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Opportunities over 40 yrs

Opportunities over 40 yrs. In TRANSFUSION MEDICINE (1978- 2017) Pearl Toy M.D. Professor Emeritus. I have no relevant financial relationships to disclose. LEARNING OBJECTIVES. State one problem that led to advancement in these Transfusion Medicine related issues since 1978:

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Opportunities over 40 yrs

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  1. Opportunities over 40 yrs In TRANSFUSION MEDICINE (1978- 2017) Pearl Toy M.D. Professor Emeritus

  2. I have no relevant financial relationships to disclose.

  3. LEARNING OBJECTIVES • State one problem that led to advancement in these Transfusion Medicine related issues since 1978: • Human Immunodeficiency Virus • Hepatitis B Virus • Transfusion Related Acute Lung Injury

  4. Bilateral infiltrates on CXR? Yes/No Ruled out TACO? Yes/N0 Ruled out septic transfusion reaction? Yes/No Alternate ARDS risk factor present? Yes/no a. If Yes, name the ARDS risk factor______ b. What was the lung status before or during the transfusion? ____ Stable or improving (as in TRALI) ____ Worsening (as in Transfused ARDS) Evaluation of hypoxia (P/F<300) during or <6 hrs after transfusion

  5. ARC San Jose Pheresis Program: 1978 -1980

  6. Marion Reid 1980

  7. Donald Avoy M.D. 1980

  8. Transfused HIV: 1981 - 1985 CDC MMWR Dec 10, 1982 Epidemiologic Notes and Reports Possible Transfusion-Associated Acquired Immune Deficiency Syndrome (AIDS) – California

  9. No test for HIV in the blood supply: 1981-1985 HOSPITAL (ACADEMIC) Assistant Professor, UCSF SF General Hospital Increasing numbers of AIDS patients DONOR CENTER (COMMUNITY) Director, ARC, San Jose Increasing numbers of reports of AIDS, associated with transfusion

  10. Before HIV testing was available in 1985: 12,000 – 25,000 cases of Transfusion-Associated HIV ( CDC)

  11. San Jose ARC Director Hat (1983 – 1984) DONOR QUESTIONING DONOR TESTING What? How? Where? Did the donor understand the information? 1984: Surrogate test 1985: HIV test

  12. Lauren O’Brien M.D

  13. Positive Effect: Birth of “Transfusion Medicine” NIH Coined the NEW term “TRANSFUSION MEDICINE” NIH Started the TRANSFUSION MEDICINE ACADEMIC AWARDS in 1983, and funding FOR Transfusion medicine research Transfusion Medicine community Improved responses transfusion-associated infections

  14. Hepatitis B

  15. The key to Hepatitis B eradication Prevention of vertical transmission of hepatitis B by Perinatal HBIG and HBV vaccine (plasma or genetically engineered) to infants of HBsAg and HBeAg + mothers Studies: NYBC, UCLA, UCSF 1981-1993 P.I.: Cladd Stevens M.D.

  16. Passive-Active Prophylaxis Against Perinatal HBV:NYBC, UCSF, UCLA Study (1981-1993) Infants Born to HBsAg+/HBeAg+ mothers ≈ 275 BABIES in the BAY AREA were saved from becoming hepatitis B carriers

  17. Acute Hepatitis B in USA by Year Plasma-derived HBV Vaccine licensed, for those at high risk (parenteral, sexual and perinatal). Recombinant HBV Vaccine Licensed July 1986 25,000 20,000 All Babies of HBsAg+ Mothers Test All Pregnant Women Number of Cases 15,000 2005 and 2006 ACIP Recommendations for “Elimination”of HBV. 10,000 All Infants 5,000 All Newborns All 0-18 y.o. 1980 2010 2005 1995 1985 1990 2000 Year Reported CDC Data

  18. Incidence of HCC in 1983-2004in Taiwanese Children Birth Mo/Yr 0.8 Risk Factors O.R. 7/73-6/79 0.7 7/79-6/84 Mother: HBsAg- 1.0 HBsAg+ 29.5 7/84-6/98 (vaccine era) 0.6 Vaccine 3x 1.0 Vaccine <3x 4.3 0.5 HCC Incidence/100,000 person years 0.4 Mother HBsAg+ and … HBeAg-: HBIG 1.0 HBeAg+: HBIG 5.1 HBeAg+: no HBIG 9.4 0.3 0.2 0.1 15-19 10-14 6-9 Age (years) at HCC Diagnosis Chang, NEJM, 1997;336:1855 Chang, J Nat Cancer Inst, 2009;202:1348 Chiang, JAMA, 2013;310:974

  19. Surprise in 2002:TRALI patient……dies Received cognate anti-HLA in a plateletpheresis unit BUT: Other recipients of cognate anti-HLA from the same donor did not get TRALI NEED for MORE RESEARCH: NIH WORKING GROUP, CHAIR Definition presented at Canadian Consensus Conference

  20. TRALI Definition Toy P et al (Crit Care Med 2005;33:721-6) Kleinman SH et al (Transfusion 2004; 44;1774-89) TRALI is new ARDS during or <6 hr after transfusion TRALI is new ARDS during or <6 hr after transfusion Possible TRALI: temporally related to another ARDS risk factor present

