Von Willebrand Disease (VWD)

Von Willebrand disease (VWH) is the most common inherited blood clotting disorder in humans (occurring in 1% of the population). An acquired form can sometimes result from other medical conditions.1 It is caused by a deficiency in the quality or quantity of von Willebrand factor (VWF), a multimeric protein required for platelet adhesion. There are three types of hereditary VWD; type 1, type 2 and type 3. Type 2 includes several subtypes.2

What is the diagnosis of "Low VWF"?

In 2008, a new "Low VWF" diagnostic category was proposed, which includes individuals whose von Willebrand factor levels are below the normal reference range but not low enough to have von Willebrand disease (in the 30-50 IU/dL range).3

Type 1

60-80% of all VWH cases fall into the type 1 VWH. It may be caused by VWF not being secreted into the circulation or by VWF clearing faster than normal. Symptoms are usually mild. While patients may be asymptomatic, some patients may experience post-operative bleeding (including dental procedures), visible easy bruising, or menorrhagia (heavy menstrual periods). A minority of type 1 cases may present with severe hemorrhagic symptoms. There is also a subtype of VWF called Type 1C, in which clearance is increased and prolonged bleeding occurs.2,4

Type 2

10-20% of von Willebrand patients fall into this group. People with type 2 VWH have normal VWF levels, but the factor is not working as it should. Type 2 VWH is divided into four subtypes: type 2A, type 2B, type 2M and type 2N. Symptoms are moderate to severe.4,5

Type 2A

The ability of qualitatively defective von Willebrand factors to form large VWF multimers is impaired, resulting in a reduction in the amount of large VWF multimers. It results in decreased platelet-dependent function and low RCoF activity. Only small VWF multimer units are detected in the circulation. Von Willebrand factor antigen (VWF: Ag) test is low or normal. The activity of ristocetin co-factor is low when compared to that of von Willebrand antigen5,6

Type 2B

The ability of qualitatively defective VWF to bind to the glycoprotein Ib (GPIb) receptor on platelets is abnormally increased, resulting in self-attachment to platelets followed by rapid clearance of bound platelets and large VWF multimers from the blood. Thrombocytopenia may occur. Large VWF multimers are reduced or absent from circulation.5,6

Type 2M

It is characterized by a reduced level of large multimers in plasma and markedly increased proteolysis. Small multimers fail to provide effective platelet adhesion and interaction with connective tissue.7-9

Type 2N

In this type, VWF fails to bind to FVIII. In type 2N, factor VIII level is lower compared to VWF: Ag. This can lead to confusion with hemophilia A.10

Type 3

There is an undetectable VWF level. For this reason, it is often referred to as the severe form of VWH.11 It is characterized by severe mucosal and joint bleeding.10

Acquired vWD

Acquired vWD is a rare disease caused by the development of antibodies to vWF. Acquired vWD can be caused by a variety of mechanisms, including lymphoproliferative, cardiovascular, and myeloproliferative diseases, and typically resolves with treatment of the cause.12

References
  1. "Von Willebrand disease: MedlinePlus Medical Encyclopedia". www.nlm.nih.gov. Retrieved 18-01-2021
  2. Anne Goodeve, Paula James et al. von Willebrand Disease. PMID: 20301765 Bookshelf ID: NBK7014
  3. Nichols WL, Hultin MB, James AH, Manco-Johnson MJ, Montgomery RR, Ortel TL, Rick ME, Sadler JE, Weinstein M, Yawn BP (March 2008). "von Willebrand disease (vWD): evidence-based diagnosis and management guidelines, the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel report (USA)". Haemophilia. 14 (2): 171–232
  4. https://www.hemophilia.org/bleeding-disorders-a-z/types/von-willebrand-disease. Retrieved 18.01.2021
  5. National Heart, Lung, and Blood Institute. The diagnosis, evaluation, and management of von Willebrand Disease. http://www.nhlbi.nih.gov/guidelines/vwd/index.htm. Published 2007.
  6. Favaloro EJ. Appropriate laboratory assessment as a critical facet in the proper diagnosis and classification of von Willebrand disorder. Best Pract Res Clin Haematol 2001;14:299-319
  7. Zimmerman TS, Dent JA, Ruggeri ZM, Nannini LH. Subunit composition of plasma von Willebrand factor. Cleavage is present in normal individuals, increased in IIA and IIB von Willebrand disease, but minimal in variants with aberrant structure of individual oligomers (types IIC, IID, and IIE). J Clin Invest 1986;77:947-51.
  8. Ruggeri ZM, Pareti FI, Mannucci PM, Ciavarella N, Zimmerman TS. Heightened interaction between platelets and factor VIII/von Willebrand factor in a new subtype of von Willebrand's disease. N Eng J Med 1980;302:1047-51.
  9. Lankhof H, Damas C, Schiphorst ME, IJssdijk MJ, Bracke M, Sixma JJ, et al. Functional studies on platelet adhesion with recombinant von Willebrand factor type 2B mutants R543Q and R543W under conditions of flow. Blood 1997;89:2766-72.
  10. Sadler JE. A revised classification of von Willebrand disease. For the subcommittee on von Willebrand Factor of the scientific and standardization committee of the International society on thrombosis and haemostasis. Thromb Haemost 1994;71:520-5.
  11. Sadler JE, Budde U, Eikenboom JC, Favaloro EJ, Hill FG, Holmberg L, et al. Update on the pathophysiology and classification of von Willebrand disease: A report of the subcommittee on von Willebrand factor. J Thromb Haemost 2006;4:2103-14.
  12. Brian Odom, Iyad Khourdaji et al. Acquired von Willebrand Disease Secondary to Clear Cell Renal Cell Carcinoma. J Endourol Case Rep. 2018; 4(1): 114–116.