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Von Willebrand disease

Table 1: VWF/FVIII concentrates available for the treatment of von Willebrand disease Product, manufacturer

Purification method Alphanate, Grifols Biostate, CSL Biotherapies

Factor 8Y, Bio Products Laboratory

Fanhdi, Grifols Haemate-P, CSL Behring

Immunate, Baxter BioScience

Wilate, Octapharma Wilfactin, LFB

Precipitation/heparin ligand CT

Precipitation/heparin ligand CT

Cryoprecipitation, heparin and glycine precipitation

Precipitation/heparin ligand CT

Multiple precipitation Ion exchange CT

Precipitation, ion exchange and size exclusion CT

Ion exchange, affinity CT Viral inactivation SD; dry heat SD; dry heat Dry heat, 80°C, 72 hr S/D; dry heat

Pasteurisation SD; vapor heat

SD; dry heat SD; NF; dry heat

VWF specific activity (U/mg protein)

>100 100 >50 >100 >80 70 ± 30 >100 >80

VWF:RCo/Ag (ratio)*

0.9 0.83 0.6 0.8

0.8 0.6

0.9-1.0 0.7

Abbreviations: VWF, von Willebrand factor; RCo, ristocetin cofactor; Ag, antigen; FVIII, factor VIII; S/D, solvent/detergent; CT, chromatography; NF, nanofiltration. *Data derived from: Mark Brooker. Registry of clotting factor concentrates. Ninth Edition. World Federation of Haemophilia 2012.

progestogen drugs. Adjuvant therapies are antifibrinolytic amino acids, such as tranexamic acid and epsilon aminocaproic acid, that improve haemostasis without affecting plasma VWF levels.7

is focused on the use of plasma-derived concentrates in VWD patients.

Virally inactivated concentrates The infusion of virally inactivated FVIII/ VWF plasma-derived concentrates is indicated for those VWD patients in whom DDAVP is usually ineffective (‘severe’ type 1, type 2, type 3) or when there is the prediction of prolonged treatments (major surgical procedures or bleedings, severe traumas). The main characteristics of commercially available intermediate and high-purity products containing VWF/ FVIII are reported in Table 1. The first prospective study that evaluated the PK and clinical efficacy of the virus-inactivated VWF/FVIII concentrate Alphanate®

was carried out in 2002 in 53

VWD patients receiving treatment for 87 bleeding episodes and in 39 patients receiving treatment before 71 surgical or invasive diagnostic procedures.8

Table 2: Treatment of von Willebrand disease with VWF/FVIII concentrates Indication

Treatment regimen This chapter Major surgery Minor surgery Dental extraction

Spontaneous or traumatic bleeding

Secondary long-term prophylaxis

40-60 IU/kg every 12 hours initially then once daily until wound healing is complete

30-50 IU/kg once daily (may require only 1–3 days)

20–30 IU/kg (usually a single dose prior to procedure)

20–60 IU/kg once daily until bleeding stops (usually 2-4 days).

40-60 IU/kg two-three times/ weekly

the management of this disorder due to its high VWF content (VWF:RCo/FVIII ratio: 2.5).9

in acute

Two prospective studies have documented in 2003 and 2004 the safety and efficacy of Haemate P®


type 3 patients, the half-life of FVIII activity (FVIII:C) was approximately twice that of VWF:Ag (23.8 hours versus 12.9 hours), owing to the endogenous production of FVIII. A good clinical response with this VWF/FVIII concentrate was observed in 86% of the spontaneous bleeding episodes and in 71% of surgical or invasive procedures.8

The VWF/FVIII concentrate Haemate P® has been widely used in VWD 12

patients since the early 1980s and is currently considered the gold standard for

spontaneous bleeding (excellent/good results in 98% of the cases) and surgical procedures (excellent/good results in 100% of the cases).10,11 Another prospective study that applied pharmacokinetics (PK) analysis to the choice of the dosage in the management of surgical patients was published in 2007.12

cases with VWD undergoing elective surgery and showed that Haemate P®


whose preoperative median VWF:RCo loading dose of 62.4 IU/kg was based on the PK study, provided an excellent or good hemostasis in 96% of cases on the day of surgery and 100% on the next few days. Notably, this study demonstrated for the first time that the incremental

recovery of FVIII and VWF measurements is constant over a wide range of doses of VWF/ FVIII concentrate (linear dose-response), and that the pre-treatment PK results provide a reliable basis for serial dosing decisions. Another more recent prospective trial evaluating the safety and efficacy of a new volume-reduced formulation of Haemate P®

in 121 VWD patients

documented in 2013 a good-to-excellent treatment response in 93-99% of the interventions.13

Retrospective and This trial enrolled 29

prospective studies have also been published on other VWF/FVIII products, documenting their clinical safety and efficacy.14-16


instance, a recently published pooled analysis from four prospective studies enrolling 44 VWD patients on the safety and efficacy of the VWF/FVIII concentrate Wilate showed an excellent or good clinical efficacy in 96% of the 1095 spontaneous or post-traumatic bleeding episodes.16 Table 2 gives treatment

Target plasma VWF:RCo/FVIII:C level

50–100 U/dL; maintain levels for 3–10 days

>30 U/dL >30 U/dL for >12 hours >30 U/dL

VWF:RCo/FVIII (ratio)*

1.2 2.0 1.8 1.2 2.4 0.75 1.0 60

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