Eikenboom J, Castaman G. et al. Phenotype and genotype of a cohort of families historically diagnosed with type 1 von Willebrand disease in the European study, molecular and clinical markers for the diagnosis and management of type 1 von Willebrand disease (MCMDM-1VWD). Blood 2007; 109 (01) 112-121
    CrossrefPubMedSearch in Google Scholar
  • 18 James PD, Notley C, Hegadorn C. et al. The mutational spectrum of type 1 von Willebrand disease: results from a Canadian cohort study. Blood 2007; 109 (01) 145-154
    CrossrefPubMedSearch in Google Scholar
  • 19 Federici AB, Mannucci PM, Castaman G. et al. Clinical and molecular predictors of thrombocytopenia and risk of bleeding in patients with von Willebrand disease type 2B: a cohort study of 67 patients. Blood 2009; 113 (03) 526-534
    CrossrefPubMedSearch in Google Scholar
  • 20 Castaman G, Tosetto A, Federici AB, Rodeghiero F. Bleeding tendency and efficacy of anti-haemorrhagic treatments in patients with type 1 von Willebrand disease and increased von Willebrand factor clearance. Thromb Haemost 2011; 105 (04) 647-654
    Thieme ConnectPubMedSearch in Google Scholar
  • 21 Castaman G, Federici AB, Tosetto A. et al. Different bleeding risk in type 2A and 2M von Willebrand disease: a 2-year prospective study in 107 patients. J Thromb Haemost 2012; 10 (04) 632-638
    CrossrefPubMedSearch in Google Scholar
  • 22 Bowman M, Riddel J, Rand ML, Tosetto A, Silva M, James PD. Evaluation of the diagnostic utility for von Willebrand disease of a pediatric bleeding questionnaire. J Thromb Haemost 2009; 7 (08) 1418-1421
    CrossrefPubMedSearch in Google Scholar
  • 23 Biss TT, Blanchette VS, Clark DS. et al. Quantitation of bleeding symptoms in children with von Willebrand disease: use of a standardized pediatric bleeding questionnaire. J Thromb Haemost 2010; 8 (05) 950-956
    CrossrefPubMedSearch in Google Scholar
  • 24 Rodeghiero F, Tosetto A, Abshire T. et al; ISTH/SSC joint VWF and Perinatal/Pediatric Hemostasis Subcommittees Working Group. ISTH/SSC bleeding assessment tool: a standardized questionnaire and a proposal for a new bleeding score for inherited bleeding disorders. J Thromb Haemost 2010; 8 (09) 2063-2065
    PubMedSearch in Google Scholar
  • 25 Ruggeri ZM. Von Willebrand factor: looking back and looking forward. Thromb Haemost 2007; 98 (01) 55-62
    PubMedSearch in Google Scholar
  • 26 Bodó I, Eikenboom J, Montgomery R, Patzke J, Schneppenheim R, Di Paola J. von Willebrand factor Subcommittee of the Standardization and Scientific Committee of the International Society for Thrombosis and Haemostasis. Platelet-dependent von Willebrand factor activity. Nomenclature and methodology: communication from the SSC of the ISTH. J Thromb Haemost 2015; 13 (07) 1345-1350
    CrossrefPubMedSearch in Google Scholar
  • 27 Federici AB. Current and emerging approaches for assessing von Willebrand disease in 2016. Int J Lab Hematol 2016; 38 (Suppl. 01) 41-49
    CrossrefPubMedSearch in Google Scholar
  • 28 Favaloro EJ, Pasalic L. Laboratory diagnosis of von Willebrand disease in the age of the new guidelines: considerations based on geography and resources. Res Pract Thromb Haemost 2023; 7 (05) 102143
    CrossrefPubMedSearch in Google Scholar
  • 29 Lattuada A, Preda L, Sacchi E, Gallo L, Federici AB, Rossi E. A rapid assay for ristocetin cofactor activity using an automated coagulometer (ACL 9000). Blood Coagul Fibrinolysis 2004; 15 (06) 505-511
