Transfusion challenges in transplantation fields

Transcription

1 Transfusion challenges in transplantation fields Unité d hématologie transfusionnelle Département des Spécialités de Médecine Dr. S. Waldvogel Abramowski Swisstransfusion 2018 Friday 24 th August 2018 Stem cells part S.Waldvogel

2 Hematopoietic progenitor cell transplantation (HPCT) : a special case Y Infusion HPC Engraftment Posttransplantation S.Waldvogel

3 HPCT : a mixture of red cell antigens Systems are by definition independently inherited

4 Markers : in vivo culture of cord blood cell Red cell immune reaction don t thwart transplantation, but erythropoiesis. Effect of red cell incompatibility on clinical outcome is not as significant as HLA mismatch, risk of infection, age and gender of the donor CFU stage : earliest point of ABO presentation Southcott, and al. Blood S.Waldvogel 2018 Thickness of the barres : % o positive cells 4

5 Transplantation : What else? Transfusion in transplantation field : check-list Manage ABO mismatch Watch for erythrocyte immunization (donor) Prevent alloimmunization from HLA antigen Manage immunodeficiency WHAT ELSE? Processing of HPC graft not discussed in this presentation S.Waldvogel

6 ANTIBODIES DIRECTED AGAINST RED CELL ANTIGEN Manage ABO mismatch Allo-antibody Auto-antibody Naturaly occuring antibody Immune : anti-d, anti-k; anti-e, anti-c; anti-u, anti-jka, anti-fy Warm anti-body (IgG) Cold agglutinins (IgM) Donath Landsteiner («cold» IgG) Regular antibody (anti-a, anti- PP1Pk) Irregular antibody (anti-a1,: anti-m; anti-lea; anti- Leb ) Waldvogel Sophie 6

7 ABO : histo-antigens, like H, LE*, I ABO antigens have a higher expression on epithelial tissues than red cells and platelets. ABO antigens are expressed on epithelial and endothelial tissues (not bone or muscle). ABO level of expression is related to the level of cell maturity Two types : A and A 2 2ꓸ 10 5 /red cell Anti-A and B : not a significant barrier to HSCT * Not synthetized by erythroblasts seriously S.Waldvogel

8 ABO Incompatibility HPC transplantation Major (ex : A O) Pure red cell aplasia Minor (ex : O A) Passenger Lymphocyte, auto-hemolysis Solid organ transplantation, with specific conditioning or A2 donor Solid organ transplantation without preparation S.Waldvogel

9 ABO Incompatibility HPC transplantation Bidirectional (ex : A B) Iso (ex : 0 0) No solid organ transplantation Solid organ transplantation S.Waldvogel

10 Search for an unrelated donor : risk ABO incompatibility Patient Major(%) Minor Bidirectional (%) O A B AB Calcul : 0:45%; A:45%; B:8%; AB:2% Repercussions for a transfusion service : Iso-groupe : 40% Major : 25% Minor: 25% Mixed : 10% Waldvogel Sophie 10

11 Transplantation CSH HUG, N=518, Unité d hématologie transfusionnelle Département des Spécialités de Médecine N % Iso Major Minor Bidirectional More than expected because of related donors Waldvogel Sophie 11

12 ABO Hemolytic transfusion reaction : prevention Recipient Donor O A B AB O O O O O A O A O A B O O B B AB O A B AB S.Waldvogel

13 ABO Hemolytic transfusion reaction : prevention Recipient Donor O A B AB O O A B AB A A A AB AB B B AB B AB AB AB AB AB AB S.Waldvogel

14 Major ABO incompatibility D A B AB R O O O Survival of plasmocytes depends on preparative regimen : Myeloablative or reduced intensity Delayed red blood cells engraftment and pure red cell aplasia (PRCA) : Acute GVHD, young age and HPC-A are associated with faster red cell engraftment (Stussi et al. Hematologica 2008). Risk factors for PRCA : high pre-transplant isoagglutinins. AB AB A B S.Waldvogel

15 Isoagglutinins before transplantation (LIHT ) Unité d hématologie transfusionnelle Département des Spécialités de Médecine Isoagglutinins A are almost always higher S.Waldvogel

16 D21 tx, Major A O incompatibility HSC A O, 3 weeks S.Waldvogel

17 J60 post TX, A O, major Transfusion Waldvogel Sophie 17

18 J180 post TX, A O, major Waldvogel Sophie 18

19 J180 post TX, A O, major, greffe haploïdentique Transfusiondependent Isoagglutinins (recipient immunity) Transfuso-dependant (EU and PU) Waldvogel Sophie 19

