LAUSR

Dear Editor, The paper by Zegers et al is of interest because practising haemostasis clinicians are challenged frequently by how to optimally investigate a bleeding tendency and because patients with bleeding of unknown cause (BUC), account for 47%-73% of patients with significant bleeding symptoms referred for assessment.1-3 We welcome the proposal of a diagnostic strategy but would like to raise a number of points related to this. There are many factors which may lead to elevated bleeding scores in the absence of an inherited bleeding disorder. Unfortunately, the authors of this study did not state whether a patient had a clinical explanation for perioperative bleeding or postpartum haemorrhage. This would have been instructive to discount bleeding due to clear clinical explanations (eg a lacerated artery) and thus only include patients that met a threshold for having a clinical diagnosis of a bleeding tendency, made by an experienced physician. In the study by Zegers et al, there was no adjustment for the gynaecological specific bleeding score which could have led to a substantial reduction in the overall mean for female patients although postpartum haemorrhage was over represented in the patients with bleeding of unknown cause (BUC). This is important because gynaecological bleeding may overtly bias the bleeding score and it is important to determine that females have a bleeding score comparable to males once the adjustment for gynaecological bleeding has been made, thus supporting that there is a true abnormal bleeding tendency. Data on 124 patients registered at the East of England haemophilia comprehensive care centre with unclassified bleeding disorders (UBD; these patients clinically have a bleeding disorder but normal haemostatic tests) have recently been published.4 The mean bleeding score (condensed MCMDM-1 VWD score) was 6.6 for men (standard deviation [SD] 1.4) and 9.7 in women (SD 3.3). After deduction of scores for menorrhagia and postpartum haemorrhage, the mean bleeding score for women was 6.4 (3.3) which was not significantly different to the male score (P = .11). Accounting for the bias in females due to gynaecological bleeding in this way is essential to conclude a true abnormal bleeding tendency. Zegers et al included patients with BUC who were referred because of a family history (n = 29) or abnormal preoperative tests (n = 6) alongside those with a personal history of bleeding (n = 82). The reasons why the patients could have an elevated bleeding score (or whether they did) was not explored further which could give meaningful insights into the cause of their symptoms. The paper also highlights the limitations of bleeding assessment tools, which whilst being able to give a numerical bleeding score, do not appear to meaningfully add to the diagnostic armamentarium of patients with BUC. The screening strategy could potentially have missed patients with platelet function disorders because PFA was used which is known to be insensitive to platelet function defects.5 This raises the wider issue of the optimal algorithm for working up a patient with a suspected bleeding disorder. The authors include whole exome sequencing in their diagnostic algorithm. We would flag up the recent publication of the ThromboGenomics data (a genetic panel of all known genes associated with bleeding and platelet disorders) that showed a diagnostic rate of <5% in patients with BUC/UBD. We, therefore, concluded that genetic testing should not be recommended for routine use in this patient cohort due to the resource implications and lack of diagnostic capability.6 Nevertheless, we recognize that some disorders such as thrombomodulin coagulopathy and East Texan bleeding disorder may be detected using these techniques but not with standard laboratory tests of haemostasis and could potentially be misdiagnosed as UBD/BUC.7,8 Establishing diagnoses for patients with UBD/BUC will aid treatment decisions for when they undergo invasive procedures or child birth. Tranexamic acid and desmopressin have been described as efficacious; however, this is based on case series, rather than evidence from randomized controlled trials.4,9 These data from Zegers et al highlight the unmet need for diagnostic criteria for patients with UBD/BUC and highlights the importance of further studies into this cohort of patients alongside investigations into the pathophysiology of bleeding disorders and management. In this regard, a recent consensus-based document proposed by an international group of experts has been promoted by the European Hematology Association and could offer some hints for future study planning.10 The document offers a systematic patient-centred approach governed by the overarching principle that, outside the research setting, any test should result in being of clinical utility for the patient.