Heredity_ ABO _ Platelets

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Heredity_ ABO _ Platelets Powered By Docstoc
					ABO and Platelet Selection:
  Beyond Standard 5.14

      Laura Cooling MD, MS
    Associate Professor, Pathology
      Associate Medical Director
        University of Michigan
Standard 5.14
Selection of Compatible Blood and
Components for Transfusion
No specific policy for platelets

• 5.14.1. Recipients shall received ABO group-
  specific whole blood or ABO-compatible RBC
  components.
• 5.14.4. …policy concerning transfusion of
  components containing significant amounts of
  incompatible ABO antibodies or unexpected
  red cell antibodies.
    What is ABO-Compatible?


Analogous to whole blood
• Platelet-compatible
• Plasma-compatible
• Type-specific / ABO-identical
    Platelet-Compatible

    Major ABO Compatibility
Donor platelets  Recipient plasma
        ABO Ag on Platelets
Megakaryocyte Origin
• Developmentally-regulated
  – H, AB with  megakaryocyte ploidy
• Clonal variation in ABO expression

                  CFU-GM
                                   Monocyte
                                                 No AB
                                   Granulocyte

 H+                      ABO               RBC
Stem    GEMM
Cell                                       Platelets
                CFU-Meg/E
         ABO Ag on Platelets
Endogenous                   Exogenous
• Glycoproteins              • Glycosphingolipids
• N- or O-linked             • Plasma
   – GPIIb/IIIa, GP1b,       • Secretor phenotype
   – PECAM (CD31)
   – GP1a, GPIV, GPV
                             • Type 1 chain
• Glycosphingolipids            – Type 1 ABH
  – Type 2 chain                – ALeb
  – Type 3 chain (group A)      – BLeb
 IIb                        IIIa
                                   Iba




Cooling, Transfusion 2001
ABO and Platelet Transfusion
Major ABO Incompatibility-Platelets
• Decreased post-transfusion recovery
• Incompatible platelet crossmatch
• Platelet refractoriness due ABO
Effect of ABO Incompatibility on Platelet Recovery
            Aster R. Blood 1965; 26:732-42




                           B PLT




               A PLT
                                       AB PLT
A/O=52%


     B/O=17%



          A/B=0%
 Factors that influence platelet recovery after
 transfusion. Jimenez et al. Transfusion 2003

Impact of ABO on PLT recovery & survival (split apheresis)

   <0.001                Same donor 2 recipients
        <0.007              •   ABO platelet compatible
                            •   ABO incompatible
                 <0.04
                            •   1, 4, and 24 hours
    An Evaluation of Crossmatching, HLA and ABO
 Matching for Platelet Transfusion to Refractory Patients.
  Heal J, Blumberg N, Masel D. Blood 1987;70:23-30
Retrospective study 51 refractory patients
• 60% transfusions- CCI with ABO-incompatible PLTs
• ABO independent & synergistic w/ XM-incompatibility


     40% in CCI                      85%  in CCI
ABO and Platelet Transfusion
Major ABO Incompatibility-Platelets
• Decreased post-transfusion recovery
• Incompatible platelet crossmatch
• Increased incidence/earlier onset
  refractoriness secondary to HLA
• Increased # & frequency transfusions
Transfusion of ABO-mismatched platelets
  leads to early platelet refractoriness.
    Carr et al, Br J Haematol 1990; 75:408-13

                             ABO-
                          Mismatched      ABO-Matched
% Patients              Platelets (n=13) Platelets (n=13)
Refractory                     69%                       8%

anti-HLA Ab                    38%                       8%

anti-platelet Ab               31%                       8%

Increased                      54%
(3-fold) titers*
* Increased titers sudden and associated with onset of
refractoriness
                      Carr et al. Br J Haematology 1990;75:408-13

                                             ABO Type Specific Platelets
% Platelet Recovery




                                                  Platelet Refractoriness
                                                  (% recovery < 30%)
                                                  = 10 transfusions
                        ABO Mismatched
                      Platelet Transfusion
Increase in Cost for Platelet Transfusion Support
 Cost Effectiveness during Induction Therapy for Acute Leukemia.
             Blumberg N et al. Transfusion 1993;33:A16

                    ABO-random, ABO-specific, ABO-specific,
                    nonleukodepleted nonleukodepleted    leukodepleted

  No. Pts.                64               22                40

  # Platelets (x)        148              117                98
  admision
  HLA-Platelets         47%              27%               2.5%
  (% Pts)

