Linda M. Hawthorne, MHS, MT(ASCP)SBB LSU Health Sciences Center- Shreveport lhawth@lsuhsc.edu April 2011

2. Linda M. Hawthorne, MHS, MT(ASCP)SBBLSU Health Sciences Center- Shreveportlhawth@lsuhsc.eduApril 2011 Blood Selection Strategies for SCD Patients: The LSU Approach

3. Illustrate different blood selection options for this interesting patient subset

4. Objectives After this presentation participants should be able to: • Discuss rationales for separate SCD transfusion protocols • Cite transfusion protocol alternatives for SCD patients • Discuss efficacy of the LSUHSC HCTP protocol

5. Sickle Cell Disease (SCD) • Most common single gene disorder in US blacks affecting 1 in 500 African Americans • Also common in persons from Mediterranean countries: Greece, Turkey, Italy; the Arabian peninsula and the Indian subcontinent • Many Spanish-speaking persons in the US, the Caribbean and parts of South and Central America are affected • 1 in 1000 to 1400 Hispanics

6. World Health Organization 350,000 deaths/year

7. Sickle cell disease (SCD) • Abnormality due to mutation in the sixth amino acid residue of β-globin chain from glutamic acid to valine • Hgb tetramer may polymerize upon O2 loss causing formation of characteristic crescent or sickle-shaped RBCs

8. Variants of Sickle Cell Disease • The common variants of sickle cell disease are homozygous sickle cell disease (hemoglobin SS disease), doubly heterozygous sickle hemoglobin C disease (hemoglobin SC disease) and the sickle ß-thalassemias.

9. Sickle cell disease (SCD) • Abnormal RBCs are fragile, causing chronic hemolysis resulting in • Chronic anemia • Vaso-oclusive events causing pain and damage to many body organs • spleen, kidneys, lung, and brain

10. Autosomal recessive inheritance ~8% carrier rate ~72,000 affected

11. Clinical manifestations • Acute chest syndrome, acute intrahepatic sequestration, acute multiorgan failure syndrome, acute splenic sequestration, • acute symptomatic anemia, aplastic crisis, • bacterial and malarial infections, chronic organ failure, pianism • complicated pregnancy, eye surgery, frequent pain episodes • primary and secondary prevention or treatment of stroke

12. Treatment of Manifestations • Supportive therapy for pain • Hydration and anti-inflammatory agents • Prevention/treatment of infections • Splenectomy, cholecystectomy • Hydroxyurea • Transfusion to reduce % Hb S

13. Transfusion Needs • Survival increased significantly partly due to transfusion therapy • Simple or exchange transfusion • Episodic • Chronic • 11% children will have strokes • 10% have elevated transcranial Doppler measure indicating increased risk of stroke • Chronic transfusions required

14. Potential transfusion risks • Iron overload • Transfusion transmitted disease • Alloimmunization to red cell antigens • Delays/Inability to find compatible blood • Notably increased rate of alloimmunization • racial disparity of antigen types • other variables (dose, degree of foreignness of antigens, immunogenicity)

15. Exposure to foreign antigens by transfusion or pregnancy MAY elicit immune response. Dependent on group studied and test sensitivity, alloantibodies found in 0.3% to 38% of population

16. SURG SCD TRAUMA ICU GYN OB BMT DLY SCD

17. Blood donors • Average blood donor • white male • college-educated • married • 30-50 • above average income • Typical urban blood inventory • 90% white • 10% black

18. Blood transfusion example Relatively close antigen match so few alloantiodies formed, if any. Exposure to multiple foreign antigens some very likely to stimulate alloantibodies.

20. Racial disparity of RBC antigens % Positive for antigens (US frequencies) Caucasians Blacks C 70 34 E 30 21 K 9 2 Fy(a) 66 10 Jk(b) 73 49 Fy(b) 83 23 S 55 31

21. IMMUNOGENECITY RED BLOOD CELL ALLOIMMUNIZATION AFTER BLOOD TRANSFUSION January 2008 Henk Schonewille

22. One Hospital’s Experience

23. Original LSUHSC SCD Protocol • Routine testing as for all patients • ABO/Rh and antibody screening • Antibody screens negative • Transfused red cell units • ABO/Rh immediate spin compatible • HBS negative • Clinically significant antibody present/history • Transfused red cell units • ABO/Rh AHG compatible • Antigen negative • HBS negative

