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Is it time to re-evaluate the gold standards in blood banking ?

Is it time to re-evaluate the gold standards in blood banking ?. Jerry A. Holmberg, MT(ASCP)SBB, Ph.D. June 6, 2013 201 Florida Association of Blood Banks. Agenda. Current status of transfusions in the U.S. Traditional serological typing methods

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Is it time to re-evaluate the gold standards in blood banking ?

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  1. Is it time to re-evaluate thegoldstandardsin bloodbanking? Jerry A. Holmberg, MT(ASCP)SBB, Ph.D. June 6, 2013 201 Florida Association of Blood Banks

  2. Agenda Current status of transfusions in the U.S. Traditional serological typing methods Red cell genotyping as a supplemental method Regulatory considerations Recent Blood Product Advisory Committee discussion | Re-evaluating the Gold Standards| Holmberg | 24April2013 | CBBS 2013

  3. Disclaimer All blood group genotyping tests commercially available in the US and Canada are for research use only. Not for use in diagnostic procedures. | Re-evaluating the Gold Standards| Holmberg | 24April2013 | CBBS 2013

  4. Transfusions/1,000 Population Comparison in Selected Countries 2009 National Blood Collection and Utilization Survey Kamper-Jorgensen Transfusion 2009; 49:888-894 Cobain Transfusion Medicine 2007; 17, 10-15 | Re-evaluating the Gold Standards| Holmberg | 24April2013 | CBBS 2013

  5. 2009 HHS Blood Collection and Utilization Survey of RBC Use by Hospital Service 2009 Health and Human Services’ Blood Collection and Utilization Survey | Re-evaluating the Gold Standards| Holmberg | 24April2013 | CBBS 2013

  6. Transfusion Risk Risk Communication Risk Management Risk Assessment | Re-evaluating the Gold Standards| Holmberg | 24April2013 | CBBS 2013

  7. Challenges in Transfusion Medicine 31 22 Source: FDA 2013, http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/ReportaProblem/TransfusionDonationFatalities Notes: TRALI is transfusion related acute lung injury, which occurs within 6 hours of a transfusion. HTR is hemolytic transfusion reaction, which results in destruction of red cells and is usually caused by incompatibility. TACO is transfusion associated circulatory overload and is characterized by a sharp increase in blood pressure.

  8. Challenges in Transfusion Science • RBC Alloimmunization: lessons from sickle cell disease • Alloimmunization in general public is 0.5-1.5% • Alloimmunization in individuals receiving 3 or more units is 8.4% • A review of 12 publications found a mean rate of 25% in SCD Miller ST et al. TRANSFUSION 2013;53:704-709. • RBC Alloimmunization in SCD prevalence in 2010 • Editorial (TRANSFUSION 2013;53:692-695.) • DrsTreml and King advocates for genotype matching and leads to the conclusion that alloimmunizationrates remain high partially to transfusions at institutions not providing extended matching | Re-evaluating the Gold Standards| Holmberg | 24April2013 | CBBS 2013

  9. Challenges in Transfusion Science • RBC Alloimmunization in transfused patients with myelodysplastic syndrome or chronic myelomonocyticleukemia • Alloimmunization occurs in 15% of MDS and CMML • Alloimmunization mostly involves Rh system and Kell • Antigen matching should include Kell and CcEe Sanz C et al. TRANSFUSION 2013;53:710-715. • Immunohematologicand patient safety benefit of a centralized transfusion database • Puget Sound advocates for universal transfusion records since many patients bounce from hospital to hospital Delaney M TRANSFUSION 2013;53:771-776. | Re-evaluating the Gold Standards| Holmberg | 24April2013 | CBBS 2013

  10. The Future • Are we moving towards more personalized transfusion medicine? • Impact on collections? • Impact on testing? • Impact on data management? • Impact on outcomes? | Re-evaluating the Gold Standards| Holmberg | 24April2013 | CBBS 2013

  11. Agenda Current status of transfusions in the U.S. Traditional serological typing methods Red cell genotyping as a supplemental method Regulatory considerations Recent Blood Product Advisory Committee discussion | Re-evaluating the Gold Standards| Holmberg | 24April2013 | CBBS 2013

