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Christine Cserti-Gazdewich, MD FRCPC Assistant Professor, University of Toronto

Trojan Antibodies and Transplant Malware: Improbable Sensitizations & Hemolytic Passenger Lymphocyte Syndromes. Christine Cserti-Gazdewich, MD FRCPC Assistant Professor, University of Toronto Departments of Laboratory Hematology (Pathology) & Clinical Hematology (Medicine)

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Christine Cserti-Gazdewich, MD FRCPC Assistant Professor, University of Toronto

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  1. Trojan Antibodies and Transplant Malware:Improbable Sensitizations & Hemolytic Passenger Lymphocyte Syndromes Christine Cserti-Gazdewich, MD FRCPC Assistant Professor, University of Toronto Departments of Laboratory Hematology (Pathology) & Clinical Hematology (Medicine) Blood Transfusion Laboratory, University Health Network Toronto, Ontario, Canada office 416-340-5390, pager 416-790-9597, email Christine.Cserti@uhn.on.ca Canadian Blood Services Transfusion Medicine Resident Topic Teaching Session: Tuesday, October 5th 2010, 12:00 – 1:00 pm Conference Dial-In: 1-866-752-7690, Passcode 1775282 www.transfusionmedicine.ca NO CONFLICTS OF INTEREST. FUNDING FOR RESEARCH FROM PUBLIC FOUNDATIONS ONLY.

  2. Princess Margaret Hospital Ontario Regional Blood Coordinators Toronto General Hospital Toronto Western Hospital University Health Network provincial blood management Holland Ortho & Arthritic Centre Sunnybrook Hospital Women’s College Hospital Canadian Blood Services Sunnybrook Health Sciences Centre national blood provider St Michael’s Hospital Ontario Transfusion Coordinators Hospital for Sick Children provincial blood conservation Mount Sinai Hospital Trillium Gift of Life Network TRANSFUSION MEDICINE COLLABORATIVE provincial organ network University of Toronto teaching hospitals: Hospital Transfusion Services

  3. Goals • Re-orient to sensitization biology in transfusion medicine • Appreciate what is known about hemolytic passenger lymphocyte syndromes (PLS) in transplantation • Note some twists in ABO-incompatible stem cell transplantation • Consider new insights into “accommodation”

  4. It All Starts With This One Tube… crossmatch sample group & reserve blood group group & screen D.A.T. plasma cross & type type and cross indirect Coomb's red cell antibody screen

  5. ABO Types in the General Population • A donor plasma: • anti-B IgM • O donor plasma: • anti-A,B IgG • anti-A & anti-B IgG & IgM • AB donor plasma: • no anti-A or anti-B • B donor plasma: • anti-A IgM

  6. 30 blood group antigen systems (ABO, Rh, …) containing structures that are naturally “polymorphic” (278 antigens + 38 in “collections/series”)

  7. Who Are The Antibody-Makers Anyway? • anyone whose immune system has seen a foreign red cell at any other time in their lives • the parous (85% of child-bearing age females) • feto-maternal hemorrhage (FMH), especially at parturition • any transfusion history • up to 1-3% of the healthy donor population • up to 1/3rd of those with a hospital admission history • any tissue grafts or transplants (solid organs, hematopoietic progenitor [stem] cells), inevitably contaminated with passenger erythrocytes

  8. “Antibody Makers” • 13% of people are “antibody makers” • difference between -makers and -others appears, at least in part, to be absence vs integrity of T-reg-suppressive activity

  9. Guy (Gal) Walks In The Door… What Are The Chances? INTRINSIC SEROCONVERSION RISK HOW RECENT & HOW DURABLE THE ANTIBODY IS EXPOSURE X X 1 – 5 % of the population has a positive red cell antibody screen

  10. Targets for Graft versus Host Attack HLA Antigens (Platelets, Tissues)… ie- GVHD Red Cell Antigens… ie- Passenger Lymphocyte Syndrome (PLS)

  11. Diversity (Polymorphisms) Set Up The Tissue Incompatibility Fight extensive variations therein… ALLOIMMUNIZATION

  12. Diversity (Polymorphisms) Set Up The RBC Incompatibility Fight Kell: K vs k, others ABO Duffy: Fya vs Fyb Rh(D) Kidd: Jka vs Jkb subtle (eg SNP) variations therein… complete absence or presence etc: MNS, P, Lutheran, Lewis, Diego, Scianna, Dombrock, Colton, LW, Chido/Rodgers, Gerbich, Cromer, Knops, Indian other Rh(CE) antigens: C vs c E vs e ISOIMMUNIZATION ALLOIMMUNIZATION

