Adverse Reactions Associated with Methylene Blue Inactivated Fresh Frozen Plasma (MB FFP)

Transcription

1 Adverse Reactions Associated with Methylene Blue Inactivated Fresh Frozen Plasma (MB FFP) Constantina Politis Hellenic Coordinating Haemovigilance Centre (SKAE)

2 Background Pathogen inactivation is expected to reduce the risk of transfusion associated infections and immunomodulation disturbances Pathogen reduction technologies applied for the safety of therapeutic FFP S/D procedure used in plasma pools Methylene Blue and light used in single FFP units Intercept Blood System used in single FFP units Mirasol PRT System used in single FFP units Octaplas/ OctaplasLG

3 Background Directive 2002/98/EC instructs EU Member States to make use of scientific progress in the Detection Inactivation Elimination of transfusion transmissible pathogenic agents The Council of Europe recommends active haemovigilance and post marketing assessment of pathogen reduced products

4 Aim of the study The safety and quality of MB FFP for transfusion of patients with coagulopathy with or without bleeding and other clinical indications for plasma transfusion, over a period of 10 years in comparison with the use of quarantine FFP Disease categories TTP 3 rd degree burns, wounds trauma Massive transfusion Septicaemia Cardiovascular disorders Other

5 Methods Use of the Theraflex MB Plasma system including the Plasmaflex for leucodepletion and Blueflex for MB and photoproduct removal Use of Quarantine FFP (40% leucoreduced prior to storage) Data from 8 Blood Establishments supplying FFP to 13 large hospitals including 4 university clinics Type of FFP Units Patients Theraflex MB FFP 132,325 26,320 Quarantine FFP 314,895 57,718 Total FFP 447,220 84,038

6 Quality Coagulation changes Fibrinogen and Factors V and VIII Stago Diagnostica assays Cytokine concentration IL 6, IL 8 MCSF free and total Biosource and Diacel Elisa testing Examined in 0.5% of MB FFP units in the initial years of the study (C.Politis et al, Vox Sang. 2007;92) Parameters examined Safety Seroconversion In patients negative for HIV, HCV, HBV 6 months after transfusion with MB FFP (period before NAT) Adverse reactions Non infectious Infectious Allergic NHFTR TRALI TAD Other Viral, bacterial, other

7 Results

8 Coagulation Factor Activity and Cytokines Concentrations in FFP following MB inactivation (n=88 units) Parameter Before MB mean (SD) After MB mean (SD) Loss (%) Fibrinogen (mg/dl) (47.5) (37.4) 18 Factor VII (%) 81.9 (17.1) 63.1 (13.3) 18 Factor V (%) (18.3) 95.5 (19.1) 22 IL 6 (pg/ml) 2.18 (1.93) 0.73 (0.91) 63.1 IL 8 (pg/ml) 6.77 (3.87) 4.34 (2.72) 68.5 GMCSF free (pg/ml) 2.14 (1.46) 1.42 (1.11) 65.3 GMCSF total (pg/ml) 0.73 (0.78) 0.4 (0.63) 58.3 C.Politis et al, Vox Sang. (2007);92;

9 Coagulation Factor Losses Cytokine Concentrations 30% 58% - 68% Within internationally accepted range

10 Clinical use of FFP MB FFP Quarantine FFP 5.0 units / patient 5.5 units / patient Use of both types of FFP varies considerably among the 13 hospitals reporting to the 8 blood establishments of the study

11 Greece Total Adverse Reactions, Adverse Reaction MB FFP Quarantine FFP n Incidence n Incidence Allergic/Anaphylactic 3* 1:44, :10,858 NHFTR 0 0:132, :17,494 TRALI 0 0:132, :104,695 TACO 0 0:132, :314,895 TAD 0 0:132, :157,447 Bacterial 0 0:132, :52,482 Other 0 0:132, :314,895 Total 3 1:44, :5,248 *Mild allergic reactions in three patients with TTP, trauma and septicaemia respectively Difference between MB FFP and quarantine FFP p<0.0001

12 Greece Total Adverse Reactions by severity, Adverse Reaction MB FFP Quarantine FFP (132,325 units) (314,895 units) Grade 1 Grades 2 3 Grade 1 Grades 2 3 Allergic/Anaphylactic 3* NHFTR TRALI TACO TAD Bacterial Other Total Incidence 1:44,108 0:132,325 1:7,157 1:19,681 *all mild (grade 1)

