Close
close
November 16th, 2004

WFH Joint Symposium Review – Natural Proteins in the Treatment of Blood Disorders: Return to Reason


Dr Günter Auerswald (Bremen, Germany. The Role of Plasma-Derived Factor VIII-von Willebrand Factor Concentrates in the ITI Treatment of Haemophilia A Patients with Inhibitors). [The presentation for Dr Auerswald was made by Dr Wolfhart Kreuz].

Nowadays, inhibitors are the main problem of haemophilia A treatment, with an incidence between 0 and 52 %, according to several studies. Immune tolerance induction (ITI) is viewed as the most appropriate approach for inhibitor elimination. The success rate of ITI is known to depend on many variables, including patient-related parameters, such as inhibitor titre at the start of ITI and peak inhibitor titre, patient age, possibly mutation and HLA type as well as therapy-related parameters, such as regimen, “high-dose” vs. “low-dose”, and concomitant immune stimulation through vaccination or inflammatory conditions.

Clearly recognised is that ITI success depends on the period between development of an inhibitor and the commencement of ITI, and the dose and frequency of FVIII. Less clear in this context until recently has been the relationship between the type of FVIII preparation, and whether it contains VWF.

The experience of three centres in Germany, Bonn, Frankfurt, Bremen, which have carried out ITI using uniformly the same high dose protocol and the same definitions of success is summarised.

Comparing patients who underwent ITI in the period 1979-1993 with those post 1993, a success rate of 91 % was achieved using pdFVIII preparations which contained VWF. In contrast, a success rate of only 29 % was achieved when ITI was attempted with the same kind of high purity FVIII preparation as was used at the time when the inhibitor developed. This was either monoclonally purified pdFVIII or recombinant FVIII, in both cases lacking VWF. When the preparation was changed from high purity FVIII to pdFVIII containing VWF in the 10/14 unsuccessful cases, the success rate of ITI rose to 8/10 (80 %). This was in the range previously experienced although it took about four times as long to achieve.

A similar trend was given by ITI results from Bonn and Bremen in the periods pre-1990 and 1990 to July, 2001. Until 1990, when the only concentrates used were those containing VWF, the success rate of ITI was 87 %. Thereafter, a difference in success rate was seen, depending on the type of concentrate: pdFVIII containing VWF was more effective in ITI than rFVIII.

These success rates were compared to those in the literature. In 102 ITI cases using the Bonn protocol and giving only VWF-containing concentrates, the success rate was 88 %, compared to [other] treatments in other countries where the concentrate did not contain VWF and the success rate was 63 % in 78 patients.

The majority of inhibitors are specific for the light chain of the FVIII molecule. There are theoretical considerations that, because VWF binds to the C2 domain of FVIII, it may sterically interfere with inhibitor binding. In addition, VWF may also protect FVIII against proteolysis, allowing prolonged presentation of FVIII to the immune system and improved immune tolerance.

Concluding, FVIII concentrates containing VWF may have less immunogenic potential. It appears reasonable to treat those patients who fail ITI under another type of FVIII preparation with a pdFVIII preparation containing VWF.


© Octapharma AG, 2004