We read with great interest the article by Curnow et al,
[1 ] describing treatment of von Willebrand disease (VWD), as published in a recent issue
of the journal, together with other interesting articles related to such disorders,
as appearing in a recent issue of Seminars in Thrombosis & Hemostasis . We therefore wish to report our experience of the first successful use of a highly
purified plasma von Willebrand factor (VWF) concentrate containing little FVIII in
the long-term prophylaxis of severe vWD in Slovakia.
VWD is the most common inherited bleeding disorder caused by a quantitative and/or
qualitative abnormality in the adhesive plasma protein VWF.[2 ] VWF represents a high-molecular-weight adhesive glycoprotein that plays an essential
role in the primary hemostasis by promoting platelet adhesion to the subendothelium
and platelet plug formation at the sites of vascular injury. VWD is classified into
three major types: partial quantitative deficiency (type 1), qualitative deficiency
(type 2), and complete quantitative deficiency (type 3). VWD type 2 is further divided
into four variants (2A, 2B, 2N, 2M), based on the characteristics of the dysfunctional
VWF.[1 ]
[3 ] Individuals presenting with clinical manifestations of VWD may have a mild, moderate,
or severe bleeding tendency since childhood, usually proportional to the degree of
the VWF deficiency/defect.[4 ] There are two principle treatments of choice in VWD: desmopressin (DDAVP) and substitution
therapy with blood products containing VWF (with/without factor VIII; FVIII). Other
forms of treatment can be considered as adjunctive or alternative to those mentioned
above.[5 ]
We present a male patient (now aged 34 years) with VWD type 3 ([Table 1 ]). Our study was conducted in accordance with the Declaration of Helsinki. It was
also approved by the institutional ethics committee on human research and informed
consent was obtained. Early after birth, several spontaneous bleeding manifestations
presented, which, over subsequent years, continued with many mucosal and joint bleeding
episodes; these promoted the development of arthropathy. Substitution therapy was
historically administered “on demand” during these events. From 1999, the then 17-year-old
patient was subsequently treated with regular prophylactic administration of VWF/FVIII
plasma-derived concentrates. Despite preventive administration, the patient continued
to have recurrent mucosal bleeding and epistaxis, albeit with less frequent bleeding
into joints. From December 2015, he was switched from a concentrate containing both
VWF and FVIII to a highly purified plasma VWF concentrate containing little FVIII
(Willfact; LFB Biomedicaments, France).
Table 1
Laboratory tests of the patient with VWD type 3
Normal control
Platelets (×10−9 /L)
212
140–400
Bleeding time (min)
9
2–5
PFA-100 Col/ADP (s)
> 300
62–100
PFA-100 Col/Epi (s)
> 300
82–150
PT (s)
11.7
10.4–12.6
aPTT (s)
46.4
22–32
TT (s)
11.9
15–22
Fbg Clauss method (g.L−1 )
2.0
1.8–3.8
VWF:RCo (IU/mL)
0.008
0.5–1.4
VWF:Ag (IU/mL)
0.009
0.6–1.5
FVIII:C (IU/mL)
0.052
0.6–1.5
Ristocetin-induced
platelet aggregation (%)
< 1
60–90
Multimers
no VWF multimers present
all VWF multimers present
Abbreviations: ADP, adenosine diphosphate; VWF:Ag, von Willebrand factor antigen;
aPTT, activated partial thromboplastin time; Epi, epinephrine; Fbg, fibrinogen; PFA,
platelet function analyzer; PT, prothrombin time; TT, thrombin time; VDW, von Willebrand
disease; VWF:RCo, von Willebrand factor ristocetin cofactor.
