Potential approaches to prevent uncommon hemolytic side effects of AB0 antibodies in plasma derivatives

Biologicals 33 (2005) 41e48 www.elsevier.com/locate/biologicals

Potential approaches to prevent uncommon hemolytic side effects of AB0 antibodies in plasma derivatives Christoph Buchta), Maria Macher, Paul Ho¨cker Department Transfusion Medicine, University Clinic for Blood Group Serology and Transfusion Medicine, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria Received 1 May 2004; accepted 11 October 2004

Abstract Since hemolytic reactions in patients after administration of plasma derivatives like immunoglobulins or coagulation factor preparations have been described, titers of anti-A and anti-B-antibodies have to be below defined levels for batch release of these plasma-derived therapeutic products according to the European Pharmacopoeia. We have summarized clinical relevance of AB0 antibodies in plasma derivatives and related legal issues in the European Union, United States of America, and Japan. We have also discussed potential approaches for the prevention of hemolytic side effects with feasible steps in preparation of plasma derivatives, viz., (1) selection of donors, (2) exclusion of ‘‘dangerous donors’’, (3) optimizing ratio of the types of plasma, (4) removal of antibodies, (5) production of blood-group-specific plasma derivatives, (6) rejection of batches of plasma derivatives with high titers of antibodies, and (7) crossmatching before administration. For harmonization of standards for anti-A and anti-B in plasma-derived therapeutics the regulators and manufacturers will have to realistically deal with complex clinical, practical, and economic issues. Ó 2004 The International Association for Biologicals. Published by Elsevier Ltd. All rights reserved.

1. Introduction Annually, about 35 million liters of plasma are processed worldwide through a complex sequence of steps to manufacture plasma derivatives. Albumin, immunoglobulins, and coagulation proteins are the three main groups of plasma derivatives used in clinical medicine. The process of production of plasma derivatives starts with the collection of plasma and finally results in a number of stable industrially manufactured drugs. The methods used for separation and purification

Abbreviations: AHF, antihemophilic factor; DCT, direct Coomb’s test; DDAVP, 1-deamino-8-D arginine vasopressin; IVIG, immunoglobulins for intravenous use; PCR, polymerase chain reaction; vWF, von Willebrand factor. ) Corresponding author. Tel.: C43 1 40400 5312; fax: C43 1 40400 5321. E-mail address: [email protected] (C. Buchta).

of plasma proteins are based on different principles, all using diverse physicochemical properties of the protein molecules. Some preparations are very pure, e.g. albumin, in others, contamination with unwanted proteins is inevitable. Thus, administration of plasma derivatives can be associated with exposure of the patient to plasma proteins other than those intended for treatment. The presence of antibodies to human blood cell antigens in plasma derivatives has been known for many years. Antibodies to blood group AB0-antigens are mainly a result of group 0 individuals with high titers of blood group antibodies, so-called ‘‘dangerous-0-donors’’ [1]. Even though these antibodies in plasma derivatives usually are of little pathological consequence, adverse reactions after administration of large amounts of diverse plasma derivatives have been repeatedly reported. Safety conditions and quality control standards for the release of batches of drugs are defined in

1045-1056/04/$30.00 Ó 2004 The International Association for Biologicals. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.biologicals.2004.10.004

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pharmacopoeia, issued by health authorities. In the case of some plasma derivatives, among others, tests for red cells antibodies are mandatory in some countries. Approaches to reduce the incidence of adverse effects due to antibodies to blood group antigens A and B are discussed here and are evaluated as far as practical and economic issues are concerned.

