Recombinant Factor VIII Products and Hemophilia A: Efficacy, Safety, and Inhibitor Development

This issue of Seminars in Thrombosis and Hemostasis reviews the development, efficacy, safety, and inhibitor formation of the newly manufactured recombinant factor VIII preparations for treatment of hemophilia A. About 50 years ago hemophilic bleedings were managed with whole blood, preferably direct from donor to patient. Fluid overload was at that time a great concern. Once fresh frozen plasma was prepared, it became the treatment of choice because the required factor VIII activity could now be infused in one-half the volume. A major step in volume reduction was the finding that cryoprecipitate contains virtually all of the factor VIII activity present in plasma. The next goal was to remove as many of the nonessential proteins, especially fibrinogen, from the cryoprecipitate, thus creating the first plasma-derived factor VIII concentrates. Then came the time when the transmission of viral contaminants, initially hepatitis B, later HIV, became the greatest concern. This led to ways to make these concentrates relatively virus safe. Although these newer plasma-derived concentrates greatly changed the quality of life for hemophiliacs and changed their life expectancy to almost normal, concerns remained that contaminants, known or not yet known, might have an impact. Once the gene structure of factor VIII was identified, this knowledge was used for developing recombinant products in which either the entire molecule or that part of the structure that contains the biological activity is produced. It is hoped that the possibility of potential viral transmission is abolished with these concentrates, but side effects, especially the concern for inhibitor development, are to be considered. This issue of Seminars in Thrombosis and Hemostasis addresses these problems.

The first article by Lee reviews the experiences obtained with administering three recombinant factor VIII concentrates to previously treated hemophilia A patients. Two of these concentrates contain the full-length factor VIII molecule; in the third concentrate, the B-domain is removed. Clinical responses were very good with all three preparations, recovery after infusion and half-life were about the same and no major side effects were identified. In view of the good recoveries, the author suggests that the customary dosing scheme, 25 to 29 IU/kg, be reduced to 20 IU/kg.

The following contribution, by Barrowcliffe and coworkers, reviews the problems with assaying factor VIII activity with accuracy in plasma as well as in concentrates. There are principally three methods: one-stage, two-stage, and chromogenic substrate based. Although the one-stage assays are widely used for routine factor VIII assays, because of automation, convenience, and low cost, many problems arise, especially related to use of different reagents. Major differences also exist when the assays are used to determine activity in concentrates, plasma derived or recombinant. Recommendations for improving accuracy of one-stage assays in particular are reiterated, and strict adherence to them is advocated. Ultimately, the chromogenic substrate-based factor VIII assay appears to be the most accurate for activity measurements in plasmas and concentrates.

Mikaelsson and Oswaldsson next describe the problems encountered when factor VIII activity is measured by different methods in patients who received recombinant concentrates. Again major discrepancies are observed with different techniques. Postinfusion factor VIII levels in patients treated with recombinant products are on the one hand 30 to 50% lower when measured with one-stage assays and compared with chromogenic substrate-based methods. On the other hand, levels are higher with one-stage methods when plasma-derived concentrates are infused. Again, better agreement exists between chromogenic substrate-based assays and antigenically measured factor VIII. The main reason for these discrepant results is the source of phospholipids used for one-stage assays. Reagents that resemble most closely the natural platelet factor 3 yield considerably better correlations. The dilute thromboplastin time gives better values than the traditional one-stage assays. An additional problem is the discrepancy between standards used to assay factor VIII. It is advocated that product-specific standards be used.

The development of inhibitors in patients with hemophilia A remains a serious complication of treatment. Saint-Remy discusses the immunology of these inhibitors. Although the ultimate reason for inhibitor development is largely unknown, major advances have been made in understanding some of the aspects. The overall incidence of inhibitors has unfortunately not changed with improved treatment options. The role of B and T lymphocytes in this process is described. In addition, the ways inhibitors may affect factor VIII function are reviewed, as are the epitopes in the factor VIII molecule against which inhibitors are formed. Finally, potential ways to modify the responses that cause inhibitors to develop are reviewed.

