Preanalytical issues that may cause misdiagnosis in haemophilia and von Willebrand disease

Abstract

von Willebrand disease (VWD) and haemophilia represent common inherited or acquired bleeding disorders, but many laboratories and clinicians continue to struggle with their diagnosis or exclusion. Difficulties in achieving a correct diagnosis or exclusion of VWD or haemophilia might be due to analytical issues. Sometimes assays may generate a wrong result (ie an analytical error) or may have limitations in their dynamic range of measurement and/or their level of low analytical sensitivity. Less well recognized is the influence of preanalytical issues on the diagnosis of VWD or haemophilia. Therefore, this narrative review aims to provide an overview of some important preanalytical aspects that may affect the diagnosis of VWD or haemophilia, as well as a range of solutions that may help in mitigating or abrogating their influence. The review includes discussion of the more commonly noted preanalytical issues, such as haemolysis/icterus/lipaemia, and sample collection, processing and transport. However, we also extensively discuss other less well-recognized preanalytical issues, including clinical requests, anticoagulants and anticoagulant therapy, and laboratory test choices to name a few.

Postanalytical considerations that may improve the diagnosis or exclusion of haemophilia and von Willebrand disease

“…), (c) transport and processing of sample(s) (appropriate or has this compromised sample quality?). More comprehensive details around these preanalytical issues are provided elsewhere …”

“…Thus, test results as reported to clinicians usually reflect accurate measurements of the analyte for the presented sample (eg in a recent report, the overall analytical error rate for individual tests associated with VWD diagnosis was <0.5%, meaning very few errors are associated with analytical failures) . However, what is less guaranteed is that the presenting sample actually represents an adequate sample reflective of the patient under investigation …”

“…For VWD, the sheer number of tests available, their variable methodology, variable sensitivity to low VWF levels or high molecular weight VWF, as well as the different composite test panels in use, often compromise VWD diagnosis/exclusion, as otherwise reported . In brief, VWF expresses several activities, including: (a) platelet binding (mostly via glycoprotein [Gp] Ib), (b) subendothelial matrix binding (mostly via collagen), (c) FVIII binding.…”

“…Tests as performed represent analytical events and how tests are performed in response to clinical requests are preanalytical decisions ‐ both potentially impairing the final interpretations or outcomes. As previously noted, the clinician is key to the diagnostic journey . Clinicians evaluate their patient, makes some sort of Bayesian, pretest probability assessment and may then order some laboratory tests to confirm or refute their suspicions.…”

“…Less well‐recognized is the influence of preanalytical issues on diagnosing VWD or haemophilia . To address this deficiency in knowledge, we recently published an article aimed to provide an overview of important preanalytical issues affecting the diagnosis of these conditions, as well as a range of solutions that may help in mitigating or abrogating their influence . The current narrative review aims to add to this background of knowledge by addressing issues related to the postanalytical phase, being test reporting and resultant clinical actions.…”