 Cost savings:        $263,000/yr HLA-matched
                      $2663/patient admission
     Factors Influence Clinical Response to
          ABO-Incompatible Platelets
  RECIPIENT               PRODUCT
• ABO Type     • Storage Time       • ABO Type
  - O > > A, B   -  ABO w/ time      - A1 > B > O,A2
• ABO Titers     -  Activation     • Subgroups
  - Immune       -  Synthesis        - A1 > > A2
  - High titer        GPIIb/IIIa      - High-expressor
  > 1000 IgG*                       • Sex
  > 500 IgM*                        • Race
• Immune complexes                  • Megaryocytes
*Brand, Transfusion1986
                                      - Clonal differences
                                      - weak  strong ABO
                Broad distribution of A-antigen (%HPA)
                         on Group A Donors
                           35
Group A donors (A1 + A2)

                           30                                                    A all


                           25
                                             X= 32 + 22%
                           20


                           15


                           10                                             High
                                                                       Expressors
                            5


                            0
                                0   5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95

                                              % HPA+ platelets
                    A-antigen on Human Platelets
                    A expression = A1 RBC phenotype


                A                           B                  C
                        CD41+
CD41 (log PE)




                                                          A1       A2
                         HPA+
                                                     HPA +




                                            Low - high

                HPA (log FITC)

                                            D                  E
                            (%) Platelets




Cooling, Blood 2005                                      HPX       O
Transfusion Efficacy of ABO major-mismatched PLTs in
    children is inferior to that of ABO-identical PLTs
         Julmy et al, Transfusion 2009; 49: 21-33

                                     OR       P
          ABO Identical              1.0       -
          ABO-Incompatible          3.97   <0.001
             A1 Donor               9.30   <0.001
             A1/B Donor             5.81    0.002
             A2 Donor               1.13     NS

  1. ABO independent risk factor for platelet refractoriness
  2. A2 platelets were equivalent to ABO-identifical
 High Expressor Phenotype (HXP)
                A       B       C
                                         CD41+




                         CD41 (log PE)
                                                                             A1
                                          HPA+
• 2-8 fold  A/B expression                                              HPA +
       • Type 1, bimodal population
       • Type 2, uniform population
• 4-7% donors (A,B,AB) (log FITC)
                    HPA

• Autosomal dominant                                                 D 2 HPX E
                                                                     Type




                                             Percent (%) Platelets
   – Genetic basis unknown
                                                                           HPX
      • Consensus FUT1, A1/B alleles
      • No association with 5’ enhancers
• Platelet refractoriness
                                                                      HPA Fluorescence
  Plasma-Incompatible or
  “Out-of-Group” Platelets

      ABO Minor-Incompatible
Donor Plasma Recipient ABO Type
 ABO and Platelet Transfusion

Plasma-Incompatible Platelets
• “out-of-group” or minor-incompatible
• Common: 30-40% nationwide
  – Limited inventory specific ABO types
  – Minimize outdate & product wastage
  – HLA-selected/matched platelets
 ABO and Platelet Transfusion
Plasma-Incompatible Platelets
• Oncology patients
  – No  Hct or  RBC utilization


Potential Medical Risks:
  –   Hemolytic transfusion reactions
  –   Decreased platelet transfusion response
  –   Increased transfusion reaction rate?
  –   Increased morbidity & mortality?
ABO and Hemolytic Transfusion Reactions
Relatively uncommon
  – Literature Est. <1:1000 - < 1:25000
US Data
• 2 million platelet transfusions/year
  – 30-40% out-of-group
  – 200-000 to 400,000 platelet transfusions
  – < 50 reported in literature/chat rooms
• Univ. of Michigan (2000-2010)
  – 3/>100,000 platelet transfusions
     • All were apheresis platelets
    Platelet-Associated Acute Hemolytic
           Transfusion Reactions

Reported Cases tend to be severe:
  – 2-10 gm drop in Hgb
  – + DAT (IgG, C3)
  – Laboratory findings of hemolysis
  – Cases of DIC, death
    Platelet-Associated HTR
Product Factors     Patient Factors
• Type of Product   • Genetic Factors
  – Apheresis         – ABO type
  – Pooled            – Secretor status
  – Modified        • Blood volume
• Donor               – Age
  – ABO type          – Volume transfused
  – ABO titer
     • Sex
     • Diet
  Product Factors: Donor
Donor Factors
• ABO
  – > 90% implicated donors = Group O
• High titer
  – Saline:      128-16,384
  – AHG:         1024-32,000
• Risk Factors
  –  Multiparous women
  – Dietary supplements
Probiotics: The latest health fad
                                      Straws for
   Adults           Children        very young kids!




