Kreuz_subbed.qxp 12/2/09 15:10 Page 14
Coagulation Disorders Haemophilia
Inhibitors in Haemophilia A – Ongoing Research and Clinical Practice
a report by
Wolfhart Kreuz,
1
Carmen Escuriola-Ettingshausen
1
and Günter Auerswald
2
1. Centre of Paediatrics III, Department of Haematology, Oncology and Haemostaseology, Johann-Wolfgang-Goethe University Hospital, Frankfurt;
2. Prof.–Hess Children’s Hospital, Klinikum Bremen-Mitte, Bremen
Haemophilia A is the most common plasmatic bleeding disorder, excellence, as well as clinical studies on reasonably small numbers of
caused by congenitally reduced activity of coagulation factor VIII (FVIII). patients. Final prospective and controlled studies with large patient
Affected patients suffer from a more or less severe bleeding tendency, cohorts have the goal of moving such therapies from a well-justified to
mainly in the joints, muscles and organs, which, untreated, leads to an evidence-based approach. As long as such evidence-based data are
haemophilic arthropathy and high mortality. To date, there is no cure not available, clinical decisions for every single patient can be based
for the disease. So, the aim of haemophilia treatment is to prevent or only on long-term clinical and scientific experience and subjective
treat bleeding episodes, mainly by substitution of the missing opinion.
1
This was also the case in the past, but nevertheless led to the
coagulation factor. During the last few decades, haemophilia treatment development of safe and effective FVIII concentrates and the
has reached a very high standard, at least in well-developed countries. introduction of prophylaxis and home self-infusion in order to avoid
Major milestones have been the development of safe and effective FVIII haemophilic arthropathy. Today, inhibitor formation and treatment of
concentrates, either plasma-derived (pd) or recombinant (r), the patients with inhibitors are the main challenges of haemophilia
introduction of prophylaxis and home self-infusion for patients with therapy;
2
again, long-term clinical and scientific experience is available,
severe haemophilia A and the development of therapies for immune but there are only very few evidence-based data and no randomised
tolerance induction (ITI). Depending on the availability of sufficient controlled trials.
3,4
What conclusions can be drawn from the existing
amounts of FVIII, these therapeutic approaches can dramatically clinical and scientific experience in order to find the best treatment for
improve the situation of patients; at best, it is possible to almost patients and to avoid or treat inhibitors?
normalise quality of life (QoL), social integration and life expectancy.
Safe and Effective Factor VIII Products
This progress and high standard of haemophilia therapy is a result of In the late 1960s, FVIII concentrates became available. They were very
about 30 years of empiricism, clinical experience and scientific well accepted, because due to the low volume of FVIII they allowed
effective therapy for the first time. Unfortunately, in the 1970s and
early 1980s product-related virus transmission, especially of hepatitis
Wolfhart Kreuz is a senior staff member in the Department
of Paediatrics and Clinical Director of the Comprehensive
viruses and HIV, caused a major set-back in the young history of
Care Centre for Thrombosis and Haemostasis at Johann-
effective haemophilia therapy. Measures were taken to solve the
Wolfgang-Goethe University Hospital in Frankfurt. He is a
problem, mainly by optimising the purification process, implementing
leader of scientific research groups engaged in haemophilia,
von Willebrand disease, thrombosis, immunodeficiencies and
steps for virus inactivation and establishing systems for quality
hereditary angioedema. He is a member of several scientific
assurance and quality control.
societies and scientific boards and the author of numerous
original publications and review articles, some of them in
highly ranked journals. As early as the second half of the 1970s, a method to pasteurise the
extremely unstable FVIII proteins was developed
5
that effectively
Carmen Escuriola-Ettingshausen is a staff member in the
inactivated very high titres of enveloped viruses and high titres of non-
Department of Paediatric Haematology and Oncology at the
Children’s Hospital of the Johann-Wolfgang-Goethe
enveloped viruses.
6
The first pasteurised FVIII product was licensed in
University Hospital in Frankfurt. Dr Escuriola-Ettingshausen is early 1981. Other manufacturers developed and implemented other
a member of the German, Swiss and Austrian Society for
inactivation procedures, for example the first dry-heat treatment (at
Thrombosis and Haemostasis Research (GTH) and the
International Society for Thrombosis and Haemostasis (ISTH).
60°C for 72 hours), which later proved to be not very safe,
7
or
She completed her MD at the University of Frankfurt and her
different methods using solvents and detergents (S/D). S/D methods
specialist training in paediatrics in the Department of
Paediatrics at the University Hospital Frankfurt.
very effectively inactivate enveloped viruses by destroying their outer
lipid membranes, but in contrast to pasteurisation have no effect on
Günter Auerswald is Head of the Department of
non-enveloped viruses. Therefore, S/D inactivation had to be
Comprehensive Care in Haemostasis and Thrombosis at the completed by a second complementary step with inactivation potential
Children’s Hospital in Bremen. He has over 20 years of
against non-enveloped viruses, for example a dry-heat treatment at
experience in clinical studies of haemostaseology, viral
safety, von Willebrand concentrates and antiepileptic drugs.
very high temperatures. Effective virus-elimination and virus-
He is internationally renowned for the treatment of inhibitors
inactivation steps have been implemented in the production process of
and has published extensively on this subject. Dr Auerswald
is a member of the major associations of haemophilia,
all pdFVIII products for about 20 years, and no additional virus
including the American Society of Hematology (ASH) and the transmission has been observed with these products. In parallel, and
International Society of Thrombosis and Haemostasis (ISTH).
with the aim of unlimited supply, technologies have been developed to
produce human FVIII in cultures of genetically modified hamster cells.
14 © TOUCH BRIEFINGS 2008
Page 1 |
Page 2 |
Page 3 |
Page 4 |
Page 5 |
Page 6 |
Page 7 |
Page 8 |
Page 9 |
Page 10 |
Page 11 |
Page 12 |
Page 13 |
Page 14 |
Page 15 |
Page 16 |
Page 17 |
Page 18 |
Page 19 |
Page 20 |
Page 21 |
Page 22 |
Page 23 |
Page 24 |
Page 25 |
Page 26 |
Page 27 |
Page 28 |
Page 29 |
Page 30 |
Page 31 |
Page 32 |
Page 33 |
Page 34 |
Page 35 |
Page 36 |
Page 37 |
Page 38 |
Page 39 |
Page 40 |
Page 41 |
Page 42 |
Page 43 |
Page 44 |
Page 45 |
Page 46 |
Page 47 |
Page 48 |
Page 49 |
Page 50 |
Page 51 |
Page 52 |
Page 53 |
Page 54 |
Page 55 |
Page 56 |
Page 57 |
Page 58 |
Page 59 |
Page 60 |
Page 61 |
Page 62 |
Page 63 |
Page 64 |
Page 65 |
Page 66 |
Page 67 |
Page 68 |
Page 69 |
Page 70 |
Page 71 |
Page 72 |
Page 73 |
Page 74 |
Page 75 |
Page 76 |
Page 77 |
Page 78 |
Page 79 |
Page 80 |
Page 81 |
Page 82 |
Page 83 |
Page 84 |
Page 85 |
Page 86 |
Page 87 |
Page 88 |
Page 89 |
Page 90 |
Page 91 |
Page 92 |
Page 93 |
Page 94 |
Page 95 |
Page 96 |
Page 97 |
Page 98 |
Page 99 |
Page 100