    CrossrefPubMedSearch in Google Scholar
  • 30 Cabrera N, Moret A, Caunedo P. et al. Comparison of a new chemiluminescent immunoassay for von Willebrand factor activity with the ristocetin cofactor-induced platelet agglutination method. Haemophilia 2013; 19 (06) 920-925
    CrossrefPubMedSearch in Google Scholar
  • 31 Lawrie AS, Stufano F, Canciani MT, Mackie IJ, Machin SJ, Peyvandi F. A comparative evaluation of a new automated assay for von Willebrand factor activity. Haemophilia 2013; 19 (02) 338-342
    CrossrefPubMedSearch in Google Scholar
  • 32 Stufano F, Lawrie AS, La Marca S, Berbenni C, Baronciani L, Peyvandi F. A two-centre comparative evaluation of new automated assays for von Willebrand factor ristocetin cofactor activity and antigen. Haemophilia 2014; 20 (01) 147-153
    CrossrefPubMedSearch in Google Scholar
  • 33 Patzke J, Althaus H, Obser T. et al. Evaluation of a new VWF activity assay based on GPIba in the absence of ristocetin. Haemostesiologie 2010; 30: P07-3
    PubMedSearch in Google Scholar
  • 34 Flood VH, Gill JC, Morateck PA. et al. Gain-of-function GPIb ELISA assay for the molecular and clinical biology of VWD. Blood 2011; 117: e67-e74
    CrossrefPubMedSearch in Google Scholar
  • 35 Favaloro EJ. Collagen binding assay for von Willebrand factor (VWF:CBA): detection of von Willebrands Disease (VWD), and discrimination of VWD subtypes, depends on collagen source. Thromb Haemost 2000; 83 (01) 127-135
    Thieme ConnectPubMedSearch in Google Scholar
  • 36 Federici AB, Canciani MT, Forza I, Cozzi G. Ristocetin cofactor and collagen binding activities normalized to antigen levels for a rapid diagnosis of type 2 von Willebrand disease—single center comparison of four different assays. Thromb Haemost 2000; 84 (06) 1127-1128
    PubMedSearch in Google Scholar
  • 37 Flood VH, Gill JC, Friedman KD. et al; Zimmerman Program Investigators. Collagen binding provides a sensitive screen for variant von Willebrand disease. Clin Chem 2013; 59 (04) 684-691
    CrossrefPubMedSearch in Google Scholar
  • 38 Haberichter SL, Castaman G, Budde U. et al. Identification of type 1 von Willebrand disease patients with reduced von Willebrand factor survival by assay of the VWF propeptide in the European study: molecular and clinical markers for the diagnosis and management of type 1 VWD (MCMDM-1VWD). Blood 2008; 111 (10) 4979-4985
    CrossrefPubMedSearch in Google Scholar
  • 39 Eikenboom J, Federici AB, Dirven RJ. et al; MCMDM-1VWD Study Group. VWF propeptide and ratios between VWF, VWF propeptide, and FVIII in the characterization of type 1 von Willebrand disease. Blood 2013; 121 (12) 2336-2339
    CrossrefPubMedSearch in Google Scholar
  • 40 van Genderen PJ, Boertjes RC, van Mourik JA. Quantitative analysis of von Willebrand factor and its propeptide in plasma in acquired von Willebrand syndrome. Thromb Haemost 1998; 80 (03) 495-498
    PubMedSearch in Google Scholar
  • 41 Federici AB, Mazurier C, Berntorp E. et al. Biologic response to desmopressin in patients with severe type 1 and type 2 von Willebrand disease: results of a multicenter European study. Blood 2004; 103 (06) 2032-2038
    CrossrefPubMedSearch in Google Scholar
  • 42 Castaman G, Lethagen S, Federici AB. et al. Response to desmopressin is influenced by the genotype and phenotype in type 1 von Willebrand disease (VWD): results from the European Study MCMDM-1VWD. Blood 2008; 111 (07) 3531-3539
