Out-of-Group PlateletTransfusion

Shealynn B. Harris, M.D.

March 23, 2006

Case Presentation

Child presents to Emergency Departmentwith symptomatic anemia

. Hb = 6.1 g/dL and Hct = 16.2%

. Recent history of dark urine. Recent transfusion

Blood Bank: Initial Testing

ABO and Rh Typing

I A-positive I

Antibody Screen Results

3 out of 3 screening cells NEGATIVE

CAT (ordered separately by clinical team)

IgG 2+; C3 NEGATIVE; ELUATE NEGATIVE

1

Forward Reverse Rh

Anti-A Anti-B A1Cells B Cells Anti-D

2+ a a 2+ 3+

Additional History

. "Brown" urine and serum

. Transfused the week ofpresentation at "someplace 3hours away" .

.History of Acute Myeloid Leukemia(AML)

Additional History. Cord blood transplant 6 months prior

- A-to-O major ABO mismatch

. Chronic Graft-versus-Host Disease (cGVHD)

. Multiple Medications- Prophylactic antimicrobials (penicillin)-Immunosuppressants

Additional Labs

2

Pit Count (175-475 X103/uL) 126x103

Reticulocyte Count (0.5-3.0%) 7.9

Reticulocyte Production Index (0.5-1.5 %) 1.3

Total Bilirubin (0-2.0 mg/dL) 6.3

Direct Bilirubin (0-0.3 mg/dL) 2.6

Haptoglobin (30-200 mg/dL) <10

BUN (7-22 mg/dL) 40

Creatinine (0.3-1.0 mg/dL) 0.7

Urine: hemoglobin, urobilinogen, coarse granular casts

Peripheral Smear: Low Power

. '!:>.' ~. Yo '"<J. .""~.. '1.111. ~ 'Ift."""'Q 0.0 .."'" " " .'" . 0'" .~~'!1>I..'tx;.. ,fit.. ~ ~.. ... ..' .e. Ow. 04 .It .~0- 0 . or .0 - .,:.'",.@i' ": 11.. c: 'tf 'It>(' ~$ i . .."tk. ,:<¥J'.0."'" '., <!Oi$1>.~" '...

~WI1...I' !J " eo. "-0 ..,.t.." ,'!III""" 0 '0 ~ ".t,...o O"O~ft:'... ..o. tot. "tI'~ ". "",,0 .,CO.,-. ..~':} .. .. or 0 .. .. ~" .,p,tI"'" ~;')Q ~@4o,,~?6' Hb =4 5 g/dL ). "0.(; Ofi .

Peripheral Smear: High Power

Hemolytic Anemia:Immune Mediated

. Alloimmune Hemolytic Anemia- No identifiable antibody specificity on RBC

panel. WarmAIHA

- OAT positive with IgG on RBCs- No identifiable antibody specificity on screen

and no panagglutinin- Eluate negative

3

Hemolytic Anemia:Immune Mediated

.Drug-induced Hemolytic Anemia- Penicillin

.3% of pts on high-dose IV therapy with positiveDAT

.<1% hemolyze, usually EXTRAVASCULAR (lgG)

Patient needs blood...

. Patient is A-positive by initial testing with nodiscrepancy between front and back type

. Crossmatch with A RBC units:

INCOMPATIBLE

. Crossmatch with 0 RBC units: COMPATIBLE

Patient needs blood...

. More transfusion history- Outsidebloodbankgivesrecenttransfusion

history. 11/16: A+ PLT, A+ RBC. 11/23: A+ PLT. 12/1: A+ RBC. 12/2: 0- PLT

- VSS and asymptomatic during recenttransfusion

4

ImmunohematologyReferenceLab Results

. Anti-A IgG identified at 37/AHG

. No IgM identified

. Repeat reverse type with A cells-Immediate spin: NEGATIVE- 37/AHG: 2+

. Patient receives 1 0 RBC unit and

responds well

Anti-A: Donor or Recipient

. Passively-acquired from 0 Platelet unit- Minor mismatch

- Donor with "high titer" anti-A, anti-B,and/or anti-A,B

- Finite amount of antibody, undetectablein a few days

- Often not clinically significant

Anti-A: Donor or Recipient

. Posttransplant immune hemolysis- Major mismatch (A-to-O)

