Steve Kitchen
PhD
Head Clinical Scientist
Sheffield
Haemophilia and Thrombosis Centre
Royal Hallamshire Hospital
Sheffield, UK
Von Willebrand disease (VWD) is the most common inherited bleeding disorder in humans. The prevalence in the general population is often quoted as 1%, based on published population studies from the USA and Europe.(1,2) However, this is based on the incidence of laboratory features consistent with VWD, and it is important to differentiate this from patients presenting with the bleeding symptoms associated with VWD, which may be more like 1 in 10,000, at least for tertiary hospitals in the developed world.(3) There is overlap between normal subjects and subjects with mild forms of VWD in relation to both laboratory findings and clinical features. This complicates the diagnosis of mild VWD. The international community has recognised this difficulty and has published guidelines on the diagnosis of VWD.(4,5) To confirm a diagnosis of type 1 VWD (see below), there needs to be not just laboratory features consistent with the disease5 but also evidence of appropriate bleeding symptoms and a positive family history or an appropriate genetic defect. Suspicion of the presence of VWD should lead to close dialogue with a haematologist with experience of the disorder. Patients with confirmed VWD should be managed in conjunction with such experts.
The primary defect in VWD is a deficiency of Von Willebrand factor (VWF), a large plasma protein that functions to assist platelets in the formation of a haemostatic plug at the site of blood vessel damage. A second critical function is to bind, transport and stabilise clotting factor VIII, an essential component in the formation of the fibrin strands, which stabilise the primary platelet plug at the site of the blood vessel damage.
Clinical symptoms
The bleeding symptoms in VWD differ from those associated with haemophilia A or haemophilia B. In VWD the predominant symptoms are nosebleeds and bleeds in the mucosa, GI tract or skin. Menorrhagia is common in women with VWD. Excessive bleeding often occurs after surgical interventions, childbirth or trauma. Only the most severe forms of VWD, which are particularly rare, are associated with bleeds into the joints or muscles in the way that might be expected in severe haemophilia A or B patients.
Subtypes of VWD
There are three main types of VWD. Type 1 is characterised by reduced concentrations of functionally normal VWF protein. This is the most common type, representing more than 80% of VWD. Milder forms can be difficult to diagnose, and it is these cases where there is overlap with normal subjects in relation to laboratory features. Type 2 VWD is caused by the presence of a qualitative defect – where an abnormal version of VWF is present. Bleeding symptoms are often significantly worse than in type 1 VWD. Type 2 VWD is further subdivided into type 2A, 2B, 2M and 2N.(4) The most severe problems can occur in type 3 VWD, where there is total or almost total lack of VWF, which maybe undetectable by laboratory methods. Fortunately this is extremely rare, representing less than 1% of VWD patients. The prevalence is therefore perhaps 1 per million of the population, although this maybe higher in communities where consanguineous marriages are common. Type 3 has autosomal recessive inheritance pattern. Type 2A 2B and 2m have dominant inheritance patterns, whereas 2N is recessive.
Diagnosis of VWD
In VWD the prothrombin time and thrombin time are within the normal range. In the majority of cases the activated partial thromboplastin time (APTT) is prolonged. The APTT is unaffected by the presence or absence of VWF but is very much influenced by the level of factor VIII. As mentioned above, VWF stabilises factor VIII, and in VWD a reduced level of VWF leads to a lower concentration of factor VIII, which in turn prolongs the APTT. Normal subjects have factor VIII levels of between 50 and 200 IU/dl. Most type 1 VWD patients have levels of 10–45 IU/dl. The APTT is always prolonged above the upper limit of the normal range when factor VIII is below 25–30 IU/dl. When factor VIII is between 30 and 50 IU/dl, the APTT maybe marginally prolonged by 1–4 seconds or may occasionally be normal. This means that occasional patients with very mild VWD have an APTT that is just within the normal range. Fortunately the majority of Type 1 VWD patients do have a prolonged APTT, and this is usually the first laboratory clue that VWD may be present. There are very many other causes of prolonged APTT, and a high proportion of patients with prolonged APTT do not have VWD. Diagnosis therefore requires confirmatory testing along with collection of a careful personal and family bleeding history.
The level of factor VIII should be determined when there is suspicion of VWD, where there is a clear bleeding history and especially where these are accompanied by a prolongation of APTT. Reduced factor VIII occurs in VWD but also in haemophilia A. It is important to make the differential diagnosis since clinical management is different. The level of VWF is normal or raised in haemophilia A and is always low in VWD when a functional assay is used. VWF can also be measured in an antigen assay. In a few rare cases of VWD the VWF antigen level is normal, so the best test is a functional assay, which is always reduced in VWD, except for type 2N. There are several different tests of VWF function, which include VWF ristocetin cofactor activity and VWF collagen binding activity.
The relationship between VWF:Ag and VWF:Activity is useful for diagnosis of Type 2 qualitative defects. Description of types 2A, 2B, 2M and 2N VWD is beyond the scope of this article, and the reader is referred to Sadler for detailed information.(4) It should be noted, however, that the management of these subtypes is different and so full diagnosis in an expert centre is necessary. Subtyping is necessary since the clinical management varies according to the type of VWD present.(6)
Type 2N is unusual in that the level and function of VWF is normal by most assays. There is a defect of VWF present, and this abnormal VWF does not bind and stabilise factor VIII. Type 2N is extremely rare, representing <1% of cases of VWD.
Both factor VIII and VWF are acute-phase reactants, and reduced levels may temporarily normalise during illness. Levels also rise in pregnancy, and diagnosis of VWD should be made when these temporarily raised levels have returned to baseline. Any low levels indicating possible VWD should be confirmed on a second sample.
Conclusions
VWD is the most common congenital bleeding disorder in the world. Diagnosis requires a combination of laboratory results and clinical symptoms. Bleeding can be severe, and therefore successful diagnosis is required to inform the clinical management. In this respect, advice should be sought from haematologists with up-to-date expertise in the management of bleeding disorders.
References
- Werner EJ, Broxson EH, Tucker EL, Giroux DS, Shults J, Abshire TC. Prevalence of von Willebrand disease in children: a multiethnic study. J Paediatr 1993:123;893-8.
- Rodeghiero F, Castaman G, Dini E. Epidemiological investigation of the prevalence of von Willebrand disease. Blood 1987;69:454-9.
- Lillicrap D. Von Willebrand disease – phenotype versus genotype: deficiency versus disease. Thromb Res 2007;S11-S16.
- Sadler JE. A revised classification of von Willebrand disease. Thromb Haemost 1994;71:520-5.
- Sadler JE, Rodeghiero F, on behalf of the ISTH SSC Subcommittee on Von Willebrand factor. Provisional criteria for the diagnosis of VWD type 1. J Thromb Haemost 2005;3:775-7.
- Pasi KJ, Collins PW, Keeling DM, Brown SA, Cumming AM, Dolan GC, Hay CRM, Hill FGH, Lagffan M, Peake IR. Management of von Willebrand disease: a guideline from the UK Haemophilia Centres Doctors organisation. Haemophilia 2004;10: 218-31.