20 Pure red cell aplasia (PRCA) Recipient s plasma cells survive myeloablation Anemia and reticulopenia at D60. Inverse correlation between isoagglutinin titer and reticulopenia Treatment : adapt treatment to induce graft vs host effect, plasma exchange (short effect and rapid rebound). Duration PRCA : months>>>years. S.Waldvogel

21 Correlation between chimerism and residual anti-a? Date du prél. : Nature du prél. : Sang Sang Sang Moelle Sang Chimérisme granulocytes <3 <3 <3 <3 <3 Chimérisme cellules mononucléées Anti-A (titre, IgM) <3 <3 <3 <3 < Les résultats sont donnés en pourcentage de matériel de type receveur O recipient A related donor, reduced conditionning

22 ANTIBODIES DIRECTED AGAINST RED CELL ANTIGEN Allo-antibody Auto-antibody Naturaly occuring antibody Immune : anti-d, anti-k; anti-e, anti-c; anti-u, anti-jka, anti-fy Warm anti-body (IgG) Cold agglutinins (IgM) Donath Landsteiner («cold» IgG) Regular antibody (anti-a, anti- PP1Pk) Irregular antibody (anti-a1,: anti-m; anti-lea; anti- Leb ) Waldvogel Sophie 22

23 A2 phenotype and HPC transplantation ~20% from group A Allo anti-a1 (irregular and naturally occurring) : 2% A2 and 25% A2B. Mild to delayed transfusion reaction Significance of anti-a1 in transplantation? One case uneventful Recipient Donor S.Waldvogel

24 Conclusion of the authors : Safe transplantation provided that the antibody is not reactive at 37 Fadeyi et al. Transfusion : one A1 liver transplantation cancelled S.Waldvogel

25 Minor incompatibility in transplantation HPC with minor incompatibility has much in common with solid organ transplantation D O O O A B R A B AB AB AB Passenger lymphocyte syndrome : more lasting effect in HPC transplantation than solid organ transplantation, but hemolysis is limited to the elimination of recipient erythrocytes. Auto-immunity S.Waldvogel

26 J14 post TX, O A, mineur transfusions Waldvogel Sophie 26

27 Hemolysis and ABO mismatch SCT DAT Elution Isoagglutinins Mismatch Diagnostic IgG or negative Anti-A,-B,-AB Detectable in graft or recipient serum Major, bidirectional or Hemolysis at graft infusion (passive) IgG or negative IgG+/- C3d Anti-A,-B-AB Antitody wide specificity (not ABO) Possibly detectable, from donor Possibly detectable, but not involved in hemolysis minor Minor or bidirectional Minor or bidirectional>>>m ajor IgG Anti-A1 Can mask anti-a1 IgG Donor or recipient from A2 blood group IgG or negative Positive or negative Anti-A>> anti-b Negative Possibly detectable, from blood donor product. Possibly detectable, but not involved in hemolysis Any or no Any or no Passenger lymphocyte syndrom Autoimmune hemolytic anemia (warm>>cold) Alloimmunization Passive immunization (platelet component, IVIG ) Microangiopathy, medication S.Waldvogel T I M E

28 Autoimmune hemolytic anemia (AHA) Two months- three years after transplantation. Warm > cold Often after an alloimmunization. Unknown mechanism? T-lymphocytes dysregulation? Viral infection (CMV)? Ttt: immunosupression Immuno-hemotological work up : Alloadsorption with two types of red cells : donor and recipient. Waldvogel Sophie 28

29 ABO mismatched solid organ transplantation Anti-H (o antigen) reactivity : O > A2 > B > A2B > A1 > A1B Transfusion strategy : avoid incompatible plasma HUG, transplantation across the (major) ABO barrier : 2 ABO-incompatible liver transplantations (A2B A, A2 0, neonates) and 28 ABO incompatible kidney transplantations (between ). S.Waldvogel

30 Blood group switch : criteria No antibody against donor-type blood group TDA and elution : negative Blood group typing ABO and D RHD : 1, 2, 3, 4, 5 without red cell chimerism (mixed field) A B J60 S.Waldvogel

31 Transfusion strategy : ABO mismatch (our protocol) Any transfusion has to be compatible with donor and recipient at any time Security protocol within the transfusion software Unité d hématologie transfusionnelle Département des Spécialités de Médecine S.Waldvogel

32 Watch for irregular antibodies (donor and recipient) ANTIBODIES DIRECTED AGAINST RED CELL ANTIGEN Allo-antibody Auto-antibody Naturaly occuring antibody Immune : anti-d, anti-k; anti-e, antic; anti-u, anti-jka, anti-fy Warm anti-body (IgG) Cold agglutinins (IgM) Donath Landsteiner («cold» IgG) Regular antibody (anti-a, anti- PP1Pk) Irregular antibody (anti-a1,: anti-m; anti-lea; anti- Leb ) Waldvogel Sophie 32

