HAEMOSTASIS
von Willebrand disease: classification, testing, diagnosis and treatment
Alain Gadisseur provides an in-depth review of von Willebrand disease in relation to the study of von Willebrand factor, its classification, laboratory testing, mutation studies, and treatment of the disease.
von Willebrand disease (vWD) is the most frequently occurring hereditary bleeding disease but it is not well known. Haemophilia, by comparison, is much rarer but it is an infamous condition. Most people know about the connection between royal families and haemophilia, but little is known about the possibility of von Willebrand disease (vWD) in any of the royal families. In haemophilia, most affected patients suffer severe bleeds,
and classification and diagnosis are straightforward; if factor VIII levels go down then haemophilia is likely due to factor VIII mutation. In contrast, in vWD the bleeding history is not straightforward, as it can show either a very mild or very severe presentation. Diagnosis is not always clear, nor is the definition. Some people give the definition of vWD as being von Willebrand factor (vWF) levels below 30 IU/dL, others below 50 IU/dL.
Classification is not related to the bleeding symptoms, and factor VIII levels can fluctuate. von Willebrand factor also fluctuates so one is never quite sure what is being measured. So, vWD is present in 1–3% of the population, has no gender preference, presents with mucocutaneous bleeding symptoms (ie gingival bleeding, epistaxis, skin haematoma), and in women presents as increased menstrual bleeding.
von Willebrand factor Unlike most coagulation proteins, vWF is not produced by the liver but by endothelial cells, and is present in the plasma in a large multimeric form. It is the largest protein in the blood. It undergoes conformational change under shear stress, when it goes from a globular form to an elongated form which then exposes the functional areas (A1, A2, A3). von Willebrand factor has three main
functions, two of which are binding to collagen, which is exposed when the blood vessel is damaged (A1, A3), and binding to platelet GpIb (A1). These two functions are part of primary haemostasis. The third function is binding to factor VIII to prevent rapid degradation of factor VIII, which makes it part of plasmatic coagulation; thus, vWF plays a part in two coagulation mechanisms. In von Willebrand disease there is a
quantitative or qualitative defect in the vWF. The domain structure of the protein includes D1D2, the propeptide that is cleaved from the mature vWF, the D'D3 domains which are responsible for factor VIII binding, and the three main functional areas (A1, A2, A3). Domain A1 binds to GpIb (platelet binding), A2 contains the cleaving site for ADAMTS13 (proteolytic cleavage), and A3 is the binding site for collagen.
The domain structure of von Willebrand factor, with ligands and laboratory tests. 406
Classification There have been some changes to the classification since the 1980s, when it was attempted based on the multimeric pattern, and this resulted in 50 different forms, which
AUGUST 2016 THE BIOMEDICAL SCIENTIST
Nevit Dilmen
www.ncbi.nlm.nih.gov
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