Estimating the pathogen safety of manufactured human plasma products: application to fibrin sealants and to thrombin

Bernard Horowitz, Michael Busch, Bernard Horowitz, Michael Busch

Abstract

Background: Plasma fractionators have implemented many improvements over the past decade directed toward reducing the likelihood of pathogen transmission by purified blood products, yet little has been published attempting to assess the overall impact of these improvements on the probability of safety of the final product.

Study design and methods: Safety margins for human immunodeficiency virus (HIV), hepatitis C virus (HCV), hepatitis B virus (HBV), hepatitis A virus (HAV), parvovirus B19, and variant form of Creutzfeldt-Jakob disease (vCJD) were calculated for the two fibrin sealants licensed in the United States and for thrombin. These products were selected because their use in a clinical setting is, in most cases, optional, and both were relatively recently approved for marketing by the US Food and Drug Administration (FDA). Moreover, thrombin and fibrinogen both undergo two dedicated virus inactivation steps and/or removal steps in accord with the recommendations of regulatory agencies worldwide. Safety margins were determined by comparing the potential maximum viral loads in contaminated units to viral clearance factors, ultimately leading to the calculation of the residual risk per vial.

Results: The residual risk of pathogen transmission per vial was calculated to be less than 1 in 10(-15) for HIV, HCV, HBV, and HAV for both fibrinogen and thrombin. Owing to the greater quantities that can be present and its greater thermal stability, the calculated risk for parvovirus transmission was 1 in 500,000 vials for fibrinogen and less than 1 in 10(7) per vial for thrombin. Assuming that vCJD is found to be present in plasma donations, its risk of transmission by these purified and processed plasma derivatives would appear to be very low.

Conclusions: The pathogen safety initiatives implemented by plasma fractionators over the past 10 to 20 years have resulted in products with excellent pathogen safety profiles. Of the agents examined, parvovirus continues to have the lowest calculated margin of safety. Despite this, parvovirus transmissions should be rare. Manufacturers are encouraged to continue exploring processes to further enlarge parvovirus safety margins and to continue exploring ways of eliminating prions.

Figures

Figure 1
Figure 1
Process outlines for fibrinogen and thrombin.
Figure 2
Figure 2
S/D inactivation of vesicular stomatitis virus added to an antihemophilic factor concentrate.
Figure 3
Figure 3
Validated viral kill on vapor heating of fibrinogen (currently used Baxter process). BVDV (▪) and PRV (▴) were undetectable upon reaching 60°C, and HIV (◆) and HAV (▪) were undetectable after 5 and 1 hour, respectively, at 60°C. (●) Mouse minute virus.