    CrossrefPubMedSearch in Google Scholar
  • 43 Laffan MA, Lester W, O'Donnell JS. et al. The diagnosis and management of von Willebrand disease: a United Kingdom Haemophilia Centre Doctors Organization guideline approved by the British Committee for Standards in Haematology. Br J Haematol 2014; 167 (04) 453-465
    CrossrefPubMedSearch in Google Scholar
  • 44 Federici AB. Towards a more automatic and rapid laboratory diagnosis of von Willebrand disease. Thromb Res 2016; 141: 198-201
    CrossrefPubMedSearch in Google Scholar
  • 45 Favaloro EJ, Bonar R, Chapman K. et al. Differential sensitivity of von Willebrand factor activity assays to large and small VWF molecular weight forms: a cross-laboratory study comparing ristocetin cofactor, collagen binding and monoclonal antibody-based assays. J Thromb Haemost 2012; 10: 1043-1054
    CrossrefPubMedSearch in Google Scholar
  • 46 Favaloro EJ, Mohammed S, Vong R. et al. How we diagnose 2M von Willebrand disease (VWD): use of a strategic algorithmic approach to distinguish 2M VWD from other VWD types. Haemophilia 2021; 27 (01) 137-148
    CrossrefPubMedSearch in Google Scholar
  • 47 Favaloro EJ. Commentary on the ASH ISTH NHF WFH 2021 guidelines on the diagnosis of VWD: reflections based on recent contemporary test data. Blood Adv 2022; 6 (02) 416-419
    CrossrefPubMedSearch in Google Scholar
  • 48 Federici AB. Validation of a rapid diagnostic approach in inherited and acquired defects of VWF by automatic tests assessed before and after DDAVP trial: results from the Chinese-Italian CREWILACT Study. Abstract 1705265, accepted at the WFH Congress, Madrid 21–24 April 2024
    PubMed

Address for correspondence

Augusto B. Federici, MD
Hematology and Transfusion Medicine, School of Medicine of the University of Milan, L. Sacco University Hospital
Via GB Grassi 74, 20154 Milan
Italy   

Publication History

Article published online:
01 July 2024

© 2024. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

  • References

  • 1 Leebeek FWG, Eikenboom JCJ. Von Willebrand's Disease. N Engl J Med 2016; 375 (21) 2067-2080
    CrossrefPubMedSearch in Google Scholar
  • 2 Rodeghiero F, Castaman G, Dini E. Epidemiological investigation of the prevalence of von Willebrand's disease. Blood 1987; 69 (02) 454-459
    CrossrefPubMedSearch in Google Scholar
  • 3 Werner EJ, Broxson EH, Tucker EL, Giroux DS, Shults J, Abshire TC. Prevalence of von Willebrand disease in children: a multiethnic study. J Pediatr 1993; 123 (06) 893-898
    CrossrefPubMedSearch in Google Scholar
  • 4 Federici AB, Castaman G, Mannucci PM. Italian Association of Hemophilia Centers (AICE). Guidelines for the diagnosis and management of von Willebrand disease in Italy. Haemophilia 2002; 8 (05) 607-621
    CrossrefPubMedSearch in Google Scholar
  • 5 Laffan M, Brown SA, Collins PW. et al. The diagnosis of von Willebrand disease: a guideline from the UK Haemophilia Centre Doctors' Organization. Haemophilia 2004; 10 (03) 199-217
    CrossrefPubMedSearch in Google Scholar
  • 6 Pasi KJ, Collins PW, Keeling DM. et al. Management of von Willebrand disease: a guideline from the UK Haemophilia Centre Doctors' Organization. Haemophilia 2004; 10 (03) 218-231
    CrossrefPubMedSearch in Google Scholar
  • 7 Nichols WL, Hultin MB, James AH. et al. von Willebrand disease (VWD): evidence-based diagnosis and management guidelines, the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel report (USA). Haemophilia 2008; 14 (02) 171-232