  12. Contents • Preface • About the Author • Acknowledgments • 1. Blood and the cells it contains • Blood contains cells, proteins, and sugars • Red blood cells transport oxygen • White blood cells are part of the immune response • Platelets help blood to clot • Your complete blood count • Hemoglobin binds oxygen • Resources • 2. Blood group antigens are surface markers on the red blood cell membrane • Antigens stimulate an immune response • Red blood cell antigens can be sugars or proteins • Red blood cell antigens determine your blood group • Blood groups differ around the world • The classification of blood cell antigens • References • 3. Blood transfusions and the immune system • How to launch an immune response against transfused red blood cells • "Blood type and cross match" • Transfusion reactions: Immune-mediated • Transfusion reactions: Non-immune • 4. Hemolytic disease of the newborn • Maternal antibodies cross the placenta and attack fetal red blood cells • Sensitization occurs during the first pregnancy • HDN occurs in subsequent pregnancies • The Coombs test detects Rh incompatibility between mother and fetus • Preventing HDN • References • 5. The ABO blood group • At a glance • Background information • Basic biochemistry • Clinical significance of ABO antibodies • Molecular information • References • 6. The Hh blood group • At a glance • Background information • Basic biochemistry • Clinical significance of H antibodies • Molecular information • References • 7. The Rh blood group • At a glance • Background information • Basic biochemistry • Clinical significance of Rh antibodies • Molecular information • References • 8. The Kell blood group • At a glance • Background information • Basic biochemistry • Clinical significance of Kell antibodies • Molecular information • References • 9. The Duffy blood group • At a glance • Background information • Basic biochemistry • Clinical significance of Duffy antibodies • Molecular information • References • 10. The Kidd blood group • At a glance • Background information • Basic biochemistry • Clinical significance of Kidd antibodies • Molecular information • References • 11. The Diego blood group • At a glance • Background information • Basic biochemistry • Clinical significance of Diego antibodies • Molecular information • References • 12. The MNS blood group • At a glance • Background information • Basic biochemistry • Clinical significance of MNS antibodies • Molecular information • References < PrevNext > Print View Bookshelf ID: NBK2264 Chapter 2Blood group antigens are surface markers on the red blood cell membrane Before the 1900s, it was thought that all blood was the same, a misunderstanding that led to frequently fatal transfusions of animal blood into humans and hazardous transfusions of blood between people. Human blood is not the same—people belong to different blood groups, depending upon the surface markers found on the red blood cell. The cells that make up the body's tissues and organs are covered with surface markers, or antigens. Red blood cells are no different. This chapter will describe the types of red blood cell antigen and explain why they are so important in medicine today. Antigens stimulate an immune response Go to: An antigen is any substance to which the immune system can respond. For example, components of the bacterial cell wall can trigger severe and immediate attacks by neutrophils. If the immune system encounters an antigen that is not found on the body's own cells, it will launch an attack against that antigen. Conversely, antigens that are found on the body's own cells are known as "self-antigens", and the immune system does not normally attack these. The membrane of each red blood cell contains millions of antigens that are ignored by the immune system. However, when patients receive blood transfusions, their immune systems will attack any donor red blood cells that contain antigens that differ from their self-antigens. Therefore, ensuring that the antigens of transfused red blood cells match those of the patient's red blood cells is essential for a safe blood transfusion. Red blood cell antigens can be sugars or proteins Go to: Blood group antigens are either sugars or proteins, and they are attached to various components in the red blood cell membrane. For example, the antigens of the ABO blood group are sugars. They are produced by a series of reactions in which enzymes catalyze the transfer of sugar units. A person's DNA determines the type of enzymes they have, and, therefore, the type of sugar antigens that end up on their red blood cells. In contrast, the antigens of the Rh blood group are proteins. A person's DNA holds the information for producing the protein antigens. The RhD gene encodes the D antigen, which is a large protein on the red blood cell membrane. Some people have a version of the gene that does not produce D antigen, and therefore the RhD protein is absent from their red blood cells. The figure below shows the red blood cell membrane and some of the blood group antigens attached to it. Aside from the sugar (glycan or carbohydrate) antigens, the red blood cell membrane contains three types of protein that carry blood group antigens: single-pass proteins, multi-pass proteins, and glycosylphosphatidylinositol (GPI)-linked proteins. Click on the blood groups to find out more about the antigens that define it. Red blood cell antigens determine your blood group Scientific Overview Blood Group Antigens Dean L. Blood Groups and Red Cell Antigens [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2005. Chapter 2, Blood group antigens are surface markers on the red blood cell membrane. Available from: http://www.ncbi.nlm.nih.gov/books/NBK2264/ | Re-evaluating the Gold Standards| Holmberg | 24April2013 | CBBS 2013