  21. TRALI: Transfusion activates neutrophils

  22. Platelet-neutrophil aggregates in TRALI

  23. ARDS: Plasma leaks into air spaces Platelet-neutrophil aggregates in blood Megakaryoctes in lungs make platelets.

  24. ARDS: Plasma and fluid leaks into both lungs

  25. Most common conditions that can cause ARDS, without transfusion • Pneumonia • Aspiration • Sepsis • Shock • Trauma • - both lungs • - multiple fractures

  26. >60 Conditions can cause ARDS, without transfusion • Examples: • Lung transplant, graft failure • Hematopoietic stem cell transplant, chemoradiation • Cardiopulmonary bypass • Many drugs • Genetic mutation of surfactant protein-B

  27. Cause of ARDS, no Tx: Aspiration or Pneumonia

  28. Cause of ARDS, no Tx: Sepsis Toxic granulations Plasma leaks out of blood

  29. Cause of ARDS, no Tx: Shock

  30. Cause of ARDS, no Tx: Multiple fractures

  31. Cause of ARDS: TRALI or known ARDS risk factor? • PROBLEM: ARDS transfusion in a patient who already has one of >60 ARDS risk factors: • Pneumonia • Aspiration • Sepsis • Severe Trauma • Lung transplant, graft failure • Hematopoietic stem cell transplant, chemoradiation • Cardiopulmonary bypass, lung surgery • Many drugs • Genetic mutation of surfactant protein-B • Other

  32. Possible TRALI • Definition in our study: • ARDS in a patient with a • ARDS risk factor and related • Worseninglung function • <12 hrsBEFORE transfusion

  33. TRALI: A case-control study P.I.: Pearl Toy MD For the TRALI SCCOR Study Group (Funding 2005-2010) TRALI: Incidence and Risk Factors

  34. Electronic surveillance of Clinical Lab data at UCSF and Mayo Clinic Arterial blood gas results: PaO2/FiO2 AND Blood product issued  Alert Sent to StUDYCOOrDINATORS who Screen the patient CXR and history

  35. TRALI SCCOR STUDY GROUP UCSF: Pearl Toy MD (P.I.) Michael A. Gropper MD, PhD Mark R. Looney MD Clifford Lowell MD, PhD Michael A. Matthay MD Edward L. Murphy MD, MPH Philip J. Norris MD Richard B. Weiskopf MD Rosa Sanchez Rosen MD Monique Koenigsberg RN Deanna Lee Ping Wu Statistician: Peter Bacchetti PhD BCP: Nora Hirschler MD Dan Hindes ADVISORS: Michael Busch MD, PhD Steve Kleinman MD Ram Kakaiya MD Thomas Price MD David Stroncek MD MAYO CLINIC: Breandan Moore MD (deceased) OgnjenGajic MD Rolf Hubmayer MD Joseph McConnell PhD Gregory Wilson RRT Tami Krpata Deborah Rasmussen Cindy Metcalfe MAYO HLA Lab: Manish J. Gandhi MD Jeffrey L. Winters MD Steve DeGoey Nancy Ploeger ARC Neutrophil Lab: David Mair MD Randy Schuller Harvard: Genomics Michelle Gong MD David Christiani MD 36

  36. AIMS 1. TRALI Incidence -- How often? 2. TRALI Risk Factors -- Why?

  37. CASE CONTROL STUDY 89 TRALI cases (976 involved units) 164 transfused controls (1054 involved units)

  38. TRALI incidence In 2006, the pre-mitigation incidence was 1: 4,000 units transfused In 2009, the post-mitigation incidence was 1: 12,000 units transfused

  39. 5 4 3 2 1 0 2006 2007 2008 2009 Annual TRALI Incidence: Mitigation in 2007- 8 Incidence per 104 units transfused Year

  40. 8.0 6.0 4.0 2.0 0.0 Possible TRALI Overall P = 0.38 P for trend = 0.78 Incidence per 104 units transfused 2006 2007 2008 2009 YEAR

  41. Male-predominant plasmaSchmickl et al

  42. Male predominant plasma: Less TRALI riskSchmickl CN et al. Crit Care Med 2014

  43. Higher IL8 before transfusion Liver surgery (transplantation) Peak airway pressure >30 cm H2O Current smoking Chronic alcohol abuse Shock Positive fluid balance PATIENT RISK FACTORS by multivariate analysis

  44. TRANSFUSION RISK FACTORS

  45. % Units with Antibody among TRALI and Control units

  46. Total quantity antibody received FOR EACH UNIT: Ab quantity = Antibody strength x volume (Ab strength: NBG ratio, MFI) FOR EACH PATIENT: Sum of quantities in all involved units

  47. Multivariate Analysis PREDICTORS: Transfusion factors Patient factors, before transfusion OUTCOME: TRALI vs. Control

  48. 1. Totalquantity of HLA Class II cognate antibody (MFI>1500), per 10-fold increase OR 3.2 (1.52, 6.7), p=0.002 Total volume of HNA antibody positive by GIFT, per 100 mL increase OR 1.71 (1.18, 2.5), p=0.004 Transfusion Risk Factors Significant in MV analysis

  49. non-cognate HLA Class II antibody weak cognate HLA Class II antibody, MFI<1500 HLA Class I antibody Any particular HLA or HNA Ab specificity MICA antibody …………………………………….. cytokines, sCD40L, VEGF LysoPC neutrophil priming activity age of RBC units LIMITATION: Confidence intervals of ORs were wide Transfusion factors: No strong evidence for risk

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