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Importance of Pharmacokinetics in the Treatment of von Willebrand Disease
Table 1: International Society on Thrombosis and Haemostasis
type 3 patients – was almost double that of 12.9 hours for vWF:Ag due
Classification of von Willebrand Disease
to endogenous FVIII:C. Importantly, studies with the first-generation
FVIII/vWF concentrates highlighted that the recommended dosages of
Phenotype Description
vWF:RCo should be similar to those of FVIII. This is because in vivo
Quantitative defects
recovery of the two haemostatic components is similar.
15–18
Type 1 Partial quantitative deficiency of vWF
Type 3 Virtual complete deficiency of vWF
Qualitative defects
Next-generation Factor VIII/
Type 2A Decreased vWF-dependent platelet adhesion and von Willebrand Factor Concentrates
a selective deficiency of high-molecular-weight
Recently, a new-generation, high-purity, albumin-free, double-virus
vWF multimers
inactivated FVIII/vWF concentrate, designed specifically for the treatment
Type 2B Increased affinity for platelet glycoprotein lb
of vWD, has been introduced. This new product, Wilate, has the
Type 2M Decreased vWF-dependent platelet adhesion without
physiological ratio of FVIII to vWF of 0.8 (see Table 2). Thus, Wilate has
a selective deficiency of high-molecular-weight
vWF multimers
the potential to minimise the risk of thrombogenicity caused by the FVIII
Type 2N Markedly decreased binding affinity for factor VIII
‘overshoot’ observed with the administration of other vWF/FVIII
vWF = von Willebrand factor. Source: adapted from Sadler et al.
3
concentrates. In addition, the FVIII/vWF ratio close to one may simplify the
replacement dosing in the post-operative scenario to maintain adequate
Table 2: Selected Plasma-derived Concentrates
haemostatic FVIII activity levels in vWD patients.
Containing von Willebrand Factor
Concentrate vWF:RCo/FVIII:c Ratio
A prospective multicentre study in 47 vWD patients investigated the
Haemate P 2.5 pharmacokinetics, clinical efficacy and safety of Wilate in acute bleeding
Alphanate 1.2
episodes and surgical prophylaxis. In the study, the pharmacokinetics of
Wilate 0.8
Wilate was evaluated in 20 vWD patients. The interim analysis found a
vWF = von Willebrand factor; RCo = ristocetin co-factor activity; FVIII = factor VIII.
mean half-life of vWF:RCo in type 3 vWD patients (n=8) of 17.5 hours.
Mean recovery for vWF:RCo was 1.5% per IU/kg and 2% per IU/kg for
vWD, Haemate P, has a vWF:RCo/FVIII:c ratio of 2.5. The first Haemate P FVIII:c. The efficacy and safety of Wilate was studied in 20 patients
pharmacokinetic study was conducted in 1998 and involved four patients undergoing 24 elective or urgent surgical procedures. The overall efficacy
with type 3 vWD.
11
The median half-life for vWF:RCo was 11.3 hours and (achievement of haemostasis) of Wilate was rated as excellent or good for
15.2 hours for vWF antigen (vWF:Ag). A high concentration of multimers 23/24 procedures (96%).
19
Currently, controlled clinical trials to evaluate
appeared after transfusion of Haemate P; however, only small levels of the safety and efficacy of Wilate in major surgeries are ongoing in both
vWF protein were present after 48 hours. Retrospective data vWD and haemophilia A patients.
demonstrated an excellent to good response in 99% of surgical
procedures and in 97% of bleeding episodes. A Canadian study was the Conclusion
first to use vWF:RCo to determine the dose of Haemate P to administer Recently, there has been considerable progress in the safety and efficacy
during bleeding episodes and surgeries.
12
Excellent to good clinical of transfusional therapies for vWD not responsive to or contraindicated
responses were noted in 99% of surgical procedures, 97% in bleeding to DDAVP. Furthermore, a growing body of pharmacokinetic data for the
episodes, 86% in other cases and 100% in prophylaxis. There were no various concentrates has helped to improve and refine the use of
reports of adverse effects in the study. Similar results have been noted in FVIII/vWF concentrates in vWD replacement therapy. The introduction of
other pharmacokinetic trials of Haemate P in Italy and the US.
15–17
a new-generation product with a FVIII/vWF ratio close to one is an
important addition to the vWD armamentarium and has the potential to
The Alphanate Study Group published results reporting an efficacy of improve the treatment of vWD. A high-purity vWF concentrate with little
75% for controlling bleeding episodes in type 3 patients and types 1 and FVIII content has also become available (Wilfactin), but in type 3 patients
2 patients treated with the concentrate Alphanate who were DDAVP- a priming dose of FVIII concentrate needs to be co-administered in
ineffective.
18
Alphanate has a vWF:RCof/FVIII:c ratio of 1.2. This study emergency situations to ensure adequate haemostasis because it can
was the first to assess the dose and efficacy of Alphanate not only in type take up to 24 hours for endogenous FVIII synthesis to reach sufficient
3 vWD but also in types 1 and type 2 vWD patients. A good clinical levels. Continuing scientific and commercial efforts to further elucidate
response was noted in 71% administered on short-term prophylaxis with the structure and function of the vWF gene and protein will hopefully
Alphanate before invasive or surgical procedures. Importantly, the help to provide new paradigms and products for the diagnosis and
authors reported that the average half-life of FVIII:c – at 23.8 hours in treatment of vWD. ■
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EUROPEAN HAEMATOLOGY 2007 17
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