References

    1. Key NS, Negrier C. Coagulation factor concentrates: past, present and future. Lancet 2007;370:439‐48.
    1. Abusriwil H, Stockley RA. Alpha‐1‐antitrypsin replacement therapy: current status. Curr Opin Pulm Med 2006;12:125‐31.
    1. Toubi E, Etzioni A. Intravenous immunoglobulin in immunodeficiency states: state of the art. Clin Rev Allergy Immunol 2005;29:167‐72.
    1. Solomon B. Intravenous immunoglobulin and Alzheimer's disease immunotherapy. Curr Opin Mol Ther 2007;9:79‐85.
    1. Laursen I, Houen G, Hojrup P, Brouwer N, Krogsoe LB, Blou L, Hansen PR. Second‐generation nanofiltered plasma‐derived mannan‐binding lectin product: process and characteristics. Vox Sang 2007;92:338‐50.
    1. Lariviere B, Rouleau M, Picard S, Beaulieu AD. Human plasma fibronectin potentiates the mitogenic activity of platelet‐derived growth factor and complements its wound healing effects. Wound Repair Regen 2003;11:79‐89.
    1. Poulle M, Burnouf‐Radosevich M, Burnouf T. Large‐scale preparation of highly purified human C1‐inhibitor for therapeutic use. Blood Coagul Fibrinolysis 1994;5:543‐9.
    1. Jackson MR. Fibrin sealants in surgical practice: an overview. Am J Surg 2001;182(2 Suppl):1S‐7S.
    1. Dorion RP, Hamati HF, Landis B, Frey C, Heydt D, Carey D. Risk and clinical significance of developing antibodies induced by topical thrombin preparations. Arch Pathol Lab Med 1998;122:887‐94.
    1. Ortel TL, Mercer MC, Thames EH, Moore KD, Lawson JH. Immunologic impact and clinical outcomes after surgical exposure to bovine thrombin. Ann Surg 2001;233:88‐96.
    1. Schoenecker JG, Johnson RK, Lesher AP, Day JD, Love SD, Hoffman MR, Ortel TL, Parker W, Lawson JH. Exposure of mice to topical bovine thrombin induces systemic autoimmunity. Am J Pathol 2001;159:1957‐69.
    1. Su Z, Izumi T, Thames EH, Lawson JH, Ortel TL. Antiphospholipid antibodies after surgical exposure to topical bovine thrombin. J Lab Clin Med 2002;139:349‐56.
    1. Streiff MB, Ness PM. Acquired FV inhibitors: a needless iatrogenic complication of bovine thrombin exposure. Transfusion 2002;42:18‐26.
    1. Lawson JH, Lynn KA, Vanmatre RM, Domzalski T, Klemp KF, Ortel TJ, Niklason LE, Parker W. Antihuman factor V antibodies after use of relatively pure bovine thrombin. Ann Thorac Surg 2005;79:1037‐8.
    1. Kamoda S, Ishikawa R, Kakehi K. Capillary electrophoresis with laser‐induced fluorescence detection for detailed studies on N‐linked oligosaccharide profile of therapeutic recombinant monoclonal antibodies. J Chromatogr A 2006;1133:332‐9.
    1. Hepner F, Cszasar E, Roitinger E, Lubec G. Mass spectrometrical analysis of recombinant human growth hormone (Genotropin® reveals amino acid substitutions in 2% of the expressed protein. Proteome Sci 2005;3:1.
    1. Brand CM, Leadbeater L, Bellati G, Marotta F, Ideo G. Antibodies developing against a single recombinant interferon protein may neutralize many other interferon‐alpha subtypes. J Interferon Res 1993;13:121‐5.
    1. Oberg K, Alm G, Magnusson A, Lundqvist G, Theodorsson E, Wide L, Wilander E. Treatment of malignant carcinoid tumors with recombinant interferon alfa‐2b: development of neutralizing interferon antibodies and possible loss of antitumor activity. J Natl Cancer Inst 1989;81:531‐5.
    1. Berrini A, Borromeo V, Secchi C. Monoclonal antibodies can reveal immunoreactivity differences between pituitary and recombinant bovine growth hormone. Hybridoma 1994;13:485‐9.
    1. US Food and Drug Administration. Guidance for industry: Q5A viral safety evaluation of biotechnology products derived from cell lines of human or animal origin. September 1998. Available from: URL:
    1. Schreiber GB, Busch MP, Kleinman SH, Korelitz JJ. The risk of transfusion‐transmitted viral infections. The Retrovirus Epidemiology Donor Study. N Engl J Med 1996;334:1685‐90.