13 Distribution of Adverse Reactions by Severity n=44 (1:7,157) Q FFP n=16 (1:19,681) MB FFP n=0 Grade 1 Grade 2-3

14 Greece Allergic adverse reactions (AARs), Type of FFP AARs Severity grades Imputability levels n Incidence MB FFP 3* 1:44, Quarantine FFP 29 1:10, Total 32 1:13, Difference p< *1 in 2005 and 2 in 2009

15 Safety Parameters No seroconversion or viral ARs associated with either type of FFP arose within this study Report of HIV transmission A hospital, not using MB FFP and NAT for blood screening for HIV/HCV/HBV, reported to SKAE the transmission of HIV with the transfusion of one unit of whole blood derived quarantine FFP in 2005 Investigation of the implicated donor showed that donation took place during the serological window period

16 Conclusions The incidence of ARs is statistically significantly higher in quarantine FFP than in MB FFP Only three mild allergic ARs associated with transfusion of MB FFP (imputability level 2 3) were observed High frequencies of allergic and anaphylactic as well as NHFTR and bacterial ARs were observed in association with quarantine FFP. TRALI (3 cases), TACO (1 case) and TAD (1 case) associated with quarantine FFP were also reported This study demonstrates the safety and quality of MB FFP

17 Next steps Future work focusing on clinical endpoints and cost effectiveness modeling of risk assessment for emerging infections should be done in compliance with the recommendations of the Council of Europe

18 Sources of European haemovigilance data Greece France, the Agence Française de Sécurité Sanitaire des Produits de Santé (Afssaps) Austria, the Central Institute for Blood Transfusion, University Clinic Innsbruck United Kingdom, (SHOT) Annual Reports Spain, the Centro de Transfusión de Galicia (CTG) and the Centro de Transfusión de la Comunidad Valenciana Belgium, the Agence Fédérale des Médicaments et des Produits de Santé (AFMPS)

19 European haemovigilance data Country Number of units YEAR transfused TOTAL Greece n 12,616 33,522 33,610 29, ,161 % of total 1.1% 2.8% 2.8% 2.5% 9.75% France n 0 58, , , ,989 % of total 0.0% 4.9% 17.2% 20.7% 45.58% Austria n 0 0 2,962 4,592 7,554 % of total 0.0% 0.0% 0.2% 0.4% 0.67% UK n 9,228 19,860 18,408 14,268 61,764 % of total 0.8% 1.7% 1.5% 1.2% 5.52% Spain n 37,500 39,062 41,075 36, ,358 % of total 3.2% 3.3% 3.5% 3.1% 13.8% Belgium n 83,419 88,953 84,625 90, ,096 % of total % TOTAL n 142, , , ,545 1,189,922 % of total

20 Global distribution of Severity Grade 2 4 AARs by country Greece France Austria UK Spain Belgium AARs /10,000 by country No AARs 109, ,925 7,554 61, , ,086 Total 109, ,989 7,554 61, , ,096 Comparing the rates in the different countries (association Fisher s exact test with the Bonferroni s correction of the α error, the comparisons are considered significant at the limit of 0.003), the rate of AAR is significantly higher in France than in Greece, Spain and Belgium (p < 0.05). No other differences between countries were found.

21 Global distribution of Grade 2 AAR by country Greece France Austria UK Spain Belgium AAR /10,000 by country No Grade 2 AAR 96, ,974 7,554 52, , ,677 Total 96, ,989 7,554 52, , ,677 Comparing the rates in the different countries (association Fisher s exact test), the rates of Grade 2 AAR were not significantly different between countries.

22 Comparing the Grade 3 4 AAR rates in the different countries (association Fisher s exact test with the Bonferroni s correction of the α error, the comparisons are considered significant at the limit of 0.003), the rate of Grade 3 4 AAR is significantly lower in Greece, Spain and Belgium compared to France (p < 0.05). No other differences between countries were found. Global distribution of Grade 3 to 4 AAR by country Greece France Austria UK Spain Belgium AAR /10,000 by country No Grade 3 4 AAR 96, ,940 7,554 52, , ,671 Total 96, ,989 7,554 52, , ,677

23 Overall conclusion The incidence of AARs is significantly higher with Quarantine plasma compared to MB FFP in Greece In contrast to France based on their respective haemovigilance data in Belgium, Greece, UK, Spain and Austria no unusual allergic event rates have been observed leading to continuous usage of MB plasma

24 Thank you Nikos Beloyiannis - Idealist Greek partisan, victim of the civil war Hungarian Village named after The man with the red carnation