*Marcus Picard-Maureau, Marek Z. Paśka
Platelet transfusion associated risks and improvement of platelet transfusion safety with Amotosalen/UVA pathogen inactivation technology
Ryzyka związane z transfuzją płytek krwi i sposoby podniesienia bezpieczeństwa przy użyciu technologii inaktywacji patogenów z wykorzystaniem Amotosalenu i światła UVA
Despite multiple improvements in the last decades like enhanced disinfection of the donor’s venipuncture site, leukoreduction, and the introduction of new donor screening tests there is a residual risk of pathogen transmission by transfusion of platelets. There are 77 transfusion-transmissible infectious pathogens currently known, and the number is growing constantly (1). The highest platelet transfusion-associated risk is still the bacterial contamination, with an average rate of 1:1000-1:2000 platelet concentrates being contaminated as shown by bacterial culture testing with no significant difference between apheresis and whole-blood-derived platelet units (2-4). The source of platelet contamination is in the majority of cases trace amounts of bacteria from the donors’ skin, but cases of contamination from transient donor bacteremia due to translocation from gut, small wounds or other sources cannot be excluded. In platelet units, many bacteria species find ideal growth conditions during storage which is performed at room temperature. Bacterial culture screening post production fails to detect large numbers of bacterially infected units and does not provide protection against septic transfusion reactions (STR) (5, 6). A recent active surveillance study from an American tertiary care academic hospital showed an average rate of transfused contaminated platelet concentrates of 1:2572 (20 of 51.440) despite negative initial bacterial culture testing post production (6). In multiple cases the patients showed signs of STR (retrospective analysis of patient charts), which were not recognized/reported by the treating physicians. There is evidence pointing towards a significant underreporting of STR (6, 7). Hemovigilance data from France, Belgium and Switzerland for the years 2005-2016 showed that the rate of septic transfusion reactions may be completely abolished by the implementation of pathogen inactivation (Amotosalen/UVA) (7). This approach holds more promise than the continuous implementation of new tests for newly emerging pathogens or the attempts to improve for example the performance of the existing tests for bacteria.
Interestingly, new Human-Immunodeficiency-Virus (HIV) and Hepatitis-B-Virus (HBV) variants have been ranked as high perceived risk for blood safety (position 2 and 10 of 77 respectively) during an international panel of experts rating (8). Indeed there are multiple cases of HIV and HBV transmission by blood transfusion described, which occurred despite serological and nucleic acid testing (NAT), likely because of viral variants and/or low viral loads below the limit of detection (9-11). A Polish study questions the effectiveness of the current donor deferral policy to reduce the risk of blood donations from donors carrying viruses in the early phase of infection (window period) when viral detection by standard blood screening measures often fails (12). The authors revealed that donor questionnaires about their risk behavior prior to donation were often not answered correctly. Besides these “classical” threats to transfusion, Hepatitis E is now one of the pathogens in the focus of the discussions. The seroprevalence for Hepatitis-E-Virus (HEV) is relatively high in Poland, and a recent study identified one of 2109 donors as HEV-positive by NAT, extrapolating 267 potential cases of transfusion-transmitted HEV annually (13). However, the clinical significance of such transmissions is questionable. A British study showed that only one of 43 patients which were infected by HEV during transfusion developed mild symptoms of hepatitis (14), and a German study showed that 6 patients which were infected by HEV during transfusion did not develop any symptoms (15). HEV is usually transmitted fecal-orally; the virus in blood is morphologically different from the virus found in feces and less infectious (16). HEV transmission by blood donation may still be a risk for immunosuppressed patients requiring multiple transfusions, which could potentially develop chronic infection (17). Outbreaks and spread of emerging arboviruses like Dengue Virus (DENV), Chikungunya Virus (CHIKV), West Nile Virus (WNV), Zika Virus (ZIKV) or Yellow Fever Virus (YFV) are an increasing threat for blood safety. The vector mosquitos capable of transmitting such pathogens are spreading through Europe from south to North, already endemic at the Mediterranean coast (Spain, France, Italy, Croatia, Greece) and south-east Europe (Bulgaria, West-Turkey) and introduced in Austria, Germany and even the Netherlands (18). WNV is currently endemic (2017 season) in Austria, Turkey, Northern Italy, Hungary, Croatia, Bulgaria, Greece and Spain (18). Since approx. 80% of virus-carriers are asymptomatic and may donate blood (19), there is a high risk for blood safety. Chikungunya outbreaks have been reported in France and Italy; recently an outbreak in the Lazio region (Rome) was confirmed in September 2017 (18) and led to a halt in platelet production for many blood banks. In the years 2010-2014, 1510 confirmed DENV infection cases have been reported in the European Union (18). Since this infection proceeds asymptomatic in approx. 80% of carriers (20), they represent a high potential risk as donors, and also a significant underreporting in the recipients is expected.
Especially in the field of hemato-oncology, recipients of blood transfusions have an impaired health, and are often immunocompromised. Pathogens which would lead to no or mild symptoms in healthy individuals may impact that patient group severely. Taking a significant underreporting of such infections due to non-detection and non-recognition into account (6, 7), additional layers of safety would be beneficial. Pathogen inactivation technology is a proactive approach to inactivate bacteria, viruses and parasites in blood components, further reducing the risk of STR.