24. Complex Cases HOSP. NO. PATIENT NAME BIRTHDATEAGE SEX HOSP ID 080###### AA 12/18/1985 25Y F LSU ABO/RH: B POS RED CELL UNITS TRANSFUSED: 4 LAST TRANSFUSION: 11/29/2009 ANTIGEN/ANTIBODY DATA: ANTI-E ANTI-S ANTI-Fy(A) ANTI-K BLOOD BANK PROBLEMS: POSITIVE FOR WARM AUTOANTIBODIES SICKLE CELL PATIENT GENERAL COMMENTS: ANTI E, ANTI K IDENTIFIED HISTORY OF ANTI S,FYA 672##### BL 02/14/1964 47Y F LSU ABO/RH: O POS RED CELL UNITS TRANSFUSED: 23 LAST TRANSFUSION: 02/22/2011 ANTIGEN/ANTIBODY DATA: ANTI-C ANTI-S ANTI-Fy(A) ANTI-Fy(B) ANTI-K ANTI-Le(A) ANTI-Le(B Anti little e HIGH TITER LOW AVIDITY ANTIBODIES BLOOD BANK PROBLEMS: POSITIVE FOR WARM AUTOANTIBODIES SICKLE CELL PATIENT FILTERED PRODUCTS ONLY PATIENT TRANSFUSION REACTION GENERAL COMMENTS: ANTI FY3 SUSPECTED CH/RG SPECIFICITY 04/04 DR ONG NOTIFIED NO UNITS AVAILABLE AT BLOOD SUPPLIER 753##### MP 02/25/1967 44Y F LSU ABO/RH: O POS RED CELL UNITS TRANSFUSED: 10 LAST TRANSFUSION: 11/17/2006 ANTIGEN/ANTIBODY DATA: ANTI-C ANTI-E ANTI-S ANTI-Fy(A) ANTI-Jk(B) ANTI-Le(A) POSITIVE FOR HIGH TITER LOW AVIDITY BLOOD BANK PROBLEMS: SICKLE CELL PATIENT POSITIVE FOR WARM AUTOANTIBODIES FILTERED PRODUCTS ONLY GENERAL COMMENTS: ANTI McCd, ANTI K RULED OUT 2002 606##### BM 08/17/1960 50Y M LSU ABO/RH: O POS RED CELL UNITS TRANSFUSED: 8 LAST TRANSFUSION: 09/13/1996 ANTIGEN/ANTIBODY DATA: ANTI-E ANTI-S ANTI-CW ANTI-Fy(A) ANTI-K BLOOD BANK PROBLEMS: SICKLE CELL PATIENT POSITIVE FOR WARM AUTOANTIBODIES

25. Case Study (1990) BH- 45 yr old male (SCD) 2 unit XM for surgery in AM, Hgb 7.0 No BB history at LSUHSC but seen at age 10 Transfused one unit last month on visit to Texas Antibody Identification Anti- D, E, M, Fy(a), Jk(b) Patient is D mosaic Roughly 1% compatibility A positive Next admit 2006- Screens Negative!!!

26. Research New Protocol Publications 1995 Physician Complaint/ Request

27. Physician’s request to change protocol Fully antigen matched units!!!!!

28. Racial disparity of RBC antigens % Negative for antigens (US frequencies) Caucasians Blacks C 30 66 E 70 79 K 91 98 Fy(a) 34 < 2/1000 90 ~12% Jk(b) 27 51 Fy(b) 20 77 S 45 69

29. 1 Step Literature search for alternate protocols

30. Transfusion protocols for SCD patients • Routine transfusion • Racially matched • Fully antigen matched • Partial antigen matched • “Mixed” protocol

31. Audience Transfusion protocols ? • Routine transfusion • Racially matched units • Fully antigen matched • Partially antigen matched • “Mixed” protocol

32. ... Assess area “standard of care” 2 Step

33. Standard of care??? • No definite consensus • All protocols perceived • acceptable care • no ethical problems with any protocol

34. Justification of protocol change 3 Step • Assess “fit” of protocol alternatives • Alloimmunization rate at LSUHSC • Cost/Benefit analysis of protocols • Reagents • Antiserum for CEK versus ALL • Increased tech time • Impact on blood supply • CEK negatives most easily from Rh neg

35. Study 1Review of original protocol Purpose- Assess need of change • Figure alloimmunization rate • Retrospective record review • SCD patients • 6 year period (1991-97)

36. Methods • N = 162 • Set criteria for inclusion in study • no alloantibodies present on initial testing • at least one post transfusion testing • Data assessed • frequency of antibody production • # of units before alloimmunization • identification of antibodies formed

37. Results (Original Protocol) • Responders (25/162) ~15% • 25 formed alloantibodies • 18 (72%) single alloabs • 7 (28%) multiple alloabs • Majority anti- C, E, K • 75% formed alloabs ≤ 15 units • Non-responders ~ 85%

38. HCTP Protocol (initial 2 unit XM) Time- ~3 hours Cost- $610 Additional units $150 each Few allos? Reduced TRXN Cost/Benefit of change (CEK match compromise) Original (initial 2 unit XM) Time- 45 min Cost- $150 Additional units $50 each % form alloabs Occasional Trnx

39. Full matching easiest if Transfusion Service with collection facilities Full ownership of resources Access to donor race info Few SCD patients Committed area base of African American donors Persuasive Arguments 4 Step