  13. Antigen Function ADHESION MOLECULES TRANSPORTERS AND CHANNELS CARBOHYDRATES LW XG FY LU OK IN SC MER2 JMH RH RHAG JK DI LAN CO GIL XR JR ABO P1PK LE GLOB H I FORS COMPLEMENT REGULATION STRUCTURAL OR UNKNOWN ENZYMES CH/RG CROM KN H I FORS MNS GE DO KELYT | Re-evaluating the Gold Standards| Holmberg | 24April2013 | CBBS 2013

  14. Traditional Serological Testing Methods • Limitations of serology to detect antigens in some cases • Recent transfusion (mixed field) • Warm auto-antibody • Antisera • Limited availability of some rare antisera • Quality • Weak expression of some RBC antigens • Impractical to screen large numbers of donors for all potential antigens • Typing for rare antigens is often not performed • Potential allo-immunization or reactions • Can be time consuming and costly | Re-evaluating the Gold Standards| Holmberg | 24April2013 | CBBS 2013

  15. European PerspectiveBritish Committee for Standards in Haematology 1. Guidelines for the Blood Transfusion Services in the UK 2012 2. Guidelines for pre-transfusion compatibility procedures in blood transfusion laboratories, British Committee for Standards in Haematology Transfusion Medicine doi: 10.1111/j.1365-3148.2012.01199.x • 4.8.4. Where there is a discrepancy in reaction strength between different anti-D reagents, or where the reagent fails to give a clear-cut strong positive reaction,1 a decision to investigate further needs to be made based on whether the development of anti-D is likely to cause clinical problems. • 7.9. Females of child-bearing potential • 7.9.1. Females of child-bearing potential should receive K negative red cells unless they are unavailable in an emergency (Lee & de Silva, 2004; BCSH, 2006a). • 7.16. Foetaltransfusions • 7.16.2. D negative, K negative (and further antigen negative where appropriate) units should be crossmatched against the maternal plasma by IAT if the maternal plasma contains red cell antibodies of likely clinical significance. | Re-evaluating the Gold Standards| Holmberg | 24April2013 | CBBS 2013

  16. European PerspectiveBritish Committee for Standards in Haematology Guidelines for pre-transfusion compatibility procedures in blood transfusion laboratories, British Committee for Standards in Haematology Transfusion Medicine doi: 10.1111/j.1365-3148.2012.01199.x Guidelines for the Blood Transfusion Services in the UK 2012) 4.1.4. Interpretation of D grouping has become more complex, with the increase in variety of monoclonal reagents, and molecular testing. The historical distinction between weak and partial D, based on whether the individual is able to make anti-D, has become blurred and a new algorithm is included in Fig. 1. | Re-evaluating the Gold Standards| Holmberg | 24April2013 | CBBS 2013

  17. European PerspectiveBritish Committee for Standards in Haematology Guidelines for pre-transfusion compatibility procedures in blood transfusion laboratories, British Committee for Standards in Haematology Transfusion Medicine doi: 10.1111/j.1365-3148.2012.01199.x Guidelines for the Blood Transfusion Services in the UK 2012) | Re-evaluating the Gold Standards| Holmberg | 24April2013 | CBBS 2013

  18. Agenda Current status of transfusions in the U.S. Traditional serological typing methods Red cell genotyping as a supplemental method Regulatory considerations Recent Blood Product Advisory Committee discussion | Re-evaluating the Gold Standards| Holmberg | 24April2013 | CBBS 2013

