Von Willebrand disease
recommendations in VWD patients using plasma-derived VWF/FVIII concentrates. Overall, dosages given once daily or every other day and ranging from 20 to 60 IU/kg of VWF:RCo/FVIII:C (depending on the risk and severity of bleeding) are hemostatically effective for treating spontaneous bleeding episodes or for preventing bleeding during surgical or invasive procedures in VWD patients with severely reduced FVIII/VWF plasma levels (less than 10 U/dL). Patients with severe forms of VWD (for example, FVIII:C levels < 5 U/dL) may bleed frequently into the joints and therefore benefit from regular replacement therapy (secondary long-term prophylaxis), which should also be useful in patients with angiodysplasia-associated recurrent gastrointestinal bleeding.17,18 Plasma-derived concentrates containing
VWF are contraindicated in those rare patients with type 3 VWD who develop alloantibodies ( those homozygous for gene deletions or nonsense mutations), because they often cause life-threatening anaphylactic reactions.19
be effectively treated with recombinant FVIII, administered by continuous intravenous infusion, or with recombinant activated factor VII.19
adverse reaction that may occur during repeated VWF/FVIII concentrate infusions is the development of venous thromboembolic episodes. In such cases, the accumulation of FVIII that is exogenously infused together with that endogenously synthesised and stabilised by the infused VWF may lead to plasma FVIII:C levels much above 150 U/dL, which have been recognised as an important risk factor for venous thromboembolism.20 Therefore, when repeated and closely spaced infusions of VWF/FVIII concentrates are necessary, such as during major surgical procedures, FVIII:C plasma levels should be measured daily. To avoid excessive post-infusion FVIII:C levels, a highly purified plasma VWF concentrate containing very little FVIII has been developed for exclusive use in VWD (Wilfactin®
).21 However, as
post-infusion levels of FVIII:C rise slowly, peaking between 6 and 8h, co- administration of a priming dose of FVIII is necessary if prompt haemostasis is required in patients with baseline FVIII:C levels of 30 U/dL or lower. Thus, potential indications for VWF concentrates devoid of FVIII include elective major surgery, particularly when repeated infusion are foreseen in patients at high risk of thrombosis (old age, cancer surgery,
orthopedic surgery) and long-term prophylaxis. Finally, a phase I clinical study on PK and safety of a recombinant VWF concentrate has being recently published22
to guide therapy. Haemophilia 2003;9:688–95. and a phase III clinical study
evaluating its PK, safety and efficacy in the treatment of bleeding episodes in VWD is currently recruiting patients.23
Plasma-derived VWF/FVIII concentrates play a key role in the management of VWD patients who are unresponsive or poorly responsive to desmopressin (DDAVP) and, in spite of their different VWF and FVIII contents, all commercially available products have demonstrated an excellent safety and clinical profile. The future trials will assess whether or not the new recombinant product would represent a therapeutic advance for such patients. l
These patients can
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8. Mannucci PM, Chediak J, Hanna W, Byrnes J, Marlies L, Ewenstein BM, and the Alphanate Study Group. Treatment of von Willebrand disease with a high-purity factor VIII/von Willebrand factor concentrate: a prospective, multicenter study. Blood 2002;99:450–6.
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10. Gill JC, Ewenstein BM, Thompson AR, Mueller-Velten G, Schwartz BA, Humate-P Study Group. Successful treatment of urgent bleeding in von Willebrand disease with factor VIII/von Willebrand factor concentrate (Humate-P): use of the ristocetin cofactor assay (VWF:RCo) to measure potency and
11. Thompson AR, Gill JC, Ewenstein BM, Mueller-Velten G, Schwartz BA, Humate-P Study Group (2004) Successful treatment for patients with von Willebrand disease undergoing urgent surgery using factor VIII/von Willebrand factor concentrate (Humate-P). Haemophilia 2004;10:42–51.
12. Lethagen S, Kyrle PA, Castaman G, Haertel S, Mannucci PM, the Haemate P Surgical Study Group. Von Willebrand factor/factor VIII concentrate (Haemate P) dosing based on pharmacokinetics: a prospective multicenter trial in elective surgery. J Thromb Haemost 2007;5:1420–30.
13. Castaman G et al. Efficacy and safety during formulation switch of pasteurized VWF/FVIII concentrate: results from an Italian prospective observational study in patients with von Willebrand disease. Haemophilia 2013;19:82–8.
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15. Federici AB et al. Clinical efficacy of highly purified, doubly virus-inactivated factor VIII/von Willebrand factor concentrate (Fanhdi) in the treatment of von Willebrand disease: a retrospective clinical study. Haemophilia 2002;8:761–7
16. Berntorp E, Wyndyga J, European Wilate Study Group. Treatment and prevention of acute bleedings in von Willebrand disease-efficacy and safety of Wilate, a new generation von Willebrand factor/ factor VIII concentrate. Haemophilia 2009;15:122–30.
17. Federici AB. Highly purified VWF/FVIII concentrates in the treatment and prophylaxis of von Willebrand disease. The PRO.WILL study. Haemophilia 2007;13:15–24.
18. Franchini M, Mannucci PM. Von Willebrand disease-associated angiodysplasia: a few answers, still many questions. Br J Haematol 2013, in press.
19. James PD, Lillicrap D, Mannucci PM. Alloantibodies in von Willebrand disease. Blood. 2013 Jan 7. [Epub ahead of print]
20. Mannucci PM. Venous thromboembolism in von Willebrand disease. Thromb Haemost 2002;88:378–9.
21. Goudemand J et al. Pharmacokinetic studies on Wilfactin, a von Willebrand factor concentrate with a low factor VIII content treated with three virus- inactivation/removal methods. J Thromb Haemost 2005;3:2219–27.
22. Mannucci PM et al. Pharmacokinetics and safety of a novel recombinant human von Willebrand factor manufactured with a plasma-free method: a multicenter prospective clinical trial. Blood 2013 (in press).
23. Pharmacokinetics, Safety and Efficacy of Recombinant Von Willebrand Factor (rVWF) in the Treatment of Bleeding Episodes in Von Willebrand Disease (VWD). ClinicalTrials.gov
NCT01410227. Available from: http://clinicaltrial.gov/ct2/show/NCT
01410227?term=recombinant+von+willebrand+fact or&rank=2 Last access: February 19, 2013.
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