    CrossrefPubMedSearch in Google Scholar
  • 8 Federici AB, Bucciarelli P, Castaman G. et al. Management of inherited von Willebrand disease in Italy: results from the retrospective study on 1234 patients. Semin Thromb Hemost 2011; 37 (05) 511-521
    Thieme ConnectPubMedSearch in Google Scholar
  • 9 Federici AB, Bucciarelli P, Castaman G. et al. The bleeding score predicts clinical outcomes and replacement therapy in adults with von Willebrand disease. Blood 2014; 123 (26) 4037-4044
    CrossrefPubMedSearch in Google Scholar
  • 10 Abbonizio F, Arcieri R. Associazione Italiana Centri Emofilia (AICE), Giampaolo A. Registro Nazionale delle Coagulopatie Congenite. Rapporto 2018; 20 (14) 1-18
    PubMedSearch in Google Scholar
  • 11 O'Sullivan JM, Tootoonchian E, Ziemele B. et al. Von Willebrand disease: gaining a global perspective. Haemophilia 2023; 29 (04) 1104-1112
    CrossrefPubMedSearch in Google Scholar
  • 12 Corrales-Medina FF, Federici AB, Srivastava A. et al. A need to increase von Willebrand disease awareness: vwdtest.com—a global initiative to help address this gap. Blood Rev 2023; 58: 101018
    CrossrefPubMedSearch in Google Scholar
  • 13 Connell NT, Flood VH, Brignardello-Petersen R. et al. ASH ISTH NHF WFH 2021 guidelines on the management of von Willebrand disease. Blood Adv 2021; 5 (01) 301-325
    CrossrefPubMedSearch in Google Scholar
  • 14 Rodeghiero F, Castaman G, Tosetto A. et al. The discriminant power of bleeding history for the diagnosis of type 1 von Willebrand disease: an international, multicenter study. J Thromb Haemost 2005; 3 (12) 2619-2626
    CrossrefPubMedSearch in Google Scholar
  • 15 Castaman G, Rodeghiero F, Tosetto A. et al. Hemorrhagic symptoms and bleeding risk in obligatory carriers of type 3 von Willebrand disease: an international, multicenter study. J Thromb Haemost 2006; 4 (10) 2164-2169
    CrossrefPubMedSearch in Google Scholar
  • 16 Tosetto A, Rodeghiero F, Castaman G. et al. A quantitative analysis of bleeding symptoms in type 1 von Willebrand disease: results from a multicenter European study (MCMDM-1 VWD). J Thromb Haemost 2006; 4 (04) 766-773
    CrossrefPubMedSearch in Google Scholar
  • 17 Goodeve A, Eikenboom J, Castaman G. et al. Phenotype and genotype of a cohort of families historically diagnosed with type 1 von Willebrand disease in the European study, molecular and clinical markers for the diagnosis and management of type 1 von Willebrand disease (MCMDM-1VWD). Blood 2007; 109 (01) 112-121
    CrossrefPubMedSearch in Google Scholar
  • 18 James PD, Notley C, Hegadorn C. et al. The mutational spectrum of type 1 von Willebrand disease: results from a Canadian cohort study. Blood 2007; 109 (01) 145-154
    CrossrefPubMedSearch in Google Scholar
  • 19 Federici AB, Mannucci PM, Castaman G. et al. Clinical and molecular predictors of thrombocytopenia and risk of bleeding in patients with von Willebrand disease type 2B: a cohort study of 67 patients. Blood 2009; 113 (03) 526-534
    CrossrefPubMedSearch in Google Scholar
  • 20 Castaman G, Tosetto A, Federici AB, Rodeghiero F. Bleeding tendency and efficacy of anti-haemorrhagic treatments in patients with type 1 von Willebrand disease and increased von Willebrand factor clearance. Thromb Haemost 2011; 105 (04) 647-654
    Thieme ConnectPubMedSearch in Google Scholar