    1. Dodd RY, Notari EP, Stramer SL. Current prevalence and incidence of infectious disease markers and estimated window‐period risk in the American Red Cross blood donor population. Transfusion 2002;42:975‐9.
    1. Janssen MP, Over J, Vanderpoel CL, Cuijpers HT, Vanhout BA. A probabilistic model for analyzing viral risks of plasma‐derived medicinal products. Transfusion 2008;48:153‐62.
    1. Mosesson MW. Fibrinogen and fibrin structure and functions. J Thromb Haemost 2005;3:1894‐904.
    1. Horowitz B. Blood protein derivative viral safety: observations and analysis. Yale J Biol Med 1990;63:361‐9.
    1. Hewitt PE, Llewelyn CA, Mackenzie J, Will RG. Creutzfeldt‐Jakob disease and blood transfusion: results of the UK Transfusion Medicine Epidemiological Review study. Vox Sang 2006;91:221‐30.
    1. Burnouf T, Padilla A. Current strategies to prevent transmission of prions by human plasma derivatives. Transfus Clin Biol 2006;13:320‐8.
    1. Cohen MS, Pilcher CD. Amplified HIV transmission and new approaches to HIV prevention. J Infect Dis 2005;191:1391‐3.
    1. Wawer MJ, Gray RH, Sewankambo NK, Serwadda D, Li X, Laeyendecker O, Kiwanuka N, Kigozi G, Kiddugavu M, Lutalo T, Nalugoda F, Wabwire‐Mangen F, Meehan MP, Quinn TC. Rates of HIV‐1 transmission per coital act, by stage of HIV‐1 infection, in Rakai, Uganda. J Infect Dis 2005;191:1403‐9.
    1. Pilcher CD, Joaki G, Hoffman IF, Martinson FE, Mapanje C, Stewart PW, Powers KA, Galvin S, Chilongozi D, Gama S, Price MA, Fiscus SA, Cohen MS. Amplified transmission of HIV‐1: comparison of HIV‐1 concentrations in semen and blood during acute and chronic infection. AIDS 2007;21:1723‐30.
    1. Fiebig EW, Wright DJ, Rawal BD, Garrett PE, Schumacher RT, Peddada L, Heldebrant C, Smith R, Conrad A, Kleinman SH, Busch MP. Dynamics of HIV viremia and antibody seroconversion in plasma donors: implications for diagnosis and staging of primary HIV infection. AIDS 2003;17:1871‐9.
    1. Katayama K, Kumagai J, Komiya Y, Mizui M, Yugi H, Kishimoto S, Yamanaka R, Tamatsukuri S, Tomoguri T, Miyakawa Y, Tanaka J, Yoshizawa H. Titration of hepatitis C virus in chimpanzees for determining the copy number required for transmission. Intervirology 2004;47:57‐64.
    1. Busch MP, Caglioti S, Robertson EF, McAuley JD, Tobler LH, Kamel H, Linnen JM, Shyamala V, Tomasulo P, Kleinman SH. Screening the blood supply for West Nile virus RNA by nucleic acid amplification testing. N Engl J Med 2005;353:460‐7.
    1. Glynn SA, Wright DJ, Kleinman SH, Hirschkorn D, Tu Y, Heldebrant C, Smith R, Giachetti C, Gallarda J, Busch MP. Dynamics of viremia in early hepatitis C virus infection. Transfusion 2005;45:994‐1002.
    1. Yoshikawa A, Gotanda Y, Minegishi K, Taira R, Hino S, Tadokoro K, Ohnuma H, Miyakawa K, Tachibana K, Mizoguchi H; Japanese Red Cross NAT Screening Research Group. Lengths of hepatitis B viremia and antigenemia in blood donors: preliminary evidence of occult (hepatitis B surface antigen‐negative) infection in the acute stage. Transfusion 2007;47:1162‐71.
    1. Satake M, Taira R, Yugi H, Hino S, Kanemitsu K, Ikeda H, Tadokoro K. Infectivity of blood components with low hepatitis B virus DNA levels identified in a lookback program. Transfusion 2007;47:1197‐205.
    1. Komiya Y, Katayama K, Yugi H, Mizui M, Matsukura H, Tomoguri T, Miyakawa Y, Tabuchi A, Tanaka J, Yoshizawa H. Minimum infectious dose of hepatitis B virus in chimpanzees and difference in the dynamics of viraemia between genotype A and C. Transfusion 2008;48:286‐84.
    1. Busch MP, Murthy KK, Hirschkorn DF, Herring BL, Delwart EL, Racanelli V, Rehermann B, Alter HJ. Infectivity of donations from eclipse and ramp‐up stages of HCV in chimpanzees. Abstract S39‐030H. Amer Assn of Blood Banks Annual Meeting 2007, Anaheim, CA., Oct 2007. Transfusion 2007;47(9 Suppl):17A.
