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Professor in Haemostasis and Thrombosis/Director
Centre for Haemophilia and Thrombosis
University Hospital Skejby
The history of von Willebrand’s disease (VWD) dates back to the 1920s, when the Finnish physician Erich von Willebrand(1) observed and reported on a new bleeding disorder in the land Islands. VWD occurs equally often in females and males and is characterised by a quantitative or qualitative defect, causing the amount or function of von Willebrand factor (VWF) to be reduced in blood. VWF is an extremely large protein and serves an important function in normal haemostasis through its ability to promote adherence of platelets to collagen around the injured vessel wall. Furthermore, VWF offers a protective role for factor VIII and, consequently, this factor may be reduced in VWD. If VWF is deficient or dysfunctional, prolonged bleeding will occur. Bleeding in subcutaneous tissues and from mucous membranes are the most typical symptoms (see Table 1).(2) In the severest of cases, joint bleeds may occur due to concomitant deficiency in factor VIII, and bleeding may be life-threatening.
Definition and phenotypic variants in VWD
The clinical and biochemical hallmarks that define VWD are an increased propensity to mucocutaneous bleeding and an abnormality in concentration, function, or both, of VWF in plasma. Recommended abbreviations for the biochemical functions of VWF are provided in Table 2.(3)
VWD is not a single disease entity but rather a quite large series of variants caused by a multitude of different mutations, and VWD is classified into three major categories based on the biochemical phenotype, as assessed by a defined set of analytical procedures (see Table 3).(4) The subclass diagnosis only partly relates to a molecular diagnosis but is helpful for guidance of optimal treatment of bleeds in the individual patient. Dominant as well as recessive heritage exists.
The majority of patients (around 70%) suffer from the mildest variant, denoted type 1, while a type 2 form is found in 25-27% of patients and 3-5% suffer from type 3.
The clinical bleeding symptoms may vary. The most common symptom is bleeding from mucosal membranes in nose and mouth, the gastrointestinal canal and, in females, manifesting as increased menstrual bleeding (menorrhagia). In the more severely affected cases anaemia and iron deficiency may result from recurrent bleeds, particularly in women. Following surgery wound haematomas may occur, and there may be unusual bleeding following tooth extractions and minor surgical procedures such as adenotomy and tonsillectomy. Patients completely devoid of VWF synthesis (homozygous or doubly heterozygous), as in type 3 variants, have severely lowered levels of factor VIII, giving a clinical picture that resembles moderate haemophilia A because joint and muscle bleeds are seen.
The diagnosis is based on results of the laboratory parameters listed in Table 4. The ristocetin cofactor of VWF most closely predicts the risk of bleeding and, in general, this method is used to evaluate the severity of the condition. As mentioned, the level of factor VIII:C also influences the haemostatic function. A rare variant form, called type 2N, may be difficult to distinguish from mild haemophilia A since quite low levels of factor VIII are found due to mutations occurring in the amino acid sequences of VWF that bind and protect factor VIII.
Bleeding risk in VWD
The most frequent subclass of VWD, type 1, is characterised by a relative deficiency in VWF. It has been difficult to establish a cutoff point that separates disease from normal. A quite large EU-financed study under the acronym of MCMDM-VWD1 has recently been completed and various aspects of the study have been reported.(5) Analysis of the sensitivity/specificity of the diagnostic test shows a likelihood of VWD if the level of VWF is below 35-40% of normal, while persons with higher levels of VWF do not qualify for a diagnosis of VWD type 1 (Tosetto A, et al; submitted manuscript). Milder bleeding problems may be seen in persons having VWF levels at between 35% and 50% of normal.
Patient groups with all other variants (types 2 and 3) of VWD will invariably suffer from bleeding when exposed to trauma or surgery and require regular treatment in such situations.
Treatment of bleeds in VWD
Pharmacological management and control of bleeding in VWD can be allocated into three major categories:
In females with excessive menstrual bleeding (menorrhagia), combined oestrogen/gestagen medication (eg, oral contraceptives) are often very helpful in reducing the intensity of bleeding.
Tranexamic acid medication is useful in the prevention and management of mucosal bleeds. In persons with a diagnosis of a bleeding disorder, the doses of tranexamic acid and modes of administration often adopted comprise:
Release of endogenous stores of VWF
Desmopressin acetate (DDAVP(R), Minirin(R); Sanofi-Aventis, Ferring) administered in doses of 0.3mmg/kg causes release of VWF from endothelial cells through interaction with V2 receptors in the vessel wall. Along with an increase in VWF, factor VIII also elevates temporarily, and in many cases of type 1 VWD normalisation of VWF is noted.(6) DDAVP can be administered by nasal, subcutaneous and IV routes.
DDAVP is prescribed for therapeutic purposes only if the outcome of a trial in the outpatient clinic has shown a clear benefit of the drug.
Since DDAVP reduces renal filtration, repeated administration of DDAVP may cause fluid retention, hyponatraemia and convulsions. As a general rule in our clinic, the allowable number of doses of DDAVP is limited to three over a total treatment period of 48 hours.
Unspecific treatment and DDAVP together provide sufficient haemostasis in minor bleeds in many type 1 VWD patients.
Substitution with a plasma-derived concentrate
A number of factor VIII concentrates exist in which one finds a high amount of well-preserved VWF.(7,8) The general view is that the VWF protein should display a distribution of multimeric forms of VWF similar to and, ideally, identical to those found in normal plasma.
Furthermore, the product should be manufactured from the plasma of healthy persons interviewed and tested rigorously to exclude the possibility of dangerous viral contaminants such as hepatitis B and C as well as HIV1. In addition, the final product should undergo a robust viral inactivation/removal procedure.
Commercial VWF containing factor VIII concentrates are often labelled by their content of factor VIII; in a few instances the label also states the content in terms of VWF units.(8)
The initial dose of VWF in serious bleeds and surgery should be around 50 IU/kg, whereas minor bleeds may require somewhat smaller doses, depending on the outcome of a previously assessed in vivo response to a test dose of the concentrate.
Patients with VWD have a perfectly normal secretion of factor VIII, and a reduced level in VWD is solely caused by the deficiency in VWF. In conjunction with prolonged treatment, using a factor VIII/VWF-containing concentrate, the factor VIII level may rise dramatically because of simultaneous endogenous secretion and exogenous delivery. Abnormally high levels of factor VIII have been linked with risk of thrombosis,(9) and so factor VIII must be monitored closely in the postoperative period.
Concentrates of VWF manufactured by recombinant cell technologies do not yet exist.
Continued research and empirical observations have contributed to improved knowledge of the molecular biology, diagnostic requirements and optimal treatment of patients with von Willebrand’s disease. Management of patients with these rare disorders is not based on medical evidence but rather supported by mechanistic approaches and general experience.