BLOOD SAFETY BIBLIOGRAPHY - THERAFLEX MB-Plasma THERAFLEX UV-Platelets SSP+ - Lead the way in blood safety - Macopharma

 
BLOOD SAFETY BIBLIOGRAPHY - THERAFLEX MB-Plasma THERAFLEX UV-Platelets SSP+ - Lead the way in blood safety - Macopharma
Lead the way in blood safety

BLOOD SAFETY
BIBLIOGRAPHY
•THERAFLEX MB-Plasma
•THERAFLEX UV-Platelets
•SSP+
BLOOD SAFETY
BIBLIOGRAPHY

     2019
THERAFLEX MB-Plasma scientific publications
         Macopharma is an innovative Company in global healthcare with expertise in the              Year                                    Authors, title and references
         fields of Transfusion, Infusion and Biotherapy. One of Macopharma’s aims is to provide
                                                                                                            Faddy HM, Fryk JJ, Hall RA, Young PR, Reichenberg S, Tolksdorf F, Sumian C, Gravemann U, Seltsam
         a comprehensive range of products for the pathogen reduction of infectious agents
                                                                                                            A, Marks DC. Inactivation of yellow fever virus in plasma after treatment with methylene blue
         in the different blood components. This is aligned with Macopharma’s product                2019   and visible light and in platelet concentrates following treatment with ultraviolet C light.
         development strategy of the continuous quest, through partnerships, for improved                   Transfusion 2019; 10.1111/trf.15332.
         safety, efficacy, and quality of transfusion, infusion and cellular therapy.
                                                                                                            Gravemann U, Handke W, Sumian C, Alvarez I, Reichenberg S, Müller TH. & Seltsam A. Plasma
                                                                                                     2018   temperature during methylene blue/light treatment influences virus inactivation capacity and
         The THERAFLEX MB-Plasma system has been designed to inactivate both, recognized                    product quality. Vox Sang 2018; 113:368-77.
         and emerging pathogens in plasma. The Pathogen Reduction technology for plasma

                                                                                                                                                                                                                         MB-Plasma
                                                                                                                                                                                                                         THERAFLEX
         has been developed in partnership with the Blood Centre of the German Red Cross                    Eickmann M, Gravemann U, Handke W, Tolksdorf F, Reichenberg S, Muller TH, Seltsam A.
                                                                                                            Inactivation of Ebola virus and Middle East respiratory syndrome coronavirus in platelet
         Chapters of NSTOB, Springe. It is a user-friendly in-house treatment for single units       2018   concentrates and plasma by ultraviolet C light and methylene blue plus visible light,
         of plasma adapted for the inactivation of pathogens in Fresh Frozen Plasma from                    respectively. Transfusion 2018; 58:2202-7.
         aphaeresis or whole blood. MB-treated plasma produced with the THERAFLEX MB-Plasma
         procedure is in clinical use in 20 countries worldwide and more than 7 million MB-plasma           Babigumira JB, Lubinga SJ, Castro E, Custer B. Cost-utility and budget impact of methylene blue-
                                                                                                     2018   treated plasma compared to quarantine plasma. Blood Transfus 2018; 16:154-162.
         units have been treated and subsequently transfused to date.
                                                                                                            Noens L, Vilariño MD, Megalou A, Qureshi H. International, prospective haemovigilance study on
                                                                                                     2017
         The THERAFLEX UV-Platelets system is a joint development by the German Red Cross                   the methylene blue-treated plasma. Vox Sang 2017; 112: 352-359.
         Blood Services and Macopharma, aiming at the inactivation of known and emerging

                                                                                                                                                                                                                         UV-Platelets
                                                                                                                                                                                                                         THERAFLEX
                                                                                                            Fryk JJ, Marks DC, Hobson-Peters J, Watterson D, Hall RA, Young PR, Reichenberg S, Sumian C,
         pathogens in platelet products. The technology is based on the exposure of plasma-          2017   Faddy HM. ZIKV virus in plasma is inactivated after treatment with methylene blue and light
         reduced platelet concentrates to UV-C light only, requiring no additional photoactive              illumination. Pathology 2017; 49:S115
         substance. It is a simple and fast, one-step inactivation process using SSP+ as platelet
                                                                                                            Backholer L, Wiltshire M, Proffitt S, Cookson P, Cardigan R. Paired comparison of methylene blue-
         additive solution, and substitute for plasma. Clinical trials are in progress.              2016   and amotosalen-treated plasma and cryoprecipitate. Vox Sang 2016; 110:352–361

         The Platelet Additive Solution SSP+ (“PAS-E”) is the most suitable PAS on the market.              Fryk JJ, Marks DC, Hobson-Peters J, Prow NA, Watterson D, Hall RA, Young PR, Reichenberg S,
         It is designed to partially replace plasma in the preparation and storage of buffy-coat     2016   Sumian C, Faddy HM. Dengue and chikungunya viruses in plasma are effectively inactivated
                                                                                                            after treatment with methylene blue and visible light. Transfusion 2016; 56:2278–2285.
         derived platelet concentrates or apheresis platelet units. The solution enables platelets
         to be stored at 22°C ± 2°C, under gentle agitation, for up to 7 days following collection          Thiele T, Hron G, Kellner S, Wasner C, Westphal A, Warkentin TE, Greinacher A, Selleng K. Thrombin
         and according to local regulations.                                                                generation, ProC®Global, prothrombin time and activated partial thromboplastin time in
                                                                                                     2016

                                                                                                                                                                                                                          SSP+
                                                                                                            thawed plasma stored for seven days and after methylene blue/light pathogen inactivation.
                                                                                                            Blood Transfus 2016; 14:66-72.
         Since 2002, more than 11 million units of Macopharma Platelet Additive Solution have
         been distributed in 55 countries worldwide.                                                        Larrea L, Ortiz-de-Salazar MI, Martinez P, Roig R. Quantitative analysis of plasma proteins in whole
                                                                                                     2015   blood-derived fresh frozen plasma prepared with three pathogen reduction technologies.
                                                                                                            Transfus Apher Sci 2015; 52:305-10.
         Macopharma is proud to share with you the most relevant articles showing the benefits
         of these blood safety technologies.                                                                Reichenberg S, Gravemann U, Sumian C, Seltsam A. Challenge study of the pathogen reduction
                                                                                                     2015   capacity of the THERAFLEX MB-Plasma technology. Vox Sang 2015;109:129-137.
         We wish you an enjoyable and fruitful reading.
                                                                                                            Balaguer A, Moret A, Solves P, Bonanad S, Carpio N, Sanz MA. Quality of thawed plasma
                                                                                                     2015   inactivated with methylene blue after 48-hour storage. Transfus Apher Sci 2015; 52:141-142.

                                                                                                            Muniz-Diaz E, Puig L. Allergic and anaphylactic reactions to methylene-blue-treated plasma in
                                                                                                     2014   Catalonia in the period 2008-2013. Blood Transfus. 2014; 12:628-630.

                                                                                                            Politis C, Kavallierou L, Hantziara S, Parara M, Zervou E, Katsarou O, Hatzitaki M, Fountouli P, Gioka
                                                                                                            A, Tzioura K, Koumarianos S, Asariotou M, Richardson C. Haemovigilance data on the use of
                                                                                                     2014   methylene blue virally inactivated fresh frozen plasma with the Theraflex MB-Plasma System in
                                                                                                            comparison to quarantine plasma: 11 years’ experience. Transfus Med 2014; 24:316-320.

                                                                                                            Rapaille A, Reichenberg S, Najdovski T, Cellier N, de Valensart N, Deneys V. FVIII and fibrinogen
                                                                                                     2014   recovery after THERAFLEX MB-Plasma procedure following plasma source and treatment time.
                                                                                                            Blood Transfus 2014; 12:226-231

                                                                                                            Coene J, Devreese K, Sabot B, Feys HB, Vandekerckhove P, Compernolle V. Paired analysis of
                                                                                                     2014   plasma proteins and coagulant capacity after treatment with three methods of pathogen
                                                                                                            reduction. Transfusion 2014; 54:1321-1231.

