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Von Willebrand disease

Von Willebrand disease

In this chapter, the focus shifts to the use of plasma-derived concentrates in von Willebrand disease patients

Pier Mannuccio Mannucci MD Scientific Direction, IRCCS Cà Granda Maggiore Policlinico Hospital Foundation, Milan, Italy Massimo Franchini MD Department of Transfusion Medicine and Hematology, Carlo Poma Hospital, Mantova, Italy

Von Willebrand disease (VWD) is the most common genetic bleeding disorder, with a prevalence of approximately 1% according to population studies,1

from either a quantitative or qualitative deficiency of von Willebrand factor (VWF), a plasma glycoprotein with essential platelet-dependent function in primary haemostasis and a carrier for factor VIII in the circulation.2


VWD has been classified in different types. Type 1 and 3 VWD reflect the partial or virtually complete quantitative deficiency of VWF, while type 2 VWD reflects qualitative defects of VWF. Type 1 is the most common form of VWD and is transmitted as an autosomal dominant trait with incomplete penetrance. Type 1 VWD is characterised by a mild-to- moderately severe reduction in plasma levels of VWF antigen (VWF:Ag) and ristocetin cofactor activity (VWF:RCo). In type 1 VWD, VWF is functionally normal, as is usually the pattern of plasma VWF multimers, and plasma levels of FVIII are usually reduced in proportion to VWF. Type 1 patients manifest a spectrum of


mucocutaneous bleeding symptoms, the severity of which usually correlates with the degree of their VWF and FVIII deficiencies. Type 2A is the most frequent qualitative defect of VWF, inherited mainly with an autosomal dominant pattern. The hallmark of type 2A VWD is a low VWF:RCo to VWF:Ag ratio (<0.7), with lack of larger and intermediate size VWF multimers and impaired ristocetin-induced platelet agglutination (RIPA) in platelet-rich plasma. Like type 2A, the inheritance pattern of type 2B VWD is mainly autosomal dominant. The laboratory hallmark of the most typical and frequent forms of type 2B VWD is heightened RIPA: this is usually accompanied by mild-to- moderate thrombocytopaenia, mildly reduced to normal FVIII and VWF:Ag, reduced VWF:RCo and absence of large multimers in plasma, even though an intact multimeric pattern is seen in some patients. In type 2M VWD, the VWF multimeric distribution is normal, but platelet- dependent VWF activities are reduced. Type 2N VWD is characterised by normal levels of VWF:Ag and VWF:RCo and normal multimeric pattern, but by low plasma levels of FVIII due to increased clearance of FVIII, which binds poorly to VWF as a consequence of a qualitative abnormality of VWF. Type 2N VWD therefore resembles mild hemophilia A, but its inheritance pattern is autosomal recessive. Type 3 VWD is inherited as an autosomal recessive trait and is characterised by undetectable levels of

VWF in plasma (and platelets) and very low plasma levels (1-5 U/dL) of FVIII. Therefore, patients with type 3 VWD have a severe bleeding tendency, characterised not only by mucocutaneous haemorrhages (epistaxis, menorrhagia, gastrointestinal bleeding) but also by haemarthroses and haematomas, as in moderately severe haemophilia.3 In VWD the aim of therapy is to correct the dual defect of hemostasis, that is to say, the abnormal platelet adhesion- aggregation and the abnormal intrinsic coagulation due to low levels of FVIII. Unlike with patients with haemophilia in whom treatment may be administered regularly to prevent bleeding, patients with VWD generally have less frequent and less severe clinical bleeding and usually receive treatment only in anticipation of an invasive procedure or for trauma. An exception may be patients with type 3 VWD, and some patients with type 2A and 2B who might receive replacement therapy regularly particularly if they bleed repeatedly into the joints and gastrointestinal tract (secondary prophylaxis). The mainstays of treatment are autologous replacement therapy with the synthetic drug desmopressin (DDAVP) and allogeneic replacement therapy with plasma-derived VWF/FVIII or VWF concentrates devoid of FVIII.4-6

There are also adjunctive

treatments that act upon VWF-mediated hemostasis, that is to say, platelet transfusion and combined oestrogen- 11

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