Molecular Genetics of von Willebrand Disease

Abstract

In 1926, Dr Erik von Willebrand first described the autosomal bleeding disorder that we now call von Willebrand disease (VWD). Since then, the protein responsible – eponomously named von Willebrand factor (VWF) – has been identified, the gene encoding the protein has been localized , the gene sequence has been determined and many mutations within the gene that lead to a deficiency or dysfunction of VWF and cause VWD have been characterized. Through the concerted efforts of scientists and clinicians, there is now considerable understanding of the molecular genetics of VWD and, through studies done both in vitro and in vivo, the mechanism of disease has been revealed for many of the characterized gene defects. Despite the complexities of both the VWF protein and its gene, we have a detailed picture of the molecular genetics of VWD. This review aims to provide an informative summary of current knowledge.

Key concepts

  • von Willebrand factor (VWF) is a polymeric (multimeric) blood protein that is essential for the initial stages of blood clot formation.

  • VWF has several biological activities that are important for its role in haemostasis, including binding to platelet glycoprotein Ib, coagulation factor VIII, collagen.

  • VWF has a complex biochemistry that is influenced by independent modifiers such as ABO blood group and the metalloprotease ADAMTS13.

  • von Willebrand disease (VWD) is classified into three types according to the quantity and functional activity of VWF: type 1, type 2 and type 3. Type 2 VWD is further subdivided according the functional defect present: type 2A, 2B, 2M and 2N.

  • The genetic basis for VWD is highly heterogeneous; the disease shows dominant inheritance for some mutations and recessive inheritance for others.

  • Mutations that cause milder forms of the disease show variable penetrance and this, in part relates to other modifying factors such as ABO blood group and possibly ADAMTS13.

  • The relationship between cause and effect is understood for some mutations but not for all.

Keywords: von Willebrand factor; von Willebrand disease; primary haemostasis; ADAMTS13; platelets; Bleeding

Figure 1.

Structural and functional domains of VWF. (a) Internal homologies within VWF give rise to the repeated structural domains A–D (Mancuso et al., ; Verweij et al., ). The C‐terminus contains a cysteine‐rich region known as the cysteine knot (CK) domain. Numbers within each domain correspond to exons in VWF; the scale below the domains represents amino acid residue number (the translation initiation methionine is residue 1). (b) Schematic showing the extent of pre‐, pro‐ and mature VWF (Verweij et al., ). (c) VWF functional domains and ADAMTS13 proteolysis site relative to pre‐pro‐VWF (panel B) and the structural domains of the protein (panel A). RGD abbreviates the peptide motif Arg‐Gly Asp recognized by GPIIbIIIa. (d) Distribution of mutations found in VWD type 1, 2A, 2B, 2M and 2N (based on the international VWF database at URL http://www.vwf.group.shef.ac.uk/ on 5 June 2008). In type 2M VWD, the single mutation in domain A3 (p.Ser1731Thr) is listed as ‘unclassified’ in the international database; however its attributes are consistent with the current definition of type 2M VWD.

Figure 2.

Multimer profiles for plasma VWF. Normal plasma (N) contains multimers ranging from low molecular weight (LMW) to high molecular weight (HMW). Each main multimer band is accompanied by an upper satellite band and a lower satellite band, giving the appearance of a triplet structure. The satellite bands are produced by ADAMTS13 proteolysis. Two different profiles found in type 1 VWD are illustrated, one showing a quantitative decrease in VWF but otherwise normal profile, the other showing ultra‐large VWF in the presence of multimers that show decreased proteolysis (Vicenza). The type 2A VWD plasma illustrated reflects a Group 2 mutation causing increased ADAMTS13‐mediated proteolysis, evidenced by a relative increase in the satellite bands concurrent with the loss of high‐ and intermediate‐molecular weight multimers. The type 2B VWD plasma illustrated lacks HMW multimers, and the triplet structure suggests enhanced proteolysis by ADAMTS13. The multimer analysis shown is from the author's laboratory.

Figure 3.

A Model for VWF participation in clot formation. (a) At a site of vessel damage, activated endothelial cells (grey) release VWF which remains anchored to the luminal cell surface. (b) The flow of passing blood stretches VWF and subjects it to shear stress. (c) The GPIb binding sites on VWF are exposed and platelets bind. (d) The VWF‐platelet string may interact with collagen in the subendothelium; alternatively the VWF, which is under shear stress in the blood flow, may be proteolysed by ADAMTS13. Clot growth reflects, in part, the balance between these occurrences. This model could also be applied to plasma VWF bound to collagen at exposed subendothelium, and to VWF released from aggregating activated platelets.

Figure 4.

Schematic of plasma VWF multimer profiles in various subtypes of VWD. Profiles reflect the steady balance of all biochemical processes from translation to clearance. Defects may affect more than one process directly or indirectly. For example, in type 2A VWD, some defects in the A2 domain greatly enhance proteolysis, whereas defects in the D2 or CK domains compromise multimerization and proteolysis is minimal or abnormal. Some defects affect only VWF function and do not alter the multimer profile (e.g. type 2N). A normal multimer profile is illustrated on the left hand side (N). Profiles are depicted above VWF to illustrate that the location of a defect often reflects its effect upon the protein. It is important to note that the profiles shown are not restricted to mutations in the areas indicated. For example, the type 2A (IIC) profile can also arise from mutations in the D3 domain, whereas mutation of the CK domain can cause a type 2A (IIE) pattern. IIA, IIB, IIC, IID and IIE refer to historic nomenclature for the identification of subtypes. Type 2M mutations (see text) are not represented in this schematic.

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Further Reading

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Mendolicchio GL and Ruggeri ZM (2005) New perspectives on von Willebrand factor functions in hemostasis and thrombosis. Seminars in Hematology 42: 5–14.

Meyer D, Fressinaud E, Hilbert L et al. (2001) Type 2 von Willebrand disease causing defective von Willebrand factor‐dependent platelet function. Best Practice & Research. Clinical Haematology 14: 349–364.

Michiels JJ (ed.) (2008) Proceedings of the European VWF VWD Workshop. Antwerp: University Press Antwerp.

Tuddenham EGD and Cooper DN (1994) The molecular genetics of haemostasis and its inherited disorders. In: Tuddenham EGD and Cooper DN (eds) Osford Monographs on Medical Genetics No 25. Oxford: Oxford Medical Publications.

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John Bowen, Derrick(Dec 2008) Molecular Genetics of von Willebrand Disease. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0021447]