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Coagulation Disorders Haemophilia
Treatment of Haemophilia A with Recombinant
Antihaemophilic Factor VIII Products
a report by
Robert Klamroth
Director, Haemophilia Treatment Centre, Vivantes Hospital, Berlin
Haemophilia A (classic haemophilia) is an X-chromosome-linked bleeding patients with haemophilia A has been developed.
4,5
More recently, an
disorder occurring in approximately one in 5,000–10,000 males rFVIII product has been developed without the use of human or bovine
worldwide.
1,2
Haemophilia A is caused by a partial or total deficiency of albumin with the aim of further eliminating the potential risk of viral
functionally active coagulation factor VIII (FVIII). Haemophilia produces transmission.
6
In addition to the risk of viral transmission, other product
abnormal bleeding that may be mild, moderate or severe depending on the characteristics such as efficacy, tolerability, immunogenicity (development
degree of FVIII deficiency. Individuals with severe haemophilia A have FVIII of inhibitors), dosage and administration are also considered when
levels <1% of normal activity (<0.01IU/ml), whereas moderate (factor level selecting a treatment option for patients with haemophilia A. This article
0.01–0.05IU/ml) to mild (factor level >0.05–0.40IU/ml) forms have 1–5% summarises the available evidence for these characteristics of
and 5–40% of normal activity, respectively.
1
In patients with severe recombinant antihaemophilic factor products for managing haemostasis
haemophilia A, the first bleeding typically occurs during early childhood. The in patients with moderate/severe haemophilia A.
bleeding can involve any anatomical region but most commonly involves
the joints (frequently elbows, knees and ankles) and muscles. Joint Recombinant Antihaemophilic Factor Products
haemorrhages can result in severe arthropathy and degenerative damage, as
found in osteoarthritis, as well as inflammatory processes similar to Product Specifics
rheumatoid arthritis.
3
In contrast to severe haemophilia A, which is Several recombinant antihaemophilic products – including
characterised by spontaneous bleeding and/or severe bleeding after minor Recombinate™ (Baxter Healthcare),
7
Kogenate
®
Bayer (Kogenate
®
FS;
trauma, mild haemophilia A may go undiagnosed until adulthood due to the Bayer Healthcare),
8
Helixate
®
NexGen (Helixate
®
FS; Bayer Healthcare,
lack of spontaneous bleeding. The diagnosis of haemophilia A is confirmed distributed by CSL Behring),
9
ReFacto
®
(Wyeth Pharmaceuticals)
10
and
by the finding of normal platelet count and function, normal bleeding time, Advate™ (Baxter Healthcare)
11
(see Tables 1 and 2) – are commercially
normal prothrombin time and normal von Willebrand factor (VWF). FVIII available for the treatment of haemophilia A. These are categorised
binding activity is present, but there is prolonged activated partial according to their product characteristics, including:
thromboplastin time (aPTT) and reduced FVIII activity (FVIII:C).
1,2
The
diagnosis is completed by molecular genetic testing to identify the • type of host cell and production details;
genetic defect. • degree of purity;
• viral removal/inactivation processes; and
Haemophilia A is incurable, but treatment with antihaemophilic therapy • presence/absence of animal proteins or human albumin.
can stop or prevent bleeding episodes, reduce the associated morbidity,
improve quality of life and normalise life expectancy. For patients with mild Purity and Formulation
haemophilia A, treatment with desmopressin (DDAVP) is usually sufficient There is wide variability among the rFVIII concentrates with respect to final
to manage bleeding episodes.
2
However, for patients with mild product purity, as reflected by units of specific activity (IU FVIII:C) per
haemophilia A who do not respond adequately to DDAVP, and for those milligram of total protein (see Table 2). ‘Purity’ refers to the amount of
with moderate or severe forms of the disease, replacement of the deficient desired ingredient (FVIII) relative to other protein ingredients (such as
factor with commercially prepared FVIII concentrates is generally required. albumin as stabiliser). These products contain between 2,000 and 13,000
Infusion of these concentrates temporarily increases the plasma level of units of FVIII activity per milligram of protein depending on the type of FVIII
FVIII and improves clinical symptoms when given on demand for bleeding molecule (full-length versus BDD), the purification process and whether or
episodes or during emergency situations or prophylactically to prevent not albumin is used as a stabiliser. The currently available rFVIII products are
spontaneous bleeding (e.g. in severe haemophilia) or for elective surgery. considered very safe as a result of the inclusion (in most of them) of
improved virus inactivation and removal steps in the manufacturing process,
Two different types of FVIII concentrates are available for treatment: which minimises the risk of infection from plasma-based additives and DNA
concentrates purified from donated plasma, with or without VWF, and technology. The methods currently in use include:
FVIII products manufactured with recombinant technologies and purified
from cell-culture harvest medium. In the past 25 years, advances in the
Robert Klamroth is Director of the Haemophilia Treatment Centre and Assistant Medical
screening of donors and donated plasma, techniques to remove and/or
Director of the Clinic for Internal Medicine/Angiology and Coagulation Disorders at the Vivantes
inactivate viruses in concentrates and recombinant technology have
Hospital in Berlin. One of his primary interests is the utility of recombinant replacement factors
for the treatment of life-threatening bleeding disorders. Dr Klamroth graduated from the Freie
remarkably increased the safety and purity of FVIII products. In addition
Universität Berlin in 1994 and received his specialisation in internal medicine in 2001.
to the full-length FVIII products, a B-domain-deleted (BDD) recombinant
FVIII (rFVIII) concentrate that shows clinical haemostatic efficacy in
© TOUCH BRIEFINGS 2007 11
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