4   BLOOD SAFETY BIBLIOGRAPHY 2019                                                                                                                                                  BLOOD SAFETY BIBLIOGRAPHY 2019   5
Year                                       Authors, title and references                                          Year                                  Authors, title and references

                 Alvarez I, Reichenberg S, di Nicola S. Plasma transfusion volume and liver transplantation safety.             Crettaz D, Sensebé L, Vu DH, Schneider P, Depasse F, Bienvenut WV, Quadroni M, Tissot JD.
                 Transfusion 2013; 53(10):2353-2354. Letter to the Editor on Bartelmaos T, Chabanel A, Léger J,          2004   Proteomics of methylene blue photo-treated plasma before and after removal of the dye by
       2013      Villalon L, Gillon MC, Rouget C, Gomola A, Denninger MH, Tardivel R, Naegelen C, Courtois F, Bardiaux          an absorbent filter. Proteomics 2004; 4:881-891.
                 L, Giraudeau B, Ozier Y. Plasma transfusion in liver transplantation: a randomized, double-blind,
                 multicenter clinical comparison of three virally secured plasmas. Transfusion 2013; 53(6):1335-1345            Hornsey VS, Young DA, Docherty A, Hughes W, Prowse CV. Cryoprecipitate prepared from
                                                                                                                         2004   plasma treated with methylene blue plus light: increasing the fibrinogen concentration.
                 Seltsam A, Müller TH. Updated hemovigilance data do not show an increased risk of allergic                     Transfusion Medicine 2004; 14:369–374.
                 reactions for methylene blue-treated plasma. J Allergy Clin Immunol 2013; 131(4):1253-1254
       2013      Reply to: Mertes PM, Demoly P, Alperovitch A, Bazin A, Bienvenu J, Caldani C, et al. Methylene blue–           Mohr H, Knüver-Hopf J, Gravemann U, Redecker-Klein A, Müller TH. West Nile virus in plasma is
                                                                                                                         2004   highly sensitive to methylene blue-light treatment. Transfusion 2004; 44(6):886–890.
                 treated plasma: an increased allergy risk? J Allergy Clin Immunol 2012; 130:808-812.

                                                                                                                                                                                                                                           MB-Plasma
                                                                                                                                                                                                                                           THERAFLEX
                                                                                                                                Williamson LM, Cardigan R, Prowse CV. Methylene blue-treated fresh-frozen plasma: what is its
                 Seltsam A, Müller TH. Update on the use of pathogen-reduced human plasma and platelet                   2003
       2013      concentrates. Br J Haematol 2013; 162(4):442-454.
                                                                                                                                contribution to blood safety? Transfusion 2003; 43:1322-1329.

                                                                                                                                Garwood M, Cardigan RA, Drummond O, Hornsey VS, Turner CP, Young D, Williamson LM, Prowse
                 Bost V, Odent-Malaure H, Chavarin P, Benamara H, Fabrigli P, Garraud O V. A regional                    2003   CV. The effect of methylene blue photoinactivation and methylene blue removal on the
       2013      haemovigilance retrospective study of four types of therapeutic plasma in a ten-year survey                    quality of fresh-frozen plasma. Transfusion 2003; 43:1238-1247.
                 period in France. Vox Sang 2013; 104(4):337-341.
                                                                                                                                Hornsey VS, Drummond O, Young D, Docherty A, Prowse CV. A potentially improved approach to
                 Steinmann E, Gravemann U, Friesland M, Doerrbecker J, Müller TH, Pietschmann T, Seltsam A. Two          2001   methylene blue virus inactivation of plasma: the Maco Pharma Macotronic system. Transfus
       2013      pathogen reduction technologies-methylene blue plus light and shortwave ultraviolet light-                     Med 2001; 11:31-36.
                 effectively inactivate hepatitis C virus in blood products. Transfusion 2013; 53(5):1010-1018.

                                                                                                                                                                                                                                           UV-Platelets
                                                                                                                                                                                                                                           THERAFLEX
                                                                                                                                Hornsey VS, Krailadsiri P, MacDonald S, Seghatchian J, Williamson LM, Prowse CV. Coagulation
                 Thiele T, Kellner S, Hron G, Wasner C, Nauck M, Zimmermann K, Wessel A, Warkentin TE, Greinacher        2000   factor content of cryoprecipitate prepared from methylene blue plus light virus-inactivated
       2012      A, Selleng K. Storage of thawed plasma for a liquid plasma bank: impact of temperature and                     plasma. Br J Haematol 2000; 109:665-670.
                 methylene blue pathogen inactivation. Transfusion 2012; 52(3):529-536.
                                                                                                                                Aznar JA, Bonanad S, Montoro JM, Hurtado C, Cid AR, Soler MA, De Miguel A. Influence of
                 Seghatchian J, Struff WS, Reichenberg S. Main properties of the THERAFLEX MB-Plasma system for          2000   methylene blue photoinactivation treatment on coagulation factors from fresh frozen plasma,
       2011      pathogen reduction. Transfus Med Hemother 2011; 38:55-64.                                                      cryoprecipitates and cryosupernatants. Vox Sang 2000; 79:156-160.

                                                                                                                                Aznar JA, Molina R, Montoro JM. Factor VIII/von Willebrand factor complex in methylene blue-
                 Hacquard M, Lecompte T, Belcour B, Geschier C, Jacquot C, Jacquot E, Schneider T. Evaluation            1999   treated fresh plasma. Transfusion 1999; 39:748-750.
       2011      of the hemostatic potential including thrombin generation of three different therapeutic
                 pathogen-reduced plasmas. Vox Sang 2012; 102(4):354-361.                                                       Ludicone P, Andreoni M, Martorana M-C, Nicastri E, Azzi A, Quintiliani L. Photodynamic Treatment
                                                                                                                         1999   of Fresh Frozen Plasma by Methylene Blue: Effect of HIV, HCV and Parvovirus B 19. Infus Ther

                                                                                                                                                                                                                                            SSP+
                 Cardigan R, Philpot K, Cookson P, Luddington R. Thrombin generation and clot formation in                      Transfus Med 1999; 26:262-266.
       2009      Methylene blue-treated plasma and cryoprecipitate. Transfusion 2009; 49(4):696–703.
                                                                                                                                Müller-Breitkreutz K, Mohr H. Hepatitis C and human immunodeficiency virus RNA degradation
                 Gravemann U, Kusch M, Koenig H, Mohr H, Müller TH. Thrombin Generation Capacity of Methylene            1998   by methylene blue/light treatment of human plasma. J Med Virol 1998; 56:239-245.
       2009      Blue-Treated Plasma Prepared by the THERAFLEX MB6Plasma System. Transfus Med Hemother
                 2009; 36:122-127.                                                                                              Mohr H, Bachmann B, Klein-Struckmeier A, Lambrecht B. Virus inactivation of blood products by
                                                                                                                         1997   phenothiazine dyes and light. Photochem Photobiol 1997; 65:441-445.
                 Seghatchian J, Walker WH, Reichenberg S. Updates on pathogen inactivation of plasma using
       2008      THERAFLEX methylene blue system. Transfus Apher Sci 2008; 38:271–280.                                          Mohr H, Lambrecht B, Selz A. Photodynamic virus inactivation of blood components. Immunol
                                                                                                                         1995   Invest 1995; 24(1&2):73-85.
                 Wainwright M, Mohr H, Walker WH. Phenotiazinium derivatives for pathogen inactivation in blood
       2007      products. J Photochem Photobiol 2007; 86(1):45–58.                                                             Müller-Breitkreutz K, Mohr H, Briviba K, Sies H. Inactivation of viruses by chemically and
                                                                                                                         1995   photochemically generated singlet molecular oxygen. J Photochem Photobiol 1995; 30:63-70.
                 Politis C, Kavallierou L, Hantziara S, Katsea P, Triantaphylou V, Richardson C, Tsoutsos D,
                                                                                                                                Tissot JD, Hochstrasser DF, Schneider B, Morgenthaler JJ, Schneider P. No evidence for protein
                 Anagnostopoulos N, Gorgolidis G, Ziroyannis P. Quality and safety of fresh frozen plasma
       2007      inactivated and leucoreduced with the Theraflex methylene blue system including the Blueflex            1994   modifications in fresh frozen plasma after photochemical treatment: an analysis by high-
                                                                                                                                resolution two-dimensional electrophoresis. Br J Haematol 1994; 86:143-146.
                 filter: 5 years’ experience. Vox Sang 2007; 92(4):319–326.
                                                                                                                                Lambrecht B, Norley SG, Kurth R, Mohr H. Rapid inactivation of HIV-1 in single donor preparations
                 Gironés N, Bueno JL, Carrión J, Fresno M, Castro E. The efficacy of photochemical treatment with        1994   of human fresh frozen plasma by methylene blue/light treatment. Biologicals 1994; 22:227-231.
       2006      methylene blue and light for the reduction of Trypanosoma cruzi in infected plasma. Vox Sang
                 2006; 91(4):285–291.                                                                                           Mohr H, Knüver-Hopf J, Lambrecht B, Scheidecker H, Schmitt H. No evidence for neoantigens in
                                                                                                                         1992   human plasma after photochemical virus inactivation. Ann Hematol 1992; 65:224-228.
                 Yarranton H, Lawrie AS, Purdy G, Mackie IJ, Machin SJ. Comparison of von Willebrand factor
       2004      antigen, von Willebrand factor-cleaving protease and protein S in blood components used for                    Lambrecht B, Mohr H, Knüver-Hopf J, Schmitt H. Photoinactivation of viruses in human fresh
                 treatment of thrombotic thrombocytopenic purpura. Transfus Med 2004; 14(1):39–44.                       1991   plasma by phenothiazine dyes in combination with visible light. Vox Sang 1991; 60(4):207-213.