33 Unité d hématologie transfusionnelle Département des Spécialités de Médecine Immunogenicity: D>K>E>c>Fya>Jka>S Geneva, allotransplatation S.Waldvogel

34 Platelet pools and residual red cells Unité d hématologie transfusionnelle Département des Spécialités de Médecine C-ter KEL RH MNS FY JK Platelets pools are sources of alloimmunization S.Waldvogel

35 Immune hemolysis without ABO mismatch SCT DAT Elution TIA Diagnostic IgG or negative Anti-D, c, JK, K, Non ABO antibodies detectable in graft or recipient serum Hemolysis at graft infusion (passive) IgG Anti-D, c, K, JK Non ABO antibodies detectable, donor>>>recipient immunity IgG+/- C3d Anti-D, c, K, JK or wide specificity Non ABO antibodies detectable Alloimmunization, including passenger lymphocytes Autoimmunization Genotyping of the recipient is a key condition for the diagnostic (oral mucosa or pre-transplantation) S.Waldvogel

36 Passenger lymphocyte syndrom : AB or non- ABO (K1, JK1 ) : minor incompatibility Solid organ transplantation Start : D10-D28 Stop hemolysis : few weeks, when lymphocytes reactivity stops. HSC transplantation Start : D10-D28 Stop hemolysis : when antigens are cleared. Transfusion strategy : selection of red cell units negative for the antigen until disappearance of antibody (solid organ) or indefinitely (HSCT) S.Waldvogel

37 Anti-HLA prevention Anti-HLA prevention Residual leucocytes or platelets can induce HLA antibodies HLA is highly immunogenic and polymorphic HLA I : nucleated cells and platelets HLA II : B lymphocytes, monocytes and activated T lymphocytes Anti-HLA : TRALI, transfusion refractoriness 30% female have anti-hla after the second pregnancy S.Waldvogel

38 Donor specific antibodies (DSA) and solid organ transplantation Anti-HLA : risk factor for antibody mediated rejection (kidney) Hyperacute, acute and chronic graft rejection Particularly : HLA A,B, DR Haploidentical HSCT or solid organ transplantation : Selection of platelet components from apheresis (single donor) units S.Waldvogel

39 Residual leucocytes (quality control 2017, Geneva, Swiss specificity : < /unit) Blood product Residual leukocytes per unit Erythrocytes (h-f) 0,06-0,05 Platelets (buffy coat 0,230 and apheresis) Plasma 0,016

40 Irradiation Manage immunosuppression After a transfusion : microchimerism of T lymphocytes for months to years. TA-GVH : 4 to 30 days after transfusion Leukofiltration is not enough Start : as soon as a HPCT is planned Solid organ transplantation : not an indication of irradiation Stop : no evidence available, no validated test to delineate complete immunologic reconstitution. Platelets inactivation is considered as a valuable measure to prevent TA-GVH.

41 Cytomegalovirus Manage immunosuppression 50-75% du CMV of pregnant women. According AABB, leucocyte < /U prevent CMV transmission Most of the transfusion services consider leukofiltration as efficacious enough to prevent CMV transmission. Platelets inactivation is also considered as a valuable measure to prevent CMV-transmission. No evidence of a second strain (recipient CMV+) infection transmitted by transfusion. An urgent transfusion should never be delayed by the lack CMVseronegative blood product. Risk factors : seronegative recipient; T-cell depleted, cord blood and haploidentical transplantation.

42 Prospective study : 23 HPCT, CMV D-R- and transfusion (Germany) Follow-up : D0-D100 (CMV highly sensitive NAT an serology) Blood components not tested but leucoreduced Result : risk of transfusion transmitted CMV : 0% (CI 95%, %) 17/23 had passive IgG seroconversion Thiele et al., Transfusion 2011 S.Waldvogel

43 Pathogen inactivation Since 2011 in Switzerland 35% plasma Effective for the majority of infectious agent Reduced CMV transmission risk Gamma-irradiation superfluous S.Waldvogel

44 Transfusion : Immuno-hematological management in real life How far? RH KEL1 : prevention Complex alloimmunization Auto-immunization Rare blood Shortage of supply S.Waldvogel

45 Platelet transfusion Isogroupe ABO transfusion of platelet components is impossible in practice (shortage of supply); CE PFC CP MCP HUG distribution : ) S.Waldvogel

46 Transfusion : practical issues Supply problem, particularly O RHD negative 21% 34% S.Waldvogel

47 Prevention of irregular antibodies : RH, KEL, MNS RH and KEL antigens are highly immunogenic Non-RH matched STC : prevention Shortage of phenotype (r r rr, R2R2, R1R1) Switch at engraftment (example : Donor R1R1 Recipient rr) Post-transplantation allo-antibodies are mostly produced by donor lymphocytes S.Waldvogel