  13. The Vocabulary of Immune Violence MAJOR vs MINOR incompatibility ACTIVE vs PASSIVE immunity

  14. MAJOR incoming donor’s cellular antigens are the incompatible target host-source immunity mounts the attack PRODUCT REJECTION by a fighting recipient eg. ABO incompatible RBC mistransfusion A into O: donor A cells destroyed by host O plasma eg. acute rejection of organs “MINOR” donor-source immunity mounts the attack host’s cellular antigens are the incompatible target HOST REJECTION by a fighting donor eg. GVHD from a solid organ transplant, a transfusion, or a BMT eg. TRALI Directions of Incompatibility

  15. ACTIVE renewable humoral (via cellular) fighting power PASSIVE finite (humorally contained) fighting power Active vs Passive Immunity n  ∞ n = x most forms of MINOR incompatibility all forms of MAJOR incompatibility some forms of MINOR incompatibility passenger donor plasma cell recipient plasma cell graft* product

  16. GVHD: What does it take? • living passenger lymphocytes • proliferative stimulus: something recognizably different in the host to attack • invulnerability: some way for the passengers to “get away with it” • host too immune suppressed • host “immune oblivious” (eg. homozygous haploidentical donor indistinguishable from self)

  17. passenger donor plasma cell graft Passenger Lymphocyte Syndromes host RBC minor incompatibility scenario of donor-origin (graft-associated) alloimmune hemolytic anemia of host RBCS aka. HUMORAL GRAFT VERSUS HOST DISEASE FOR THE BLOOD BANK

  18. PLS – The Implicated RBC Antigen Spectrum (Usual Victims) • ABO>Rh >minor RBC antigens: • probability of minor discrepancy • 25% for ABO vs <15% for Rh • presence of preformed Ab or primary historical sensitizations • ~100% for ABO vs 0.3% for Rh(D) • Rh: usually from donors who have been alloimmunized previously • prior donor alloimmunization “almost necessary” 555-fold

  19. First Reports of Anti-RBC PLS • 1964 – 1st hemolytic ABO PLS Marchioro, NYAS • 1985 – 1st hemolytic anti-D PLS Swanson, Transfusion • 1990 – 1st multiorgan (L, K) PLS Ramsey, aaBB

  20. PLS – “Lymphoid” Load Spectrum (Usual Aggressors) (heart-) lung kidney HPC: PB > BM small bowel, pancreas liver • dead or alive… • graft (usually) unaffected • at least 10 6 – 10 7

  21. Timing For “Serologically Expressive” Chimerism • median onset: 9 days (5 – 17) • median duration: 4.5 weeks (2 – 23) • undetectable by 3 months • the records: • fastest onset: 12 h • most delayed onset: 45 d • longest persistence: 2 years for Ab (2 mo for HA)

  22. The Role of Incidental HLA Matching (“graft stealth” by tolerance of inadvertently HLA-similar passengers) • borne out in TA- & SOT- GVHD literature • anti-RBC PLS may also be more likely with inadvertent HLA matching

  23. Things That May Make it Worse • density of vulnerable antigen • group A recipients • use of non-B-cell suppressive IST • cyclosporine • pro-hemolytic ± complement-fixing capabilities of antibody • inflammation / cytokines • TNF-α & IL-1 (conditioning or ischemic injuries) • co-stimulatory interactions: CD40 - CD154, CD28 - B7 • IL-2 RαCD25-dependent clonal expansion with Th1 – CTL response • overly receptive RES/MPS

  24. Things That May Make it Better (or Preventatively Subdue it?) • post- (or pre-?) transplant graft irradiation • reducing immunosuppression = de-repression revenge • evolution towards non-hemolytic antibody properties • promotion of activity of inhibitory FcR • “non-hemolytic red cell antigen loss” • senescence of passenger lymphocytes • Ag-Ab excesses  negative feedback to memory B cells

  25. Transfusion Care in PLS • issuing antigen-negative blood, compatible with respect to graft-origin antibodies, and not just the same blood type as the host • failure to do so = “Incorrect Blood Component Transfused” (IBCT) medical error event… +/- ABO mis-transfusion • top-up transfusions… or therapeutic red cell exchange (TREX)

  26. Is There a Role for Apheresis? Red cell replacement of removed plasma (hybrid TPRE) Whole blood removal eg. manual red cell exchange, replacing with pRBC ± plasma/NS/albumin (reconstituted whole blood) Therapeutic red cell exchange (TREx) Top-up transfusion

  27. When Sh/(C)ould Therapeutic Plasma Exchange Be Offered? • removal of pathologic antibody • IgM > IgG • high titer > low titer • “detox” of RBC breakdown products • for extreme cases with intravascular hemolysis • plasma free hemoglobin: ? danger thresholds ? • massive acute hemolysis (MAH): free plasma hemoglobinemia > 60 µmol/L = > 387 mg/dL (N: 0.5 – 5 mg/dL) • stromal factors & DIC

  28. Other Management Options • rituximab • graft irradiation • splenectomy • cytotoxic agents, prednisone adjustments • combination therapy: RBC/TREX, IST, apheresis, splenectomy

  29. A Passenger Lymphocyte Traceback Story… Why does my D+ patient now have anti-D after transplant? -passive sensitization? -partial D with alloimmunization? -active (passenger lymphocyte-mediated) sensitization?