6   BLOOD SAFETY BIBLIOGRAPHY 2019                                                                                                                                                                    BLOOD SAFETY BIBLIOGRAPHY 2019   7
THERAFLEX MB-PLASMA
                                             ABSTRACTS SCIENTIFIC PUBLICATIONS
                                                        2012-2019

                                     Inactivation of yellow fever virus in plasma after
                                     treatment with methylene blue and visible light and

                                                                                                                                                           MB-Plasma
                                                                                                                                                           THERAFLEX
                                     in platelet concentrates following treatment with
                                     ultraviolet C light.

                                     Faddy HM, Fryk JJ, Hall RA, Young PR, Reichenberg S, Tolksdorf F, Sumian C, Gravemann U, Seltsam A, Marks DC.

                                     Transfusion 2019; 10.1111/trf.15332

                                                                                                                                                           UV-Platelets
                                                                                                                                                           THERAFLEX
                                     BACKGROUND:
                                     Yellow fever virus (YFV) is endemic to tropical and subtropical areas in South America
                                     and Africa, and is currently a major public health threat in Brazil. Transfusion transmission
                                     of the yellow fever vaccine virus has been demonstrated, which is indicative of the
                                     potential for viral transfusion transmission. An approach to manage the potential YFV
                                     transfusion transmission risk is the use of pathogen inactivation (PI) technology systems,
                                     such as THERAFLEX MB-Plasma and THERAFLEX UV-Platelets (Macopharma). We aimed
                                     to investigate the efficacy of these PI technology systems to inactivate YFV in plasma or
                                     platelet concentrates (PCs).

                                                                                                                                                            SSP+
                                     STUDY DESIGN AND METHODS:
                                     YFV spiked plasma units were treated using THERAFLEX MB-Plasma system (visible light
                                     doses: 20, 40, 60, and 120 [standard] J/cm(2) ) in the presence of methylene blue
                                     (approx. 0.8 μmol/L) and spiked PCs were treated using THERAFLEX UV-Platelets system
                                     (ultraviolet C doses: 0.05, 0.10, 0.15, and 0.20 [standard] J/cm2). Samples were taken
                                     before the first and after each illumination dose and tested for residual virus using a
                                     modified plaque assay.

                                     RESULTS:
                                     YFV infectivity was reduced by an average of 4.77 log or greater in plasma treated with
                                     the THERAFLEX MB-Plasma system and by 4.8 log or greater in PCs treated with THERAFLEX
                                     UV-Platelets system.

                                     CONCLUSIONS:
                                     Our study suggests the THERAFLEX MB-Plasma and the THERAFLEX UV-Platelets systems
                                     can efficiently inactivate YFV in plasma or PCs to a similar degree as that for other
                                     arboviruses. Given the reduction levels observed in this study, these PI technology
                                     systems could be an effective option for managing YFV transfusion-transmission risk in
                                     plasma and PCs.

8   BLOOD SAFETY BIBLIOGRAPHY 2019                                                                                    BLOOD SAFETY BIBLIOGRAPHY 2019   9
Plasma temperature during methylene blue/light                                               Inactivation of Ebola virus and Middle East respiratory
          treatment influences virus inactivation capacity and                                         syndrome coronavirus in platelet concentrates and
          product quality.                                                                             plasma by ultraviolet C light and methylene blue plus
                                                                                                       visible light, respectively.
          Gravemann U, Handke W, Sumian C, Alvarez I, Reichenberg S, Müller TH & Seltsam A.

          Vox Sang 2018; 113:368-77.                                                                   Eickmann M, Gravemann U, Handke W, Tolksdorf F, Reichenberg S, Muller TH, Seltsam AA.

                                                                                                       Transfusion 2018; 2018; 58:2202-7.

          BACKGROUND:
          Photodynamic treatment using methylene blue (MB) and visible light is in routine use for
                                                                                                       BACKGROUND:
          pathogen inactivation of human plasma in different countries. Ambient and product
                                                                                                       Ebola virus (EBOV) and Middle East respiratory syndrome coronavirus (MERS-CoV) have
          temperature conditions for human plasma during production may vary between
                                                                                                       been identified as potential threats to blood safety. This study investigated the efficacy of
          production sites. The influence of different temperature conditions on virus inactivation
                                                                                                       the THERAFLEX UV-Platelets and THERAFLEX MB-Plasma pathogen inactivation systems to
          capacity and plasma quality of the THERAFLEX MB-Plasma procedure was investigated
                                                                                                       inactivate EBOV and MERS-CoV in platelet concentrates (PCs) and plasma, respectively.
          in this study..
                                                                                                       STUDY DESIGN AND METHODS:
          METHODS:
                                                                                                       PCs and plasma were spiked with high titers of cell culture-derived EBOV and MERS-
          Plasma units equilibrated to 5 – 2°C, room temperature (22 – 2°C) or 30 – 2°C were
                                                                                                       CoV, treated with various light doses of ultraviolet C (UVC; THERAFLEX UV-Platelets) or
          treated with MB/light and comparatively assessed for the inactivation capacity for three
                                                                                                       methylene blue (MB) plus visible light (MB/light; THERAFLEX MB-Plasma), and assessed for
          different viruses, concentrations of MB and its photoproducts, activity of various plasma
                                                                                                       residual viral infectivity.
          coagulation factors and clotting time.
                                                                                                       RESULTS:
          RESULTS:
                                                                                                       UVC reduced EBOV (≥ 4.5 log) and MERS-CoV (≥ 3.7 log) infectivity in PCs to the limit of
          Reduced solubility of the MB pill was observed at 5 – 2°C. Photocatalytic degradation of
                                                                                                       detection, and MB/light decreased EBOV (≥ 4.6 log) and MERS-CoV (≥ 3.3 log) titers in
          MB increased with increasing temperature, and the greatest formation of photoproducts
                                                                                                       plasma to nondetectable levels.
          (mainly azure B) occurred at 30 – 2°C. Inactivation of suid herpesvirus, bovine viral
          diarrhoea virus and vesicular stomatitis virus was significantly lower at 5 – 2°C than at
                                                                                                       CONCLUSIONS:
          higher temperatures. MB/light treatment affected clotting times and the activity of almost
                                                                                                       Both THERAFLEX UV-Platelets (UVC) and THERAFLEX MB-Plasma (MB/light) effectively
          all investigated plasma proteins. Factor VIII (-17.7 +/- 8.3%, 22 – 2°C) and fibrinogen
                                                                                                       reduce EBOV and MERS-CoV infectivity in platelets and plasma, respectively.
          (-14.4 +/- 16.4%, 22 – 2°C) showed the highest decreases in activity. Increasing plasma
          temperatures resulted in greater changes in clotting time and higher losses of plasma
          coagulation factor activity.

          CONCLUSIONS:
          Temperature conditions for THERAFLEX MB-Plasma treatment must be carefully controlled
          to assure uniform quality of pathogen-reduced plasma in routine production. Inactivation
          of cooled plasma is not recommended.

10   BLOOD SAFETY BIBLIOGRAPHY 2019                                                                                                                                                   BLOOD SAFETY BIBLIOGRAPHY 2019   11
Cost-utility and budget impact of methylene blue-                                               International, Prospective Haemovigilance Study on
          treated plasma compared to quarantine plasma.                                                   Methylene Blue-Treated Plasma.

                                                                                                                                                                                                                  MB-Plasma
                                                                                                                                                                                                                  THERAFLEX
          Babigumira JB, Lubinga SJ, Castro E, Custer B.                                                  Noens L, Vilariño MD, Megalou A, Qureshi H.

          Blood Transfus 2018; 10.2450/2016.0130-16.                                                      Vox Sang 2017; 112: 352-359.

          BACKGROUND:                                                                                     BACKGROUND AND OBJECTIVES:
          Methylene blue and visible light treatment and quarantine are two methods used to               Methylene Blue is a phenothiazine dye, which in combination with visible light has
          reduce adverse events, mostly infections, associated with the transfusion of fresh-frozen       virucidal and bactericidal properties, disrupting the replication of a broad range of
          plasma. The objective of this study was to estimate and compare the budget impact               enveloped viruses and some non-enveloped viruses. The study objective was to collect
          and cost-utility of these two methods from a payer’s perspective.                               data on adverse reactions occurring with Methylene Blue plasma administered in a

                                                                                                                                                                                                                  UV-Platelets
                                                                                                                                                                                                                  THERAFLEX
                                                                                                          routine clinical practice environment and document their characteristics and severity.
          MATERIALS AND METHODS:
          A budget impact and cost-utility model simulating the risks of hepatitis B virus, hepatitis C   MATERIALS AND METHODS:
          virus, cytomegalovirus, a West Nile virus-like infection, allergic reactions and febrile non-   This was an open label, multi-centre, non-controlled, non-randomized, non-interventional
          haemolytic transfusion reactions achieved using plasma treated with methylene blue              study. Patients who receive a Methylene Blue plasma transfusion were observed for any
          and visible light (MBP) and quarantine plasma (QP) was constructed for Spain. QP costs          signs and symptoms (adverse reactions) within 24 hours after the start of the transfusion,
          were estimated using data from one blood centre in Spain and published literature.              in different hospitals for a study duration of at least one year.
          The costs of producing fresh-frozen plasma from whole blood, apheresis plasma, and
          multicomponent apheresis, and separately for passive and active methods of donor                RESULTS:
          recall for QP were included. Costs and outcomes over a 5-year and lifetime time horizon         19,315 Methylene Blue plasma units were transfused. There were 8 patients with adverse

                                                                                                                                                                                                                   SSP+
          were estimated.                                                                                 reactions recorded during the study, one of them serious. Two had more than one
                                                                                                          reaction (2 and 4, respectively). Three patients had previous transfusions with Methylene
          RESULTS:                                                                                        Blue plasma only.
          Compared to passive QP, MBP led to a net increase of € 850,352, and compared to
          active QP, MBP led to a net saving of € 5,890,425 over a 5-year period. Compared to             CONCLUSION:
          passive QP, MBP increased the cost of fresh-frozen plasma per patient by € 7.21 and had         Methylene Blue Plasma has a very acceptable safety profile with a rate of Serious
          an incremental cost-utility ratio of € 705,126 per quality-adjusted life-year. Compared to      Adverse Reactions of 0.5/10,000 units.
          active QP, MBP reduced cost by € 50.46 per patient and was more effective.

