Clinical decision making: Red blood cell alloantibodies

Clinical decision making: Red blood cell alloantibodies Beth H. Shaz, MD Chief Medical Officer, VP New York Blood Center; Clinical Associate Professor Emory University School of Medicine 1

5 non-abo fatal hemolytic reactions: 2 lab errors, 2 no pretx errors, 1 emergency transfusion 2

Adverse Reaction Rate per 1,000 Units Transfused 60 Hospitals Reporting Type of Reaction Total Rate Total Number of Reactions Acute Hemolytic 0.03 5 Definitive 0.02 4 Possible 0.01 1 Allergic 0.35 62 Definitive 0.12 21 Possible 0.20 35 Probable 0.03 6 Not Determined. 0 Delayed hemolytic, Immune 0.03 6 Definitive 0.02 4 Probable 0.01 2 Delayed hemolytic, Non-Immune 0.01 1 Definitive 0.01 1 Probable. 0 Delayed Serologic Transfusion Reaction 0.15 27 Definitive 0.15 27 Possible. 0 Not Determined. 0 Febrile non-hemolytic 1.42 254 Definitive 1.13 201 Possible 0.30 53 www.aabb.org

January 2016 4

Johns Hopkins 1986-7: 54,562 RBCs transfused to 8535 patients 34 DSTR (1:1605 per transfused unit, 1:151 patients transfused) 6 DHTR (1:9094 per transfused unit, 1:500 patients transfused) 8

1:1200 1:611 1:6944 1:3146 All of the following criteria were required for a diagnosis of DHTR or DSTR to be considered: 1) a new antibody identified in the patient s serum, 2) a positive DAT demonstrating the presence of IgG, 3) an eluate from the patient s RBCs demonstrated the presence of the same antibody that was identified in the serum, and 4) antigen typing of the patient s RBCs demonstrated mixed-field typing for the antigen toward which the antibody in the patient s serum and in the eluate was directed. Mayo clinic 10

RBC Transfusion in Sickle Cell Disease 46% of the children were transfused a mean of 24 RBC products while 87% of the adults were transfused a mean number of 23 RBC products over a 10-year period Studies reported an alloimmunization rate in the range of 19 to 43% in transfused patients with SCD. One study reported an alloimmunization rate of 29% in pediatric and 47% in adult SCD patients, with more females than males being alloimmunized. The number of delayed hemolytic and/ or serologic transfusion reactions was 8% (adult) and 9% (pediatric) and the incidence of hyperhemolysis was 1.6% (adult) and 5.1% (pediatric). Shaz: Trans Med Rev 2008;22:202-14. 11

Features, evaluation and management of DHTRs in SCD Clinical symptoms Laboratory findings Acute management Occurs 6-10 d after transfusion Mimic vaso-occlusive pain episode or transfusion reaction Hemoglobinuria Decreased hemoglobin levels from pretransfusion values Close hemodynamic and laboratory monitoring Coordinate testing with laboratory Symptoms include: Reticulocytopenia Avoid transfusion Back, abdominal or extremity pain Fever Signs of worsening anemia Pallor or jaundice Dark urine Neurological signs Positive DAT/antibody screen Allo-/autoantibody detection Low post-transfusion HbA values High dose steroids or IVIG 12

Results of RBC alloimmunization Increased difficulty of antigen negative crossmatch compatible RBC products. Increased risk of hemolytic transfusion reactions. Increased rates of autoantibodes. 86% of SCD patients with autoantibodies have alloantibodies. Autoantibodies may result in clinically significant hemolysis and difficulty finding RBC compatible RBC products. 13

Anti-e Anti-c Josephson: Transfus Med Rev 2007;21:118-133 14

Prophylactic Phenotypic Matching Prophylactic phenotypic matching of nonalloimmunized SCD patients reduces the rate of alloimmunization from 30% to 7% or less. Accurate RBC phenotypes are needed for phenotype matching programs. 15

Recommendations for RBC transfusion of patients with SCD SCD patients without prior antibody formation (nonalloimmunized): ABO Rh(D) C, E, and K SCD patients with prior antibody formation (alloimmunized): S Jk(b) Fy(a) 16

Alloimmunization risk 18

99 patients Phenotyped and receiving serological matched for: ABO; Rh (C, c, D, E, e); Kell (K, k); Duffy (Fya, Fyb); Kidd (Jka, Jkb); Lewis (Lea, Leb); and MNS (M, N, S, s) 20