2. Clinical relevance of the AB0 system antibodies in blood products and plasma derivativesdHemolytic complications after administration of plasma derivatives The effects of the passively acquired antibodies are mitigated by dilution in the recipient’s plasma and neutralization by the soluble blood group substances in the recipient’s plasma. Occasionally, however, a positive direct antiglobulin test or even frank hemolysis of the recipient’s red cells has been reported after transfusion of AB0-incompatible antibodies in whole blood, red blood cells, platelet concentrates, antihemophilic factor (AHF) concentrate, and granulocyte concentrates. Not only antibodies to the AB0 system, but also other irregular antibodies, like anti-D, anti-C, -E, -G, -V or -Fya have been detected in plasma derivatives [2]. These antibodies may not cause acute hemolysis, but they can bind to antigens on erythrocytes and cause a positive direct Coomb’s test (DCT) and further activate macrophages in the spleen and accelerate the destruction of erythrocytes. The passive transfer of AB0 agglutinins directed against A or B antigen on the recipient’s red cells (minor incompatibility) occasionally causes serious consequences. When the donor plasma or plasma products with incompatible antibodies are infused, rapid dilution of the antibodies occurs in the patient’s plasma. In this setting of minor incompatibility, the number of antibody molecules transfused is rapidly diluted in whole blood volume of the patient, so that the red cell may bind only a few antibody molecules. On most occasions the number of antibody molecules bound per cell is too low for macrophage recognition of IgG coated cells or for appreciable amounts of complement to be activated. Additionally, the A and B blood group substances free in the plasma neutralize some antibodies [1,3,4]. Despite the protective factors listed above, destruction of the patient’s red cells by antibodies in the donor plasma and contaminating plasma derivatives has been reported [5,6].

concentrate must usually be administered over an extended period of time, and since the concentration methods used to prepare the Factor VIII product cause contamination with IgM and IgG, the amount of AB0 antibody in the recipient’s plasma may eventually reach a level at which it causes destruction of some of the recipient’s red cells [7,8]. Several cases where this has occurred have been reported [9e16]. Hach-Wunderle [11] found anti-A titers up to 1:512 and anti-B titers up to 1:256 in four different batches of Factor VIII concentrate. Immune hemolysis after administration of Factor IX concentrates has also been described [17]. The references for clotting factors causing hemolysis are listed in Table 1. 2.2. Immunoglobulins Immunoglobulin concentrates contain isohemagglutinins and alloantibodies to human blood group antigens that may be passively transfused to patients who receive these products [18e21]. Niosi found anti-A and anti-B in all six commercial human-immune-serum globulin preparations he tested for presence of blood group antibodies. Two of them had an anti-A titer of 1:128, one a titer of 1:64, anti-B titer was a maximum of 1:32. The typical titer of anti-A seems to be 1:16 and of anti-B 1:8 [22]. Most patients who developed hemolysis received IVIG with anti-A/B titers of at least 1:32, though significant hemolysis can occur with lower titers as well [23]. A few cases of acute Coombs-positive hemolytic anemia developing during or shortly after IVIG infusions have been published, two of them being particularly severe [24e27]. In both cases, hemolysis mediated by antibodies to blood group antigens (anti-A and anti-D) could be demonstrated. References concerning hemolytic reactions after administration of IVIG are listed in Table 2. Clearly as the result of methods used to concentrate IVIG, anti-A and anti-B will be among the immunoglobulins present in potent form [28]. In spite of this there are relatively few reports in the literature about deleterious effects following the passive transfer of anti-A and/or anti-B in immunoglobulins [29e36]. Maybe physicians are used to hemolytic episodes after administration of immunoglobulins and this is why reports on these events are uncommon. The reports listed in Table 2 show that hemolytic reactions do occur after administration of plasma derivatives even with titers of antibodies to the AB0 system lower than 1:64 and are thus compatible with requirements for batch release in European Pharmacopoeia.

2.1. Coagulation factor preparations 2.3. Albumin The passive transfer of AB0 antibodies in cryoprecipitate and Factor VIII concentrates causes frequent problems. Since cryoprecipitate or Factor VIII

There are no reports about hemolytic reactions after administration of albumin preparations [37e39].

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C. Buchta et al. / Biologicals 33 (2005) 41e48 Table 1 Reported hemolysis after administration of coagulation factors Reference

Hach-Wunderle [11] Orringer [14] Ragni [17] Rosati [9] Seeler [8]

Soni [13]

Preparation

Pat. BG

F VIII F VIII F VIII F IX F VIII F VIII F VIII CryoC

AC AC BD BD AC AC AC 0C

Cryo F VIII F VIII

ABC AC ABC

AHG test in plasma derivative

AHG test in pat. serum after administration

Anti-A

Anti-B

Anti-A

Anti-B

32e512 256 n.r. 2, 64 256, 1.024 4e128

32e256 n.r. 16 2, 32 n.r. 4e128

16 (DAT positive) (DAT positive) (DAT positive) (DAT positive) 256 pos incr. from 4 to 32

64

128

64

(DAT positive) (DAT positive) 4

n.r. n.r. incr. from 8 to 64

n.d.

