Acquired von Willebrand Syndrome [AVWS]

Acquired von Willebrand Syndrome [AVWS]
Jun 19, 2021 11:29pm

From Dr. Jasmina Aluwahlia, regarding detection of anti Von Willebrand factor antibodies.

"Hello George, how does one screen for anti-VWF antibodies in a suspected case of acquired AVWS? We assay the VWF :Ag and VWF :GPIbR on a automated coagulometer. The VWF :GPIbR is based on a latex immunoassay. Is there any protocol that can be used on coagulometers using these assays, considering these tests are not truly functional assays. Thanks, Jasmina."

Hello, Jasmina, and thank you for your question. I believe this is the first time we've addressed AVWS on Fritsma Factor. First, click here for an excellent review, Franchini M, Mannucci M. Acquired von Willebrand syndrome: focused for hematologists. Haematologica 2020; 105: 2032–7.

Some brief points from the Mannucci review. AVWS prevalence is rising due in part to its association with cardiac disorders and the use of left ventricular assist devices. AVWS is also associated with a variety of autoimmune disorders. In the first instance, von Willebrand factor is consumed by mechanical stress, in the latter, non-neutralizing antibodies degrade and clear VWF. In most cases, symptoms appear in mid to late adulthood and are not detected in first-degree kin. Laboratory results resemble hereditary von Willebrand disease results, often duplicating VWD type 2A where the VWF :GPIbR/VWF:Ag ratio [activity versus concentration] is 0.7 or lower. Labs routinely use multimeric analysis to document reduction or loss of large VWF multimers that reflect the ratio and account for the bleeding.

Treatment decisions are attempted on the basis of the presence or absence of the autoantibody. Patients whose AVWS is immune-mediated bleed more that those whose mechanism is mechanical. The article suggests that lab directors attempt mixing studies using normal plasma in an attempt to demonstrate an inhibitory pattern, however non-neutralizing autoantibodies that bind VWF are often cleared, so a negative mixing study pattern is non-diagnostic. As a generalization, the lab and clinic must combine physicial examination and history with assay outcomes to reach a diagnostic conclusion. The article continues with a careful description of treatment approaches. It appears there is no clear laboratory answer to Jasmina's question.
Again, thank you for your question, and please let me know how your case is resolved.

2 Comments

From Dr. Jasmina Aluwahlia, regarding detection of anti Von Willebrand factor antibodies.

"Hello George, how does one screen for anti-VWF antibodies in a suspected case of acquired AVWS? We assay the VWF :Ag and VWF :GPIbR on a automated coagulometer. The VWF :GPIbR is based on a latex immunoassay. Is there any protocol that can be used on coagulometers using these assays, considering these tests are not truly functional assays. Thanks, Jasmina."

Hello, Jasmina, and thank you for your question. I believe this is the first time we've addressed AVWS on Fritsma Factor. First, click here for an excellent review, Franchini M, Mannucci M. Acquired von Willebrand syndrome: focused for hematologists. Haematologica 2020; 105: 2032–7.

Some brief points from the Mannucci review. AVWS prevalence is rising due in part to its association with cardiac disorders and the use of left ventricular assist devices. AVWS is also associated with a variety of autoimmune disorders. In the first instance, von Willebrand factor is consumed by mechanical stress, in the latter, non-neutralizing antibodies degrade and clear VWF. In most cases, symptoms appear in mid to late adulthood and are not detected in first-degree kin. Laboratory results resemble hereditary von Willebrand disease results, often duplicating VWD type 2A where the VWF :GPIbR/VWF:Ag ratio [activity versus concentration] is 0.7 or lower. Labs routinely use multimeric analysis to document reduction or loss of large VWF multimers that reflect the ratio and account for the bleeding.

Treatment decisions are attempted on the basis of the presence or absence of the autoantibody. Patients whose AVWS is immune-mediated bleed more that those whose mechanism is mechanical. The article suggests that lab directors attempt mixing studies using normal plasma in an attempt to demonstrate an inhibitory pattern, however non-neutralizing autoantibodies that bind VWF are often cleared, so a negative mixing study pattern is non-diagnostic. As a generalization, the lab and clinic must combine physicial examination and history with assay outcomes to reach a diagnostic conclusion. The article continues with a careful description of treatment approaches. It appears there is no clear laboratory answer to Jasmina's question.
Again, thank you for your question, and please let me know how your case is resolved.

By Dr Jasmina Ahluwalia
Jun 22, 2021 3:54am
Thank you George for sharing this paper. Perhaps one of the reasons why there is some lack of clarity of what needs to be done is that we do not have / or have missed " idiopathic cases " i.e unrelated to a known disorder that predisposes to AVWS as listed in the manuscript. Interestingly, both acquired hemophilia and AVWS have some shared clinical presentations like GI bleeds and skin bleeds.
We tend to think of and screen such patients for acquired hemophilia with incubated mixing tests, especially if the aPTT is prolonged. I wonder if one should always also include a VWF:Ag and some activity assay in all elderly who come with bleeding lest we miss this entity. If we have abnormal results, what to do next will still be a question.
Currently I do not have a patient, just an inquisitive clinical colleague who wondered if we could screen for this.
I look forward to experiences of those who may have encountered these in the lab.
Thanks. Jasmina
By Dr Emmanuel Favaloro
Jun 23, 2021 4:13am
Hi Jasmina, VWF antibodies are uncommon, even in AVWS. Most cases of AVWS are due to either reduction of HMW VWF (eg aortic stenosis) or absorption of VWF (eg malignancies) or reduced production of VWF (eg thyroid dysfunction). To search for VWF antibodies, I would recommend a Bethesda like assay using several VWF activity assays. So, just like a FVIII inhibitor assay, but using VWF activity assays. A recommended paper: Coleman R, Favaloro EJ, Soltani S, Keng TB. Acquired von Willebrand disease: potential contribution of the VWF:CB to the identification of
functionally inhibiting auto-antibodies to von Willebrand factor. J Thromb
Haemost. 2006;4:2085-8. doi: 10.1111/j.1538-7836.2006.02072.x. PMID: 16961622.

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