  19. Bloodgen Consortium Courtesy of Dr. Nuria Nogues, Barcelona | Re-evaluating the Gold Standards| Holmberg | 24April2013 | CBBS 2013

  20. Genotyping for RBC Antigens • Case for genotyping • Basis for predicting phenotypes from genotyping results • 324 blood group antigens recognized • 33 blood group systems / 40 unassigned antigens • Most blood group polymorphisms are now understood • Potential clinical application • Determination of blood type in transfused patients • Patients with “allo” or “auto” antibodies • warm autoantibodies • positive direct antiglobulin test • Resolution of phenotype discrepancies | Re-evaluating the Gold Standards| Holmberg | 24April2013 | CBBS 2013

  21. Potential Clinical Application of RBC Molecular Courtesy of Dr. Nuria Nogues, Barcelona • Detection of rare but significant antigens • Typing for antigens when antisera are not available • Identification of a fetus at risk for HDFN • Determination of parental zygosity • Typing of fetal blood • Mass screening of donors for antigen-negative blood • Identification of null and novel alleles | Re-evaluating the Gold Standards| Holmberg | 24April2013 | CBBS 2013

  22. German Consensus on Blood Group Genotyping In 2000 a German consensus statement was developed on the use of blood group genotyping and its potential application in clinical situations (Legler et al. InfusioinstherTransfusionmed 2000; 27: 215-16) In fetus from amniotic fluid or trophoblastic cells (chorionic villi) In multiply transfused patients, if standard serology fails In case of auto and allo-immunohemolytic anemia, if standard serology fails For weak D types and other variant RH alleles, if serology is inconclusive | Re-evaluating the Gold Standards| Holmberg | 24April2013 | CBBS 2013

  23. Fetal Blood Group Typing in Europe • Fetal RhD type can be predicted reliably from the fetal DNA in the plasma of D neg pregnant women from beginning of 2nd trimester. Courtesy of Dr. Nuria Nogues, Barcelona 23 Prior to 2001 the usual source of fetal DNA was a sample of amniotic fluid or chorionic villi. Cell-free fetal DNA is detectable in the blood of pregnant women  amount increasing throughout gestation. | Re-evaluating the Gold Standards| Holmberg | 24April2013 | CBBS 2013

  24. Fetal Blood Group Typing in sensitized pregnant women European Experience Courtesy of Dr. Nuria Nogues, Barcelona Non-invasive fetal blood group typing from maternal plasma cell-free fetal DNA is now a clinical reality. Offered by many laboratories in Europe, to identify the fetus not at risk of HDFN. Different assays are currently used for reliable genotyping of D, C, c, E and K by quantitative real-time PCR techniques. | Re-evaluating the Gold Standards| Holmberg | 24April2013 | CBBS 2013

  25. Fetal RHD typing: Application to all D neg pregnant women European Experience • Trials of high-throughput methods have demonstrated that accurate fetal D testing in all D- pregnant women is feasible. • Fetal RHD typing to target antenatal anti-D prophylaxis already introduced in Denmark (2010) and the Netherlands (2011). TRANSFUSION Volume 52, April 2012 | Re-evaluating the Gold Standards| Holmberg | 24April2013 | CBBS 2013

  26. Blood Donors Molecular Typing Barcelona Blood Center Experience Focused on specific groups of donors: • Extensive genotyping of blood donors from immigrant populations  Aim: Identify blood donors expressing low-incidence antigens (Dia, Jsa, Mia, Cob, Kpa) or donors with rare phenotypes: Di(a+b), Co(a-b+), Fy(a-b-), HPA-1(a-b+)  Utility: - For transfusion (rare phenotype blood units) - RBC panel units (Antibody identification) - Diagnostic (reagent cells) Courtesy of Dr. Nuria Nogues, Barcelona 26 | Re-evaluating the Gold Standards| Holmberg | 24April2013 | CBBS 2013

  27. Blood Donors Molecular Typing Barcelona Blood Center Experience • RHDGenotyping of D negativeblooddonorswithRhC and/orRhE positive • Used the BLOODchip Reference platform  Utility: - Quality control of D negative units - Estimate the real incidence of Del units  1.6%  Total of 2.200 blood donors extensively genotyped Courtesy of Dr. Nuria Nogues, Barcelona | Re-evaluating the Gold Standards| Holmberg | 24April2013 | CBBS 2013

