LabMed

Von Willebrand Disease - Congenital

At a Glance

Von Willebrand disease is an inherited bleeding disorder with only very rare acquired cases. A family history of bleeding, especially one that affects both males and females, should prompt consideration of von Willebrand disease. Because it is a mild bleeding disorder in most patients, many patients report a negative bleeding history. The signs and symptoms of bleeding vary among patients with von Willebrand disease. Some evaluations are initiated as a result of easy bruising, others following excessive bleeding with dental extractions or surgery, and others in patients with recurrent epistaxis or excessive menstrual bleeding. Any of these indicators of bleeding should prompt consideration of von Willebrand disease.

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

A standard panel for the assessment of von Willebrand disease includes tests for von Willebrand factor antigen, ristocetin cofactor, and factor VIII. A follow-up test that evaluates the distribution of von Willebrand factor multimers may also be useful in certain circumstances.

Von Willebrand disease is organized into three types: types 1, 2, and 3. Type 2 has several subtypes. These include type 2A, 2B, 2M, and 2N. The vast majority of individuals with von Willebrand disease have type 1. The results of the tests in the von Willebrand factor panel provide an initial clue about the type of von Willebrand disease that may be present. Further evaluation of a patient to determine the type of von Willebrand disease involves the use of von Willebrand multimer analysis.

In type 1, the results of the three tests in the von Willebrand factor panel are usually proportionately decreased. The multimer analysis is rarely required to diagnose type 1 von Willebrand disease. The modest and proportional decrease in von Willebrand factor antigen and ristocetin cofactor with a normal or slightly low factor VIII is sufficient evidence to identify a patient with type 1 von Willebrand disease.

In type 2A, both the intermediate and large sized multimers are absent. In patients with type 2 von Willebrand disease, ristocetin cofactor is decreased significantly more than the von Willebrand factor antigen, and both of these are usually much lower than in patients with type 1. The von Willebrand factor multimer analysis is very useful in the identification of this subtype, because it demonstrates the absence of both intermediate and large sized multimers.

In type 2B, the largest multimers are absent from the plasma, but they are present in the blood, bound to the surface of platelets. This is a result of an abnormal von Willebrand factor, which has increased affinity for the platelets. As in type 2A, ristocetin cofactor is decreased much more than the von Willebrand factor antigen, and both of these values are usually much lower than in patients with type 1 disease.

The von Willebrand multimer analysis is also useful in identifying patients with type 2B, because it demonstrates the selective decrease in high molecular weight multimers from the patient plasma. An additional test to aid in the identification of patients with this disorder assesses the ability of the patient's platelets to aggregate to very low doses of ristocetin, which occurs because the patient's platelets are coated with large multimers of von Willebrand factor. This is another hallmark of type 2B von Willebrand disease.

Type 2M von Willebrand disease occurs as a result of decreased von Willebrand factor function, despite the presence of a large multimers of von Willebrand factor. Very specialized tests are used to assess patients for this rare subtype.

Type 2N von Willebrand disease masquerades as hemophilia A, with low levels of factor VIII and normal von Willebrand factor levels. In this disorder, the von Willebrand factor binds poorly to factor VIII, and this decreased binding shortens the half-life of factor VIII, resulting in a low factor VIII level. Specific assays can be performed to evaluate the affinity of von Willebrand factor for factor VIII and assess the patient for the presence of this rare subtype of von Willebrand disease.

Type 3 is a severe deficiency of von Willebrand factor. The values for von Willebrand factor antigen and ristocetin cofactor are extremely low. In addition, von Willebrand multimer analysis may be useful to demonstrate the virtual absence of all von Willebrand factor multimers.

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.

First, all of the tests in a 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% in the presence of a stimulus to the acute phase response can have a value of 90%. 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 can lead to the incorrect conclusion that a patient does not have a von Willebrand disease. Thus, normal results from a single evaluation should not rule out a diagnosis of von Willebrand disease, particularly if there is a bleeding history or evidence of a stimulus to the acute phase response.

Second, if there is a decrease in the factor VIII, it is often too modest to prolong the partial thromboplastin time (PTT) in patients with von Willebrand disease. The assessment for von Willebrand disease requires the performance of the panel listed, because the PTT is an unreliable screening test for von Willebrand disease.

Third, 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.

Fourth, the mean value for von Willebrand factor antigen varies with the blood type of the patient. Patients with type O blood have a mean von Willebrand factor level 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 a 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 they have clinically significant bleeding and respond positively to treatment with desmopressin (DDAVP), just like patients with von Willebrand disease.

What Lab Results Are Absolutely Confirmatory?

Genetic alterations in the von Willebrand factor gene are reasonably well defined for the type 2 mutations. Finding such a mutation provides absolute confirmation of von Willebrand disease and its type and subtype. However, there are no genetic identifiers to provide a conclusive diagnosis of this disorder for the most common type, type 1. Therefore, most cases of 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?

As noted, if the presence of type 1 von Willebrand disease is suggested by the results of the three tests in the initial von Willebrand factor evaluation (factor VIII, von Willebrand factor antigen, and ristocetin cofactor), no testing for von Willebrand factor multimers is necessary. It should also be noted that children younger than 6 months of age have a higher reference range for von Willebrand factor than individuals older than 6 months of age. Thus, a value that might be considered normal in an adult could actually be low in a child younger than 6 months of age.

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