          DISCUSSION:
          Plasma collection method and quarantine approach had the strongest influence on the
          budget impact and cost-utility of MBP. If QP relies on plasma from whole blood collection
          and passive quarantine, it is less costly than MBP. However, MPB was estimated to be
          more effective than QP in all analyses.

12   BLOOD SAFETY BIBLIOGRAPHY 2019                                                                                                                                         BLOOD SAFETY BIBLIOGRAPHY 2019   13
ZIKV virus in plasma is inactivated after treatment with                                                 Paired comparison of methylene blue- and
          methylene blue and light illumination.                                                                   amotosalen-treated plasma and cryoprecipitate.

                                                                                                                                                                                                                           MB-Plasma
                                                                                                                                                                                                                           THERAFLEX
          Fryk JJ, Marks DC, Hobson-Peters J, Watterson D, Hall RA, Young PR, Reichenberg S, Sumian C, Faddy HM.   Backholer L, Wiltshire M, Proffitt S, Cookson P, Cardigan R.

          Pathology 2017; 49: S115.                                                                                Vox Sang 2016; 110:352–361.

          AIM:                                                                                                     BACKGROUND AND OBJECTIVES:
          The emergence of Zika virus (ZIKV) in the Americas has resulted in a public health                       Cryoprecipitate is used in the treatment of patients with acquired hypofibrinogenaemia.
          emergency. Three documented cases of ZIKV transfusion-transmission highlights that this                  Studies have not directly compared cryoprecipitate produced following pathogen
          virus is a potential threat to blood transfusion safety. An approach to manage this risk                 inactivation (PI) of fresh-frozen plasma (FFP) using different systems. The effects of
          is pathogen inactivation, such as the THERAFLEX MB-PLASMA system. We examined the                        methylene blue (MB) and am otosalen (AS) PI systems on the quality of FFP and

                                                                                                                                                                                                                           UV-Platelets
                                                                                                                                                                                                                           THERAFLEX
          effectiveness of this system to inactivate ZIKV in plasma at different visible-light doses.              cryoprecipitate were investigated in a paired study.

          METHODS:                                                                                                 MATERIALS AND METHODS:
          ZIKV was spiked into pooled plasma (n=3), then treated with the THERAFLEX MB-Plasma                      Seven group A and 7 group O pools of plasma were prepared and split into individual
          system. Pre- and post-treatment samples were taken at each illumination dose (0, 20,                     units and rapidly frozen to produce FFP. Units of FFP were thawed and either PI treated
          40, 60, 120 J/cm2) and viral infectivity determined by plaque assay. The reduction in viral              with MB or amotosalen, or left untreated (control). Samples of FFP along with the
          infectivity was calculated.                                                                              corresponding cryoprecipitate were tested for a range of coagulation factors, thrombin
                                                                                                                   generation (TGT) and rotational thromboelastometry (ROTEM).
          RESULTS:
          Treatment of plasma with the THERFALEX MB-Plasma system resulted in ≥5.68 log10                          RESULTS:
          reduction in ZIKV infectivity at 120 J/cm2, with residual viral infectivity reaching the limit of

                                                                                                                                                                                                                            SSP+
                                                                                                                   AS-FFP showed a smaller decrease following treatment for most coagulation factors
          detection of the assay with treatment at 40 J/cm2.                                                       analysed than MB-FFP, except fibrinogen (antigen) and factor VII, partly due to lower
                                                                                                                   volume losses. There was no significant difference between treatment methods for
          DISCUSSION:                                                                                              fibrinogen content of cryoprecipitate with treated units meeting current UK specification,
          Our study has shown the THERAFLEX MB-PLASMA system can reduce the infectivity of ZIKV                    or TGT and ROTEM parameters studied.
          to the limit of detection of the assay used at one third of the standard illumination dose.
          Our data suggest this system may be an effective option for managing ZIKV transfusion-                   CONCLUSIONS:
          transmission risk in plasma.                                                                             MB-cryo contained a significantly higher content of FVIII and lower content of FXIII when
                                                                                                                   compared to AS-cryo, with no difference in fibrinogen activity.

14   BLOOD SAFETY BIBLIOGRAPHY 2019                                                                                                                                                  BLOOD SAFETY BIBLIOGRAPHY 2019   15
Dengue and chikungunya viruses in plasma are                                                                      Thrombin generation, ProC®Global, prothrombin time
          effectively inactivated after treatment with methylene                                                            and activated partial thromboplastin time in thawed
          blue and visible light.                                                                                           plasma stored for seven days and after methylene blue/
                                                                                                                            light pathogen inactivation.

                                                                                                                                                                                                                                                       MB-Plasma
                                                                                                                                                                                                                                                       THERAFLEX
          Fryk JJ, Marks DC, Hobson-Peters J, Prow NA, Watterson D, Hall RA, Young PR, Reichenberg S, Sumian C, Faddy HM.

          Transfusion 2016; 56:2278–2285.                                                                                   Thiele T, Hron G, Kellner S, Wasner C, Westphal A, Warkentin TE, Greinacher A, Selleng K.

                                                                                                                            Blood Transfus 2016; 14:66-72.

          BACKGROUND:
          Arboviruses, such as dengue viruses (DENV) and chikungunya virus (CHIKV), pose a risk to
                                                                                                                            BACKGROUND:
          the safe transfusion of blood components, including plasma. Pathogen inactivation is
                                                                                                                            Methylene blue pathogen inactivation and storage of thawed plasma both lead to

                                                                                                                                                                                                                                                       UV-Platelets
          an approach to manage this transfusion transmission risk, with a number of techniques

                                                                                                                                                                                                                                                       THERAFLEX
                                                                                                                            changes in the activity of several clotting factors. We investigated how this translates into
          being used worldwide for the treatment of plasma. In this study, the efficacy of
                                                                                                                            a global loss of thrombin generation potential and alterations in the protein C pathway.
          the THERAFLEX MB-Plasma system to inactivate all DENV serotypes (DENV-1 through
          DENV-4) or CHIKV in plasma, using methylene blue and light illumination at 630 nm, was
                                                                                                                            METHODS AND MATERIALS:
          investigated.
                                                                                                                            Fifty apheresis plasma samples were thawed and each divided into three subunits. One
                                                                                                                            subunit was stored for 7 days at 4 °C, one was stored for 7 days at 22 °C and one was
          STUDY DESIGN AND METHODS:
                                                                                                                            stored at 4 °C after methylene blue/light treatment. Thrombin generation parameters,
          Pooled plasma units were spiked with DENV-1, DENV-2, DENV-3 DENV-4 or CHIKV and
                                                                                                                            ProC®GlobalNR, prothrombin time and activated partial thromboplastin time were
          treated with the THERAFLEX MB-Plasma system at four light illumination doses: 20, 40, 60
                                                                                                                            assessed on days 0 and 7.
          and 120 (standard dose) J/cm². Pre- and post-treatment samples were collected and
          viral infectivity determined. The reduction in viral infectivity was calculated for each dose.

                                                                                                                                                                                                                                                        SSP+
                                                                                                                            RESULTS:
                                                                                                                            The velocity of thrombin generation increased significantly after methylene blue treatment
          RESULTS:
                                                                                                                            (increased thrombin generation rate; time to peak decreased) and decreased after
          Treatment of plasma with the THERAFLEX MB-Plasma system resulted in a ≥4.46 log
                                                                                                                            storage (decreased thrombin generation rate and peak thrombin; increased lag time
          reduction in all DENV serotypes and CHIKV infectious virus. The residual infectivity for each
                                                                                                                            and time to peak). The endogenous thrombin generation potential remained stable after
          was at the detection limit of the assay used at 60 J/cm², with dose-dependency also
                                                                                                                            methylene blue treatment and storage at 4 °C. Methylene blue treatment and 7 days of
          observed.
                                                                                                                            storage at 4 °C activated the protein C pathway, whereas storage at room temperature
                                                                                                                            and storage after methylene blue treatment decreased the functional capacity of the
          CONCLUSIONS:
                                                                                                                            protein C pathway. Prothrombin time and activated partial thromboplastin time showed
          Our study demonstrated the THERAFLEX MB-Plasma system can reduce the infectivity of
                                                                                                                            only modest alterations.
          all DENV serotypes and CHIKV spiked into plasma to the detection limit of the assay used
          at half of the standard illumination dose. This suggests this system has the capacity to
                                                                                                                            CONCLUSION:
          be an effective option for managing the risk of DENV or CHIKV transfusion transmission
                                                                                                                            The global clotting capacity of thawed plasma is maintained at 4 °C for 7 days and
          in plasma.
                                                                                                                            directly after methylene blue treatment of thawed plasma. Thrombin generation and
                                                                                                                            ProC®Global are useful tools for investigating the impact of pathogen inactivation and
                                                                                                                            storage on the clotting capacity of therapeutic plasma preparations.

