Virus Safety of Hemophilia Treatment in Germany and Austria: A Tribute to Norbert Heimburger, Ph.D.

[*]The topic of this supplemental issue of Seminars in Thrombosis and Hemostasis is virus safety and treatment of hemophilia with plasma-derived factor concentrates. It is dedicated to Professor Norbert Heimburger, Ph.D., whose pioneering work at the Behringwerke in Marburg, Germany, at the end of the 1970s resulted in factor VIII and factor IX concentrates that were free of viral contamination. These concentrates saved the lives of numerous patients with hemophilia, especially those children who had not been exposed to potentially contaminated concentrates as yet. Although the effects on hemophilia patients was most dramatic, the technology was also applied to other concentrates, such as antithrombin (AT), factor XIII, C₁ esterase inhibitor, fibrinogen, and prothrombin complex concentrates (PPSB), just to name a few.

Dr. Heimburger's work was, however, by no means limited to developing virus-safe plasma products. he was very much involved in manufacturing reagents for coagulation-related testing, and many of the products, at one time distributed by the Behringwerke, carried and still carry his ``fingerprints.'' Besides being a superb scientist, Dr. Heimburger was also one of the kindest and easily accessible coworkers at the Behringwerke. For many of us, he represented ``Mr. Behring.'' There was no question or problem too small to receive the benefit of Dr. Heimburger's insight into his thinking and vast experience. It was a genuine pleasure to work with him, and I owe him personal thanks for all of the cooperation from which I benefited during my career.

It is thus entirely appropriate to dedicate this supplemental issue to this great scientist and to have colleagues testify to their experiences with products developed by Dr. Heimburger.

After greetings from the German Hemophilia Society and from the Gesellschaft für Thrombose-und Hämostaseforschung by Professor Scharrer, Professor Sutor gives us an opportunity to learn not only about the scientific career of Dr. Heimburger but also about his personal development. This brief eulogy shows Dr. Heimburger as a scientist and as a genuine human being.

The first contribution by Professor Schimpf reviews his experience with treating hemophiliacs at the Hemophilia Center Heidelberg. Before the availability of virus-safe concentrates, nearly 100% of hemophilia patients were infected with hepatitis viruses, although only about 20% developed overt jaundice. This was all before the disastrous infections with HIV became apparent. Schimpf describes the early studies with virus-safe concentrates and illustrates the benefits of good cooperation between clinicians and industry.

Next, Dr. Heimburger reviews his work on developing virus-safe concentrates for therapeutic use. The starting material was initially cryoprecipitate, a rich source of factor VIII, fibrinogen, von Willebrand factor, factor XIII, and fibronectin. The greatest difficulty in manufacturing factor VIII concentrates was the well-known ``lability'' of factor VIII activity caused by proteases. A long series of ``failures'' ultimately led to a successful recovery of factor VIII complex. Next was the task of making these concentrates virus free, which was ultimately achieved by pasteurization. These basic steps led to the development of several virus-safe factor VIII concentrates that were marketed by the Behringwerke.

Gürtler reviews the hepatitis viruses A to G. The present concepts of transfusion safety as they relate to donor selection and blood testing are discussed. This is followed by an extensive and thorough review of the viruses causing hepatitis and its consequences. Also, other blood-borne virus contaminations are presented.

Goeser extensively discusses the clinical aspects of infections with the hepatitis viruses, including the management of these patients. Although hepatitis A and E normally resolve without serious consequences, hepatitis B can have a grave prognosis. Highly active forms lead to cirrhosis. Treatment is difficult. Also, a remarkable percentage of patients with hepatitis C go on to develop cirrhosis of the liver. All can become chronic and then develop into cirrhosis or into hepatocellular carcinoma.

Next, Pollmann and Richter retrospectively review the status of infections in hemophilia patients treated at the Hemophilia Care Center at the University of Münster. Prior to the availability of factor concentrates, hemophiliacs had a rather short life expectancy. This drastically changed when concentrates became available, but with this came considerable risks of viral infections, especially hepatitis B and later hepatitis C. As many as 80 to 90% of hemophilia patients became infected. Data from several countries document this dilemma. Later, HIV infections complicated treatment further. Some reduction was noted when donors of plasma were carefully selected and screened, but the problem remained and compromised the life expectancy of patients.

Lenk and Schneider reflect back on the experience of hemophilia management in that part of Germany formerly known as East Germany. Cryoprecipitate was the main source of factor VIII, and this was usually prepared locally at individual blood banks. Initially, preparations were made from only 2 donors, later from 10. Occasionally, larger pools were used. Side effects increased with greater donor pools, but HIV infections were very low in the 1980s. As compared with other countries, the incidence of hepatitis infections was relatively low. The main problem with cryoprecipitate was that it was very difficult to manage severe bleedings or to cover patients properly during major surgical procedures.

Kreuz and colleagues describe the early experience with pasteurized, virus-safe factor concentrates in hemophilia patients from several treatment centers in Germany. These preparations became commercially available in 1981 and met all guidelines and standards established by various professional organizations. The use of these new concentrates reduced the infection rate not only with hepatitis-related viruses but also with HIV, which became a very serious problem in the beginning of the 1980s. Pasteurization thus proved to be an effective way to minimize virus infections with plasma derived clotting factor concentrates.

Muntean and coworkers report on their experience using pasteurized human clotting factor concentrates over a 16-year period involving 727 patient years. This multicenter survey, in which all but one treatment center in Austria participated, revealed that with the use of these virus-safe concentrates, no hepatitis or HIV was transmitted. This study surveyed not only factor VIII and IX concentrates, but also other clotting related preparations. Only an increase in seroconversion against human parvovirus B19 was noted early in the use of these concentrates. Also, other side effects, such as inhibitor development, were not increased.

Zimmermann et al, from the Hemophilia Center at Heidelberg, describe the infection rate with hepatitis C in hemophilic patients treated with virus-safe concentrates. Of 38 children with hemophilia, who were born after 1980 and treated exclusively with pasteurized concentrates, only 1 developed antibodies to the hepatitis C virus. A comparison between two groups of hemophiliacs for GBV-C, a new hepatitis virus, revealed an infection rate of 46% in patients treated with non- virus-safe preparations but only a 5% rate when treated with the pasteurized concentrates, again clearly indicating the superior safety of the virus-safe concentrates.

Gröner and co-workers describe the manufacturing process and the built-in safeguards against viral contamination of a plasma derived AT concentrate (Kybernin℗ P). AT concentrates are used for treating patients with congenital and acquired AT deficiencies. The manufacturing procedure starts with a careful selection of donors, so that the starting plasma already carries a high degree of safety concerning viral contamination. The manufactured product is of high purity and activity, and the ultimate pasteurization safeguards against viral contaminants, as shown by various viral removal steps.

The last contribution by Leithäuser and coworkers reports on some non-clotting-related activities of AT, namely its anti-inflammatory potential. AT prevents microvascular leakage and leukocyte and endothelial cell interactions in animal experiments of sepsis. The authors studied these effects in a rat model using fluorescence microscopy and lipopolysaccharide from Escherichia coli as sepsis trigger. Without AT supplementation, a considerable increase in microvascular permeability and leukocyte adhesion was seen that could be greatly ameliorated by the infusion of AT concentrate. These experiments clearly reiterate the anti-inflammatory properties of AT.

The contributions by all authors are greatly appreciated. Special thanks go to Dr. Hartmut Pollmann for organizing this tribute to Professor Heimburger at the University of Münster in December 1996 and thus recognizing this pioneering work in making clotting factor concentrates virus safe, thereby saving the lives of numerous hemophilic and nonhemophilic patients.