  • 21 Castaman G, Federici AB, Tosetto A. et al. Different bleeding risk in type 2A and 2M von Willebrand disease: a 2-year prospective study in 107 patients. J Thromb Haemost 2012; 10 (04) 632-638
    CrossrefPubMedSearch in Google Scholar
  • 22 Bowman M, Riddel J, Rand ML, Tosetto A, Silva M, James PD. Evaluation of the diagnostic utility for von Willebrand disease of a pediatric bleeding questionnaire. J Thromb Haemost 2009; 7 (08) 1418-1421
    CrossrefPubMedSearch in Google Scholar
  • 23 Biss TT, Blanchette VS, Clark DS. et al. Quantitation of bleeding symptoms in children with von Willebrand disease: use of a standardized pediatric bleeding questionnaire. J Thromb Haemost 2010; 8 (05) 950-956
    CrossrefPubMedSearch in Google Scholar
  • 24 Rodeghiero F, Tosetto A, Abshire T. et al; ISTH/SSC joint VWF and Perinatal/Pediatric Hemostasis Subcommittees Working Group. ISTH/SSC bleeding assessment tool: a standardized questionnaire and a proposal for a new bleeding score for inherited bleeding disorders. J Thromb Haemost 2010; 8 (09) 2063-2065
    PubMedSearch in Google Scholar
  • 25 Ruggeri ZM. Von Willebrand factor: looking back and looking forward. Thromb Haemost 2007; 98 (01) 55-62
    PubMedSearch in Google Scholar
  • 26 Bodó I, Eikenboom J, Montgomery R, Patzke J, Schneppenheim R, Di Paola J. von Willebrand factor Subcommittee of the Standardization and Scientific Committee of the International Society for Thrombosis and Haemostasis. Platelet-dependent von Willebrand factor activity. Nomenclature and methodology: communication from the SSC of the ISTH. J Thromb Haemost 2015; 13 (07) 1345-1350
    CrossrefPubMedSearch in Google Scholar
  • 27 Federici AB. Current and emerging approaches for assessing von Willebrand disease in 2016. Int J Lab Hematol 2016; 38 (Suppl. 01) 41-49
    CrossrefPubMedSearch in Google Scholar
  • 28 Favaloro EJ, Pasalic L. Laboratory diagnosis of von Willebrand disease in the age of the new guidelines: considerations based on geography and resources. Res Pract Thromb Haemost 2023; 7 (05) 102143
    CrossrefPubMedSearch in Google Scholar
  • 29 Lattuada A, Preda L, Sacchi E, Gallo L, Federici AB, Rossi E. A rapid assay for ristocetin cofactor activity using an automated coagulometer (ACL 9000). Blood Coagul Fibrinolysis 2004; 15 (06) 505-511
    CrossrefPubMedSearch in Google Scholar
  • 30 Cabrera N, Moret A, Caunedo P. et al. Comparison of a new chemiluminescent immunoassay for von Willebrand factor activity with the ristocetin cofactor-induced platelet agglutination method. Haemophilia 2013; 19 (06) 920-925
    CrossrefPubMedSearch in Google Scholar
  • 31 Lawrie AS, Stufano F, Canciani MT, Mackie IJ, Machin SJ, Peyvandi F. A comparative evaluation of a new automated assay for von Willebrand factor activity. Haemophilia 2013; 19 (02) 338-342
    CrossrefPubMedSearch in Google Scholar
  • 32 Stufano F, Lawrie AS, La Marca S, Berbenni C, Baronciani L, Peyvandi F. A two-centre comparative evaluation of new automated assays for von Willebrand factor ristocetin cofactor activity and antigen. Haemophilia 2014; 20 (01) 147-153
    CrossrefPubMedSearch in Google Scholar
  • 33 Patzke J, Althaus H, Obser T. et al. Evaluation of a new VWF activity assay based on GPIba in the absence of ristocetin. Haemostesiologie 2010; 30: P07-3
    PubMedSearch in Google Scholar
  • 34 Flood VH, Gill JC, Morateck PA. et al. Gain-of-function GPIb ELISA assay for the molecular and clinical biology of VWD. Blood 2011; 117: e67-e74