    1. Ma M, Piatak M, Fritts L, Lu D, Lifson J, Busch MP, Miller CJ. Transmission of simian immunodeficiency virus (SIV) by plasma collected prior to detectable viremia, and infectivity of ramp‐up versus chronic stages. Abstract S40‐030H. Amer Assn of Blood Banks Annual Meeting 2007, Anaheim, CA, Oct 2007. Transfusion 2007;47(9 Suppl):17A‐18A.
    1. Hijikata M, Shimizu YK, Kato H, Iwamoto A, Shih JW, Alter HJ, Purcell RH, Yoshikura H. Equilibrium centrifugation studies of hepatitis C virus: evidence for circulating immune complexes. J Virol 1993;67:1953‐8.
    1. Brummelhuis HG, Over J, Duivis‐Vorst CC, Wilson‐de Sturler LA, Ates G, Hoek PJ, Reerink‐Brongers EE. Contributions to the optimal use of blood. IX. Elimination of hepatitis B transmission by (potentially) infectious plasma derivatives. Vox Sang 1983;45:205‐16.
    1. Prince AM, Horowitz B, Baker L, Shulman RW, Ralph H, Valinsky J, Cundell A, Brotman B, Boehle W, Rey F, Piet M, Reesink H, Lelie N, Tersmette M, Miedema F, Barbosa L, Nemo G, Nastala CL, Allan JS, Lee DR, Eichberg JW. Failure of a human immunodeficiency virus (HIV) immune globulin to protect chimpanzees against experimental challenge with HIV. Proc Natl Acad Sci U S A 1988;85:6944‐8.
    1. Prince AM, Pawlotsky JM, Soulier A, Tobler L, Brotman B, Pfahler W, Lee DH, Li L, Shata MT. Hepatitis C virus replication kinetics in chimpanzees with self‐limited and chronic infections. J Viral Hepat 2004;11:236‐42.
    1. Bruce ME, McConnell I, Will RG, Ironside JW. Detection of variant Creutzfeldt Jakob disease infectivity in extraneural tissues. Lancet 2001;358:208‐9.
    1. Llewelyn CA, Hewitt PE, Knight RS, Amar K, Cousens S, Mackenzie J, Will RG. Possible transmission of variant Creutzfeldt‐Jakob disease by blood transfusion. Lancet 2004;363:417‐21.
    1. Peden AH, Head MW, Ritchie DL, Bell JE, Ironside JW. Preclinical vCJD after blood transfusion in a PRNP codon 129 heterozygous patient. Lancet 2004;364:527‐9.
    1. Wroe SJ, Pal S, Siddique D, Hyare H, Macfarlane R, Joiner S, Linehan JM, Brandner S, Wadsworth JD, Hewitt P, Collinge J. Clinical presentation and pre‐mortem diagnosis of variant Creutzfeldt‐Jakob disease associated with blood transfusion: a case report. Lancet 2006;368:2061‐7.
    1. Cervenakova LO, Yakovleva O, McKenzie C, Kolchinsky S, McShane L, Drohan WN, Brown P. Similar levels of infectivity in the blood of mice infected with human‐derived vCJD and GSS strains of transmissible spongiform encephalopathy. Transfusion 2003;43:1687‐94.
    1. Yunoki M, Tsujikawa M, Urayama T, Sasaki Y, Morita M, Tanaka H, Hattori S, Takechi K, Ikuta K. Heat sensitivity of human parvovirus B19. Vox Sang 2003;84:164‐9.
    1. Terpstra FG, Parkkinen J, Tolo H, Koenderman AH, Ter Hart HG, Von Bonsdorff L, Torma E, Van Engelenburg FA. Viral safety of Nanogam, a new 15 nm‐filtered liquid immunoglobulin product. Vox Sang 2006;90:21‐32.
    1. Geng Y, Wu CG, Bhattacharyya SP, Tan D, Guo ZP, Yu MY. Parvovirus B19 DNA in Factor VIII concentrates: effects of manufacturing procedures and B19 screening by nucleic acid testing. Transfusion 2007;47:883‐9.
    1. Einarsson M, Morgenthaler JJ. Removal of viruses from plasma fractions by chromatography. Curr Stud Hematol Blood Transfus 1989;56:138‐45.
    1. Burnouf T. Chromatography in plasma fractionation: benefits and future trends. J Chromatogr B Biomed Appl 1995;664:3‐15.
    1. Lemon SM, Murphy PC, Smith A, Zou J, Hammon J, Robinson S, Horowitz B. Removal/neutralization of hepatitis A virus during manufacture of high purity, solvent/detergent factor VIII concentrate. J Med Virol 1994;43:44‐9.
    1. Griffith M. Ultrapure plasma factor VIII produced by anti‐F VIII c immunoaffinity chromatography and solvent/detergent viral inactivation. Characterization of the Method M process and Hemofil M antihemophilic factor (human). Ann Hematol 1991;63:131‐7.
