The von Willebrand factor (VWF) is one of the largest glycoprotein circulating in plasma: it is multimeric and multifunctional. VWF is synthesized in endothelial cells (EC) and in megakaryocytes (MK) and stored in alpha-granules of circulating platelets (PLT). Because of this complex biosynthesis inside EC and MK-PLT, the VWF can be considered one of the most important modulators of haemostasis and thrombosis. VWF acts as an adhesive glycoprotein and mediates platelet adhesion to sub-endothelium through its binding sites for the platelet receptor GpIb-α-IX and collagen as well as platelet-platelet interactions through GpIIb/IIIa complex. Apart from its adhesive functions, VWF serves as a carrier protein for factor VIII (FVIII). By the non covalent interaction between the two proteins, FVIII is protected against binding to membrane surfaces and to proteolytic attack by a variety of serine proteases, including activated protein C. Normal levels in plasma of an intact structure of the VWF/ FVIII complex are essential for normal haemostasis: in fact, its defects cause the most common inherited bleeding disorders, namely von Willebrand disease (VWD) and haemophilia A (HA)1.
The VWF/FVIII concentrates in VWD
In patients with VWD the goal of therapy is to correct the dual defect of haemostasis, i.e. the abnormal platelet adhesion and the abnormal intrinsic coagulation due to secondarily decreased FVIII levels2–4. There are two treatments of choice, desmopressin (DDAVP) or transfusional therapy with VWF/FVIII concentrates.
VWF/FVIII concentrates are usually indicated in type 3 VWD (VWD3), in type 2B (VWD2B) because DDAVP can induce transient thrombocytopenia, and in all VWD1 and VWD2 patients who are not responsive to DDAVP or who may have contraindications to its use. Minimal requirements for VWF/FVIII concentrates in VWD management are the following: 1) they must contain biologically active VWF that could correct the primary haemostasis defect and stabilise the endogenous FVIII molecule (the latter objective can be achieved independently of the content in exogenous FVIII); 2) they should be treated by virucidal methods; 3) before clinical use, they should be tested for pharmacokinetics (PK) and efficacy in retrospective or prospective clinical trials in relatively large numbers of VWD patients4.
Haemate P® /Humate-P®, an intermediate-purity VWF/FVIII concentrate, has been widely used in VWD for many years. This product was introduced into clinical practice in Europe (Haemate P®) in 1984 and in the United States (Humate-P®) in 1999. Clinical efficacy data were collected retrospectively, and showed excellent-good responses for 99% of surgeries (n=73) and for 97% of bleeding episodes. Results of a large retrospective study organised by the Canadian Hemophilia Centers were published in 20025. Other published studies include two retrospective analyses as well as two prospective, multicenter, open-label, non-randomised6–9. The results of another prospective study in elective surgery with dosing based on PK have been recently published10.
The VWF/FVIII concentrates in patients with HA and anti-FVIII inhibitors
The use of VWF/FVIII concentrates has been recently proposed also in the treatment of HA patients with anti-FVIII inhibitors. The rationale for the use of plasma derived FVIII concentrates containing VWF resides in several experimental observations11–12. Some authors suggested to test inhibitor patients against a panel of concentrates when treatment is considered because they demonstrated that concentrates manifesting a low level of reactivity with the inhibitor have a better haemostatic effect in vivo13,14. The presence of VWF may be a mechanism for a prolonged antigen presentation to the immune system and thus may have a positive impact on the outcome of immune tolerance therapy15. Several reports have been published about the epidemiology of inhibitors in HA patients treated with plasma-derived FVIII concentrates and some authors could report very reduced incidence of inhibitors in previously treated HA patients after exposure to single plasma derived intermediate or high purity FVIII concentrates containing VWF16,17. However, these data should be reproduced in a large cohort of previously untreated patients (PUP)18, as proposed in a recent international prospective study.
Footnotes
Conflicts of interest disclosure
The Author declares he has no conflicts of interest.
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