Diagnosis of von Willebrand Disease Step by Step

To make the diagnosis, the following is needed:

1. A personal history focusing on bleeding manifestations.
2. A family history of bleeding manifestations or a direct diagnosis of vWD.
3. Results of basic (and if indicated, special confirmatory) laboratory tests.

Scoring Systems

Bleeding manifestations and their severity can be objectively quantified using so-called bleeding scoring systems. One of these is the so-called ISTH BAT (Bleeding Assessment Tool), which has been validated for both adult and pediatric patients with vWD. The ISTH score is higher in type 3 vWD, higher in children with severe vWF deficiency (vWF antigen level < 10 IU/dl).

Another scoring system for pediatric patients could be the PBQ (Pediatric Bleeding Questionnaire), which includes specific bleeding symptoms in childhood. The limitation of using questionnaires in childhood may be the lack of stress situations (e.g., surgeries, menstruation, childbirth, injuries, etc.), and this must be taken into account when evaluating.

Also validated are so-called self-assessment tools (e.g., BAT), where the answers are provided directly by the patient.

Laboratory Diagnosis

Laboratory diagnosis requires at least the initial determination of the following parameters:

• vWF antigen level (vWF Ag)
• vWF binding activity to platelets (vWF:RCo, vWF:GPIbM, vWF:GPIbR)
• Factor VIII (FVIII) coagulation activity

Specifics of vWF Binding Activity Tests

The determination of vWF:RCo has been used for decades. It uses the antibiotic ristocetin to induce a conformational change in vWF, exposing the A1 domain, which allows vWF to bind to platelet GPIb alpha. However, this test has a high coefficient of variability and low sensitivity, especially in patients with vWF levels < 20 IU/dl and certain polymorphism variants.

The more recent vWF:GPIbR test uses recombinant fragments of GPIb alpha bound to microparticles, thus avoiding the need for whole platelets. The test is less variable and more sensitive. The latest vWF:GPIbM assay uses recombinant fragments of GPIb alpha with 2 gain-of-function variants that induce spontaneous binding to vWF without ristocetin − thus eliminating the non-physiological ristocetin, but at the cost of introducing a non-physiological mutant receptor into the assay. Studies suggest higher sensitivity and diagnostic accuracy for both newer tests compared to traditional vWF:RCo.

Special Laboratory Tests

The combination of the above should suffice to diagnose vWD, but in many cases, it is necessary to determine the subtype of the disease using additional tests – this includes the possibility of assessing vWF binding activity to collagen (a sensitive screening test for the presence of high molecular weight multimers, the vWF:CB/vWF:Ag ratio, and specific changes for type 2M), low-dose ristocetin-induced platelet agglutination (typical changes for type 2B), FVIII-vWF binding, multimer analysis, and vWF propeptide antigen determination (indicating vWF synthesis and secretion).

Molecular Genetic Testing

Another possibility is the use of molecular genetic testing. Its significance in so-called low vWF in most cases of type 1 vWD is relatively small. However, in severe forms of type 1 vWD and in vWD types 1C, 2, and 3, it allows for an accurate diagnosis, continuation of genetic counseling within the family, and, last but not least, the choice of appropriate treatment.

Conclusion

The diagnostic algorithm for vWD is complex and belongs in the hands of a specialist. With the introduction of new parameters and procedures, the possibilities of the diagnostic process are likely to further refine in the future.

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Source: Sharma R., Haberichter S. L. New advances in the diagnosis of von Willebrand disease. Hematology Am Soc Hematol Educ Program 2019; 1: 596−600, doi: 10.1182/hematology.2019000064.