    1. Woese C. Thermal inactivation of animal viruses. Ann N Y Acad Sci 1960;83:741‐51.
    1. Tersmette M, DeGoede RE, Over J, DeJonge E, Radema H, Lucas CJ, Huisman HG, Miedema F. Thermal inactivation of human immunodeficiency virus in lyophilised blood products evaluated by ID50 titrations. Vox Sang 1986;51:239‐43.
    1. Horowitz B. Specific inactivation of viruses which can potentially contaminate blood products. Dev Biol Stand 1991;75:43‐52.
    1. Joch C. The safety of fibrin sealants. Cardiovasc Surg 2003;11(Suppl 1):23‐8.
    1. Kawamura M, Sawafuji M, Watanabe M, Horinouchi H, Kobayashi K. Frequency of transmission of human parvovirus B19 infection by fibrin sealant used during thoracic surgery. Ann Thorac Surg 2002;73:1098‐100.
    1. Brown KE, Young NS, Alving BM, Barbosa LH. Parvovirus B19: implications for transfusion medicine. Summary of a workshop. Transfusion 2001;41:130‐5.
    1. Fryer JF, Delwart E, Hecht FM, Bernardin F, Jones MS, Shah N, Baylis SA. Frequent detection of the parvoviruses, PARV4 and PARV5, in plasma from blood donors and symptomatic individuals. Transfusion 2007;47:1054‐61.
    1. Foster PR. Assessment of the potential of plasma fractionation processes to remove causative agents of transmissible spongiform encephalopathy. Transfus Med 1999;9:3‐14.
    1. Reichl HE, Foster PR, Welch AG, Li Q, MacGregor IR, Somerville RA, Fernie K, Steele PJ, Taylor DM. Studies on the removal of a bovine spongiform encephalopathy‐derived agent by processes used in the manufacture of human immunoglobulin. Vox Sang 2002;83:137‐45.
    1. Foster PR, Griffin BD, Bienek C, McIntosh RV, MacGregor IR, Somerville RA, Steele PJ, Reichl HE. Distribution of a bovine spongiform encephalopathy‐derived agent over ion‐exchange chromatography used in the preparation of concentrates of fibrinogen and factor VIII. Vox Sang 2004;86:92‐9.
    1. Foster PR, McLean C, Welch AG, Griffin BD, Hardy JC, Bartley A, MacDonald S, Bailey A. Removal of abnormal prion protein by plasma fractionation. Transfus Sci 2000;22 (1‐2):53‐6.
    1. Foster PR, Welch AG, McLean C, Griffin BD, Hardy JC, Bartley A, MacDonald S, Bailey AC. Studies on the removal of abnormal prion protein by processes used in the manufacture of human plasma proteins. Vox Sang 2000;78:86‐95.
    1. Cervenakova L, Brown P, Hammond DJ, Lee CA, Saenko EL. Factor VIII and transmissible spongiform encephalopathy: the case for safety. Haemophilia 2002;8:63‐75.
    1. Foster PR. Plasma products In: Turner ML, editor. Creutzfeldt‐Jakob disease: managing the risk of transmission by blood, plasma, and tissues. Bethesda (MD): AABB Press; 2006. p. 188‐213.
    1. Tabor E. The epidemiology of virus transmission by plasma derivatives: clinical studies verifying the lack of transmission of hepatitis B and C viruses and HIV type 1. Transfusion 1999;39:1160‐8.
    1. Horowitz B, Ben‐Hur E. Efforts in minimizing risk of viral transmission through viral inactivation. Ann Med 2000;32:475‐84.
    1. Wu CG, Mason B, Jong J, Erdman D, McKernan L, Oakley M, Soucie M, Evatt B, Yu MY. Parvovirus B19 transmission by a high‐purity factor VIII concentrate. Transfusion 2005;45:1003‐10.
    1. Schmidt I, Blumel J, Seitz H, Willkommen H, Lower J. Parvovirus B19 DNA in plasma pools and plasma derivatives. Vox Sang 2001;81:228‐35.
    1. Blumel J, Schmidt I, Willkommen H, Lower J. Inactivation of parvovirus B19 during pasteurization of human serum albumin. Transfusion 2002;42:1011‐8.
    1. CJD Incidents Panel. Fourth Annual Report 1st September 2003 to 31st August 2004 to the Advisory Committee on Dangerous Pathogens Working Group on Transmissible Spongiform Encephalopathies. Available from:
    1. Roth WK, Weber M, Buhr S, Drosten C, Weichert W, Sireis W, Hedges D, Seifried E. Yield of HCV and HIV‐1 NAT after screening of 3.6 million blood donations in central Europe. Transfusion 2002;42:862‐8.
