Von Willebrand disease

hereditary elliptocytosis and hereditary pyropoikilocytosis. Blood Cells Mol Dis 1996;22:254–8. 8 Delaunay J. The hereditary stomatocytoses: genetic disorders of the red cell membrane permeability to monovalent cations. Semin Hematol 2004;41:165–72. 9 Carella M, Stewart G, Ajetunmobi JF et al. Genomewide search for dehydrated hereditary stomatocytosis (hereditary xerocytosis): mapping of locus to chromosome 16 (16q23-qter). Am J Hum Genet 1998;63:810–6. 10 Fricke B, Argent AC, Chetty MC et al. The ‘stomatin’ gene and protein in overhydrated hereditary stomatocytosis. Blood 2003;102:2268–77. 11 Beutler E. G6PD deficiency. Review. Blood 1994;84:3613–36. 12 Dalal BI, Kollmannsberger C. Druginduced haemolysis and methaemoglobinaemia in glucose-6 phosphate dehydrogenase deficiency. Br J Haematol 2005;129:291. 13 Beutler E, Baronciani L. Mutations in pyruvate kinase. Review. Hum Mutat 1996;7:1–6. 14 van Wijk R, Rijksen G, van Solinge WW. Molecular characterisation of pyruvate kinase deficiency – concerns about the description of mutant PKLR alleles. Br J Haematol 2007;136:167–9. 15 Kutlar A. Sickle cell disease: a multigenic perspective of a single gene disorder. Review. Haemoglobin 2007;31:209–24. 16 Vichinsky E. New therapies in sickle cell disease. Review. Lancet 2002;360:629–31. 17 Williamson D. The unstable haemoglobins. Review. Blood Rev 1993;7:146–63. Von Willebrand disease (vWD) is the most common of the inherited bleeding disorders, with a prevalence of symptomatic vWD around 125 per million.1 It is caused by mutations affecting the von Willebrand factor (vWF) gene which result in either quantitative or qualitative abnormalities of vWF. Patients with vWD have a mucocutaneous pattern of bleeding, with easy bruising associated with trauma and may report spontaneous bruising. Epistaxes and menorrhagia are common features. Prolonged bleeding following haemostatic challenges, including minor cuts, dental extractions and surgical procedures, is also typical. vWF is synthesised predominantly in blood vessel endothelial cells but is also produced by bone marrow megakaryocytes and incorporated into platelet alpha granules.2 The vWF gene is located on chromosome 12. The primary gene product is a protein with a molecular weight of approximately 250 kDa. Within cells of synthesis the vWF protein undergoes polymerisation, forming a range of multimers up to 80 protein units in size. vWF multimers are secreted from blood vessel endothelial cells directly into the circulation or are retained in the cells in specialised storage granules called Weibel-Palade bodies from which they are released as a response to vascular injury. The main function of vWF is to facilitate platelet binding to blood vessel subendothelium at sites of vascular damage in high shear flow environments such as small arteries and the microvasculature (Fig 1).3 Once platelets are anchored in place, vWF enables aggregation of platelets recruited to the site of injury culminating in the formation of a haemostatically effective platelet plug. The high molecular weight multimer forms of vWF are required for these platelet interactions. vWF also functions as the carrier protein for clotting factor VIII (FVIII), protecting it from proteolytic degradation in the circulation and transporting it to sites of vascular injury to enable it to carry out its crucial role in coagulation. Qualitative and quantitative defects in vWF result in impairment of the haemoJonathan T Wilde MD FRCP FRCPath, Consultant in Haemostasis, University Hospital, Birmingham NHS Foundation Trust