BLOOD SAFETY BIBLIOGRAPHY - THERAFLEX MB-Plasma THERAFLEX UV-Platelets SSP+ - Lead the way in blood safety - Macopharma
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Lead the way in blood safety BLOOD SAFETY BIBLIOGRAPHY •THERAFLEX MB-Plasma •THERAFLEX UV-Platelets •SSP+
BLOOD SAFETY
BIBLIOGRAPHY
2019THERAFLEX 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 5Year 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 7THERAFLEX 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 9Plasma 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 11Cost-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 13ZIKV 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 15Dengue 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 17Quantitative 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 19Haemovigilance 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 21Paired 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 23A 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 25THERAFLEX 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 27THERAFLEX 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 29The 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 31You can also read