Probiotics
•Contain mixtures of live bacteria
  – „Replenish‟ good bacteria in gut
  – Aid in digestion,  bloating and irregularity
  – Common use among patients GI d/o
ABO Antibodies Stimulated by Bacteria




  Germ-Free        Germ-Free             Control
 Environment      Environment        Std Environment
 Sterile Diet      Sterile Diet       Standard Diet
                        +
                Dead E. coli (O86)
 No Anti-B        +++ Anti-B*             + Anti-B
                 *titers higher , earlier than controls
  Probiotic-associated high-titer anti-B in a group A
      platelet donor as a cause of severe HTR
           Daniel-Johnson et al. Transfusion 2009

• Long-time apheresis donor
• 4 cases HTR
• High-titer anti-B after taking probiotics
   – Inhibit anti-B with probiotic suspension


                   Control                    Donor
Method              Titer            Titer- 1   Titer-2 (2 mo)
Saline               16-64            4096          16384
AHG                 16-128            4096          16384
Product Factors: AHTR
  – 82-90 % apheresis platelets
  – Rare, pooled platelets
     • Massive transfusion (> 3L PLTs)
     • Pediatric surgery


Apheresis                   Random
• 200-400 mL/donor          • 50 mL/donor
• No dilution               • Diluted 4-6 fold

 Significant risk w/
  High-titer donor
            Patient Factors
Genetic Factors
• ABO type: A1, AB > B, A2 > > O
• Secretor status
   – Secretor may be protective
   – Soluble A,B substances
   – Neutralize donor ABO antibody
• Clinical & historical precedent:
   – Conditioned “whole blood”
   – Pooled plasma (WWII, Uniplas, Bioplasma FDP)
   – TPEX in ABO-incompatible organ transplants
    Soluble A-Substance is influenced by
  A Subtype (A1, A2) & AB RBC Phenotype
                                                              Soluble A-Substance in Human Plasma
                                                     70
         Soluble A-Substance (mean antigen, ELISA)
                                                          A1 donors rich
                                                     60
                                                          In soluble A
                                                     50


                                                     40


                                                     30


                                                     20


                                                     10


                                                     0
                                                          O       B      A2       A1     A1B        A2B


Adapted from Achermann et al, Transfusion & Apheresis Sci 2005
 Antibody Neutralization in “Mixed” Pools
            Cooling et al, Transfusion 2009




Neutralize anti-A and anti-B with 1 non-O platelet/5 pack
Soluble A Associated with A1 and Se
 Adapted from Achermann et al, Transfusion & Apheresis Sci 2005

                                                Soluble A-Substance by ABO, Secretor Type
                                              300



          Soluble A-Substance (mean, ELISA)   250


                                              200


                                              150


                                              100


                                               50


                                               0
                                                     O   A2 A2 A1B A1B A1 A1 A1
                                                         NS Se NS Se NS Se Se
                                                                         Leb+ Leb-

Question: A1/NS and AB at increased risk from group O PLTs?
          Decreased risk A1, Le (a-b-) ?
      Patient Factors: AHTR
Genetic Factors
  – ABO type
  – Secretor status
• Blood volume
• Age
  – ? Risk in neonates and young children
     • Small blood volume
     • Delay in Secretor
      Other potential risks with
   Out-of-Group PLT Transfusions

• HTR
• Stem cell transplantation
  – Delayed RBC engraftment (allo‟s)
  – Increased morbidity post-transplant
  – Increased risk VOD
Associations not causal links
ABO Incompatible Plasma in Platelet Concentrates
      May Increase Allogenic BMT Toxicity.
                                   Benjamin et al. Transfusion 1999
  Probability of Survival




                            100


                            50


                             0
                              20   40   60    80   100 120 140 160 180
                                             Days post BMT
                            ABO Major-Plasma Random   ABO Major-Plasma Compatible
      ABO-Incompatible allo-PSCT/BMT
•   Increased # platelet transfusions
•   Veno-occlusive Disease (VOD)*
•   Renal failure*
•   Pulmonary Insufficiency*
•   Multi-organ failure*
•   Decreased survival*
•   Increasing transfusion precede organ failure
*Number of platelet transfusions and transfusion of
    incompatible plasma independently associated with
    organ failure and increase treatment toxicity
  VOD in Children and PLT TX
    Transplantation 2005;80:314-19.
VOD= 39% (73/186) children
• 30% ABO-”plasma” compatible PLT
• 48% ABO-incompatible PLT
   – RR = 2.08, equivalent to Bulsulfan

                   PLT
 Other potential risks with Out-of-Group
           PLT Transfusions

• HTR
• Stem cell transplantation
• Surgery/Trauma?
  – Cardiac surgery
  – Trauma*
     • Incompatible plasma
     • Small increase in RR
     • Significant confounders
     Association of ABO-mismatched platelet
   transfusions with morbidity and mortality in
                 cardiac surgery.
       Blumberg et al Transfusion 2001;41:790.