    1. Stramer SL, Glynn SA, Kleinman SH, Strong DM, Caglioti S, Wright DJ, Dodd RY, Busch MP; National Heart, Lung, and Blood Institute Nucleic Acid Test Study Group. Detection of HIV‐1 and HCV infections among antibody‐negative blood donors by nucleic acid‐amplification testing. N Engl J Med 2004;351:760‐8.
    1. Coste J, Reesink HW, Engelfriet CP, Laperche S, Brown S, Busch MP, Cuijpers HT, Elgin R, Ekermo B, Epstein JS, Flesland O, Heier HE, Henn G, Hernandez JM, Hewlett IK, Hyland C, Keller AJ, Krusius T, Levicnik‐Stezina S, Levy G, Lin CK, Margaritis AR, Muylle L, Niederhauser C, Pastila S, Pillonel J, Pineau J, Van Der Poel CL, Politis C, Roth WK, Sauleda S, Seed CR, Sondag‐Thull D, Stramer SL, Strong M, Vamvakas EC, Velati C, Vesga MA, Zanetti A. Implementation of donor screening for infectious agents transmitted by blood by nucleic acid technology: update to 2003. Vox Sang 2005;88:289‐303.
    1. Schreiber GB, Glynn SA, Zerlauth G, Wright DJ, McEntire R. Estimated HIV, HCV, and HBV residual risks of source‐plasma starting material for plasma derived medicinal products. Vox Sang 2008. (in press).
    1. Parsyan A, Candotti D. Human erythrovirus B19 and blood transfusion—an update. Transfus Med 2007;17:263‐78.
    1. Schmidt M, Themann A, Drexler C, Bayer M, Lanzer G, Menichetti E, Lechner S, Wessin D, Prokoph B, Allain JP, Seifried E, Kai Hourfar M. Blood donor screening for parvovirus B19 in Germany and Austria. Transfusion 2007;47:1775‐82.
    1. Busch MP, Glynn SA, Stramer SL, Strong DM, Caglioti S, Wright DJ, Pappalardo B, Kleinman SH; NHLBI‐REDS NAT Study Group. A new strategy for estimating risks of transfusion‐transmitted viral infections based on rates of detection of recently infected donors. Transfusion 2005;45:254‐64.
    1. Kleinman SH, Busch MP. Assessing the impact of HBV NAT on window period reduction and residual risk. J Clin Virol 2006;36(Suppl 1):S23‐S29.
    1. Busch MP, Tobler LH, Gerlich WH, Schaefer S, Giachetti C, Smith R. Very low level viremia in HCV infectious unit missed by NAT. Transfusion 2003;43:1173‐4.
    1. Hsia CC, Purcell RH, Farshid M, Lachenbruch PA, Yu MY. Quantification of hepatitis B virus genomes and infectivity in human serum samples. Transfusion 2006;46:1829‐35.
    1. Modrof J, Berting A, Tille B, Klotz A, Forstner C, Rieger S, Aberham C, Gessner M, Kreil TR. Neutralization of human parvovirus B19 by plasma and intravenous immunoglobulins. Transfusion 2008;48:178‐86.
    1. Davenport R, Geohas G, Cohen S, Beach K, Lazo A, Lucchesi K, Pehta J. Phase IV study of Plas+SD: hepatitis A (HAV) and parvovirus B19 safety results. Blood 2000;96:451a.
    1. Doyle S, Corcoran A. The immune response to parvovirus B19 exposure in previously seronegative and seropositive individuals. J Infect Dis 2006;194:154‐8.
    1. Remington KM, Trejo SR, Buczynski G, Li H, Osheroff WP, Brown JP, Renfrow H, Reynolds R, Pifat DY. Inactivation of West Nile virus, Vaccinia virus, and viral surrogates for relevant and emergent viral pathogens in plasma‐derived products. Vox Sang 2004;87:10‐8.
    1. Kreil TR, Berting A, Kistner O, Kindermann J. West Nile virus and the safety of plasma derivatives: verification of high safety margins, and the validity of predictions based on model virus data. Transfusion 2003;43:1023‐8.
    1. Kreil TR, Unger U, Orth SM, Petutschnig G, Kistner O, Berting A. H5N1 influenza virus and the safety of plasma products. Transfusion 2007;47:452‐9.
    1. Yunoki M, Yrayama T, Yamamoto I, Abe S, Ikuta K. Heat sensitivity of a SARS‐associated coronavirus introduced into plasma products. Vox Sang 2004;87:302‐3.
    1. Uemura YY, Yang H, Heldebrant CM, Takechi K, Yokoyama K. Inactivation and elimination of viruses during preparation of human intravenous immunoglobulin. Vox Sang 1994;67:246‐54.

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