At a Glance

In the vast majority of cases of von Willebrand disease, the disease is an inherited bleeding disorder. Only very rare acquired cases arise in association with multiple myeloma and related disorders, as a result of neutralizing antibodies to von Willebrand factor, or in patients with aortic stenosis in which there is destruction of the high molecular weight von Willebrand factor multimers as they pass through the stenotic valve. The presence of abnormal lymphocytes or lymphocyte derived cells can produce an acquired von Willebrand disease by binding the circulating von Willebrand factor and removing it from the circulation. In this situation, the diagnosis of acquired von Willebrand disease is often considered with the onset of bleeding in a patient with a disorder involving the presence of abnormal lymphocytes.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

Congenital von Willebrand disease should be ruled out before confirming a diagnosis of acquired von Willebrand disease. A standard panel for assessment for von Willebrand disease includes tests for von Willebrand factor antigen, ristocetin cofactor, and factor VIII. Many patients with congenital von Willebrand disease have only a mild bleeding predisposition and, therefore, may not report excessive bleeding in their clinical history. A long history of minor bleeding and bruising is valuable in differentiating congenital von Willebrand disease from acquired von Willebrand disease. The other major supportive factor of a diagnosis of acquired von Willebrand disease is the new onset of a disorder in which abnormal lymphocytes are present. Similarly the presence of aortic stenosis also suggests a diagnosis of von Willebrand disease if there is bleeding.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?

There are several major challenges to the diagnosis of von Willebrand disease.

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First, all of the tests in the panel become elevated as part of the acute phase response. The increases over baseline can be two- to three-fold. Thus, a patient with a significant deficiency of von Willebrand factor in the range of 30% of normal can have a value of 90% when a stimulus to the acute phase response is present. Even minor illnesses or injuries can cause this dramatic increase in von Willebrand factor. Such increases can also be found during pregnancy and in women using oral contraceptives or other estrogen supplements. Such transient normal values often lead to the incorrect conclusion that von Willebrand disease is absent. Thus, normal results from a single evaluation for von Willebrand disease may not rule out a diagnosis of acquired or congenital von Willebrand disease, particularly if there is a bleeding history and the normal values are in the low end of the normal range.

Second, there is significant analytical variability in the ristocetin cofactor assay. A single sample retested multiple times can produce values greater than a range of at least 10-15%, making it difficult to know the true value for ristocetin cofactor.

Third, the mean value for von Willebrand factor antigen varies with the blood type of the patient. Patients with type O blood have a mean for von Willebrand factor of 74%; type A 103%; type B 110%; and type AB 126%.

Finally, the cutoff value for von Willebrand factor and ristocetin cofactor, below which patients are considered to have von Willebrand disease, has been moving downward. As a result, there are many patients with values for these laboratory tests above the cutoff for establishing a diagnosis, but with clinically significant bleeding and a positive response to treatment with desmopressin (DDAVP), just like patients with von Willebrand disease.

What Lab Results Are Absolutely Confirmatory?

Most cases of acquired von Willebrand disease suffer a modest degree of uncertainty, unless the values for von Willebrand factor and ristocetin cofactor are consistently quite low, with less than 40% of von Willebrand factor or ristocetin cofactor emerging as a threshold.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?

The most common mistake made in the interpretation of test results for von Willebrand factor is reaching a conclusion that one set of normal values rules out the presence of von Willebrand disease. For this reason, a von Willebrand factor panel is often supplemented with a marker of the acute phase response, such as fibrinogen or C reactive protein. Any elevation in such inflammatory markers provides a strong indication that the von Willebrand factor results are elevated above the patient’s true baseline and that the patient must be tested again to effectively assess for the presence of von Willebrand disease.