        Platelets:      ABO            ABO
                      Identical     mismatched
Units RBC             6.1±4.2         9.2±9.1
Days of Fever         6.0±7.2         9.5±16
Days Antibiotic       4.4±8.9         14±39
Hours in ICU          87±170         160±460
LOS (days)           13.6±14.4       18.1±21.1
Deaths (hospital)      1.9%            8.6%
 Platelet Transfusion Strategies

Transfusion Service
• Policies
  – PLT selection
  – Limitations out-of-group platelets
  – Plasma reduction/washing
Standard 5.14

Selection of Compatible Blood and
Components for Transfusion

5.14.4. The transfusion service shall have a
policy concerning transfusion of components
containing significant amounts of incompatible
ABO antibodies or unexpected red cell
antibodies.
  Strategies to Minimize HTR
Transfusion Service
• ABO-identical
• ABO-plasma compatible
• Pooled platelets
• Policies on limiting plasma volumes
  –   < 4 minor-incompatible PLT/wk
  –   < 2 minor-incompatible PLT/72 hrs
  –   1000 mL plasma/wk
  –   300-500 mL plasma/day
  –   Children: weight-based algorithm
  Strategies to Minimize HTR

• Transfusion Service
• Blood supplier
   – Increasing % non-O donors
   – Platelet additive solutions
   – Donor screening
     • Identification of “high-titer” units
     • Reserved for O-recipients only
  Issues Related to Screening

• Method
• Population/historical factors
• Critical titer
  – Clinically-significant ?
  – Inventory management
Testing Method – Recent CAP survey*
• Test tube
   – Immediate spin (IS)
   – RT incubation
   – AHG
• Gel (RT, AHG)
• Diluents
   – Saline
   – Albumin (0.5%, 6%, 22%)
   – DTT

* CAP ABT-A Antibody Titer. 2010
Difference in Titers by Tube vs Gel
                                                             Anti-A                                                            Anti-B
                                        60                                                                       60


    No. Group O Units (Pooled, n=125)
                                                                                                                                           45.2
                                                 MT=16                   42.4                                         MT=8                                                             MT=Median Titer
                                        50                                                                       50


                                        40                        30.4                                           40


                                        30                                                                       30
                                                                                                                                    25.8
                                                                                                                                                  23.4
                                                                                                                                                                                       TUBE TITER
                                                                                18.4
                                        20                                                                       20


                                        10                                                                       10
                                                            4.8
                                                                                       2.4                                    2.4                        3.2


                                                                                                                                                                                        4-fold 
                                                  0.8 0.8
                                         0                                                                       0
                                             0    1    2     4     8     16 32 64 128 256 512                         0   1   2      4      8     16 32 64 128 256 512
                                                            Anti-A Titer (Tube)                                                      Anti-B Titer (Tube)
                                        60                                                                       60
                                                 MT=64                                                                MT=32
  No. Group O Units (Pooled, n=125)




                                        50                                                                       50                                      39.5
                                                                                       37.6


                                        40                                                                       40                               31.4


                                                                                24
                                                                                                                                                                                       GEL TITER
                                        30                                                                       30
                                                                                                                                                                18.5
                                                                                              16.8
                                        20                               12
                                                                                                                 20


                                        10                                                                       10
                                                                                                                                                                       4.8
                                                            3.2                                      3.2   2.4                             2.4
                                                      0.8                                                                           0.8                                      1.6 0.8
                                         0                                                                       0
                                             0    1   2     4      8     16 32 64 128 256 512                         0   1   2      4      8     16 32 64 128 256 512
                                                             Anti-A Titer (Gel)                                                       Anti-B Titer (Gel)


                                                      P<0.0001                                                                    P<0.0001                                             T-Test
                                                                       Cooling, Transfusion 2009
                       Inter-Laboratory Variation
                      CAP Proficiency Survey ABT-A 2010
                      Same sample & method: Titers 2-256
                                    Proficiency Testing
                 40

