Platelet Transfusion State of the art and future developments

Transcription

1 Platelet Transfusion State of the art and future developments Rachel PETERMANN M.D. Msc Platelet Immunology Department National Institute of Blood Transfusion, Paris Brazilian Congress Hematology, Hemotherapy and Cell Therapy - HEMO 2016, Florianopolis, November

2 Disclosures of: R. PETERMANN Employment Research support Scientific advisory board Consultancy Speakers bureau Major stockholder Patents Honoraria Travel support Other No conflict of interest to disclose No conflict of interest to disclose No conflict of interest to disclose No conflict of interest to disclose No conflict of interest to disclose No conflict of interest to disclose No conflict of interest to disclose No conflict of interest to disclose No conflict of interest to disclose No conflict of interest to disclose Brazilian Congress Hematology, Hemotherapy and Cell Therapy - HEMO 2016, Florianopolis, November

3 PLAN 1. General introduction on platelets 2. The platelet components transfusion: in practice 3. The platelet components transfusion: state of the art and current questions 4. Conclusion: forecast and proposals Brazilian Congress Hematology, Hemotherapy and Cell Therapy - HEMO 2016, Florianopolis, November

4 GENERAL INTRODUCTION ON PLATELETS Brazilian Congress Hematology, Hemotherapy and Cell Therapy - HEMO 2016, Florianopolis, November

5 Platelets are aimed at ensuring primary hemostasis by interacting with injured endothelia Physiology: routine «maintenance» Shear pressure Pathology Minor lesions to breaches and leaks Central and peripheral thrombocytopenia Thrombopathies Brazilian Congress Hematology, Hemotherapy and Cell Therapy - HEMO 2016, Florianopolis, November

6 Platelet are sensors of abnormalities Within the vascular arborescence => hemostasis At vascularized sites: skin, mucosae => danger sensing, innate immunity Brazilian Congress Hematology, Hemotherapy and Cell Therapy - HEMO 2016, Florianopolis, November

7 New Fundamentals in Hemostasis Henri H. Versteeg, Johan W. M. Heemskerk, Marcel Levi, Pieter H. Reitsma Physiological Reviews Published 1 January 2013 Vol. 93no. 1, DOI: /physrev Brazilian Congress Hematology, Hemotherapy and Cell Therapy - HEMO 2016, Florianopolis, November

8 THE PLATELET COMPONENTS TRANSFUSION: IN PRACTICE Brazilian Congress Hematology, Hemotherapy and Cell Therapy - HEMO 2016, Florianopolis, November

9 Platelet components There are 3 ways to separate platelets from blood 1. Soft centrifugation => Platelet Rich Plasma 2. Extraction from whole blood => Buffy-Coat 3. Differential elutriation by apheresis (different types of automats) => apheresis concentrate The latter two are the commonest NB : whole blood transfusion brings platelets too Brazilian Congress Hematology, Hemotherapy and Cell Therapy - HEMO 2016, Florianopolis, November

10 Various types of platelet transfusions Donation Whole Blood Apheresis PRP Buffy Coatderived (Whole Blood) Apheresis Brazilian Congress Hematology, Hemotherapy and Cell Therapy - HEMO 2016, Florianopolis, November

11 Platelet concentrates(pcs) Single Donor Apheresis-PC Pools of Whole Blood Buffy coats derived (3-8 or more; in general 4-6, ~5) Presentation Commonly : platelet rich suspension, maintained for 1-5 d at 22±2 C under soft rotation or gentle rocking Come Concentration in either varies 100% Rare refrigerated units (minimum: plasma (4±2 C) Varies suspension 2.5x or for in a Rare frozen (cryopreserved) pool ~66% and units: according Platelet 2x10HPA 11 Additive for to a HLA SDAtyped; or private Ags Solution country PC) (PAS) plus regulations ~33% plasma Brazilian Congress Hematology, Hemotherapy and Cell Therapy - HEMO 2016, Florianopolis, November

12 Characteristics in France/Europe Whole Blood, unit Min volume : 80 to 100 ml Min platelet concentration : ph at delivery time, corrected at 22 C : 6.4 Pool : same but 2.5x10 11 for a pool of 5 SDA unit Max volume : 600 ml Min platelet concentration : 2x10 11 ph at delivery time, corrected at 22 C : 6.4 All : 10 6 residual leukocytes Min of residual red blood cells Brazilian Congress Hematology, Hemotherapy and Cell Therapy - HEMO 2016, Florianopolis, November