40. Racial disparity of RBC antigens % Negative for antigens (US frequencies) Caucasians Blacks C 30 66 E 70 19% 79 51% K 91 98 Fy(a) 34 90 Jk(b) 27 51 Fy(b) 20 77 S 45 69

41. Initial conclusions 5 Step • Worthy of less aggressive trial protocol • Firm criteria to change ONLY • New pediatric SCD patients • Chronically transfused • No history of alloantibodies • Type for C, E, K on initial workup • Transfuse with CEK matched units (ALL UNITS LEUKOREDUCED) • Full antigen profile kept on file

42. Only relatively new pediatric SCD patients to be chronically transfused No adults No multi-transfused pediatric patients ≤ 12 units transfused No existing alloabs Implementation conflicts

43. Two year assessment of HCTP • Data • Age range (10 months to 14 years) • Majority transfused once every 1-2 weeks • Range of units transfused (1-26) • Average of 8 units transfused

44. Study 2Assess efficacy of new protocol 6 Step Purpose- assess efficacy of HCTP • Determine alloimmunization rate • Prospective record review • Subject group • Pediatric SCD patients transfused CEK matched units • Tested at least once post transfusion • 2 year period (1997-1999)

45. Methods • N = 27 • Set criteria for inclusion • transfused only with “protocol” units • tested at least one subsequent time • Data assessed • frequency of antibody production • # units transfused before antibody formed • identification of antibodies formed

46. Results of HCTP study • Responders (~4%) • 1 patient formed anti-K (despite transfusion with only CEK neg units) • Several cold/warm autos • Non-responders (~96%)

47. Study 2- Conclusion • Incidence of RBC alloimmunization appears reduced in pediatric SCD patients transfused with partially antigen matched units (CEK) early in their transfusion history.

49. 7 Study #3-2005 HCTP Assessment Step Methods Newly diagnosed and current pediatric SCD (<18 year old) patients with minimal transfusion history (arbitrarily defined as  12 RBCs) were enrolled in the protocol from 1997 to date. Retrospectively, we reviewed the computer record of 112 chronically transfused SCD patients enrolled in the HCTP. All patients had been CEK phenotyped and to date had received a total of 2687 CEK negative units for which 7160 antigen typing tests were done (2687 K1 types, 2242 C types and 2231 E types). Eighty-eight patients (79%) had extended phenotyping performed. Direct cost estimates are based on antigen typing reagent (ATR) and estimated technologist time (ETT). The number of units tested per crossmatch (Mean -2*; Range 1-5) was used to compute for the total ETT. Costs of controls, test tubes, saline and AHG reagents are not included in the ATR. Conclusions We report the usefulness, albeit the considerable cost, of implementing an HCTP providing limited (CEK) phenotyping of both patients and RBC units in significantly reducing the rate of alloimmunization among our SCD population. Only three patients (2.7% versus 15.4%) have each formed one alloantibody (anti-Jkb, -Jsa and -K1) while transfused on protocol, lower than 8% reported by the STOP§ trial. Extended patient phenotyping is laborious, time consuming and Unnecessary expense that is no longer implemented in the protocol. The cost will progressively increase over time as additional patients are enrolled in the protocol and as our patients age due to increasing transfusion requirements. Providing CEK compatible units for this increasing HCTP population poses a challenge to our transfusion service as CEK negative RBCs are primarily drawn from the D-negative RBC inventory.

50. Phenotype matching of donor red blood cell units for nonalloimmunized sickle cell disease patients: a survey of 1182 North American laboratories. Osby M, Shulman IA Arch Pathol Lab Med. 2005;129(2):190. • CONTEXT: …data are limited regarding the extent to which transfusion services routinely perform red cell antigen phenotype testing of nonalloimmunized sickle cell disease patients, and then use that information to select donor RBCs lacking 1 or more of the red cell antigens that the patient's red cells do not express. • OBJECTIVE: To determine the extent…. • DESIGN: An educational subsection of a College of American Pathologists Proficiency Testing Survey (J-C 2003) assessed transfusion service practices. • The data analysis of the survey included 1182 North American laboratories. • RESULTS: Data from 1182 laboratories were included in the survey analysis, of which the majority (n = 743) reported that they did not routinely perform phenotype testing of sickle cell patients for antigens other than ABO and D. • The other 439 laboratories reported that they did routinely perform phenotype testing of sickle cell disease patients for antigens in addition to ABO and D. The majority of these 439 laboratories (three fourths; n = 330) reported that theyused these patient data for prophylactic matching with donor RBCswhen sickle cell disease patients required transfusion. When phenotype-matched donor RBCs were used,the antigens most commonly matched (85% of the time) were C, E, and K. • CONCLUSIONS: The majority of North American hospital transfusion service laboratories do not determine the red cell antigen phenotype of nonalloimmunized sickle cell disease patients beyond ABO and D. Those laboratories that do determine the red cell phenotype of nonalloimmunized sickle cell patients beyond ABO and D most commonly match for C, E, and K antigens when phenotype-matched donor RBCs are used.