Other antibodies

n.r. n.r. n.r. n.r. n.r. n.r.

n.r.

n.r. Z Not reported; incr. Z increased; n.d. Z not detected; Cryo Z cryoprecipitate; C, no hemolytic reaction, but increased levels of anti-A and anti-B after administration; indicated (bold) are cases of hemolytic episodes after administration of plasma derivatives with isoagglutinin levels ! 1:64 against patient AB0 blood group.

3. Legal issues e requirements for testing for AB0 antibodies in plasma derivates 3.1. European Pharmacopoeia In 1997 edition of European Pharmacopoeia, quality control standard 2.6.20 describes the assay to determine anti-A and anti-B hemagglutinins [40]. The assay corresponds to an indirect antiglobulin test in serial dilution using washed A1 and B cells in 5% suspension in 0.9% NaCl. After 30 min incubation time at 37  C, the red blood cells are washed three times with saline and are then incubated with polyvalent anti-human-globulin for 30 min. Without centrifugation, each dilution of the suspension is checked for agglutination microscopically. A hemolysin test for group 0 blood was last mentioned in 2nd edition of European Pharmacopoeia and even then it did not apply for plasma derivatives, but for whole blood only [41].

The purification methods for albumin provide a pure preparation. For batch release, no assay for anti-A and anti-B hemagglutinins is required. In the group of clotting factor preparations, a negative result in the agglutination test in dilution 1:64 is required for batch release of Factor VIII preparations, other clotting factor preparations do not require a hemagglutinin assay. Only immunoglobulins intended for intravenous use (IVIG) require a negative result in the agglutinin test in dilution 1:64 performed with a solution of maximum 30 g/l immunoglobulin for batch release. No further plasma derivatives are mentioned in 1997 edition of European Pharmacopoeia (Table 3). 3.2. United States Pharmacopoeia and Code of Federal Regulations, title 21 Plasma derivatives are mentioned as ‘‘biologics’’ in US Pharmacopoeia and are referred to Code of Federal

Table 2 Reports on hemolysis after administration of IVIG Reference

Brox [24] Copelan [26] Kim [29] Nakagawa [30] Nakamura [36]

Pat. BG

A 0C AC 0ÿ/BCC B AC n.r. n.r.

AHG test in plasma derivative

AHG test in patient serum after administration

Anti-A

Anti-B

Anti-A

16, ? 32 32 32 64, 128 n.r. n.r. n.r.

n.r. 4 8 32 16, 32 n.r. n.r. n.r.

positive (DAT positive) (DAT positive) (DAT positive) (DAT positive) 512 (DAT positive) (DAT positive)

CC

Other antibodies

Anti-B

n.r.

n.r. Anti-D: 4 Anti-D: 2 n.r. n.r. n.r. n.r. n.r.

n.r. Z Not reported; C, day 9 post BMT, donor 0ÿ, recipient BC; CC, second lot not available for testing, but lots were screened for isoagglutinin activity, and the titer must be 16 or less.

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Table 3 Requirements of the European Pharmacopoeia for anti-A and anti-B hemagglutinin assay for batch release Albumin Albumini humani solutio

Clotting factors No assay required

Fibrinogenum humanum cryodesiccatum Antithrombinum III humanum densatum cryodesiccatum Prothrombinum multiplex humanum cryodesiccatum Factot VII coagulationis humanus cryodesiccatus Factor VIII coagulationis humanus cryodesiccatus Factor IX coagulationis humanus cryodesiccatus

Immunoglobulins No assay required

Immunoglobulinum humanum normale1

No assay required

No assay required

Immunoglobulinum humanum normale ad usum intravenosum2 Immunosera ad usum humanum

No agglutination in dilution 1:64 following method 2.6.20 No assay required

No assay required No assay required No agglutination in dilution 1:64 following method 2.6.20 No assay required

1 Immunoglobulinum humanum hepatitidis B, Immunoglobulinum humanum hepatitidis A, Immunoglobulinum humanum anti-D, Immunoglobulinum humanum morbillicum, Immunoglobulinum humanum rubellae, Immunoglobulinum humanum tetanicum, Immunoglobulinum humanum varicellae, Immunoglobulinum humanum rabicum. 2 Immunoglobulinum humanum varicellae ad usum intravenosum, Immunoglobulinum humanum hepatitidis B ad usum intravenosum.