13 PCs in France and in Europe In France About 55% Whole Blood Buffy Coat platelet pools of 5, processed automatically (TACSI TM from TerumoBCT); no more with Orbisac TM (TerumoBCT) And about 45% SDA-PCs, PAS; 3 types of cell separators About 11% PCs have undergone PRT (Intercept TM, Cerus) None bacteriologically tested so far (will change soon; however, no need if PRT) Strict male only policy No routine HLA, HPA match 80% ABO matched (10% cell mismatch; 10% plasma mismatch) In preference, RH:1 match for females under the age of 50 and all recipients in repeated transfusion programs Irradiation upon request (~10%); no need if PRT 99,99% kept 1-5 days at 22 C (0.01% from frozen inventory) In Europe : varies from near 100% SDA to less than 10% (HLA/HPA typed); PRT implementation varies also from 0% to 100% Brazilian Congress Hematology, Hemotherapy and Cell Therapy - HEMO 2016, Florianopolis, November

14 Platelet Components issued in France (2015) ANSM, Hemovigilance Report 2015 (published in 2016) Pools processed from 5 Buffy-Coats (TACSI TM) and PAS; 56% BC; no more than 2 F donors in 5 buffy-coats Brazilian Congress Hematology, Hemotherapy and Cell Therapy - HEMO 2016, Florianopolis, November

15 The surveillance process in France Quality control in process No bacterial detection Traceability near 99.96% Mandatory hemovigilance : every single event deleterious or not must be declared by law (non optional) Case review by ANSM for bacterial contamination, protozoa contamination, TRALI etc Brazilian Congress Hematology, Hemotherapy and Cell Therapy - HEMO 2016, Florianopolis, November

16 Widely acknowledged measures that strengthen patients safety and comfort while transfused with PCs Donor selection (infectious risk) Blood testing Skin disinfection, hygiene Derivation of the 35 first ml of drawn blood Post donation information and donor sensitization Male policy only : Single Donor Apheresis Donations (100%); limitation of max 2 female whole blood buffy coats in pools; females are tested for anti-hla Ab titers Wide use of PAS ± Bacterial detection ± Pathogen Reduction Technology implementation Brazilian Congress Hematology, Hemotherapy and Cell Therapy - HEMO 2016, Florianopolis, November

17 No longer discussed: leukoreduction Reduces the residual virus carriage Accidental : HIV, Hepatitis viruses etc. Possibly common depending on the epidemiology: HTLV, CMV, EBV Eradicates the Graft versus Host disease Decreases significantly the inflammatory adverse events and the allo-immunisation to HLA class I and also class II antigens But also to HPA and possibly to red cells because of the reduction of Ag presenting cells of which B lymphocytes For several of these reasons, decrease the risk of TRALI The benefits of Transfusion Related Immuno Modulation or TRIM is not considered sufficient to warrant the benefit of leukocytes Brazilian Congress Hematology, Hemotherapy and Cell Therapy - HEMO 2016, Florianopolis, November

18 Novel or prospective measures Age of blood (3 days) Biological Response Modifiers (BRMs) removal by filtration on column absorption Others? In the pipeline: In vitro platelet production Brazilian Congress Hematology, Hemotherapy and Cell Therapy - HEMO 2016, Florianopolis, November

19 Incidence of Adverse Events in France, 2015 Platelets Concentrates Allergy: 106.7/ FNHTR: 32.7/ Immunologic incompatibility: 40.8/ Inefficacy: 8.2/ Grade 1-3 Accountability 2-3 Brazilian Congress Hematology, Hemotherapy and Cell Therapy - HEMO 2016, Florianopolis, November

20 The number of BCs delivered to patients tends to stabilise overtime in France, But the number of AEs decrease, despite sustained or increased Hemovigilance PAS This is particularly true for PCs : Start using Platelet Additive Solutions Brazilian Congress Hematology, Hemotherapy and Cell Therapy - HEMO 2016, Florianopolis, November

21 PLATELET TRANSFUSION : CURRENT DEBATES Brazilian Congress Hematology, Hemotherapy and Cell Therapy - HEMO 2016, Florianopolis, November

22 1. OLD DEBATES This is principally related to respective values of SDA-PCs versus Whole Blood derived Pooled platelet components (WBP-PCs) Clinical efficacy (hemostasis) same Infectious risks Viral : theoretically ~5 time less in SDA-PCs but the paucity of events make them equal Bacterial : According to the French surveillance system, a slightly more frequent events with WBP-PCs but more deaths with SDA-PCS considered equal Immunological hazards No specific study apart from a limited French one, 2007 equal BUT : WBP-BCs are superior to treat transfusion refractory patients with allo-abs Inflammatory hazards equal, or possible superiority for Whole Blood Derived pools Brazilian Congress Hematology, Hemotherapy and Cell Therapy - HEMO 2016, Florianopolis, November

23 in vivo recovery (%) Post transfusion platelet recovery and storage (n=3494) APC RPC ,1 29,1 31,1 28,7 28,4 27,1 26, ,4 24, storage before transfusion (days) APC RPC D D D D D Vasse J, Tardivel R et al. Vox Sang 2007, 93, s1 : 52 Brazilian Congress Hematology, Hemotherapy and Cell Therapy - HEMO 2016, Florianopolis, November