  30. case 2 case I case 3

  31. Case 1: The good news: ABO compatibility… Donor: “A Negative” Recipient: “A Positive” The bad news: the seeming Rh(D)-compatibility isn’t

  32. Case 1 • 66F presented for a R SLT for COPD • group & screen pre-op: • A, Rh(D)+ • screen negative amid a history of A+ transfusions • group & screen POD17 in the pre-transfusion investigations of her new hemolytic anemia: • A, Rh(D)+ • screen: anti-D & anti-C • DAT: anti-D & anti-C D e C

  33. Case 1 Traceback of Donor • elderly multiparous female • group A, Rh(D)-negative (rr) • screen: Anti-D Anti-E Anti-C D C E

  34. RECIPIENT: Serologically: C+ D+ e+ c- E- D e Weiner designation: R1 R1 (17% of population) C Anti-C Anti-D Anti-E D E C DONOR: e Serologically: c+ e+ C- D- E- c passenger lymphocyte Weiner designation: r r (15% of population)

  35. therapeutic plasma exchange 36 - 40

  36. Case 1: Indirect Attributable Mortality Due to PLS • POD 21, Hb 6.0 g/dL: • massive AMI (“demand-ischemic” with rAF) • grade IV EF • left with refractory CHF • cardiac dysrhythmiae & fluid imbalances • died day 330 post transplant = 10 months later = 113 days after last detectable anti-D

  37. Case 2: Recipient of the Contralateral Donor’s Lung: • 43 y old female presented for L SLT 9/28/07 • A, R1 r , negative pre-transplant screen • lifelong transfusion-free history • screened monthly due to Case 1 patient

  38. Case 2: Novel Serological Course serologically positive 120 159 acute rejection TPE 173 259 266

  39. Case 3: It happened again! RECIPIENT 3: ♂ DONOR 2: ♂ anti-C anti-D anti-V • 30 year old male presented for DLT for CF • RBC antibody screen negative pre-operatively • RBC antibody screen + POD 23 • anti-D on IAT • anti-D & anti-C on eluate of DAT • no hemolysis • ongoing persistence at follow-ups (> 6 mo) O, R1 R1 ( CC DD ee ) O, r r ( cc dd ee ) anti-C 0  anti-D

  40. Why Did anti-D PLS Happen So Often In Our Series? • expected: • (13% risk of D- to D+) x (2% risk of anti-D) x (100% transfer) = 0.3% • observed: • 3/92 or 3% [95% CI: 1 – 9 %] • 100% transfer did indeed occur based on lookback • 3 donors were found to be D-sensitized • of a denominator of 12 D- donors, rate was 25% [ 6 – 57%, 95% CI] (>12x higher than expected… )

  41. Update: 10 Sequential Cases at the UHN Over 3.87 Years of Surveillance (q 25 wk)

  42. The Only Prospective Post-Solid Organ Tranplant Sensitization Surveillance Study in the Literature: • 27% of the ABOi KTs developed +DAT • checked q 10d x 3 checks post-operatively aaBB Abstracts 2007

  43. Types Of HPCT ABO Incompatibility 75% random combinations (assuming equal prevalence of types) are incompatible (12/16)

  44. Major Incompatibility 5-ways: non-O into O, or AB into A or B recipient donor

  45. Minor Incompatibility 5-ways:O into non-O, or A or B into AB donor recipient

  46. All Possible Players…(or the Worst Case Scenario): Bidirectional Incompatibility 2-ways: A to B or B to A donor recipient

  47. Donor Distributions By Recipient PROBABILITIES given: O: 0.45 A: 0.40 B: 0.11 AB: 0.04

  48. Probability of HPCT ABO Incompatibility Among MUDs 62.5 %

  49. MAJOR INCOMPATIBLE HPCT multi-lineage marrow aplasia/hypoplasia delayed (red cell) engraftment / pure red cell aplasia (PRCA) INCOMING DONOR CELLS FOUGHT OFF (acute hemolysis of passive contaminant, delayed establishment of active production) MINOR INCOMPATIBLE HPCT delayed, potentially severe hemolytic anemia HISTORICAL RECIPIENT CELLS FOUGHT OFF (acute hemolysis of recipient cells by passive antibody, delayed hemolysis of recipient cells by active antibody) Quick Summary of Vagaries of ABOi in HPCT

  50. ABOi HPCT and Increased RBC Alloimmunization? • Described once by de la Rubia et al in 2001, in a transplant cohort of 217 transplant patients, of whom 8 had developed non-ABO RBC antibodies • ABO blood group incompatibility (p = 0.005) and patient's age (p = 0.02) were the only two variables significantly associated with the development of RBC alloantibodies • Took a peak (in 2006 while at BIDMC) at 90 consecutive transplant patients, of whom 8 had non-ABO RBC antibodies

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