    CrossrefPubMedSearch in Google Scholar
  • 35 Favaloro EJ. Collagen binding assay for von Willebrand factor (VWF:CBA): detection of von Willebrands Disease (VWD), and discrimination of VWD subtypes, depends on collagen source. Thromb Haemost 2000; 83 (01) 127-135
    Thieme ConnectPubMedSearch in Google Scholar
  • 36 Federici AB, Canciani MT, Forza I, Cozzi G. Ristocetin cofactor and collagen binding activities normalized to antigen levels for a rapid diagnosis of type 2 von Willebrand disease—single center comparison of four different assays. Thromb Haemost 2000; 84 (06) 1127-1128
    PubMedSearch in Google Scholar
  • 37 Flood VH, Gill JC, Friedman KD. et al; Zimmerman Program Investigators. Collagen binding provides a sensitive screen for variant von Willebrand disease. Clin Chem 2013; 59 (04) 684-691
    CrossrefPubMedSearch in Google Scholar
  • 38 Haberichter SL, Castaman G, Budde U. et al. Identification of type 1 von Willebrand disease patients with reduced von Willebrand factor survival by assay of the VWF propeptide in the European study: molecular and clinical markers for the diagnosis and management of type 1 VWD (MCMDM-1VWD). Blood 2008; 111 (10) 4979-4985
    CrossrefPubMedSearch in Google Scholar
  • 39 Eikenboom J, Federici AB, Dirven RJ. et al; MCMDM-1VWD Study Group. VWF propeptide and ratios between VWF, VWF propeptide, and FVIII in the characterization of type 1 von Willebrand disease. Blood 2013; 121 (12) 2336-2339
    CrossrefPubMedSearch in Google Scholar
  • 40 van Genderen PJ, Boertjes RC, van Mourik JA. Quantitative analysis of von Willebrand factor and its propeptide in plasma in acquired von Willebrand syndrome. Thromb Haemost 1998; 80 (03) 495-498
    PubMedSearch in Google Scholar
  • 41 Federici AB, Mazurier C, Berntorp E. et al. Biologic response to desmopressin in patients with severe type 1 and type 2 von Willebrand disease: results of a multicenter European study. Blood 2004; 103 (06) 2032-2038
    CrossrefPubMedSearch in Google Scholar
  • 42 Castaman G, Lethagen S, Federici AB. et al. Response to desmopressin is influenced by the genotype and phenotype in type 1 von Willebrand disease (VWD): results from the European Study MCMDM-1VWD. Blood 2008; 111 (07) 3531-3539
    CrossrefPubMedSearch in Google Scholar
  • 43 Laffan MA, Lester W, O'Donnell JS. et al. The diagnosis and management of von Willebrand disease: a United Kingdom Haemophilia Centre Doctors Organization guideline approved by the British Committee for Standards in Haematology. Br J Haematol 2014; 167 (04) 453-465
    CrossrefPubMedSearch in Google Scholar
  • 44 Federici AB. Towards a more automatic and rapid laboratory diagnosis of von Willebrand disease. Thromb Res 2016; 141: 198-201
    CrossrefPubMedSearch in Google Scholar
  • 45 Favaloro EJ, Bonar R, Chapman K. et al. Differential sensitivity of von Willebrand factor activity assays to large and small VWF molecular weight forms: a cross-laboratory study comparing ristocetin cofactor, collagen binding and monoclonal antibody-based assays. J Thromb Haemost 2012; 10: 1043-1054
    CrossrefPubMedSearch in Google Scholar
  • 46 Favaloro EJ, Mohammed S, Vong R. et al. How we diagnose 2M von Willebrand disease (VWD): use of a strategic algorithmic approach to distinguish 2M VWD from other VWD types. Haemophilia 2021; 27 (01) 137-148