16   BLOOD SAFETY BIBLIOGRAPHY 2019                                                                                                                                                                              BLOOD SAFETY BIBLIOGRAPHY 2019   17
Quantitative analysis of plasma proteins in whole                                               Challenge study of the pathogen reduction capacity of
          blood-derived fresh frozen plasma prepared with three                                           the THERAFLEX MB-Plasma technology.
          pathogen reduction technologies.

                                                                                                                                                                                                                      MB-Plasma
                                                                                                                                                                                                                      THERAFLEX
                                                                                                          Reichenberg S, Gravemann U, Sumian C, Seltsam A.

          Larrea L, Ortiz-de-Salazar MI, Martinez P, Roig R.                                              Vox Sang 2015; 109(2):129-37.

          Transfus Apher Sci 2015; 52:305-10.

                                                                                                          BACKGROUND AND OBJECTIVES:
                                                                                                          Although most pathogen reduction systems for plasma primarily target viruses, bacterial
          Several plasma pathogen reduction technologies (PRT) are currently available. We
                                                                                                          contamination may also occur. This study aimed to investigate the bacterial reduction
          evaluated three plasma PRT processes: Cerus Amotosalen (AM), Terumo BCT riboflavin
                                                                                                          capacity of a methylene blue (MB) treatment process and its virus inactivation capacity
          (RB) and Macopharma methylene blue (MB). RB treatment resulted in the shortest overall
                                                                                                          in lipaemic plasma.

                                                                                                                                                                                                                      UV-Platelets
          processing time and in the smallest volume loss (1%) and MB treatment in the largest

                                                                                                                                                                                                                      THERAFLEX
          volume loss (8%). MB treatment retained the highest concentrations of factors II, VII, X, IX,
                                                                                                          MATERIALS AND METHODS:
          Protein C, and Antithrombin and the AM products of factor V and XI. Each PRT process
                                                                                                          Bacterial concentrations in plasma units spiked with different bacterial strains were
          evaluated offered distinct advantages such as procedural simplicity and volume
                                                                                                          measured before and after the following steps of the THERAFLEX MB-Plasma procedure:
          retention (RB) and overall plasma protein retention (MB).
                                                                                                          leucocyte filtration, MB/light treatment and MB filtration. Virus inactivation was investigated
                                                                                                          for three virus types in non-lipaemic, borderline lipaemic and highly lipaemic plasma.

                                                                                                          RESULTS:
                                                                                                          Leucocyte filtration alone efficiently eliminated most of the tested bacteria by more
                                                                                                          than 4 logs (Staphylococcus epidermidis and Staphylococcus aureus) or to the

                                                                                                                                                                                                                       SSP+
                                                                                                          limit of detection (LOD) (≥ 4_8 logs; Escherichia coli, Bacillus cereus and Klebsiella
                                                                                                          pneumoniae). MB/light and MB filtration further reduced Staphylococcus epidermidis
                                                                                                          and Staphylococcus aureus to below the LOD. The small bacterium Brevundimonas
                                                                                                          diminuta was reduced by 1_7 logs by leucocyte filtration alone, and to below the LOD
                                                                                                          by additional MB/light treatment and MB filtration (≥ 3_7 logs). Suid herpesvirus 1, bovine
                                                                                                          viral diarrhoea virus and human immunodeficiency virus 1 were efficiently inactivated by
                                                                                                          THERAFLEX MB-Plasma, independent of the degree of lipaemia.

                                                                                                          CONCLUSION:
                                                                                                          THERAFLEX MB-Plasma efficiently reduces bacteria, mainly via the integrated filtration
                                                                                                          system. Its virus inactivation capacity is sufficient to compensate for reduced light
                                                                                                          transparency due to lipaemia.

18   BLOOD SAFETY BIBLIOGRAPHY 2019                                                                                                                                             BLOOD SAFETY BIBLIOGRAPHY 2019   19
Haemovigilance data on the use of methylene                                                                            FVIII and fibrinogen recovery after THERAFLEX
          blue virally inactivated fresh frozen plasma with                                                                      MB-Plasma procedure following plasma source
          the THERAFLEX MB-Plasma System in comparison to                                                                        and treatment time.

                                                                                                                                                                                                                                                      MB-Plasma
          quarantine plasma: 11 years’ experience.

                                                                                                                                                                                                                                                      THERAFLEX
                                                                                                                                 Rapaille A, Reichenberg S, Najdovski T, Cellier N, de Valensart N, Deneys V.

          Politis C, Kavallierou L, Hantziara S, Parara M, Zervou E, Katsarou O, Hatzitaki M, Fountouli P, Gioka A, Tzioura K,   Blood Transfus 2014; 12:226-231.
          Koumarianos S, Asariotou M, Richardson C.

          Transfus Med 2014; 24:316-320.
                                                                                                                                 BACKGROUND:
                                                                                                                                 The quality of fresh-frozen plasma is affected by different factors. Factor VIII is sensitive
                                                                                                                                 to blood component storage processes and storage as well as pathogen-reduction
          BACKGROUND:

                                                                                                                                                                                                                                                      UV-Platelets
                                                                                                                                 technologies. The level of fibrinogen in plasma is not affected by the collection

                                                                                                                                                                                                                                                      THERAFLEX
          Haemovigilance is an effective tool for identifying adverse effects of blood components.
                                                                                                                                 processes but it is affected by preparation and pathogen-reduction technologies.
          We analyse cumulative haemovigilance data in order to compare the two secured
          therapeutic plasmas that have been in use for more than 11 years in Greece - methylene
                                                                                                                                 MATERIALS AND METHODS:
          blue-treated fresh frozen plasma (MB-FFP) and quarantine fresh frozen plasma (Q-FFP) -
                                                                                                                                 The quality of plasma from whole blood and apheresis donations harvested at different
          regarding safety and adverse events.
                                                                                                                                 times and treated with a pathogen-reduction technique, methylene blue/light, was
                                                                                                                                 investigated, considering, in particular, fibrinogen and factor VIII levels and recovery.
          MATERIALS AND METHODS:
          Data from the centralised active haemovigilance system of Greece for the period 2001-
                                                                                                                                 RESULTS:
          2011 were used to examine the association between FFP types and adverse events. Post-
                                                                                                                                 The mean factor VIII level after methylene blue treatment exceeded 0.5 IU/mL in all
          transfusion information on infectious and non-infectious adverse events was analysed.
                                                                                                                                 series. Factor VIII recovery varied between 78% and 89% in different series. The recovery

                                                                                                                                                                                                                                                       SSP+
          Events were examined by reaction type, severity and imputability to transfusion.
                                                                                                                                 of factor VIII was dependent on plasma source as opposed to treatment time. The
                                                                                                                                 interaction between the two factors was statistically significant. Mean levels of fibrinogen
          RESULTS:
                                                                                                                                 after methylene blue/light treatment exceeded 200 mg/dL in all arms. The level of
          The incidence of adverse events was higher with Q-FFP (1:3620) than MB-FFP (1:24 593)
                                                                                                                                 fibrinogen after treatment correlated strongly with the level before treatment. There
          by a factor of 6.79 [95% confidence interval (CI) 2.52-27.8]. Allergic adverse events
                                                                                                                                 was a negative correlation between fibrinogen level before treatment and recovery.
          were also commoner with Q-FFP (1:7489) than with MB-FFP (1:24 593), by a factor of 3.28
                                                                                                                                 Pearson’s correlation coefficient between factor VIII recovery and fibrinogen recovery
          (95% CI 1.17-13.7). All adverse reactions experienced by the MB plasma recipients were
                                                                                                                                 was 0.58.
          considered to be mild.
                                                                                                                                 CONCLUSION:
          CONCLUSION:
                                                                                                                                 These results show a difference in recovery of factor VIII and fibrinogen correlated with
          Haemovigilance over 11 years has demonstrated the long-term safety of MB-FFP in
                                                                                                                                 plasma source. The recovery of both factor VIII and fibrinogen was higher in whole blood
          comparison to untreated quarantine FFP. In addition to lowering the adverse event rate,
                                                                                                                                 plasma than in apheresis plasma. Factor VIII and fibrinogen recovery did not appear to
          implementing the system on a national scale in at-risk countries would presumably
                                                                                                                                 be correlated.
          reduce the transmission of severe viral infections including emerging infectious diseases
          by transfusion.