24 ITCB par million de CP Number of TTBI per million PCs overtime Blue CPA : Apheresis MCP Single Donation TOTAL Pink : Pools of Whole Blood Buffy Coat derived Yellow : Merged No more significant difference between ASD et WBD-PCs since No change since then! Brazilian Congress Hematology, Hemotherapy and Cell Therapy - HEMO 2016, Florianopolis, November

25 More allergic adverse effects with SDA-PC Andreu G, Vasse J et al. Transfus Clin Biol 2007, 14 : allergy FNHR 8 7 p = 6,7 x 10-7 incidence / 1000 PC ,95 p = 0,047 3, ,56 0,78 0,24 1,46 1,56 1,42 RPC PAS- RPC PAS+ APC PAS- APC PAS+ Whole Blood Buffy Coat Derived Pools Single Donor Apheresis Brazilian Congress Hematology, Hemotherapy and Cell Therapy - HEMO 2016, Florianopolis, November

26 AFSSAPS, 2006 SDA vs WBD-PCs : TRALI? Before the introduction of PAS and the male only policy implementations PSL TRALI France nombre de cas incidence par million PSL CPA SAD vs WBD-PCs MCPS plasma SD 0 0 CGR 53 7 MCPS 1 8 WBD-PCs PFC sécurisé CPA x 6.25 SAD-PCs Brazilian Congress Hematology, Hemotherapy and Cell Therapy - HEMO 2016, Florianopolis, November

27 Ethical issues Donor hemovigilance SDA collection exposes donors to risks Citrate intoxication Venous thromboembolism Delayed faints and possible life or travel (commuting) accidents Such incidents are not reported but are not acceptable Wastage and outdating It is more acceptable to outdate Whole Blood Buffy Coat PCs (valued for RBCs and plasma) Than specifically given in purpose--sdas Brazilian Congress Hematology, Hemotherapy and Cell Therapy - HEMO 2016, Florianopolis, November

28 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 2003, Europe Council Survey Austria Belgium Denmark Finland France Germany RD PC Aph PC 2013, France Greece Holland Iceland Whole Blood Derived Pools Irland Luxembourg Norway Sweden Switzerland United-Kingdom Europe (15 countries) Brazilian Congress Hematology, Hemotherapy and Cell Therapy - HEMO 2016, Florianopolis, November

29 In summary It can be recommended to prefer whole blood buffy coat PCs for Medical and scientific reasons Ethical issues Financial issues SDA-PCs are needed For HLA and HPA matched platelets Despite that, some situations can be solved by WBD-PCs such as FNAIT Brazilian Congress Hematology, Hemotherapy and Cell Therapy - HEMO 2016, Florianopolis, November

30 2. CURRENT DEBATES The Platelet Dose The PLADO trial Slichter, New Eng J Med, 2010 The platelet count increases with the PC dose But the interval between two transfusions looks parallel but is however slightly reduced, meaning that some platelets are consumed Recommend to transfuse less at a time : /7 kg => /10 kg? (done in France in 2015, guideline HAS) Brazilian Congress Hematology, Hemotherapy and Cell Therapy - HEMO 2016, Florianopolis, November

31 Role of ABO match Platelets express some level of A and/or B antigens, not so few actually! 4 cases : ABO identity Minor incompatibility (plasma incompatibility ) Major incompatibility (cell incompatibility ) Both Brazilian Congress Hematology, Hemotherapy and Cell Therapy - HEMO 2016, Florianopolis, November

32 RPT 40% Platelet recirculation according to ABO compatibility Julmy F, n=400 Heim D, n=9877 Transfusion 2009;49: Transfusion 2008;48: CCI 16,0 35% 30% 32% 34% 14,0 12,0 15,0 13,0 12,7 25% 10,0 11,1 20% 15% 21% 18% 8,0 6,0 10% 4,0 5% 2,0 0% 0,0 identité inc. mineure inc. majeure inc. mixte identité inc. mineure inc. majeure inc. mixte ABO Identity => Plasma incompatibility => Cell incompatibility => Both Brazilian Congress Hematology, Hemotherapy and Cell Therapy - HEMO 2016, Florianopolis, November

33 RH:1 compatibility RH:1 (Rhesus D or RH+) must be respected in female patients in childbearing age or if the recipient will be multitransfused (frequently the case for PCs, in onco-hematology) RH:-1 (Rh-) recipients would preferentially receive RH:-1 PCs, whenever possible/available If not possible: RhD prophylaxis must be considered if available Brazilian Congress Hematology, Hemotherapy and Cell Therapy - HEMO 2016, Florianopolis, November

