FVIII and VWF PK: Key Aspects in Safety and Efficiency of VWF Concentrates. Review and Reflection
Authors: Rodriguez-Lopez Manuel , Nuñez Vazquez Ramiro , Lopez Ansoar Elsa , Blanquer Blanquer Miguel , Albo Lopez Carmen 
Published: December 2024

Introduction: Long-term prophylaxis in Von Willebrand Disease (VWD) with a severe or frequent bleeding phenotype generates great interest. Additionally, there is a discrepancy regarding the composition of VWF Concentrates (VWFC), whether with or without FVIII, and within VWFC with FVIII, which is the most appropriate factor ratio. These VWFCs are of plasma origin, with one recombinant origin, rVWFC (Vonvendi®), containing only VWF. Among the plasma-derived ones, we have plasma derived Von Willebrand Factor Concentrate with FVIII (pd-VWFC) (Wilate®) with a VWF/FVIII ratio of 1:1, and other pd-VWFC with a low FVIII content (Wilfact®)(FVIII:VWF ratio &lt;0.2:1).
Methods: For this analysis, data for rVWFC comes from post hoc analysis of prospective clinical trial (CT) NCT02973087, 2 and for pd-VWFC (with FVIII), from prospective CT NCT04052698. 1 For pd-VWFC (without FVIII), data was taken from a prospective post-marketing observational study. 3
The median annual bleeding episodes (ABR), median weekly consumption (IU VWF: RCo/kg), and median weekly infusions for long-term prophylaxis with these VWFCs are compared. Safety regarding thrombotic events (TE) is also compared.
Results: pd-VWFC (with FVIII), versus rVWFC and pd-VWFC(without FVIII), shows lower weekly consumption; median 58, 92.6 and 87 IU/kg respectively, for the same median of weekly infusions (2), without loss of efficacy (median ABR 1.9, 1, and 2.35 respectively). 1,2,3
In relation to TEs, none were reported with these pd-VWFC (with or without FVIII) analized, during its clinical development, 1,3,6,9,10,11,12,15 With rVWFC, a deep vein thrombosis was reported in the context of major surgery(replacement hip).5
Discussion: Among the challenges in managing VWD is the accumulation and monitoring of FVIII, especially in intensive treatments such as surgery or severe trauma, with FVIII levels &gt;150% considered associated with thrombotic risk. 4
Regarding this risk, it could be assumed that VWFCs without FVIII would be exempt from it, but TEs were reported in scheduled surgeries with rVWFC 5 and with other VWFCs/FVIII with a lower proportion of FVIII than the pd-VWFC with FVIII analized (for example, pd-VWFC rich in VWF, Haemate P®). 4,7,8Why? The thrombotic risk seems to be a consequence of the different pharmacokinetic (PK) behavior of these products, not of the presence of FVIII. With pd-VWFC (VWF/FVIII ratio 1:1), all the VWF is fully saturated with FVIII, preventing binding to the patient's endogenous FVIII. Immediately after infusion, we could observe the peak of FVIII and VWF at the same time. Both factors are eliminated at the same rate, with no sustained FVIII accumulation during surgeries, nor thrombotic events observed. 6,10
In terms of efficacy in bleeding prophylaxis, the ABRs reported with the three VWFCs are considered acceptable. However, in terms of consumption, prophylaxis with pd-VWFC (ratio VWF/FVIII 1:1) looks more efficient. 1,2,3Why? There could be two reasons: The FVIII content in pd-VWFC (ratio VWF/FVIII 1:1): This allows a generation of higher thrombin peaks than the same amount of a pure VWFC. 13 In VWD patients, Rugeri et al. already reported that a low thrombin peak was associated with a higher risk of bleeding and suggest that decreased and delayed thrombin generation in VWD can probably be mainly attributed to a decreased plasma FVIII level in patients with this disorder..14The interaction and PK of VWF and FVIII themselves. For rVWF, the infused exogenous VWF is eliminated (half-life approximately 12-15h) and the endogenous FVIII takes time to normalize (peak level 12-24h after). 5,13 With pd-VWFC (ratio VWF/FVIII 1:1), the obtained FVIII peak is higher, coinciding with the VWF peak, generating a higher thrombin peak.13
CONCLUSSION: This analysis seems to support the idea that the balance between FVIII and VWF in the content of VWF/FVIII concentrates may be key in terms of efficacy, efficiency, and safety in the treatment and prophylaxis of VWD. More controlled clinical trials are needed to confirm these observations.