                 35

                 30
% Laboratories




                 25

                 20

                 15

                 10

                  5

                  0
                       0   1   2     4   8   16   32   64   128   256   512
                                         Anti-A Titer
                                   (Uniform Method, Tube)
Donor Screening for Anti-A, B
• Testing Method
• Population & historical factors
  – Historical vs current ABO titers
  – Industrialization
  – Dietary changes
Anti-A&B Titers Change with Time
                                        Anti-A Titers Over Time
                      50

   % Group O Donors   40


                      30
                                   2007                             1946
                      20


                      10


                      0
                           0   1    2      4   8   16   32   64     128   256   512
                                        Anti-A Titer (Saline, IS)

Historically, 10-20% group O donors “dangerous”
1940-50‟s: 13 - 40% titers > 500
1960‟s        < 1% titers = 256 or greater
              Decrease in ABO Titers with Sterile, Processed Foods
                           Japan 1986                                  70
                                                                                    Laos 2001
             100
                       Japan 1986
                                                                       60
                                                                                    Laos 2001                         Diet
              80
                                                                       50                                             Natural Foods




                                                            % Donors
% Donors




              60                                                       40

                                                                       30
              40
                                                                       20
              20
                                                                       10

              0                                                        0
                   2   4   8    16 32 64 128 256 5121024                    2   4     8    16 32 64 128 256 5121024
                                    Anti-A Titer                                                Anti-A Titer


                           Japan 2005
              40

              35
                                                    Japan 2005
                                                                                                                      Western Diet
              30

              25
                                                                                                                      Processed Food
  % Donors




              20
                                                                       Data adapted from:
              15

              10
                                                                       Differences in ABO antibody levels among blood
               5
                                                                       Donors: a comparison between past &
               0                                                       present.Mazda et al. Immunohematology 2007.
                   2   4    8       16 32 64 128 256 5121024
                                     Anti-A Titer
  Issues Related to Screening
• Method
• Donor Factors
• Critical titer
  – Clinically-significant ?
  – Impact on inventory for non-O patients
What is a Critical Titer
           % Donors vs Critical Titer
                                  (3% to 50%)

                      50


                      40
 Percent (%) Donors



                      30


                      20


                      10


                       0
                        0   100   200    300    400      500   600   700
                                        Critical Titer

             Critical titer by saline (circle) or AHG (square)

                      Cooling, Immunohematology 2007
  Variation in Critical Titers and Method
                       Test        Method           Titer     % Donor
USA                     2%        Tube, Gel       50 - 200     3-28%
England                  Y       Automation       100 -128     3-10%
                                    Tube
Scotland                 Y                           50
Italy                    Y         Gel, IAT       64 - 256
Germany                  Y           Tube            64         5%
Norway                   Y            IAT            250
Sweden                   Y       Saline, Tube     100 - 400
Switzerland                       Hemolysis          16
Finland                  Y       Saline, Tube        32        5.7%
Japan                    Y            IAT            512

Data as of 2007. Cooling Immunohematology 2007; 23:20-33
What is a reasonable “safe” vs “high” titer?
                     50                                                   30
Percent (%) Donors




                                                     Percent (%) Donors
                                            Saline                             AHG
                     40                                                   25                         AHTR
                     30                                                   20
                                     AHTR                                 15
                     20
                                                                          10
                     10
                                                                           5
                     0                                                     0
                              2048
                               256
                               512
                              1024

                              4096
                              8192
                                  2
                                  4
                                  8



                                 64
                               128
                                 16
                                 32




                                  4

                                  4




                                                                                   1024
                                                                                   2048
                                                                                   4096
                                                                                   8192
                                                                                    256
                                                                                    512
                                                                                      16

                                                                                      64




                                                                               1.638 104
                                                                               3.277 104
                                                                                       2
                                                                                       4
                                                                                       8




                                                                                    128
                                                                                      32
                          1.638 10
                          3.277 10
                     Titers w/ AHTR =       90% titer > 128 (saline, tube)
                                            100% titer > 512 (AHG)

                     Impact of low critical titers?
                     • Saline titer > 50 (16-30% product)
                     • AHG titer > 128 (30-40% product)
                                                                               Cooling 2007, 2009; Josephson 2004.
Summary
• Platelet Transfusion = whole blood
  – Compatibility of PLTs
  – Compatibility of Plasma
• Hemolysis and Risk Reduction
  – Type of product
  – Transfusion service vs supplier
  – Testing method
  – Critical titer

				
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