20   BLOOD SAFETY BIBLIOGRAPHY 2019                                                                                                                                                                             BLOOD SAFETY BIBLIOGRAPHY 2019   21
Paired analysis of plasma proteins and coagulant                                                      Update on the use of pathogen-reduced human
          capacity after treatment with three methods of                                                        plasma and platelet concentrates.
          pathogen reduction.

                                                                                                                                                                                                                        MB-Plasma
                                                                                                                                                                                                                        THERAFLEX
                                                                                                                Seltsam A, Müller TH.

          Coene J, Devreese K, Sabot B, Feys HB, Vandekerckhove P, Compernolle V.                               Br J Haematol 2013; 162(4):442-454.

          Transfusion. 2014; 54:1321-1231.

                                                                                                                The use of pathogen reduction technologies (PRTs) for labile blood components is slowly
                                                                                                                but steadily increasing. While pathogen-reduced plasma is already used routinely,
          BACKGROUND:
                                                                                                                efficacy and safety concerns impede the widespread use of pathogen-reduced
          The effect of photochemical pathogen reduction (PR) methods on plasma quality
                                                                                                                platelets. The supportive and often prophylactic nature of blood component therapy in
          has been the subject of several reports but solid comparative data for the different
                                                                                                                a variety of clinical situations complicates the clinical evaluation of these novel blood

                                                                                                                                                                                                                        UV-Platelets
          technologies are lacking.

                                                                                                                                                                                                                        THERAFLEX
                                                                                                                products. However, an increasing body of evidence on the clinical efficacy, safety,
                                                                                                                cost-benefit ratio and development of novel technologies suggests that pathogen
          STUDY DESIGN AND METHODS:
                                                                                                                reduction has entered a stage of maturity that could further increase the safety margin
          Plasma (n = 24) photoinactivated with methylene blue (MB), riboflavin (RF), or amotosalen
                                                                                                                in haemotherapy. This review summarizes the clinical evidence on PRTs for plasma and
          (AS) was compared using a pool-and-split design. Samples were taken before and after
                                                                                                                platelet products that are currently licensed or under development.
          treatment with each method and tested for coagulation factors (fibrinogen, Factor [F] II,
          FV, FVIII, F IX, FXI), natural coagulation inhibitors (Protein C [PC], protein S [PS], antithrombin
          III [AT]), prothrombin time (PT), activated partial thromboplastin time (APTT), and thrombin
          generation (TG). The three methods were mutually compared by repeated-measures
          analysis of variance.

                                                                                                                                                                                                                         SSP+
          RESULTS:
          All three PR methods cause significant reduction (p < 0.01) of activity of the procoagulant
          proteins fibrinogen, FII, FV, FVIII, F IX, and FXI. Coagulation is also affected, with significant
          changes in PT, APTT, and TG. RF treatment causes a significantly higher decrease in
          concentration of coagulation factors, PS, and AT than the other methods (p < 0.01). PT,
          APTT, and TG are also affected most by RF treatment. FII, FVIII, F IX, PC, AT, and PT are
          best preserved with the MB method and FV, FXI, and TG after AS treatment (p < 0.01).
          Coagulation factor loss due to the volume loss during PR treatment is more important for
          MB and AS than for RF.

          CONCLUSION:
          PR treatment of plasma affects coagulation proteins and coagulant capacity. For the
          RF method this effect is most pronounced, although to some extent compensated by a
          smaller volume loss.

22   BLOOD SAFETY BIBLIOGRAPHY 2019                                                                                                                                               BLOOD SAFETY BIBLIOGRAPHY 2019   23
A regional haemovigilance retrospective study of four                                      Two pathogen reduction technologies-methylene blue
          types of therapeutic plasma in a ten-year survey period                                    plus light and shortwave ultraviolet light-effectively
          in France.                                                                                 inactivate hepatitis.

                                                                                                                                                                                                                            MB-Plasma
                                                                                                                                                                                                                            THERAFLEX
          Bost V, Odent-Malaure H, Chavarin P, Benamara H, Fabrigli F & Garraud O.                   Steinmann E, Gravemann U, Friesland M, Doerrbecker J, Müller TH, Pietschmann T, Seltsam A.

          Vox Sang 2013; 104(4):337-341.                                                             Transfusion 2013; 53(5):1010-1018.

          BACKGROUND AND OBJECTIVES:                                                                 BACKGROUND:
          Our objective was to compare the frequency of adverse events (AEs) due to any of           Contamination of blood products with hepatitis C virus (HCV) can cause infections
          the 4 types of fresh-frozen plasma (FFP) prepared and delivered by the French Blood        resulting in acute and chronic liver diseases. Pathogen reduction methods such

                                                                                                                                                                                                                            UV-Platelets
          Establishment (EFS) over a 10-year period. Surveillance of AEs and vigilance was           as photodynamic treatment with methylene blue (MB) plus visible light as well as

                                                                                                                                                                                                                            THERAFLEX
          performed according to a homogeneous policy. The four types of FFP comprised of one        irradiation with shortwave ultraviolet (UVC) light were developed to inactivate viruses
          type (methylene blue [MB) that was stopped since then and of another type [amotosalen      and other pathogens in plasma and platelet concentrates (PCs), respectively. So far,
          (AI)] that was recently introduced, along with two conventional products [quarantine (Q)   their inactivation capacities for HCV have only been tested in inactivation studies using
          and solvent-detergent (SD)].                                                               model viruses for HCV. Recently, a HCV infection system for the propagation of infectious
                                                                                                     HCV in cell culture was developed. Contamination of blood products with hepatitis.
          MATERIALS AND METHODS:
          This is a retrospective study based on the national AE reporting database and on the       STUDY DESIGN AND METHODS:
          regional database system for deliveries. AEs recorded after the delivery of 1 of the       Inactivation studies were performed with cell culture-derived HCV and bovine viral
          4 types of FFP were pairwise compared, with appropriate statistical corrections.           diarrhea virus (BVDV), a model for HCV. Plasma units or PCs were spiked with high titers of
                                                                                                     cell culture-grown viruses. After treatment of the blood units with MB plus light (Theraflex

                                                                                                                                                                                                                             SSP+
          RESULTS:                                                                                   MB-Plasma system, MacoPharma) or UVC (Theraflex UV-Platelets system, MacoPharma),
          105 964 FFP units were delivered (38•4% Q, 17•9% SD, 9•7% MB and 34% AI). Statistical      residual viral infectivity was assessed using sensitive cell culture systems.
          comparisons of AEs identified only a difference in AE rates between quarantine and
          solvent-detergent plasma.                                                                  RESULTS:
                                                                                                     HCV was sensitive to inactivation by both pathogen reduction procedures. HCV in plasma
          CONCLUSIONS:                                                                               was efficiently inactivated by MB plus light below the detection limit already by 1/12 of
          FFP was confirmed to be extremely safe in general, especially if one considers ‘severe’    the full light dose. HCV in PCs was inactivated by UVC irradiation with a reduction factor
          AEs. All types of FFP were associated with extremely low occurrences of AEs. Q, SD, MB     of more than 5 log. BVDV was less sensitive to the two pathogen reduction methods.
          and AI led, respectively, to 7•14, 4•86, 1•05 and 4•16 AEs per 10 000 deliveries.
                                                                                                     CONCLUSIONS:
                                                                                                     Functional assays with human HCV offer an efficient tool to directly assess the inactivation
                                                                                                     capacity of pathogen reduction procedures. Pathogen reduction technologies such as
                                                                                                     MB plus light treatment and UVC irradiation have the potential to significantly reduce
                                                                                                     transfusion-transmitted HCV infections.

24   BLOOD SAFETY BIBLIOGRAPHY 2019                                                                                                                                                   BLOOD SAFETY BIBLIOGRAPHY 2019   25
THERAFLEX UV-Platelets scientific publications

                                                                                                                            Year                                        Authors, title and references

                                                                                                                                   Faddy HM, Fryk JJ, Hall RA, Young PR, Reichenberg S, Tolksdorf F, Sumian C, Gravemann U, Seltsam
          Storage of thawed plasma for a liquid plasma bank:                                                                       A, Marks DC. Inactivation of yellow fever virus in plasma after treatment with methylene blue
                                                                                                                            2019
          impact of temperature and methylene blue pathogen                                                                        and visible light and in platelet concentrates following treatment with ultraviolet C light.
                                                                                                                                   Transfusion 2019; 10.1111/trf.15332.
          inactivation.                                                                                                            Johnson L, Cameron M, Waters L, Padula MP, Marks DC. The impact of refrigerated storage of UVC pathogen
                                                                                                                            2019

                                                                                                                                                                                                                                                           MB-Plasma
                                                                                                                                                                                                                                                           THERAFLEX
                                                                                                                                   inactivated platelet concentrates on in vitro platelet quality parameters. Vox Sang. 2019; 114(1):47-56.

