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Pier Mannuccio Mannucci
Professor and Chairman
Angelo Bianchi Bonomi Haemophilia and Thrombosis Centre/Department of Medicine and Medical Specialties
Mangiagalli and Regina Elena Foundation
University of Milan
Von Willebrand’s disease (VWD) is an inherited bleeding disorder caused by the quantitative deficiency or dysfunction of von Willebrand factor (VWF), a large multimeric glycoprotein. VWF is essential for platelet plug formation at the sites of vascular injury (particularly through the largest multimers) and to protect the antihaemophilic factor VIII (FVIII) from inactivation and clearance.(1)
The principal clinical manifestations of VWD are excessive and prolonged bleeding after surgical interventions and mucosal tract haemorrhages such as epistaxis and menorrhagia.(2) Only the most severely affected patients have spontaneous soft-tissue bleeding, such as haematomas and haemarthroses.(2) Excessive bleeding at the time of menstruation and during childbirth is a frequent problem in women of childbearing age.(3)
VWD is classified into four different types. Type 1(which accounts for 60-80% of cases) is characterised by mild-to-moderate quantitative deficiencies of both VWF and FVIII.(4) Type 2 (which accounts for 10-30% of cases) is characterised by qualitative abnormalities of VWF and is further subdivided into types 2A, 2B, 2M and 2N.(4) Type 3 (which accounts for 1-5% of cases) is characterised by very low or undetectable levels of plasma VWF (less than 1% of normal) with low but usually detectable levels of factor VIII.(4) It is in these rare cases of type 3 VWD (one in a million) that symptoms are more frequent and severe, similar to those found in moderately severe haemophilia A.(2)
General principles of treatment
In VWD the basis of the treatment is the replacement of the deficient protein at the time of spontaneous bleeding or before invasive procedures. Prophylaxis with regular replacement therapy is not used as frequently as it is in patients with haemophilia A and B because the tendency for bleeding is usually less severe. However, prophylaxis should be contemplated in patients with type 3 VWD when they have recurrent bleeding in the joints or in the gastrointestinal tract. The mainstays of therapy are desmopressin, which induces the secretion of autologous FVIII and VWF into plasma, and plasma concentrates, which supply allogeneic forms of these moieties.
Desmopressin (1-deamino-8-d-arginine vasopressin) is a synthetic derivative of the antidiuretic hormone that transiently increases both FVIII and VWF levels in plasma.(5) The advantages of desmopressin are its relatively low cost, unlimited availability and the fact that plasma concentrates can be avoided.(6)
Desmopressin, which is administered to children and adults at a dose of 0.3Î¼g per kilogram of body weight by continuous intravenous infusion for 30 minutes, increases postinfusion plasma FVIII and VWF levels by an average three to five times the baseline levels within 30ï¿½60 minutes. Desmopressin is also available in formulations for subcutaneous injection (at a dose of 0.3Î¼g/kg) and nasal inhalation (at a fixed dose of 300Î¼g in adults and 150Î¼g in children).
Intravenous administration is preferred for treatment of acute bleeding episodes and before surgery. Subcutaneous or intranasal administrations are convenient for prophylaxis and for self-treatment at home. Patients with type 1 VWD, who have a functionally normal VWF, are more likely to have a good response to desmopressin than patients with type 2 VWD, who secrete a qualitatively abnormal moiety. Therefore, plasma concentrates containing VWF are preferable in patients with type 2 and type 3 VWD.(6)
Since the increase in FVIII and VWF levels in plasma lasts for 8-10 hours, desmopressin should be administered every 12-24 hours. However, tachy- phylaxis develops in some patients.(7) In general, treatment with desmopressin can be usefully repeated two to four times, but it is preferable to monitor the factor responses and tailor repeated treatments on the basis of the results.(6)
Virus-inactivated, plasma-derived products that contain both FVIII and VWF are used in patients who are not responsive to desmopressin.
Haemate-P(R) (Humate P(R) in the USA) is the commercial concentrate that has been evaluated more extensively in clinical studies and contains larger amounts of VWF than FVIII (by a factor of approximately two to three).(8-10) The other concentrate, Alphanateï¿½, contains similar relative amounts of FVIII and VWF.(11) A few studies indicate that other commercial concentrates of FVIII and VWF are also clinically efficacious, but the available data are more limited.(12,13) A plasma concentrate that contains highly purified VWF with very little FVIII (Wilfactin(R)) was employed in type 3 and other types of VWD. The rationale of its usage is that patients with VWD have an intact endogenous production of FVIII, provided that the deficiency of its stabiliser VWF is corrected by infusion.(14,15) The postinfusion levels of FVIII rise slowly and peak between six and eight hours; therefore, in patients with baseline FVIII levels of 20-30% or less of normal levels, coadministration of a priming dose of FVIII (for instance, a recombinant or monoclonal product) is necessary if haemostasis is to be achieved momentarily because of acute bleeding or emergency surgery.
Patients who undergo elective surgery should receive the infusion of this concentrate 6-8 hours before the procedure in order to allow enough time for the new synthesis of endogenous FVIII.
Alloantibodies that inactivate VWF and form circulating immune complexes develop in 10-15% of patients with type 3 disease who have received multiple transfusions, particularly in carriers of large gene deletions. Concentrates that contain VWF are contraindicated after this complication has occurred, since they elicit life-threatening anaphylactic reactions because of complement activation by immune complexes.(16) It is often very difficult to find an efficacious treatment for these rare cases (for instance, the recombinant activated factor VII NovoSeven(R)).(17-19)
A recombinant preparation of VWF with an intact multimeric structure and adequate post-translational modifications corrects the plasma defects in dogs with VWD.(20) The cytokine interleukin-11 increases plasma levels of FVIII and VWF in mice and in humans.(21-23) If the cytokine appears to be effective and safe in clinical trials, it may provide a new form of treatment that would complement desmopressin, with the choice of the latter when a short-term haemostatic effect is needed and of interleukin-11 when a sustained effect is needed. Although gene therapy is being evaluated for haemophilia A and B, this approach is less attractive as a treatment for VWD, which is usually not as severe and for which adequate therapeutic options are available.
The main options available for the treatment of VWD (desmopressin and plasma concentrates) are effective in controlling bleeding in most patients with the disease.
Even though virus-inactivated products appear to have an acceptable level of safety, it is hoped that the VWF that is produced by recombinant DNA techniques will soon undergo clinical trials and become available for replacement therapy.
World Federation of Hemophilia
Journal of Thrombosis and Haemostasis
Rare bleeding ï¿½disorders database