Antibodies in Two groups of Patients with SCD A. 20 patients Receiving antigen-matched for C, E, K and Minority donor units B. 26 patients Not prophylactic antigen-matched Receiving random donor units Rh common antibodies 0 Rh common antibodies 22 18- anti-e 4- anti-c Complex Rh antibodies 22 Complex Rh antibodies 30 11 anti-d (D+ patients) 8 anti-e (e+ patients) 3 anti-c (C+ patients) 4 anti-d (D+ patients) 6 anti-e (e+ patients) 20 anti-c/-ce (C+ patients) Other antibodies 9 Other antibodies 56 2 anti-jk b 1 anti-fy a 4 anti-m 1 anti-n 1 anti-js a 8 - anti-k 6 - anti-s 6 - anti-fy a 4 - anti-jk b 2 - anti-jk a 1 - anti-m 1 - anti-go a 1- anti-n 1- anti-js a 1- anti-kp a 1- anti-yta 1- anti-le a 1- anti-le b Total number of antibodies 31 Total number of antibodies 108 Average #abs/patient : Group A = 1.5 Group B = 4.2 Complex Rh /patient: Group A = 1.1 Group B = 1.1 Slide courtesy of Westhoff 21

22 182 SCD patients: 58% chronic, 15% episodic transfused patients alloimmunized

Genotyping in SCD Genotyping was applied to 144 transfused SCD patients previously phenotyped for ABO, Rh (D, C,c,E, e), K1, Fy a, Jk a. There was a discrepancy in 15 of 42 alloimmunized patients between genotype and phenotype. This was secondary to phenotype mistypes due to recent transfusion. 11/15 alloimmunized previously mistyped patients benefited from antigen-matched RBCs based on genotype, as assessed by Hg levels post-transfusion and frequency of transfusion. Ribeiro: Vox Sanguinis 2009;97, 147 152 23

Need for Blood Products from Minority Donors Patients Benefiting from a Phenotype Matched RBC Product Sickle cell disease patients Patients with multiple alloantibodies Patients with alloantibodies to high frequency antigens Patients with autoantibodies Donor Donor Center Hospital Transfusion Service Patient Hillyer, Shaz, Winkler, Reid: Transfusion Med Rev 2008;22:117-32 24

Pipeline The importance of phenotype-genotype matching NYBC s PreciseMatch program as a means of donor recruitment Phenotyping-genotyping donors (testing/processing) National registry of rare products Patient testing and registry Donor Processing Patient 25

Minority Blood Donation in the United States Do minorities donate at lower rates than whites? Why do minorities donate at lower rates than whites? Deferral/ eligibility differences? Motivation and barrier differences? Marketing differences? What are potential strategies to overcome these differences? 26

Donation rates: nationally 27

The blood donation rates were 77 donations/1000 population for whites, 22/1000 population for African Americans and 10/1000 population for Hispanics. Shaz, James, Hillyer, Schreiber, Hillyer: J Natl Med Assoc 2011, 103:351-7 28

Blood Donor Rates per 1000 Population The blood donor rates were 11/1000 population for whites, 6/1000 for African Americans and 3/1000 population for Hispanics. Shaz, James, Hillyer, Schreiber, Hillyer: J Natl Med Assoc 2011, 103:351-7 29

Retention and Donation Rates by Minority Populations New York Blood Center, 2010 Annual Donation Hispanic/ White Black Asian Frequency Latino All donations 320,710 50,050 31,392 23,219 All unique donors 174,031 32,269 19,646 15,068 Donation rate 1.84 1.55 1.6 1.54 First-Time Donors 47,099 14,069 8,214 7,131 % donated within 6 mo. 21.40% 19.30% 17.60% 18.70% % donated between 6 mo. - 1 year % of FT Sticks Deferred on 2nd Presentation within 6 months % of FT Sticks Deferred on 2nd Presentation between 6 months-1 year 16.00% 13.60% 12.70% 13.40% 3.60% 4.60% 6.20% 3.80% 2.17% 2.61% 2.90% 2.53% Return donations p= <0.0001 for each race as compared to whites Deferrals on next donation p=<0.0001 for each race as compared to whites except for Asian which was not statistically significant for either time period. Kessler, Rebosa, France, Shaz: AABB abstract 2012 30