Regulations, Title 21 Parts 600e680 [42,43]. Neither hemagglutinin tests nor hemolysin tests are required for batch release of plasma derivatives. Some authors demand that there be a federal requirement that antibody levels be determined for each lot, and that those pools of plasma with significant levels be diverted to other uses [19]. 3.3. Japan For regulatory purposes in Japan, plasma derivatives are listed in ‘‘Minimum Requirements for Biological Products’’ [44]. Testing for AB0 antibodies is not mandatory for batch release of any plasma derivative in Japan.

4. Potential strategies to reduce the risk of hemolytic transfusion reactions caused by AB0 antibodies in plasma derivatives The frequency of blood groups leads to a heterogeneous mixture of antibodies and soluble blood group substances in large plasma pools prepared for fractionation. Many antibodies will be bound to their corresponding soluble antigens and thus won’t be harmful. Some antibodies in Cohn’s factions II and III will remain free and active and readily bind to their respective red cell antigens when transfused or injected into a patient. Hemagglutinating antibodies will mainly cause a positive direct Coomb’s test (DCT) and extravascular, delayed hemolysis, while hemolytic antibodies might cause severe intravascular hemolysis. The entire process from donation of plasma to the patient receiving a plasma derivative is illustrated in

Fig. 1. The opportunities to influence the risk of hemolytic reactions caused by administration of plasma derivatives are listed for each step and discussed. 4.1. Selection of blood group AB donors Since only donors with blood group AB have neither anti-A nor anti-B, selection of blood group AB donors could be a solution to the problem. However, since their frequency in general population is about 3%, this obviously is not a useful approach. 4.2. Administration of DDAVP prior to donation It is noteworthy that the level of Factor VIII is on average 8% higher in blood group A subjects than in group 0 donors, and the level in males is about 6% higher than in females [45,46]. If DDAVP (1-deamino-8-D arginine vasopressin), a synthetic derivative of vasopressin is injected into donors 15 min before venipuncture, the yield of Factor VIII in fractions prepared from the resulting plasma is increased two-fold [47,48]. Administration of DDAVP 1 h before donation has also been described, and showed an increased Factor VIII as well, but less side effects [49]. A male blood group A donor after administration of DDAVP would be the ideal donor, as the ratio of Factor VIII to iso-antibodies (anti-B in this case) would be higher than in other donors. Since DDAVP increases activity of vWF, people receiving DDAVP are at higher risk of developing thromboembolic events. Therefore, administration of DDAVP prior to plasma donation is not a standard practice. Plasmapheresis after administration of DDAVP is limited due to a list of adverse effects caused by this pharmaceutical [50,51].

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Steps in production donor

Influence selection of AB donors

administration DDAVP prior to donation

plasma collection

Problem frequency of blood groups

adverse effects of DDAVP

exclusion of "dangerous donors"

freezing, storage

pooling

fractionation

optimize ratio of plasma with different blood groups

removal of anti-A and anti-B

frequency of blood groups

technology

dangerous when incompatible filling

preparation of blood group specific flavours

raise of costs of preparation

quality control

rejection of batches with high titers of antibodies

costs

administration

crossmatching prior to administration

equipment necessary

Fig. 1. Possible approaches to prevent hemolytic reactions caused by AB0 antibodies in plasma derivatives. Selection of blood group AB donors and optimizing ratio of plasma with different blood groups in pools for fractionation are limited due to frequency of blood groups; administration of DDAVP prior to donation will increase levels of coagulation Factor VIII and thus increase the factor VIII/AB0antibody ratio, but it’s use is limited due to adverse effects of DDAVP; exclusion of ‘‘dangerous donors’’ seems to be a promising approach, but those donors have to be identified; removal of AB0 antibodies also seems promising, but technology has to be developed; preparation of blood group specific plasma derivatives has the advantage of compatibility of plasma derivative and patient, four types of pharmaceuticals would increase manufacturing costs, and also could be dangerous to patients when administered to incompatible blood groups; rejection of batches with high titers of antibodies is economically not sensible; crossmatching prior to administration requires equipment and special training.

