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• W2080213111 abstract "We read with interest the commentary by Rodeghiero et al. 1 regarding the diagnosis of type 1 von Willebrand disease (VWD), which affects 80–90% of all patients with VWD. More than 40 years ago, Zimmerman and Edgington 2 reported that the molecules possessing factor VIII coagulant activity (FVIII:C) and von Willebrand factor (VWF) properties could be physically segregated and identified as different molecular entities. This pivotal discovery made it possible to diagnose type 1 VWD and the different VWD subtypes. The advent of mAbs, molecular biology approaches, cell adhesion under flow conditions, and transgenic animal models, among other developments, made it possible to understand the pathophysiology of VWD, the molecular diagnosis of the VWD subtypes, and the treatment alternatives for this disorder. Pathophysiologically, type 1 VWD is defined by partial quantitative deficiency of plasma VWF antigen level with a parallel decrease in VWF activity (usually measured as VWF ristocetin cofactor activity [VWF:RCo] and/or VWF collagen binding). Although this seems simple and straightforward, there is still no global consensus on the plasma VWF cut-off values for the laboratory diagnosis of this frequent subtype. A recent survey 3 showed that only 27% of North American specialized hemostasis laboratories adhered to National Heart, Lung and Blood Institute (NHLBI) expert panel guidelines 4. The objective of our study 5, referred to in the commentary by Rodeghiero et al., was to compare the various laboratory criteria recommended by authoritative groups for the diagnosis of type 1 VWD, which were based largely on expert opinion and little experimental evidence. We analyzed 4298 laboratory evaluations of patients referred to us during a 5-year period. Succinctly, the same data analyzed according to four proposed criteria led to an almost three-fold difference in the diagnostic rate of type 1 VWD, ranging from between 2.8% (NHLBI recommendation; similar to that recently adopted by the British Committee for Standards in Haematology 6) to 8.3% (Zimmerman Program for the Molecular and Clinical Biology of VWD criterion) 7. Therefore, adopting either choice leads to disparate outcomes. We think that these laboratory ranges are unacceptably broad and that their accurate demarcation should be a priority. Rodeghiero correctly criticizes the lack of bleeding score (BS) and family history in our patients; we share this concern, because, without these components, there is no disease to investigate. Diagnosing type 1 VWD on the basis of laboratory values only, without considering bleeding symptoms and inheritance, is as unreasonable as predicting VWD on the basis of the BS only. The authors are also correct in suspecting that an uncertain number of the patients included in our report could have had no abnormal bleeding had they had completed a comprehensive bleeding questionnaire. Nevertheless, this lack of information does not invalidate the central message: the wide variation in diagnotic yield obtained with the isolated analysis of the laboratory results would have not significantly changed had we incorporated the BS and family history in the laboratory diagnosis of VWD in this population. Therefore, we reanalyzed the previously published values 8 of 280 patients with unequivocal pathologic bleeding (BS of ≥ 4.1 and a positive family history in 81.3%). Table 1 compares the diagnostic yield of the proposed laboratory criteria in that population. Remarkably, the diagnostic laboratory outcome of the more conservative NHLBI recommendation is still approximately one-half of that obtained with the criterion of the European Group on VWD. This implies that, even when BS and inheritance information are considered, there is still a major diagnostic discrepancy. The Vicenza BS 9, now referred to as the bleeding assessment tool (BAT), was introduced by European experts on VWD ~ 10 years ago, and was initially linked with VWD diagnosis. Two recent reviews of the BAT have analyzed the usefulness, advantages and shortcomings of at least 10 different versions of this instrument 10, 11. There is a consensus that BATs are useful for research purposes and as a common approach to communicate and compare results on bleeding severity. However, the negative predictive value of BATs exceeds their positive predictive value for VWD diagnosis, mainly in incoming patients with no previous personal or family diagnosis, as is the case in the ‘real world’ of clinical practice. This was expected, because patients with mild inherited platelet functional disorders (PFDs), most of whom have mild–moderate clotting factor deficiencies (CFDs) and other rare bleeding disorders, have similar bleeding patterns as patients with type 1 VWD 8, 12. The same occurs in the majority of patients with the same bleeding phenotype and inheritance pattern, who have no VWD, PFDs or CFDs, and end up with a diagnosis of abnormal bleeding of undefined cause after comprehensive, repeated laboratory testing 8. Accordingly, the use of BATs in outpatient populations would provide more objective and complete information that would be useful in distinguishing normal from pathologic bleeding and that would determine the request for diagnostic laboratory tests (and not only for VWD). However, BATs would provide no substantial insights into the diagnosis of VWD in a single patient, unless that patient disclosed a familial diagnosis of VWD. Three studies, including our own, have shown