Donor Eligibility Recent mathematical models determined only 37.8% of the population is likely to be eligible to donate. This rate may be lower in African Americans. African American church: 40.2% hypertension, 32.6% high cholesterol, 21.3% anemia, 14.2% pulmonary disease, 12.5% diabetes, 11.8% sexually transmitted disease, 5.5% heart disease, 2.6% hepatitis, 2.3% epilepsy, 2.0% stroke, 1.5% sickle cell disease, 1.7% renal disease, and 6.9% other serious disease. James, Hillyer, Shaz: Transfusion 2012;52:1050-61 32

Donor Eligibility: Our Model -In 2007 to 2008, 122 million Americans (65.9% of the study population and 41.0% of the total US population) were estimated to be eligible to donate blood in the United States. -Significant differences in eligibility rates by demographic characterizers were determined (p < 0.001): * AAs (36.5%), whites (46.4%), and Hispanics (40.7%); * males (45.4%) and females (42.7%); * 18-39 years old (35.8%); and 40-69 years old (32.9%). James, Hillyer, Shaz: Transfusion 2012;52:1050-61 33

Donor deferral rate: whites (11.1%), Hispanics (14.1%), African Americans (17.9%); females (20.0%), males (6.2%). Shaz, James, Hillyer, Schreiber, Hillyer: Transfusion 2010;50:881-7 34

Top Ten Donor Deferral Reasons Shaz, James, Hillyer, Schreiber, Hillyer: Transfusion 2010;50:881-7 35

Blood Donor Status based upon the Logistic Regression Model James, Demmons, Schreiber, Hillyer, Shaz: Transfusion 2011;51:158-65 36

Our studies demonstrate. African Americans versus whites have: lower blood donation rates than whites. higher deferral rates than whites. lower donor eligibility than whites. likely have different motivators to blood donation. fear and distrust are major deterrents to blood donation. Future studies are needed to determine optimal ways to decrease barriers to donation. 37

program AIMS: GOAL: Increase collection, advanced testing, and distribution of rare (antigen negative) RBC products to significantly improve the availability of more precisely matched RBC products for patients in our diverse community who require multiple blood transfusions 38

Stages of Change Spiral like progression through the stages. Stages Precontemplation: Not thinking about donating blood. Contemplation: Thinking about donating blood in the next 6 months. Preparation: Planning on donating blood in the next 30 days. Action/ Maintenance: Donated blood at least twice in the past year and planning on donating again when next eligible. 39

Motivational Interview (MI) A set of clinical strategies that encourage people to work through ambivalence about behavior change (e.g., adopting more healthy eating, engaging in regular exercise, quitting smoking, etc.) People can also be ambivalent regarding the pro-social behavior of donating blood (i.e., perceived barriers may outweigh perceived benefits). Can a post-donation interview, based on MI strategies, promote retention? Donating blood saves lives! I want to help others. But I don t like needles! But I m very busy. Ohio University Department of Psychology 40

Post-donation telephone interview Participants 215 experienced donors Mean age = 31.1 years (SD = 13.5) Mean prior donations = 6.8 (SD = 13.9) Randomly assigned to: 1. Treatment-as-usual control, or 2. Telephone interview (~10 min) within 1 month of index donation Ohio University Department of Psychology 41

Post-donation telephone interview Topic Sample #1. Introduction and permission to interview #2. Motivations for donating Can you tell me some reasons why you donated blood the last time?" #3. Donation intention "Do you plan to donate blood again? #4. Donation barriers #5. Perceived importance of donation and donation confidence #6. Personal goals and values relating to donation Sometimes people who give blood have reservations about returning. What concerns do you have about giving blood again? On a scale of 0-10, with 0 being not at all important and 10 being extremely important, how important is it for you to donate blood? 0 or 1: Tell me why you chose a 0 or 1? 2 through 9: Tell me why you chose a instead of a (# minus 2)? 10: That s great, why a 10? What do you think giving blood says about you? #7. Individualized coping strategies What are some things you might do to solve (barrier)? #8. Summarizing the interview Before we end our conversation, let me see if I can accurately summarize what we discussed. Ohio University Department of Psychology 42

Post-donation telephone interview Sinclair, Campbell, Carey, Langevin, Bowser, & France (2010) Interview vs. Control Condition (% difference) 20 10 0-10 -20 Attitude Anxiety Confidence Intention Ohio University Department of Psychology 43

Post-donation telephone interview Sinclair, Campbell, Carey, Langevin, Bowser, & France (2010) 100 90 80 No-Interview Control Motivational Interview Return Rate (%) 70 60 50 40 30 20 10 0 67% 44% 3 6 9 12 Months OR 12 months = 2.48 (95% CI, 1.27-4.87) Ohio University Department of Psychology 44

