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

Abstract

von Willebrand disease (VWD) and haemophilia represent the most common inherited or acquired bleeding disorders. However, many laboratories and clinicians may be challenged by their accurate diagnosis or exclusion. Difficulties in diagnosis/exclusion may include analytical issues, where assays occasionally generate an incorrect result (ie representing an analytical error) or have limitations in their measurement range of and/or low analytical sensitivity. Also increasingly recognized is the influence of preanalytical issues on the diagnosis of VWD or haemophilia. Unfortunately, postanalytical considerations are often not well considered in the diagnostic process. Therefore, this narrative review aims to provide an overview of some important postanalytical considerations that may help improve the diagnosis of VWD and haemophilia. This review primarily discusses aspects around reporting of test results. However, we also discuss other less well-recognized postanalytical considerations, including the use of assay ratios to help identify differential diagnoses and then guide further investigation.

Results of genetic analysis of 11 341 participants enrolled in the My Life, Our Future hemophilia genotyping initiative in the United States

“…Alternatively, those with no variant found may have been misdiagnosed. Other causes of low FVIII levels leading to a misdiagnosis with hemophilia A include von Willebrand disease, 27 acquired hemophilia A, 28 and incorrect laboratory test results 29 . Other more rare disorders can also cause low factor levels, such as combined deficiency of coagulation factor V and VIII which causes low FVIII 30 and vitamin K dependent coagulation factor deficiency which can cause low FIX 31 …”

“…Willebrand disease, 27 acquired hemophilia A, 28 and incorrect laboratory test results. 29 Other more rare disorders can also cause low factor levels, such as combined deficiency of coagulation factor V and VIII which causes low FVIII 30 and vitamin K dependent coagulation factor deficiency which can cause low FIX. 31 We found that F8 and F9 variants predicted to be gene disrupting are common in severe hemophilia, while missense variants predominate in moderate and mild hemophilia.…”

Recent Advances in Mainstream Hemostasis Diagnostics and Coagulation Testing

“…2,4 A "prolonged" clotting test result in a patient being screened for hemophilia may justify factor testing. 91 In contrast, a "prolonged" APTT on a patient on unfractionated heparin therapy will not typically require additional testing, as this prolongation would be expected-nonetheless, additional testing may be suggested if the APTT prolongation is much longer than expected for the dose of heparin. 92,93 In such a case, perhaps evaluation of FXII deficiency or LA may be warranted, as the presenting APTT may misrepresent the patient's anticoagulant status, and downward dose adjustments may increase the risk of thrombosis.…”

“…Other postanalytical considerations may be beyond the realm of manufacturers, and include such events as result interpretation (in particular where a panel of tests are resulted and interpreted together). 90,91,94 Perhaps in the future, manufacturers of mainstream analyzers will begin to take a larger interest also in this area of postanalytics.…”