          Thiele T, Kellner S, Hron Gr, Wasner C, Nauck M, Zimmermann K, Wessel A, Warkentin TE, Greinacher A, Selleng K.          Gravemann U, Handke W, Müller TH, Seltsam A. Bacterial inactivation of platelet concentrates with the
                                                                                                                            2019   THERAFLEX UV-Platelets pathogen inactivation system. Transfusion. 2019; 59(4):1324-1332.
          Transfusion 2012; 52(3):529-536.
                                                                                                                                   Gravemann U, Handke W, Lambrecht B, Schmidt JP, Muller TH, Seltsam A. Ultraviolet C light efficiently
                                                                                                                            2018   inactivates nonenveloped hepatitis A virus and feline calicivirus in platelet concentrates. Transfusion. 2018;
                                                                                                                                   58(11):2669-74.
          BACKGROUND:
          Rapid transfusion of fresh-frozen plasma (FFP) is desired for treating coagulopathies, but                               Eickmann M, Gravemann U, Handke W, Tolksdorf F, Reichenberg S, Muller TH, Seltsam A. Inactivation of Ebola
          thawing and issuing of FFP takes more than 40 minutes. Liquid storage of plasma is a                              2018   virus and Middle East respiratory syndrome coronavirus in platelet concentrates and plasma by ultraviolet
                                                                                                                                   C light and methylene blue plus visible light, respectively. Transfusion 2018; 58:2202-7.

                                                                                                                                                                                                                                                           UV-Platelets
          potential solution but uncertainties exist regarding clotting factor stability. We assessed

                                                                                                                                                                                                                                                           THERAFLEX
          different storage conditions of thawed FFP and plasma treated by methylene blue plus                                     Kim S, Handke W, Gravemann U, Döscher A, Brixner V, Müller TH, Seltsam A. Mitochondrial DNA multiplex real-
          light (MB/light) for pathogen inactivation.                                                                       2018   time polymerase chain reaction inhibition assay for quality control of pathogen inactivation by ultraviolet
                                                                                                                                   C light in platelet concentrates. Transfusion 2018; 58(3):758-765.

          STUDY DESIGN AND METHODS:                                                                                                Seltsam A. Pathogen inactivation of Cellular Blood Products—An Additional Safety Layer in Transfusion
                                                                                                                            2017   Medicine. Front Med (Lausanne) 2017; 4:219.
          Fifty thawed apheresis plasma samples (approx. 750 mL) were divided into three subunits
          and either stored for 7 days at 4°C, at room temperature (RT), and at 4°C after MB/                                      Fryk JJ, Marks DC, Hobson-Peters J, Watterson D, Hall RA, Young PR, Reichenberg S, Tolksdorf F, Sumian C,
          light treatment. Clotting factor activities (Factor [F] II, FV, FVII through FXIII, fibrinogen,                          Gravemann U, Seltsam A, Faddy HM. Reduction of Zika virus infectivity in platelet concentrates after
                                                                                                                            2017
          antithrombin, von Willebrand factor antigen, Protein C and S) were assessed after                                        treatment with ultraviolet C light and in plasma after treatment with methylene blue and visible light.
                                                                                                                                   Transfusion 2017; 57(11):2677-2682.
          thawing and on Days 3, 5, and 7. Changes were classified as “minor” (activities within the
          reference range) and “major” (activities outside the reference range).                                                   Johnson L, Hyland R, Tan S, Tolksdorf F, Sumian C, Seltsam A and Marks D. In vitro Quality of Platelets with Low

                                                                                                                                                                                                                                                            SSP+
                                                                                                                            2016   Plasma Carryover Treated with Ultraviolet C Light for Pathogen Inactivation. Transfus Med Hemother 2016;
          RESULTS:                                                                                                                 43(3):190–197.

          FFP storage at 4°C revealed major changes for FVIII (median [range], 56% [33%-114%])                                     Van der Meer PF, Gravemann U, de Korte D, Sumian C, Tolksdorf F, Muller TH and Seltsam A. Effect of
          and Protein S (51% [20%-88%]). Changes were more pronounced when plasma was                                       2016   increased agitation speed on pathogen inactivation efficacy and in vitro quality in UVC-treated platelet
          stored at RT (FVIII, 59% [37%-123%]; FVII, 69% [42%-125%]; Protein S, 20% [10%-35%]).                                    concentrates. Vox Sang 2016; 111(2):127-34.
          MB/light treatment of thawed FFP resulted in minor changes. However, further storage for                                 Johnson L, Hyland RA, Tan S, Tolksdorf F, Sumian C, Seltsam A, Marks DC. In vitro quality of platelets with low
          7 days at 4°C revealed major decreases for FVIII (47% [12%-91%]) and Protein S (49%                               2016   plasma carryover treated with ultraviolet C light for pathogen inactivation. Transfus Med Hemother 2016;
          [18%-95%]) and increases for FVII (150% [48%-285%]) and FX (126% [62%-206%]).                                            43(3):190-197.

                                                                                                                                   Faddy HM, Fryk JJ, Prow NA, Watterson D, Young PR, Hall RA, Tolksdorf F, Sumian C, Gravemann U, Seltsam
          CONCLUSION:                                                                                                       2016   A, Marks DC. Inactivation of dengue, chikungunya, and Ross River viruses in platelet concentrates after
          Storage of liquid plasma at 4°C for 7 days is feasible for FFP as is MB/light treatment of                               treatment with ultraviolet C light. Transfusion 2016; 56(6 Pt 2):1548-55.
          thawed plasma. In contrast, storage of thawed plasma for 7 days at RT or after MB/light
                                                                                                                                   Thiele T, Pohler P, Kohlmann T, Sumnig A, Aurich K, Selleng K, et al. Tolerance of platelet concentrates treated
          treatment at 4°C affects clotting factor stability substantially and is not recommended.                          2015   with UVC-light only for pathogen reduction - a phase I clinical trial. Vox Sang 2015; 109(1):44-51.

                                                                                                                                   Van Aelst B, Devloo R, Vandekerckhove P, Compernolle V, Feys HB. Ultraviolet c light pathogen inactivation
                                                                                                                            2015   treatment of platelet concentrates preserves integrin activation but affects thrombus formation kinetics on
                                                                                                                                   collagen in vitro. Transfusion 2015; 55(10):2404-14.

                                                                                                                                   Pohler P, Müller M, Winkler C, Schaudien D, Sewald K, Müller T H, & Seltsam A. Pathogen reduction by ultraviolet
                                                                                                                            2015   C light effectively inactivates human white blood cells in platelet products. Transfusion 2015; 55(2):337-347.

26   BLOOD SAFETY BIBLIOGRAPHY 2019                                                                                                                                                                               BLOOD SAFETY BIBLIOGRAPHY 2019      27
THERAFLEX UV-Platelets
        Year                                          Authors, title and references                                                         ABSTRACTS SCIENTIFIC PUBLICATIONS
                 Tynngård N, Trinks M, Berlin G. In vitro function of platelets treated with ultraviolet C light for pathogen                          2012-2019
        2015     inactivation: a comparative study with non-irradiated and gamma-irradiated platelets. Transfusion 2015;
                 55(6):1169-77.

                 Prudent, M, D’Alessandro, A, Cazenave, JP, Devine, DV, Gachet, C, Greinacher A, Zolla, L. (2014). Proteome
        2014     changes in platelets after pathogen inactivation--an interlaboratory consensus. Transfus Med Rev 2014;             Inactivation of yellow fever virus in plasma after
                 28(2):72–83.
                                                                                                                                    treatment with methylene blue and visible light and

                                                                                                                                                                                                                                                           MB-Plasma
                                                                                                                                                                                                                                                           THERAFLEX
                 Schlenke P. Pathogen inactivation technologies for cellular blood components: an update. Transfus Med
        2014     Hemother 2014; 41(4):309-25.                                                                                       in platelet concentrates following treatment with
                 Castro E, González LM, Rubio JM, Ramiro R, Gironés N, Montero E. The efficacy of the ultraviolet C pathogen        ultraviolet C light.
        2014     inactivation system in the reduction of Babesia divergens in pooled buffy coat platelets. Transfusion 2014;
                 54(9):2207-2216.
                                                                                                                                    Faddy HM, Fryk JJ, Hall RA, Young PR, Reichenberg S, Tolksdorf F, Sumian C, Gravemann U, Seltsam A, Marks DC.
                 Steinmann E, Gravemann U, Friesland M, Doerrbecker J, Muller TH, Pietschmann T, Seltsam A. Two pathogen
        2013     reduction technologies-methylene blue plus light and shortwave ultraviolet light-effectively inactivate            Transfusion 2019; 10.1111/trf.15332
                 hepatitis C virus in blood products. Transfusion 2013; 53(5):1010–1018.

