VWF concentrates

Important properties

Several properties are to be considered when choosing a concentrate for treatment of VWD. Adequate virus inactivation is a prerequisite. The VWF may be somewhat functionally inactivated during the manufacturing process, and in vivo, which may be reflected by a low ratio between VWF activity and antigen, or by an abnormal multimeric pattern. The ratio between VWF activity and FVIII:C is important to consider when dosing the concentrate. VWF activity in relation to amount of total protein (specific activity) gives information about purity. The use of pure VWF concentrate provides the way to control/maintain the natural FVIII levels in prophylactic use.

The multimeric structure of the VWF

The VWF is a multimeric protein, the largest multimers (HMWM) probably being the most effective for binding platelets during the formation of platelet plug, i.e., in primary hemostasis. The functional and clinical importance of different multimeric sizes is, however, still not fully understood.

An aberrant multimeric structure may indicate that the VWF is dysfunctional due to proteolysis during manufacture or afterwards. The multimeric structure may be visualized with electrophoretic methods and objectified by densitometry. An indirect method is to calculate the ratio between the VWF activity (most often measured as VWF:RCo and VWF:Ag.). A low VWF:RCo/VWF:Ag ratio indicates loss of functional activity. Concentrates with a VWF:RCo/VWF:Ag ratio > 0.7 are probably to be preferred.

Ratio between VWF activity and FVIII:C

Most concentrates used for treatment of VWD contain both VWF and FVIII (except Willfact/Wilfactin, which is characterized by a high VWF:RCo/FVIII:C ratio and Veyvondi, a recombinant human von Willebrand factor product). A concentrate with a high relative amount of FVIII (a low VWF:RCo/FVIII:C ratio) may increase plasma levels of FVIII above normal, as the infused FVIII adds to the patient’s endogenously released FVIII. Even if patients with VWD may have very low basal levels of FVIII in plasma, they do have the ability to produce and release FVIII, if VWF becomes available in plasma. Therefore, the infused VWF will stimulate synthesis and release of FVIII. When repeated doses are given, FVIII levels should be monitored, and factor doses adjusted to avoid high FVIII levels (above 150-190 IU/dL). Also, the relation between the half-lives of VWF:RCo and FVIII:C should be considered. A concentrate with a short half-life of VWF:RCo in relation to FVIII:C may impose an increased risk of high FVIII levels, if it has to be dosed frequently.

Dosage of VWF concentrates

Concentrates used for VWD should be dosed according to the VWF:RCo content, which therefore must be labeled on the vials. The recovery of VWF:RCo in adults is roughly 1.5 - 2.0 IU/dL per infused IU VWF:RCo/kg body weight. A dose of 50 IU/kg can be expected to increase the VWF:RCo with about 75 - 100 IU/dL. Therefore, a loading dose of 50-60 IU VWF:RCo/kg body weight is recommended for patients with very low basal levels of VWF:RCo.

In general the half-life of VWF:RCo is considered to be equal to that of FVIII:C. Therefore, VWF concentrate is administered every 12-24 hours in association with surgery and similar conditions. VWF concentrate can also be given as a continuous infusion.

When used for prophylaxis in outpatients, a VWF concentrate administered 2-3 times per week is usually sufficient to prevent bleeds.

Levels of VWF:RCo and FVIII:C should be monitored when repeated daily doses are given over a longer period. Measurement of the VWF:Ag level is not sufficient as the VWF may become dysfunctional [1].

Concentrates for VWD approved in the Nordic countries

  • Haemate®, CSL Behring
    A plasma-derived concentrate with a VWF:RCo/FVIII:C ratio of about 2.

  • Wilate®, Octapharma
    A plasma-derived concentrate with a VWF:RCo/FVIII:C ratio of about 1.

  • Wilfactin® Willfact® /Willefact®, LFB
    Currently available in Denmark, Norway, and Finland.
    A plasma-derived concentrate with a VWF:RCo/FVIII:C ratio of approx. 60. This is to be considered to avoid exogenous additive FVIII, if the patient and/or the invasive procedure have strong thrombogenic properties. When managing a bleed, the first dose may be supported by one dose of FVIII infusion.

  • Veyvondi® (Vonvendi®), Takeda
    The first recombinant high-molecular weight VWF concentrate without FVIII. When managing a bleed, the first dose may be supported by one dose of FVIII infusion. Currently available in Sweden and Norway and Denmark.