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Coagulation Disorders
Table 3: Treatment of Different Types of von Willebrand Disease
introduced into clinical practice in Europe in 1984 (Haemate-P) and in
the US in 1999 (Humate-P). The first PK study of Haemate-P, published
Treatment of Choice Alternative and Adjunctive
in 1998, was a single-centre evaluation involving six VWD3 patients.
36
Therapy
The result of a large retrospective study organised by the Canadian
VWD1 Desmopressin Antifibrinolytics, oestrogens
haemophilia centres was published in 2002.
37
Other published studies
VWD2A VWF/FVIII concentrates Desmopressin for mild bleeding
include two retrospective analyses of Haemate P efficacy and safety in
VWD2B VWF/FVIII concentrates
VWD2M Desmopressin VWF/FVIII concentrates
Italian VWD patients,
38,39
along with two prospective, multicentre,
VWD2N Desmopressin VWF/FVIII concentrates
open-label, non-randomised studies conducted in the US on Humate-P
VWD3 VWF/FVIII concentrates Desmopressin, platelet used in urgent bleeding and surgical events.
40,41
The results of another
concentrates
prospective study in elective surgery using HaemateP/Humate-P with
VWD3 with Recombinant factor VIII Recombinant activated factor VII
dosing based on PK have recently been published.
42
alloantibodies
Wilate
®
has been used in Germany since 2005 for VWD management.
43
Table 4: Recommendations for the Infusion Test with DDAVP
4,25,26
The results of its efficacy and safety in acute bleeding episodes, surgical
Infusion protocol Administer in 30 minutes 0.3µg/kg of desmopressin in
interventions and secondary long-term prophylaxis will be published within
50ml of saline. The same dosage can also be administered
a few months. Data on the PK and clinical efficacy of Biostate
®
, a VWF/FVIII
subcutaneously. concentrate available in Australia and Asia, have also been reported.
44,45
A
Clinical and laboratory Factor VIII/VWF activities must be measured before and
plasma-derived VWF concentrate with low FVIII levels was introduced in
parameters 0.5, 1, 2 and 4 hours after the administration of
France in 1992 and the first PK study in VWD3 was published in 1996.
46
An
desmopressin. Check platelet count before and at least
improved version of this concentrate (Wilfactin
®
) that is almost devoid of
2 hours after infusion.
FVIII was evaluated in two large French and European studies and data on
Definition of responsiveness VWD patients should be considered responsive to
desmopressin if after 2 hours they show an increased
PK have already been published.
47
Results in VWD3 show no major
baseline level of FVIII: C and VWF: RCo by at least three
differences in VWF:RCo and VWF:Ag for the concentrates that did or did
times, with levels of at least 30U/dl. not contain FVIII. The only difference was an approximate six-hour delay in
FVIII increase with the concentrate devoid of FVIII. Administration of
Although no thrombotic episodes have been reported in VWD patients exogenous FVIII is recommended in VWD3 cases of acute life-threatening
treated with DDAVP, this drug should be used with caution in elderly bleeding episodes or emergency surgeries.
47
The clinical efficacy results of
patients with atherosclerotic disease and hypertension, further to the French and European studies have recently been reported.
48
reported side effects in patients with mild haemophilia A.
30,31
There is no evidence from either retrospective or prospective clinical
VWF/FVIII Concentrates studies that the six VWF/FVIII concentrates (Alphanate, Biostate,
VWF/FVIII concentrates are indicated in VWD3, in VWD2B because DDAVP Fandhi, Haemate-P/Humate-P, Wilate, Wilfactin), reported in Table 5,
can induce transient thrombocytopenia and in all VWD1 or VWD2 patients differ with regards to efficacy, as no head-to-head clinical study has
who are not responsive to DDAVP or who may have contraindications to been carried out. All of these VWF/FVIII concentrates can be effective
its use (see Table 3). Minimal requirements for plasma-derived VWF/FVIII to manage or prevent bleeding in patients with VWD.
concentrates in VWD management are: they must contain VWF and some
FVIII; they should be treated by virucidal methods; and before clinical use Treatment of Patients with Allo-antibodies to
they should be tested for pharmacokinetics (PK) and efficacy in von Willebrand Factor
retrospective or prospective clinical trials in relatively large numbers of For the rare patients with VWD3 who develop anti-VWF allo-antibodies
VWD patients.
23
Among the many VWF/FVIII concentrates available, only a after multiple transfusions, the use of VWF/FVIII concentrates not only is
few can meet these requirements (see Table 5). They can be given to stop ineffective, but may even cause post-infusion anaphylaxis due to the
bleeding episodes when they occur (treatment on demand), to prevent formation of immune complexes.
19,49
These reactions may be life-
bleeding during surgery (prophylaxis for surgery) and to prevent recurrent threatening. To overcome this drawback, a patient undergoing emergency
bleeding at specific sites (secondary long-term prophylaxis). abdominal surgery was treated with recombinant FVIII. This product
contains no VWF and could not cause anaphylactic reactions. In view of
The PK and clinical efficacy results of the first prospective study in the very short half-life of FVIII without its VWF carrier, recombinant FVIII
VWD were published in 2002.
32
This study included 53 patients had to be administered by continuous intravenous infusion at very large
receiving treatment with a double virus-inactivated VWF/FVIII doses to keep FVIII levels above 50U/dl for 10 days after surgery.
49
concentrate (Alphanate
®
) for 87 bleeding episodes and in 39 patients
receiving treatment prior to 71 surgical or invasive diagnostic Another possible therapeutic approach is recombinant-activated factor
procedures. A good clinical response was observed in 86% of the VII (rFVIIa), which can be used in VWD patients with allo-antibodies
spontaneous bleeding episodes and in 71% of the surgical or invasive according to the same dosage and regimens as for haemophilia-A
procedures.
32
Two retrospective studies and one prospective study patients with inhibitors.
50,51
have also been performed using Fandhi
®
, a concentrate manufactured
using a process very similar to that of Alphanate.
33–35
Secondary Long-term Prophylaxis
Patients with severe forms of VWD may have frequent haemarthroses,
Haemate-P
®
or Humate-P
®
, an intermediate-purity VWF/FVIII especially when FVIII levels are below 10U/dl. Some of them develop
concentrate, has been widely used in VWD. This product was target joints like patients with moderate hemophilia-A. Some also have
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