4.3. Exclusion of ‘‘dangerous donors’’ The ‘‘dangerous donors’’, individuals with extremely high levels of hemolytic anti-A or anti-B, are rare [52,53], but adding even very few donations with extremely high titers of hemolytic antibodies to plasma

Table 4 Dilution of isoantibodies by pooling Titer in one ‘‘dangerous donation’’ 1:

Titer wanted in pool !1:64

!1:32

!1:16

128 256 512 1.024 2.048 4.096 8.192 16.384 32.768 65.536

2 4 8 16 32 64 128 256 512 1.024

4 8 16 32 64 128 256 512 1.024 2.048

8 16 32 64 128 256 512 1.024 2.048 4.096

To receive an iso-antibody titer in a pool for fractionation of less than 1:64, a ‘‘dangerous donation’’ with a titer of e.g. 1:8.192 has to be mixed with 128 donations with no iso-antibodies. To reach a titer of less than 1:16, it must be mixed with 512 donations with no isoantibodies.

pools can result in high antibody titers in final batches. Testing of iso-antibodies in donor blood is a feasible strategy to identify ‘‘dangerous donors’’ and to exclude their plasma from pooling for fractionation. Daufi and Rondell described a simple direct test, which permits the detection and relative quantification of frank hemolysis [54]. This test could easily be adapted to screen for ‘‘dangerous donors’’. In testing for viral pathogens by PCR it has become routine to test pools of aliquots from donations to reduce the costs for these tests [55,56]. Pooling of aliquots of plasma donations for detection of plasma with high titers of antibodies has not been described so far, but it is a feasible strategy for detecting ‘‘dangerous donors’’ and excluding their donations from pooling. It is unclear which events boost AB0 antibodies and what makes someone a ‘‘dangerous donor’’. Until long-term surveys of the development of AB0 antibody titers are available, each single donation could be tested (Table 4).

4.4. Optimizing the ratio of plasma with different blood groups In plasma fractionation pool sizes of about 12 000 l are necessary to produce plasma derivatives economically [57]. Since an average plasma donation is about 750 ml, one such pool consists of 16 000 donations. Optimizing the ratio of plasma with different blood groups would mean adding several units of A and B plasma to each unit of 0 plasma in the pool. Thus, soluble antigens could bind antibodies and reduce the amount of free antibodies, and more importantly, the antibodies would be diluted. Due to the frequency of blood groups in population, the use of this method of binding and dilution of antibodies is of limited utility.

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4.5. Removal of anti-A- and anti-B-antibodies After the report regarding coating of particles with blood compatible immunoadsorbents in 1980, Bensinger described in 1981 the removal of anti-A or anti-B by using synthetic human blood group A or B antigen as an immunoadsorbent [58e61]. Although there are no signs of loss of biological activities in plasma treated with these methods, it is uncertain if there are any alterations in coagulation factor activities or immune globulins in plasma processed. Mazid and Kaplan described in 1992 the immunoadsorption with a synthetic blood group oligosaccharide [62]. They used calcinated diatomitetype silica particles to which a synthetic oligosaccharide hapten, viz. A-trisaccharide, representing human blood group A, is chemically attached with a linking spacer arm. The method seems to be nonhemolytic and shows no loss of biological activity of treated blood or plasma. Blomberg reported in 1993 about different methods for removal or rather reduction of anti-A and anti-B antibodies in plasma [63]. Depending on the matrix, the retention time and the antigen used, a reduction of both IgG and IgM anti-A and anti-B was achieved. Hapten leakage from the column was very low, and despite traces of albumin no nonspecific adsorption of plasma proteins to the column could be detected. In 2000, selective removal of anti-A and anti-B directly from whole blood was described, using anti-A and anti-B specific antigen on the surfaces of hollow fiber membranes [64]. None of these methods ever became routine procedures in clinical medicine or in pharmaceutical production of plasma derivatives. The removal of iso-antibodies in coagulation factor preparations would be different than in immunoglobulin preparations. Factor VIII preparations could be treated with anti-human-globulin fixed to solid phase for removing immunoglobulin. Immunoglobulin preparations may be treated with A and B substances to selectively remove the anti-A/B iso-antibodies. 4.6. Production of blood group-specific IVIG and Factor VIII preparations Production of blood group-specific IVIG and Factor VIII preparations would increase the production expenses by processing four different pools of plasma and even more by storing plasma of blood groups B and AB for longer periods before processing. The need for blood group-specific IVIG and Factor VIII preparations would correlate with distribution of blood groups in a population. Shortages in plasma derivatives of less common blood groups would be unavoidable. Furthermore, additional regulatory, storage, transport, and supply costs will be incurred in providing four kinds of plasma derivatives. Preinfusion determination of patient’s blood group would pose additional cost and attendant errors in