1. Stramer S: The potential threat to blood transfusion safety of emerging infectious disease agents. Clin Advances Hematol Oncol 2015; 13: 1-3.
2. Schrezenmaier H, Walter-Wenke G, Müller TH et al.: Bacterial contamination of platelet concentrates: results of a prospective multicenter study comparing pooled whole-blood derived platelets and apheresis platelets. Transfusion 2007; 47: 644-652.
3. Jacobs MR, Smith D, Heaton WA et al.: Detection of bacterial contamination in prestorage culture-negative apheresis platelets on day of issue with the Pan Genera Detection test. Transfusion 2011; 51: 2573-2582.
4. Walter-Wenke G, Wirsing von König CH, Däubener W et al.: Monitoring bacterial contamination of blood components in Germany: effect of contamination reduction measures. Vox Sang 2011; 100: 359-366.
5. Dumont LJ, Kleinman S, Murphy JR et al.: Screening of single-donor apheresis platelets for bacterial contamination: the PASSPORT study results. Transfusion 2010; 50: 589-599.
6. Hong H, Xiao W, Lazarus HM et al.: Detection of septic transfusion reactions to platelet transfusions by active and passive surveillance. Blood 2016; 127: 496-502.
7. Benjamin RJ, Braschler T, Weingand T, Corash LM: Hemovigilance monitoring of platelet septic reactions with effective bacterial protection systems. Transfusion 2017; 57: 2946-2957.
8. Oei W, Neslo R, Janssen MP: A consensus-based tool for ranking the risk of blood-transmissible infections. Transfusion 2016; 56: 2108-2114.
9. Dwyre, DM, Fernando LP, Holland PV: Hepatitis B, hepatitis C and HIV transfusion-transmitted infections in the 21st century. Vox Sang 2011; 100: 92-98.
10. Chudy M, Weber-Schehl M, Pichl L et al.: Blood screening nucleic acid amplification tests for human immunodeficiency virus type 1 may require two different amplification targets. Transfusion 2012; 52: 431-439.
11. O’Flaherty N, Ushiro-Lumb I, Pomeroy L et al.: Transfusion-transmitted hepatitis B virus (HBV) infection from an individual-donation nucleic acid (ID-NAT) non-reactive donor. Vox Sang 2018; 113: 300-303.
12. Czerwinski M, Grabarczyk P, Stepien M et al.: What weighs more – low compliance with self-deferral or minor medical procedures? Explaining the high rate of hepatitis C virus window-period donations in Poland. Transfusion 2017; 57: 1998-2006.
13. Grabarczyk P, Sulkowska E, Gdowska J et al.: Molecular and serological infection marker screening in blood donors indicates high endemicity of hepatitis E virus in Poland. Transfusion 2018; 58: 1245-1253.
14. Hewitt EP, Ijaz S, Brailsford SR et al.: Hepatitis E virus in blood components: a prevalence and transmission study in southeast England. Lancet 2014; 384: 1766-1773.
15. Dreier J, Knabbe C, Vollmer T: Transfusion-transmitted Hepatitis E: NAT screening of blood donations and infectious dose. Front Med 2018. DOI: 10.3389/ fmed.2018.00005 (e-journal).
16. Yin X, Li X, Feng, Z: Role of envelopment in the HEV lifecycle. Viruses 2016. DOI: 10.3390/v8080229 (e-journal).
17. Tedder RS, Ijaz S, Kitchen A et al.: Hepatitis E risks: pig or blood-that is the question. Transfusion 2017; 57: 267-272.
18. European Centre for Disease Prevention and Control (ECDC): https://ecdc.europa.eu/en/home.
19. Pisani G, Cristiano K, Pupella S, Liumbruno GM: West Nile Virus in Europe and safety of blood transfusion. Transfus Med Hemother 2016; 43: 158-167.
20. Musso D, Richard V, Broult J, Cao-Lormeau VM: Inactivation of Dengue Virus in plasma with amotosalen and ultraviolet A illumination. Transfusion 2014; 54: 2924-2930.
21. Irsch J, Lin L: Pathogen inactivation of platelet and plasma blood components for transfusion using the INTERCEPT Blood System. Transfus Med Hemother 2011; 38: 19-31.
22. Wollowitz S: Fundamentals of the psoralen-based Helinx technology for inactivation of infectious pathogens and leukocytes in platelets and plasma. Semin Hematol 2001; 38 (suppl. 11): 4-11.
23. Prowse C: Component pathogen inactivation: a critical review. Vox Sang 2013; 104: 183-189.
24. Feys HB, Van Aelst B, Devreese K et al.: Oxygen removal during pathogen inactivation with riboflavin and UV light preserves protein function in plasma for transfusion. Vox Sang 2014; 106: 307-315.
25. Ciaravino V: Preclinical safety of a nucleic acid-targeted Helinx compound: a clinical perspective. Sem Hematol 2001; 38 (suppl. 11): 12-19.