48 Donor Recipient RH : 1,2,-3,-4,5 E- c- R1R1 RH : 1,-2,3,4,-5, C-e- R2R2 R1R2 RH : 1,2,-3,-4,5 E-, c- R1R1 RH : 1,-2,3,4,-5, C-,e- R2R2 RH : -1,-2,- 3,4,5 D-,C-,Err E-,c-(19%) C-,e-(2%) D-,C-,E- (15%) E-,c-(19%) D-,C-,E-(15%) and E-,c-(19%) as soon as D+ detectable C-,e-(2%) D-,C-,E-(15%) and C-,e-(2%) as soon as D+ detectable D-,C-,E- (15%) RH : -1,-2,- 3,4,5 D-,C-Err RH :1,2,-3,4,5 E- R1r RH : 1,-2,3,4,5 C- R2r RH :1, 2,3,4,5 D-,C-,E- (15%) E-,c-(19%) C-,e-(2%) D-,C-,E- (15%) E-,c-(19%) C-,e-(2%) D-,C-,E- (15%) E-,c-(19%) C-,e- D-,C-,E- (15%) RH :1,2,-3,4,5 E- R1r RH : 1,-2,3,4,5 C- R2r RH :1, 2,3,4,5 R1R2 E-,c-(19%) c-,e-(19%) E-,c-(19%) C-,e- (2%) and E- as soon as e detectable D-,C-,E-(15%) and E- as soon as D+ detectable E- E-, C- and E- at J15 C-,e-(2%) and C- as soon as e detectable D-,C-,E-(15%) and C- as soon as D+ detectable C- E- et C- at J15 C- C-,e-(2%) D-,C-,E-(15%) and E- dès phénotype D+ E- C- E- C- D + (f-) S.Waldvogel

49 Donor Recipient RH : 1,2,-3,-4,5 E- c- R1R1 RH : 1,-2,3,4,-5, C-e- R2R2 R1R2 RH : 1,2,-3,-4,5 E-, c- R1R1 RH : 1,-2,3,4,-5, C-,e- R2R2 RH : -1,-2,- 3,4,5 D-,C-,Err E-,c-(19%) C-,e-(2%) D-,C-,E- (15%) E-,c-(19%) D-,C-,E-(15%) and E-,c-(19%) as soon as D+ detectable C-,e-(2%) D-,C-,E-(15%) and C-,e-(2%) as soon as D+ detectable D-,C-,E- (15%) RH : -1,-2,- 3,4,5 D-,C-Err RH :1,2,-3,4,5 E- R1r RH : 1,-2,3,4,5 C- R2r RH :1, 2,3,4,5 D-,C-,E- (15%) E-,c-(19%) C-,e-(2%) D-,C-,E- (15%) E-,c-(19%) C-,e-(2%) D-,C-,E- (15%) E-,c-(19%) C-,e- D-,C-,E- (15%) RH :1,2,-3,4,5 E- R1r RH : 1,-2,3,4,5 C- R2r RH :1, 2,3,4,5 R1R2 E-,c-(19%) c-,e-(19%) E-,c-(19%) C-,e- (2%) and E- as soon as e detectable D-,C-,E-(15%) and E- as soon as D+ detectable E- E-, C- and E- at J15 shortage C-,e-(2%) and C- as soon as e detectable D-,C-,E-(15%) and C- as soon as D+ detectable C- E- et C- at J15 C- C-,e-(2%) D-,C-,E-(15%) and E- dès phénotype D+ switch E- C- E- C- D + (f-) S.Waldvogel

50 Pre-transplant antibodies against recipient/donor red cell antigen Female related donor with anti-d against red cells recipient. Recipient with irregular antibodies against donor type red cells : anti- Fya, anti-a1 reactive at 37. No significant impact on red cell engraftment. Waldvogel Sophie 50

51 Anti-Fya : patient Anti-D : donor Waldvogel Sophie 51

52 Rare unrelated HLA matched donor Donor : public antigen negative, KEL2 negative (prevalence <2/1000 donors) S.Waldvogel

53 verso recto Sortie des HUG Waldvogel Sophie 53

54 Conclusion 1. Before transplantation : Phenotyping or genotyping of donor/recipient Plan transplantation in accordance with blood supply. 2. After transplantation Manage ABO mismatch Manage immunodeficiency Watch for irregular antibodies Prevent alloimmunization from HLA antigen Friends! S.Waldvogel

55 Thank you for your attention Unité d hématologie transfusionnelle Département des Spécialités de Médecine 55