34 Who is transfused (France, 2009)? CP transfusés Onco-hématologie 77 % Chirurgie 11 % 6 % Médecine Réanimation 4 % PLATELET COMPONENT RECIPIENTS Onco-Hematology, 77% Surgery, 11% Medicine, 6% Resuscitation, Intensive Care, 4% Obstetrics, 2% Pediatry, neonatalogy, 1% Others, 1% Obstétrique 2 % Néonatalogie <1 % <1 % Non classables* Quaranta JF, Transfus Clin Biol, 2009 Brazilian Congress Hematology, Hemotherapy and Cell Therapy - HEMO 2016, Florianopolis, November

35 3. NEW DEBATES 66% PAS vs 100% Plasma Strictly speaking, platelets do prefer plasma However, PAS Are designed to maintain platelet functions optimally and to not activate platelets (hemostasis, inflammation) Allow some Pathogen Reduction Technologies Reduced significantly the allergic type reactions also to some extent the FNHTRs and the TRALI occurrences (prior to the male policy only) Mitigate the ABO incompatibility (the plasma incompatibility) not allow too much plasma to be transfused when not needed (enormous amounts of proteins and foaming factors) Save plasma for fractionation => economically valuable In all, whenever possible, PAS should be preferred Brazilian Congress Hematology, Hemotherapy and Cell Therapy - HEMO 2016, Florianopolis, November

36 Pathogen reduction technologies versus bacterial detection PRTs : proved to be extremely safe (more than 10 years of experience in France and Belgium etc.) Efficacious on most bacteria, viruses, parasites : no escape yet reported Better than irradiation to prevent GvHD Do not alter PCs regarding inflammatory factors May prevent allo-immunisation (not ascertained) Easy to perform, but add costs (staff, devices and disposals, loss of platelets) Brazilian Congress Hematology, Hemotherapy and Cell Therapy - HEMO 2016, Florianopolis, November

37 Bacterial detection No system is 100% reliable False positives and negatives Not cheap Brings little according to experts Wise to display one of the two (the European Directive mandates that this is now in force; may allow extension of shelf-life of PCs to 7 days) Brazilian Congress Hematology, Hemotherapy and Cell Therapy - HEMO 2016, Florianopolis, November

38 Prophylactic vs therapeutic only Bleeding prevention due to thrombocytopenia or thrombopathies Bleeding stop But also an old debate! Brazilian Congress Hematology, Hemotherapy and Cell Therapy - HEMO 2016, Florianopolis, November

39 Age of blood? There is good clinical and experimetal evidence that fresh platelets estimated to be 3 day old lead to less inflammatory responses in recipients Less Biological Response Modifiers (Cytokines, Chemokines etc.) Less mediators of allergy (Serotonin, Histamin, etc.) Less oxydized lipid moieties Less microparticles Brazilian Congress Hematology, Hemotherapy and Cell Therapy - HEMO 2016, Florianopolis, November

40 CONCLUSION Forecast and Proposals Brazilian Congress Hematology, Hemotherapy and Cell Therapy - HEMO 2016, Florianopolis, November

41 Prefer WBD-PCs whenever possible Pools are preferred but WBD-PC units are workable Leukoreduction is definitely desirable Anti-HLA testing of female donors actually proved highly beneficial to reduce/eradicate the risk of TRALI PRT is valuable especially when there is a risk of high virus circulation or if familial transfusion are not uncommon Doses can be adapted and probably reduced as compare to as it used to be ABO match and fresh platelets increase efficacy and reduce side effects, thus are beneficial to recipients and also to the system as this reduces costs Brazilian Congress Hematology, Hemotherapy and Cell Therapy - HEMO 2016, Florianopolis, November

42 BC-PCs immunize significantly less than SDA- PCs regarding HPA, HLA antigenic specificities BC-PCs lead to less adverse events than SDA-PCs in general Brazilian Congress Hematology, Hemotherapy and Cell Therapy - HEMO 2016, Florianopolis, November

43 Acknowledgements Pr. Olivier GARRAUD, MD PhD Institut National de la Transfusion Sanguine, Paris, France EA364, Faculty of Medicine, University of Saint-Etienne (University of Lyon), France Brazilian Congress Hematology, Hemotherapy and Cell Therapy - HEMO 2016, Florianopolis, November

44 ACKNOWLEDGEMENTS Frédéric Bianchi Thomas Béranger Cécile Casale Christophe Chenet Nicolas Ferré Vincent Jallu Corinne Martageix Yasmine Mammasse Sébastien Philippe Jeannine Quesne Nathalie Seidner Brazilian Congress Hematology, Hemotherapy and Cell Therapy - HEMO 2016, Florianopolis, November

45 MUITO OBRIGADA Brazilian Congress Hematology, Hemotherapy and Cell Therapy - HEMO 2016, Florianopolis, November