Levels of plasma VWF and FVIII in individuals with VWD can be regulated by the infusion
of plasma-derived concentrates containing either VWF alone or VWF with FVIII.[1 ] Available concentrates contain different amounts of VWF and FVIII, and the appropriate
dosage should, therefore, be defined according to the specific product's characteristics.[6 ] The primary symptoms of the severe form of VWD, comprising deficiency of both VWF
and FVIII, may therefore comprise frequent hemophilia-like joint bleeds or recurrent
spontaneous mucosal bleeding (e.g., epistaxis and gastrointestinal bleeding). Therefore,
in patients with frequent bleeding, the treatment rationale is use of secondary long-term
prophylaxis.[6 ]
[7 ] Although patients with severe VWD produce FVIII, the lack of VWF prevents stabilization
of the FVIII and leads to its early degradation and an inherent plasma FVIII deficiency.
However, continued dosing with a VWF/FVIII concentrate may lead to excess plasma levels
of FVIII, because the concentrate contains FVIII and also provides VWF that in turn
stabilizes the patient's endogenous FVIII. To avoid excessive replacement therapy-induced
FVIII levels, a highly purified plasma VWF concentrate containing little FVIII has
been developed, mainly for use in VWD. Insufficient or excessive circulating levels
of FVIII achieved with replacement treatment can lead to inadequate hemostatic response
or, alternatively, to a potential risk of thromboembolic events.[8 ] Because of very low FVIII content, this particular VWF concentrate should be mainly
used in patients unresponsive to DDAVP in situations such as surgical intervention
and long-term prophylaxis; for surgical intervention, such a concentrate is suitable
when patients have only a slightly reduced or normal FVIII levels.
Our patient received the intravenous bolus dose 32 IU/kg of highly purified plasma
VWF concentrate containing little FVIII. Bolus dose increased the levels of VWF/FVIII
after 2 hours to corresponding VWF:RCo 0.295 IU/mL, VWF:Ag 0.701 IU/mL, and FVIII:C
0.223 IU/mL, respectively. The infused highly purified plasma VWF concentrate led
to a rapid change of previously low levels of VWF/FVIII, to normalization of ristocetin-induced
platelet aggregation (88%), and detection of VWF multimers ([Fig. 1 ]). The VWF plasma peak was reached between 30 minutes and 2 hours after administration.
The VWF half-life was between 8 and 14 hours, with a mean value of 12 hours. Normalization
of FVIII level was progressive, varied, and was usually between 6 and 12 hours. This
effect was sustained for 2 to 3 days. The highest levels of FVIII:C was 0.324–0.284
IU/mL, VWF:RCo 0.261 to 0.151 IU/mL, VWF:Ag 0.564 to 0.173 IU/mL, and ristocetin-induced
platelet aggregation 86 to 88% during the first 24 hours after administration. These
data are similar to those by Castaman et al.[4 ] The concentrate was well tolerated and with no side effects.
Fig. 1 The levels of von Willebrand factor ristocetin cofactor (VWF:RCo), von Willebrand
factor antigen (VWF:Ag), factor VIII coagulation activity (FVIII:C), and VWF multimers
analysis before and after administration of highly purified plasma VWF concentrate
containing little FVIII. HMW, high-molecular-weight multimers; IMW, intermediate-molecular-weight
multimers; LMW, low-molecular-weight multimers.
Clinical experience with secondary prophylaxis in VWD has been rated as excellent
or good in the large majority of case series, despite use of different schedules of
administration.[9 ]
[10 ]
In our patient, reporting a personal history of serious hemorrhage, the prophylactic
administration of VWF/FVIII concentrates has been changed to that of highly purified
plasma VWF concentrate containing little FVIII (2,500 IU/kg Willfact; patient weight
78 kg, and calculated dose 32 IU/kg) three times weekly from December 2015. Since
then, he has noticed a significant reduction in the frequency and intensity of spontaneous
bleeding. Patient's quality of life improved in comparison with prophylactic administration
of VWF/FVIII concentrates. Nevertheless, we report the first prophylactic regimen
of this concentrate used for patient with VWD in Slovakia.
In conclusion, secondary long-term prophylaxis with VWF concentrate containing little
FVIII appears to reduce the frequency and intensity of bleeds in patients with VWD
type 3. However, experience with long-term VWF concentrate prophylaxis is limited
and the optimal dosage schedule has yet to be determined. Further prospective studies
are necessary to investigate these issues.
