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Haemophilia. 2017 Sep;23(5):e436-e443. doi: 10.1111/hae.13305. Epub 2017 Jul 27.

Potential misdiagnosis of von Willebrand disease and haemophilia caused by ineffective mixing of thawed plasma.

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Department of Haematology, Institute of Clinical Pathology and Medical Research, NSW Health Pathology, Westmead Hospital, Westmead, NSW, Australia.
Sydney Centres for Thrombosis and Haemostasis, Westmead Hospital, Westmead, NSW, Australia.
Section of Clinical Biochemistry, University of Verona, Verona, Italy.



von Willebrand disease (VWD) reflects a loss or dysfunction in von Willebrand factor (VWF), while haemophilia represents a loss or dysfunction of clotting factors such as factor VIII (FVIII) or FIX. Their diagnosis requires laboratory testing, with this potentially compromised by preanalytical events, including poor sample quality. This study assessed the effect of inadequate mixing as a potential cause of VWD and haemophilia misdiagnosis.


After completion of requested testing, 48 consecutive patient samples comprising separate aliquots from single collections were individually pooled, appropriately mixed, then frozen in separate aliquots, either at -20°C or -80°C for 2-7 days. Each sample set was then thawed and the separate aliquots subjected to separate mixing protocols (several inversions, blood roller, vortex) vs a non-mix sample, and all aliquots then tested for various VWF and factor assays.


Non-mixing led to substantial reduction in VWF and factors in about 25% of samples, that in some cases could lead to misdiagnosis of VWD or haemophilia. Interestingly, there were also some differences observed with respect to different mixing protocols.


Our study identified ineffective or variable mixing of thawed plasma samples as potential causes of misdiagnosis of VWD or haemophilia. Further education regarding the importance of appropriate mixing appears warranted.


VWD; VWF; haemophilia; preanalytical error; sample mixing; von Willebrand disease; von Willebrand factor

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