    CrossrefPubMedSearch in Google Scholar
  • 47 Favaloro EJ. Commentary on the ASH ISTH NHF WFH 2021 guidelines on the diagnosis of VWD: reflections based on recent contemporary test data. Blood Adv 2022; 6 (02) 416-419
    CrossrefPubMedSearch in Google Scholar
  • 48 Federici AB. Validation of a rapid diagnostic approach in inherited and acquired defects of VWF by automatic tests assessed before and after DDAVP trial: results from the Chinese-Italian CREWILACT Study. Abstract 1705265, accepted at the WFH Congress, Madrid 21–24 April 2024
    PubMed

   Permissions and Reprints
Zoom Image
Fig. 1 Distribution of severe, moderate, and mild cases of the Italian patients with HA versus VWD. This figure has been prepared ex novo by Federici et al using data reported in reference [10]. The different percent distribution of VWD versus HA is shown in three types of gray according to the severity of both diseases: severe (dark gray), moderate (intermediate gray), and mild (light gray). Classification of VWD clinical severity is based on baseline levels of VWF activity following the definition of HA according to FVIII:C levels. Note the different percent distribution of mild cases in HA (42%) versus those in VWD (77%) (Report of ISTISAN 2018).
Zoom Image
Fig. 2 Percent of diagnostic tools available at the Italian center in 2023. In this figure, the percent of the 11 diagnostic tools that were available locally at the 43 Italian centers are shown, as retrieved from the survey organized in 2023 by AICE. Note that only three tools (BAT, VWF:Ag, and Factor VIII) are available in all centers, while five tools (VWF:CB, VWF multimers, VWF pro-peptide, VWF:FVIIIB, and VWF gene analyses) can be performed only in <50% of centers.
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Fig. 3 Suggested flowchart for simplified diagnosis of VWD types in Italy. Flowchart proposed for a more rapid diagnosis and classification of different VWD types as modified from previous publication.[44] VWD3 can be diagnosed in the case of undetectable PD-VWFact. FVIII:C is always reduced in VWD3 and in VWD2N: it can be partially reduced or normal in all the other VWD types. After bleeding history of suspected patients with VWD is collected by BAT and the family history of bleeding investigated ([Table 2]), a reduced level of VWF activity should be measured as first parameter (1) using one of the PD-VWFact tests together with FVIII:C (2), VWF.Ag (3), and VWF.CB (4). The use of DDAVP challenge test at the time of diagnosis with the assessment before and after DDAVP of platelet counts and of all four tests, with calculated PD-VWFAct/Ag, VWF:CB/Ag and FVIII/VWF:Ag ratios, might allow the provisional identification of VWD types in most patients without performing additional tests, As examples, VWD2B can be identified without using RIPA, if platelet counts are reduced from baseline after DDAVP. Different PD-VWFAct/Ag and VWF:CB/Ag ratios may suggest VWD2A or VWD2M types. Moreover, VWD patients with circulating short half-life VWF to be assessed by the increased VWF:PP/Ag ratio and the VWD2N cases with abnormal VWF:FVIIIB can be identified by evaluating the behavior of the PD-VWFAct/Ag, VWF:CB/Ag, and FVIII/VWF:Ag ratios after 1 and 4 hours after DDAVP. Therefore, DDAVP trial can immediately identify the clinical diagnosis of patients with different VWD types and cases who can be treated with DDAVP or VWF concentrates.