  28. Blood Donors Molecular Typing Finnish Red Cross Blood Service Experience • Finnish Red Cross BloodServiceexperience Routine genotyping of blood donors with ID-Core+ since September 2012 • Criteria • – blood group A or O, K neg • – previous donation within a year • – rare donors, ethnic minorities Courtesy of Dr. Nuria Nogues, Barcelona 28 | Re-evaluating the Gold Standards| Holmberg | 24April2013 | CBBS 2013

  29. Agenda Current status of transfusions in the U.S. Traditional serological typing methods Red cell genotyping as a supplemental method Regulatory considerations Recent Blood Product Advisory Committee discussion | Re-evaluating the Gold Standards| Holmberg | 24April2013 | CBBS 2013

  30. Traditional Serological Testing Methods • Regulatory Process for Serology • Biologics License Application (BLA) • Applicable regulations • 21 CFR 600-660 • 21 CFR Part 809 10 (Labeling) • 21 CFR Part 820 (Quality System Regulations) • Definitions: • Biological Product – 21 CFR Part 600.3 (h) • Blood Grouping Reagent - 21 CFR Part 660, Subpart C • Reagent Red Blood Cells – 21 CFR Part 660, Subpart D • Anti-Human Globulin – 21 CFR Part 660, Subpart F | Re-evaluating the Gold Standards| Holmberg | 24April2013 | CBBS 2013

  31. Traditional Serological Testing Methods • Hemagglutination assays (HA) defined immunohematology • Over 300 blood group antigens recognized • Reagent Approvals - FDA • Polyclonal antisera • Monoclonal antisera • Anti-Human Globulin (AHG) • Panel or screening cells with known antigens | Re-evaluating the Gold Standards| Holmberg | 24April2013 | CBBS 2013

  32. Regulatory Consideration • High degree of accuracy has been reported • FDA established molecular testing laboratory to created DNA reference panels • No licensed or approved molecular device for RBC genotyping • Pathway • Investigational device exemption (IDE) • Premarket approval (PMA) • Assurance of safety and effectiveness • Scientific evidence • 180-day review clock | Re-evaluating the Gold Standards| Holmberg | 24April2013 | CBBS 2013

  33. Regulatory ConsiderationRBC Genotyping Workshop, NIH • RBC genotyping promises significant technical and clinical benefits for transfusion medicine • Assay systems for RBC genotyping will be reviewed under the PMA pathway • FDA currently considers that: • In-house validation of RBC genotyping systems will require panels of specimens pedigreed by gene sequencing of the donor • Candidate technology should be defined within review process to permit appropriate labeling, limitations, and comparison to serology • Guidance and policy will be needed Dr. Epstein, Director of CBRR, Sept 14, 2012 | Re-evaluating the Gold Standards| Holmberg | 24April2013 | CBBS 2013

  34. Agenda Current status of transfusions in the U.S. Traditional serological typing methods Red cell genotyping as a supplemental method Regulatory considerations Recent Blood Product Advisory Committee discussion | Re-evaluating the Gold Standards| Holmberg | 24April2013 | CBBS 2013

  35. Blood Product Advisory CommitteeSupports integral labeling with historic antigen type results • December 2012, BPAC asked to comment on • Reporting based on historical RBC typing results from two donations • Validated process to confirm donor identification and accurate linkage to historical data • Confirmation of relevant negative results on the current unit prior to transfusion, when feasible to mitigate risk form historical data • Would BPAC’s response to the first questions vary if serology or molecular testing, or both were performed. • Committee supported historical data as part of the label and their responses would not vary whether the test was serologic or molecular | Re-evaluating the Gold Standards| Holmberg | 24April2013 | CBBS 2013

  36. Thank you The secret to complex serology is in the genes | Re-evaluating the Gold Standards| Holmberg | 24April2013 | CBBS 2013

  37. | Re-evaluating the Gold Standards| Holmberg | 24April2013 | CBBS 2013

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