Blood Donor CARE Project Figure 2. Contributors to intrinsic motivation. 45

Motivating NIH Type High-Priority, O- Blood Donors Short-Term to Return Project Award (R56) Preliminary finding: Relative to the control call, the motivational phone interview is significantly increasing donor autonomy 20 18 Phone interview Control This suggests that the interview s focus on each donor s unique motivators and barriers leads to stronger internal motivation to give Upon completion of recruitment and follow-up we ll know if this effect persists and translates into more frequent re-donation behavior. Relative Autonomy Index 16 14 12 10 8 PRE POST Ohio University Department of Psychology 46

PILOT WORKFLOW Data Gathering Analytics Scoring Communication Donations NYBC Donor Data Predictive Analytics Engine Data Analysis Platform Unique Donor Probability Scoring Effectively target marketing resources: emails vs. calls vs. events; incentive amounts, etc. HIGHER DONOR RATE / RETENTION 47

WHOLE BLOOD DONOR PREDICTION 2011-12 DATA TO PREDICT 2013 n = 850 n = 404 n = 127 n = 16 n = 1,984 n = 5,166 n = 22,239 48

RELATIONSHIP BETWEEN AGE/ETHNICITY AND REDONATION 49

HINDSAIT ANALYTICS PLATFORM FOR NEW YORK BLOOD CENTER SAMPLE FILTER AND EXPORT 50

HINDSAIT ANALYTICS PLATFORM FOR NEW YORK BLOOD CENTER SAMPLE VISUALIZATION 51

HINDSAIT ANALYTICS PLATFORM FOR NEW YORK BLOOD CENTER GEO CLUSTERING, 52

NEXT STEPS: MESSAGING TO ELIGIBLE AA DONORS MESSAGING STUDY: Design: Send one of 3 emails, randomly selected, equally divided Control- thank you and link to scheduling next donation and online survey of experience Need for blood message- Importance for AA to donate especially to SCD patients Need for blood message + incentive- with $25 Target gift card Outcome measure: Donor return rate and lag time to donation as a function of message type. ONLINE MOTIVATIONAL INTERVIEW STUDY: Design: All email messages invite donors to complete an online survey. For those who choose to complete the survey, half of the email recipients for each message should be directed to a motivational interview survey and the other half should be directed to a control survey (without the motivational interview component). Outcome measure: Donor return rate and lag time to donation as a function of survey type. 53

Comprehensive transfusion management: Vein to Vein Blood Services Red blood cells Platelets Plasma Specialty needs Antigen negative Clotting factors Laboratory Services Immunohematology RBC genomics Donor testing HLA Transfusion Services Medical coverage Medical consultation Information technology Blood management Cellular therapy Apheresis collections Therapeutic apheresis Cell savage Platelet rich plasma Education Heather Had a malignancy at age 5 that ultimately required the removal of several organs. She had extensive blood transfusions to support her surgeries. Patient-Care Impact Patient Impact - Positive Overall Costs - Reduced 54

Collection product goals Personalized products Molecularly matched Optimized to patient s need Concentrated, washed, rejuvenated.. Uniform/ Standardized products Pooled RBCs with uniform characteristics Freeze dried plasma Group O negative RBCs RBCs from stem cells 55

What do you do when a patient has an antibody? What is that antibody? Mayo clinic 56

Massive transfusion- Transplantation 1991-2006: 2000 adult patients undergoing liver, intestinal or multivisceral transplantation 115 patients had antibodies Transfusion management: 20 U crossmatch >20 U or multiple Ag neg 1 st & last 5-10 U University of Miami 57

What happened? No hemolytic reactions No surgery delay 58

Emergency release uncrossmatched units 480 out of 5623 received 5203 RBC U 161 patients received 581 ER RBC (2.8%) 1.21 ER RBC (range 1-14) Survival 56% No acute transfusion rxn 1/10 male developed anti-d University of Maryland UCSF 59

BIDMC 60

Unusual antibodies: Clinical significance History of causing HTR or HDFN? 62

64 Incompatible transfusion: 0.4 gm/kg IVIG 100 mg hydrocortisone IV 6-8 pre transfusion Repeat 24 hours Transfuse slowly

Lessons What is the antibody? Worry more about Jk a than E or C What is the transfusion indications? Worry more about patients with sickle cell disease and less about trauma or other massive hemorrhaging patients Patient individuality Risk/benefit of transfusion 65