that qualitative, faster and simpler collection of bleeding data through a comprehensive personal interview is as useful as the BS in incoming patients 8, 13, 14. A recent prospective report 15 showed that the best predictor of bleeding risk is a personal history of previous bleeding expressed by a high BS, requiring the intuition of dedicated physicians. This report on patients with several types of VWD convincingly showed that only a BS of > 10 could predict bleeding episodes. In fact, among 796 patients with VWD, only 75 of them (medians of 9 for BS, 6 IU dL−1 for VWF:RCo, and 29 IU dL−1 for FVIII:C; 56% and 81% with a history of previous treatments with DDAVP or VWF concentrates, respectively) had at least one spontaneous bleeding event that was severe enough to require treatment with DDAVP and/or concentrates during a 1-year follow-up. These original, objective data obtained in patients with VWD indicate that the more severe bleeders will retain their bleeding pattern and treatment requirements, at least in the near future. However, perhaps a more remarkable and unexpected result of this study is the demonstration that future bleeding events and therapy requirements were poorly predicted or not predictable at all in the great majority of unequivocal abnormal bleeders with VWD (BS of 5–10), irrespective of their VWF:RCo values. This finding in less symptomatic cases is in line with previous reports from pediatric outpatient and tertiary-care clinics 16, 17, casting serious doubt on the predictive value of the BS in patients with mild bleeding disorders. Rodeghiero et al. 1 praise the use of likelihood ratios (LRs) in determining the presence of type 1 VWD, combining LRs based on measured VWF levels, the BS, and the number of family members with reduced plasma VWF levels 18. Such an approach has some limitations: it estimates type 1 VWD to be present in 0.1% in the population, a figure that may be an overestimate or an underestimate 19, 20. Moreover, the model assumes an arbitrary cut-off value for VWF of < 40 IU dL−1 for diagnosing VWD. Also, the LRs are highly dependent on the presence of VWD in the family. Even accepting these estimates, an abnormal BS (> 3 in men and > 5 in females) results in an LR of 4, which has an only ~ 80% chance of providing an unequivocal VWD diagnosis 1. The research interest in such an exercise to approach diagnostic certainty is commendable, but unrealistic: in a busy clinical setting, incoming patients may have VWD, but also PFDs and a myriad of other disorders, and will include the ‘silent majority’ of patients with bleeding of undefined cause. Without considering the non-specific nature of the bleeding symptoms, it is hard to imagine the elaboration and real usefulness of disease-specific LRs (e.g. for VWD and PFD diagnoses). This explains why BATs and LRs in VWD studies need to be applied to patients with known familial VWD; and it would also explain why plasma VWF levels are poor predictors of VWD unless they are < 20 IU dL−1 and of future bleeding unless they are < 10 IU dL−1. It is worth remembering that, almost 20 years ago, Sramek et al. 21 found that either simple interviews or elaborate questionnaires in naïve patients had high discriminative power for distinguishing pathologic bleeders from non-bleeders. In contrast, the comparison of both approaches in patients with previously diagnosed bleeding disorders (e.g. VWD and PFD) against referred patients with abnormal bleeding but normal laboratory test results (bleeding of undefined cause) had minimal discriminatory power. These conclusions were also reached with the use of odds ratios, logistic regression analysis, positive and negative LRs, and receiver operating characteristic curves 1, 17. In conclusion, quantitative BATs are useful, objective research tools that allow the standardization of bleeding severity in patients with inherited hemorrhagic disorders, facilitating comparison among research reports. BATs are not disease-specific, but are helpful in distinguishing pathologic bleeders from individuals who bleed normally in response to injury. In this setting, BAT scores can guide the doctor's decision to request diagnostic laboratory assays. However, qualitative or semiquantitative, faster, face-to-face interviews conducted by experienced physicians appear to be equally effective in this respect. BATs are useless in the differential diagnosis of mild inherited bleeding disorders, and their power to predict bleeding is limited to the most severe forms of VWD. Koutts, recognizing the fundamental contributions of Firkin and Zimmerman to the pathogenesis and diagnosis of VWD, reminds us that evaluating and making decisions about an individual patient ‘requires the old-fashioned skill of taking a thorough and probing history from the patient and exercising clinical judgement’ 22. T. Quiroga and P. Zúñiga conducted the clinical studies, and discussed, corrected and approved the final version of the paper. J. Pereira participated in the previous discussion of this paper with valuable ideas, and corrected and approved its final version. D. Mezzano designed the response and wrote the paper. The authors state that they have no conflict of interest." @default.
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• W2080213111 date "2014-12-01" @default.
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• W2080213111 title "Diagnosing type 1 von Willebrand disease: good for patient's health or for doctor's prestige?: comment" @default.
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