Brinkhaus and coworkers describe the pharmacology of a modified factor VIII molecule infused into hemophilic dogs. The molecule was altered by removing the D-domain. This new product is called ReFacto℗. The hemostatic effect of this concentrate was very similar to responses obtained with a plasma-derived concentrate. In contrast, clearance and volume of distribution at steady state were greater for the plasma-derived concentrate. Also, binding of ReFacto to von Willebrand factor, a prerequisite for factor VIII stability in plasma, was identical to that of plasma-derived concentrates. It is predicted that ReFacto will be equally effective in treating humans with hemophilia A as it is for plasma-derived products.

In the next article, Lusher reviews the experience obtained with infusing recombinant factor VIII concentrates into hemophiliacs not previously treated. The studies have been ongoing over the last 11 years involving first-generation (Kogenate℗ and Recombinate℗) and second-generation (ReFacto℗ and Kogenate FS℗) recombinant products. Each of these products was found to be effective, safe, and well-tolerated with only minor side effects. Inhibitor formation was similar and as frequent as it was with plasma-derived concentrates. Inhibitor development appears to relate to defects in the factor VIII gene rather than to concentrate infusion.

In the next contribution, Suiter examines the achievements made in treating hemophiliacs with plasma-derived concentrates and whether patients can be switched from the older to the newer ones. The author compared two recombinant factor VIII concentrates, Helixate℗ and Helixate℗ NexGen. When previously treated hemophilia A patients were treated with these two preparations, both were equally effective with only minor side effects. The same efficacy and safety was found when previously untreated hemophiliacs received both concentrates. In addition, inhibitor development was similar. None of the patients studied experienced seroconversion of hepatitis B, hepatitis C, or HIV.

Kreuz and coworkers report on comparisons made between plasma-derived and recombinant factor VIII concentrates in treating previously untreated patients. Special emphasis is focused on inhibitor development. Patients with both severe and mild hemophilia were studied. Overall, 32% of all patients developed an inhibitor; 77% of them were high responders. Comparisons between the two treatment groups revealed no differences. The genetic predisposition for inhibitor development was comparable between the two patient groups.

Scandella discusses the characteristics of inhibitors to factor VIII. In principle, the antibodies bind to several functional sites of the factor VIII molecule that are required for binding to factor IXa, factor X, phospholipids, and von Willebrand factor. Antibodies against the A3 domain inhibit binding to factor IXa, anti-acidic region antibodies block binding to factor X, and antibodies to the C2 domain interfere with binding to phospholipids and von Willebrand factor. Using several immunologic techniques, the author identified regions in the factor VIII molecule that are specific for the various bindings required for normal clotting. These findings will be of future value in designing modalities to eradicate inhibitor development.

Wikén and Sjöberg describe work performed on plasma samples from patients treated with ReFacto. ReFacto is a B-domain depleted factor VIII concentrate. The factor VIII molecule lacks the major part of the B-domain except for 14 amino acids from the N-terminal and C-terminal ends that are linked into a 14 amino acid SQ-peptide tail in the C-terminal region of the heavy chain. The authors investigated whether this new peptide sequence might be involved in the development of inhibitors. Patients treated with ReFacto, patients treated with other factor VIIII concentrates, and healthy persons were studied. Antibodies were found in all groups. It was concluded that the new SQ-peptide sequence in ReFacto does not induce antibodies and that some other agent gives rise to them.

In the last article, Klinge and associates review hemophilia A-from basic science to clinical practice. The clinical presentation of patients with this bleeding disorder as well as the structure and function of the factor VIII molecule are described. This is followed by a discussion of treatment aspects and the occurrence of inhibitors, one of the main complications of management. This excellent article gives readers an opportunity to fully understand all aspects of hemophilia A, one of the oldest bleeding disorders known in humans.

My thanks and appreciation go to all authors for their excellent contributions that undoubtedly will enlighten readers on the management of hemophilia A patients with recombinant factor VIII concentrates, the newest and most recent development in hemophilia treatment. I also thank the guest editor, Jan J. Michiels, M.D., Ph.D., for the difficult work of assembling this issue.