clinical setting, e.g. the risk of transfusing blood to the wrong patient reported in New York State is 1:14 000 transfusions [65], and ranged from 1 in 400 (Belgium) to 1 in 27 007 (Scotland) [66e68]. Preparation of AB0specific plasma derivatives e whether administered after a negative crossmatch or not e is not a solution to the problem, because it entails additional costs and additional risks. Thus, group-specific plasma derivatives are not a realistic consideration.

4.7. Rejection of batches with high titers of AB0 antibodies Hemolytic reactions due to high titers of AB0 antibodies could possibly be prevented by lowering the acceptable limit of AB0 antibodies for batch release of plasma derivatives for intravenous use. Even though European Pharmacopoeia requires an AB0-antibody titer of less than 1:64 for batch release, serious adverse reactions cannot be excluded completely. Hemolytic reactions after administration of plasma derivatives with titers of less than 1:64 have been described and are shown in Tables 1 and 2. Keeping the limits of agglutinating antibodies is not the tool to prevent uncommon hemolytic reactions caused by plasma derivatives.

4.8. Crossmatching prior to administration Crossmatching plasma derivatives prior to application with recipient’s erythrocytes represent an in vitro test which permits predictions to in vivo behaviour of the preparation after administration to a recipient. Misbah and Chapel describe their practice to prevent hemolytic episodes by selecting IVIG batches for highdose therapy (O2 g/kg) that give a negative cross-match between the recipient’s red cells and IVIG or to use batches with known low titers (!1:4) of isoagglutinins [33,69]. Crossmatching, as most immunohematological tests, is rather expensive and technicians need experience and continuous training in performance to be fit for interpretation of the tests. Furthermore, crossmatching needs special equipment as is used in blood banks or diagnostic laboratories, but is not accessible in other departments of hospitals, where immunoglobulins are administered, and by no means in physician’s offices or in homes of patients injecting coagulation factors themselves regularly. Other anti-erythrocyte antibodies which sometimes can be found in donor’s plasma are most unlikely to cause positive reactions in crossmatches, as plasma derivatives are prepared from large pools, containing thousands of plasma donations and thus irregular antibodies would be diluted to an extent that cannot cause hemolytic reactions.

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5. Conclusions As long as plasma proteins for pharmacological or clinical use will be derived from human plasma, they will contain AB0 antibodies to different extent, more in Factor VIII preparations and immunoglobulin preparations and less or none in albumin. The cocktail of donations in a pool of plasma for fractionation contains all four blood groups with its soluble antigens and with corresponding antibodies. After elimination of several possibilities of reducing the risk of hemolytic reactions caused by plasma derivatives, exclusion of ‘‘dangerous donors’’, removal of anti-A and anti-B, and production of blood group-specific plasma derivatives remain possibilities that should be investigated. The decision has to be made whether maximum purity is the aim and product standards require removal of contaminating substances from plasma derivatives. Risks of adverse reactions due to high titers of hemolytic AB0 antibodies or antibodies to other blood group systems are minimal. Whether to accept or to prevent this risk will ultimately be an economic question to be decided in the future by authorities and fractionators.

Acknowledgements We gratefully acknowledge the continuous help of Peter L. Turecek from Baxter BioScience, Vienna, Austria, in preparation of this article.

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