Detection of von Willebrand Disease

Von Willebrand Disease

vWD is characterized by a deficiency or dysfunction of von Willebrand factor (vWF), which is crucial for platelet adhesion and aggregation in primary hemostasis. Additionally, by binding to coagulation factor VIII (FVIII), it prolongs its biological half-life, making it significant in secondary hemostasis. Therefore, in vWD, we find a disorder in platelet adhesion/aggregation and often a reduction in plasma FVIII levels.

We distinguish 3 types of vWD: type 1 is characterized by a partial quantitative deficiency of vWF, type 2 by its qualitative deficiency, and type 3 by an almost complete deficiency of vWF. In type 2, we differentiate subtypes 2A (decreased vWF-dependent platelet adhesion with missing multimers), 2B (increased affinity of vWF to glycoprotein Iba, often accompanied by thrombocytopenia), 2M (decreased vWF-dependent platelet adhesion with abnormal multimer composition), and 2N (decreased affinity of vWF to FVIII).

Clinical Manifestations

Patients with vWD exhibit heterogeneous bleeding symptoms of varying severity dictated by the degree of vWF dysfunction. The most common symptom is mucocutaneous bleeding (epistaxis, bleeding from gums, menorrhagia, gastrointestinal tract bleeding) and prolonged bleeding after surgical procedures, injuries, childbirth, and tooth extractions. In patients with severe type 3 vWD, we often encounter joint and soft tissue bleeding.

In older individuals, acquired vW syndrome with hemorrhagic manifestations similar to vWD may appear. This is also due to vWF deficiency but without the occurrence of bleeding disorder in relatives, and it usually accompanies a heterogeneous group of other diseases such as cardiovascular, immune, myeloproliferative, or lymphoproliferative diseases.

Suspected Disease

The first step in diagnosing vWD is always taking a personal and family history related to bleeding. Diverse bleeding manifestations rather than repeated bleeding in the same location suggest vWD. The severity of vWD is determined by the age at the onset of symptoms and the frequency of bleeding. For this purpose, specific questionnaires were developed, such as Tosetto et al.'s bleeding score questionnaire or the Bleeding Assessment Tool (BAT). vWD is suspected in individuals whose 1 direct relative or 2 second-degree relatives have a history of significant mucocutaneous bleeding or laboratory test results consistent with vWD.

Examination Procedure

Screening tests include the examination of primary hemostasis – determining the platelet count (note, in type 2 vWD, mild thrombocytopenia may be present) and secondary hemostasis – determining the prothrombin time (PT), which is normal in vWD, and the activated partial thromboplastin time (aPTT), which may be prolonged (with reduced FVIII levels).

Tests should always be performed to measure the coagulation activity of FVIII (FVIII:C), vWF antigen (VWF:Ag), and vWF-dependent platelet adhesion, often measured as ristocetin cofactor activity (vWF:RCo). Values of vWF:RCo and vWF:Ag < 2 standard deviations suggest vWD.

It is always advisable to determine blood group, as individuals with blood group 0 naturally have lower vWF levels.

Results can also be influenced by age, sex, race, and menstrual cycle. Therefore, the determination is carried out from 2 samples taken at least several weeks apart.

Further specialized tests for precise diagnosis are performed in specialized centers.

Conclusion

Due to the heterogeneity of vWD, diagnosing and determining the appropriate treatment requires several examinations. It is advisable to verify the consistency of results from different tests, sometimes repeated multiple times. In the near future, the availability of molecular biological methods, such as next-generation sequencing, may significantly change the diagnostics.

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Sources:
1. Baronciani L., Peyvandi F. How we make an accurate diagnosis of von Willebrand disease. Thromb Res 2020 Dec; 196: 579−589, doi: 10.1016/j.thromres.2019.07.010.
2. Tosetto A., Rodeghiero F., Castaman G. et al. A quantitative analysis of bleeding symptoms in type 1 von Willebrand disease: results from a multicenter European study (MCMDM-1 VWD). J Thromb Haemost 2006; 4 (4): 766−773, doi: 10.1111/j.1538-7836.2006.01847.x.