26. Tice RR, Gatehouse D, Kirkland D, Speit G: The pathogen reduction of platelets with S-59 HCl (Amotosalen) plus ultraviolet A light: genotoxicity profile and hazard assessment. Mut Res 2007; 630: 50-68.
27. Ciaravino V, Hannover J, Lin L et al.: Assessment of safety in neonates for transfusion of platelets and plasma prepared with amotosalen photochemical pathogen inactivation treatment by a 1-month intravenous toxicity study in neonatal rats. Transfusion 2009; 49: 985-994.
28. Knutson F, Osselaer J, Pierelli L et al.: A prospective, active haemovigilance study with combined cohort analysis of 19175 transfusions of platelet components prepared with Amotosalen-UVA photochemical treatment. Vox Sang 2015; 109: 343-352.
29. Kwon SY, Kim IS, Bae JE et al.: Pathogen inactivation efficacy of Mirasol PRT System and INTERCEPT Blood System for non-leucoreduced platelet-rich-plasma-derived platelets suspended in plasma. Vox Sang 2014; 107: 254-260.
30. Kleinman S: Pathogen inactivation: emerging indications. Curr Opin Hematol 2015; 22: 547-553.
31. Schlenke P: Pathogen inactivation technologies for cellular blood components: an update. Transfus Med Hemother 2014; 41: 309-325.
32. Santa Maria F, Laughhunn A, Lanteri MC et al.: Inactivation of Zika virus in platelet components using amotosalen and ultraviolet A illumination. Transfusion 2017; 57: 2016-2025.
33. Laughhunn A, Santa Maria F, Girard Y et al.: Robust inactivation of the yellow fever virus 17D strain can be achieved using Amotosalen and UVA light for pathogen reduction treatment (PRT) of platelet components. Transfusion 2017; 57 (suppl. 3): 201A.
34. Castro G, Merkel PA, Giclas HE et al.: Amotosalen/UVA treatment inactivates T cells more effectively than the recommended gamma dose for prevention of transfusion-associated graft-versus-host disease. Transfusion 2018. DOI: 10.1111/ trf.14589 [Epub ahead of print].
35. Cid J: Prevention of transfusion-associated graft-versus-host disease with pathogen-reduced platelets with amotosalen and ultraviolet A light. A review. Vox Sang 2017; 112: 607-613.
36. McCullough J, Vesole DH, Benjamin RJ et al.: Therapeutic efficacy and safety of platelets treated with a photochemical process for pathogen inactivation: the SPRINT trial. Blood 2004; 104: 1534-1541.
37. Garban F, Guyard A, Labussiere H et al.: Comparison of the hemostatic efficacy of pathogen-reduced platelets in patients with thrombocytopenia and malignant hematologic diseases: a randomized clinical trial. JAMA Oncol 2018; 4: 468-475.
38. Cazenave JP, Isola H, Waller C et al.: Use of additive solutions and pathogen inactivation treatment of platelet components in a regional blood center: impact on patient outcomes and component utilization during a 3-year-period. Transfusion 2011; 51: 622-629.
39. Jutzi M, Manosouri Teleghani B, Rueesch M et al.: Nationwide implementation of pathogen inactivation for all platelet concentrates in Switzerland. Transfus Med Hemother 2018. DOI: 10.1159/000489900 [Epub ahead of print].
40. Amato M, Schennach H, Astl M et al.: Impact of platelet pathogen inactivation on blood component utilization and patient safety in a large Austrian regional medical centre. Vox Sang 2017; 112: 47-55.
41. Nussbaumer W, Amato M, Schennach H et al.: Patient outcomes and amotosalen/UVA platelet utiliziation in massively transfused patients. Vox Sang 2017; 112: 249-256.
42. Osselaer JC, Messe N, Hervig T et al.: A prospective observational cohort safety study of 5106 platelet transfusions with components prepared with photochemical pathogen inactivation treatment. Transfusion 2008; 48: 1061-1071.
43. Osselaer JC, Cazenave JP, Lambermont M et al.: An active haemovigilance programme characterizing the safety profile of 7437 platelet transfusions prepared with amotosalen photochemical treatment. Vox Sang 2008; 94: 315-323.
44. Van Haute L, Benoit, Y, Bordon V et al.: Therapeutic efficacy and safety of transfusion of pathogen-inactivated platelets to pediatric patients. Vox Sang 2006; 91 (suppl. 3): 177.
45. Schwarz F, Gross J, Gortner L et al.: Transfusion of pediatric patient with pathogen-inactivated platelet concentrates. Transfus Med Hemother 2015; 41 (suppl. 1): 10.
46. Rasongles P, Angelini-Tibert MF, Simon P et al.: Transfusion of platelet components prepared with photochemical pathogen inactivation treatment during a Chikungunya virus epidemic in Ile de La Rèunion. Transfusion 2009; 49: 1083-1091.
47. Lozano L, Knutson F, Tardivel R et al.: A multi-centre study of therapeutic efficacy and safety of platelet components treated with amotosalen and ultraviolet A pathogen inactivation stored for 6 or 7 d prior to transfusion. Br J Haematol 2011; 153: 353-401.