                                                                                                                                                                                                                                                           UV-Platelets
                                                                                                                                                                                                                                                           THERAFLEX
                 Seltsam A, Müller TH. Update on the use of pathogen-reduced human plasma and platelet concentrates. Br
        2013     J Haematol 2013; 162(4):442-454.
                                                                                                                                    BACKGROUND:
                 Bashir S, Cookson P, Wiltshire M, Hawkins L, Sonoda L, Thomas S, Seltsam A, Tolksdorf F, Williamson LM, Cardigan   Yellow fever virus (YFV) is endemic to tropical and subtropical areas in South America
        2013     R. Pathogen inactivation of platelets using ultraviolet C light: effect on in vitro function and recovery and      and Africa, and is currently a major public health threat in Brazil. Transfusion transmission
                 survival of platelets. Transfusion 2013; 53(5):990–1000.
                                                                                                                                    of the yellow fever vaccine virus has been demonstrated, which is indicative of the
                 Seghatchian J, Tolksdorf F. Characteristics of the THERAFLEX UV-Platelets pathogen inactivation system - An        potential for viral transfusion transmission. An approach to manage the potential YFV
        2012     update. Transfus Apher Sci 2012; 46(2):221-229.                                                                    transfusion transmission risk is the use of pathogen inactivation (PI) technology systems,
                                                                                                                                    such as THERAFLEX MB-Plasma and THERAFLEX UV-Platelets (Macopharma). We aimed
                 Pohler P, Lehmann J, Veneruso V, Tomm J, von BM, Lambrecht B, Kohn B, Weingart C, Muller TH, Seltsam A.
        2012     Evaluation of the tolerability and immunogenicity of ultraviolet C-irradiated autologous platelets in a dog        to investigate the efficacy of these PI technology systems to inactivate YFV in plasma or
                 model. Transfusion 2012; 52(11):2414-2426.                                                                         platelet concentrates (PCs).

                                                                                                                                                                                                                                                            SSP+
                 Muller TH, Montag T, Seltsam AW. Laboratory Evaluation of the Effectiveness of Pathogen Reduction
        2011     Procedures for Bacteria. Transfus Med Hemother 2011; 38(4):242-250.                                                STUDY DESIGN AND METHODS:
                                                                                                                                    YFV spiked plasma units were treated using THERAFLEX MB-Plasma system (visible light
                 Sandgren P, Tolksdorf F, Struff WG, Gulliksson H. In vitro effects on platelets irradiated with short-wave         doses: 20, 40, 60, and 120 [standard] J/cm(2) ) in the presence of methylene blue
        2011     ultraviolet light without any additional photoactive reagent using the THERAFLEX UV-Platelets method. Vox
                                                                                                                                    (approx. 0.8 μmol/L) and spiked PCs were treated using THERAFLEX UV-Platelets system
                 Sang 2011; 101(1):35-43.
                                                                                                                                    (ultraviolet C doses: 0.05, 0.10, 0.15, and 0.20 [standard] J/cm2). Samples were taken
        2011
                 Seltsam A, Muller TH. UVC Irradiation for Pathogen Reduction of Platelet Concentrates and Plasma. Transfus         before the first and after each illumination dose and tested for residual virus using a
                 Med Hemother 2011; 38(1):43-54.
                                                                                                                                    modified plaque assay.
                 Mohr H, Gravemann U, Bayer A, Muller TH. Sterilization of platelet concentrates at production scale by
        2009     irradiation with short-wave ultraviolet light. Transfusion. 2009; 49(9):1956-1963.                                 RESULTS:
                                                                                                                                    YFV infectivity was reduced by an average of 4.77 log or greater in plasma treated with
                 Mohr H, Steil L, Gravemann U, Thiele T, Hammer E, Greinacher A, Muller TH, Volker U. A novel approach
        2009     to pathogen reduction in platelet concentrates using short-wave ultraviolet light. Transfusion. 2009;              the THERAFLEX MB-Plasma system and by 4.8 log or greater in PCs treated with THERAFLEX
                 49(12):2612-2624.                                                                                                  UV-Platelets system.

                                                                                                                                    CONCLUSIONS:
                                                                                                                                    Our study suggests the THERAFLEX MB-Plasma and the THERAFLEX UV-Platelets systems
                                                                                                                                    can efficiently inactivate YFV in plasma or PCs to a similar degree as that for other
                                                                                                                                    arboviruses. Given the reduction levels observed in this study, these PI technology
                                                                                                                                    systems could be an effective option for managing YFV transfusion-transmission risk in
                                                                                                                                    plasma and PCs.

28   BLOOD SAFETY BIBLIOGRAPHY 2019                                                                                                                                                                                  BLOOD SAFETY BIBLIOGRAPHY 2019   29
The impact of refrigerated storage of UVC pathogen                                          Bacterial inactivation of platelet concentrates with the
          inactivated platelet concentrates on in vitro platelet                                      THERAFLEX UV-Platelets pathogen inactivation system.

                                                                                                                                                                                                                 MB-Plasma
                                                                                                                                                                                                                 THERAFLEX
          quality parameters.
                                                                                                      Gravemann U, Handke W, Müller TH, Seltsam A.

          Johnson L, Cameron M, Waters L, Padula MP, Marks DC.                                        Transfusion. 2019; 59(4):1324-1332.

          Vox Sang. 2019; 114(1):47-56.

                                                                                                      BACKGROUND:
                                                                                                      The THERAFLEX UV-Platelets system (Maco Pharma) uses ultraviolet C (UVC) light for
          BACKGROUND AND OBJECTIVES:

                                                                                                                                                                                                                 UV-Platelets
                                                                                                                                                                                                                 THERAFLEX
                                                                                                      pathogen inactivation (PI) of platelet concentrates (PCs) without any additional
          Refrigeration (cold-storage) of pathogen inactivated (PI) platelet components may
                                                                                                      photoactive compound. The aim of the study was to systematically investigate bacterial
          increase the shelf-life and safety profile of platelet components, compared to
                                                                                                      inactivation with this system under conditions of intended use.
          conventional room-temperature (RT) storage. Whilst there is substantial knowledge
          regarding the impact of these individual treatments on platelets, the combined effect
                                                                                                      STUDY DESIGN AND METHODS:
          has not been assessed.
                                                                                                      The robustness of the system was evaluated by assessing its capacity to inactivate high
                                                                                                      concentrations of different bacterial species in accordance with World Health Organization
          MATERIALS AND METHODS:
                                                                                                      guidelines. The optimal use of the PI system was explored in time-to-treatment experiments
          Using a pool-and-split study design, paired buffy-coat derived platelets in 70% platelet
                                                                                                      by testing its ability to sterilize PCs contaminated with low levels of bacteria on the day of
          additive solution (SSP+; MacoPharma) were left untreated or PI-treated using the
                                                                                                      manufacture (target concentration, 100 colony-forming units/unit). The bacteria panel used
          THERAFLEX UV-Platelets System (UVC; MacoPharma). Units from each pair were split and
                                                                                                      for spiking experiments in this study included the World Health Organization International

                                                                                                                                                                                                                  SSP+
          stored at room temperature (20-24°C) or cold-stored (2-6°C) to yield RT, cold, RT-UVC
                                                                                                      Repository Platelet Transfusion Relevant Reference Strains (n = 14), commercially available
          and cold-UVC study groups (n = 8 in each group). In vitro quality and function was tested
                                                                                                      strains (n = 13), and in-house clinical isolates (n = 2).
          over 9 days.
                                                                                                      RESULTS:
          RESULTS:
                                                                                                      Mean log reduction factors after UVC treatment ranged from 3.1 to 7.5 and varied
          Cold-storage of UVC-treated platelets reduced glycolytic metabolism (glucose
                                                                                                      between different strains of the same species. All PCs (n = 12/species) spiked with up to
          consumption and lactate production) compared to RT-UVC units. Cold-UVC platelets
                                                                                                      200 colony-forming units/bag remained sterile until the end of storage when UVC treated
          demonstrated complete abrogation of HSR by day 5, increased externalisation of
                                                                                                      6 hours after spiking. UVC treatment 8 hours after spiking resulted in single breakthrough
          phosphatidylserine (annexin-V binding) and activation of the GPIIb/IIIa receptor (PAC-
                                                                                                      contaminations with the fast-growing species Escherichia coli and Streptococcus
          1 binding) above the levels observed with the individual treatments. Aggregation
                                                                                                      pyogenes.
          responses (ADP and collagen) were enhanced in the cold-UVC platelets compared to
          both RT groups, but this was primarily mediated by cold-storage. Haemostatic function,
                                                                                                      CONCLUSION:
          as measured using TEG, was similar between the groups.
                                                                                                      The UVC-based THERAFLEX UV-Platelets system efficiently inactivates transfusion-relevant
                                                                                                      bacterial species in PCs. The comprehensive data from this study may provide a
          CONCLUSIONS:
                                                                                                      valuable basis for the optimal use of this UVC-based PI system.
          Cold-storage of UVC-treated platelets reduced PI-induced acceleration of glycolytic
          metabolism. However, combining cold-storage and UVC-treatment resulted in additional
          phenotypic changes compared to each treatment individually. Further work is required
          to understand the impact of these changes in clinical efficacy.

30   BLOOD SAFETY BIBLIOGRAPHY 2019                                                                                                                                        BLOOD SAFETY BIBLIOGRAPHY 2019   31
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