- Typically see a mixed-field of donor andrecipient RBCs

- Hemolysis can be chronic if chimerismdevelops

- Continuous production of antibody as long asimmune stimulus is present

5

Anti-A: Donor or Recipient. Patient has fully converted to cord blood donor

type (group A). Blood Center has retained a sample fromapheresis-derived platelet (SOP) unit for QCtesting. Anti-A titer on group 0 SOP sample (donor)- IgM: 256- IgG: 4096. Titer on recipient sample-lgM: 2- IgG: 32

. OAT NEGATIVE at 1-week follow-up

14

Hgb and Bilirubin: Hospitalization and Follow-up

12

10 5 'iia.E

4 -c:ii

3 ~2 iii

to

:!!a~J:I1116J:

HD#1 HD#2 HD#3 HD#4 HD#S(DIC) D#12(FIU)

Case Evaluation

.What clinical factors contributed to

hemolysis?

- Recipient is blood group A

- Platelet shortage.Only 0 units available on a Friday afternoon foroutpatient transfusion

- Entire SOP unit transfused (-300 mL)- Platelet unit not volume reduced

6

Case Evaluation

I

I

I

I

I

I

I

I

I

I

I

I

I

I

I

I

.What clinical factors contributed to

hemolysis?- Recipient with small plasma volume

- "High titer" platelet unit

- History of A-to-O HSCT, decreased anti-Aneutralization due to lack of A antigen ontissues

Diagnostic Challenges.What factors complicated the identification of

the anti-A?

- Onlythe IgGisotypewas detected.Immediate spin ABa type routinely performed, which

detects IgM

- Delay in presentation.IgM-bound cells are more rapidly cleared

- Positive DAT but negative eluate. Eluate is tested with panel of group a cells

-Initial lack of an adequate transfusion history. No knowledge of group a SDP transfusion

Diagnostic Challenges

.Why was there a delay in signs andsymptoms?

- Recipient did not report symptoms to staffbut complained to mother about transientback pain

- Medications masked s/sx of AHTR(cytokine storm)

- Dark urine was noticed by mother the nextmorning but may have been present earlier

7

Platelet Transfusion:Minor ABO Mismatch

. Passively transfused donor anti-A, anti-B, or anti-A,B that bind to recipientantigens

.Apheresis-derived Platelets (SOP)- 300mL plasmaper unit-Antibodies from a singledonor

.Whole blood-derived Platelets (ROP)- 50 mLplasmaper unit- Pooldiluteseachdonor'santibodies

Platelet Transfusion:Minor ABO Mismatch

. AABB Standards- A plasma unit should be ABO compatible with

recipient's RBCs (volume - 300 mL)

- No ABO compatibility requirement for platelet units

. ABO-matched platelet products areconsidered first-line therapy

Platelet Transfusion:Minor ABO Mismatch

. Limitations to providing ABO-matchedplatelets- Limited supply of Platelets

- Crossmatch-compatible and HLA-matchedrequirements may necessitate out-of-grouptransfusion

- Frequency of donor blood groups

- Encourage group 0 donors to donate duringshortage

8

How big is this problem?

Platelet Transfusions:

13 Reported HTR in Adults

9

Author, Year Age ABO Pit Type PltABO Saline AHG OutcomeTiter Titer

Zoes, 1977 44 AB RDP 0 256 NR NR

McLeod, 1982 45 A SDP 0 1280 10,240 S

Pierce, 1985 58 B RDP 0 512 32,000 S

Ferguson, Ig88 66 A RDP 0 256 >4,000 S

Reis, 1989 56 B SDP 0 NR 4,096 S

Murphy, 1990 30 A SDP 0 256 1,024 NR

Malr, 1998 28 A SDP 0 128 NR S

MacManigal, 1999 72 AS SDP 0 NR NR S

La..son, 2000 44 A SDP 0 16,384 NR S

Valbonesi, 2000 51 A SDP 0 >8,000 NR S(dry)

Ozturk, 2003 21 A SDP 0 NR NR S

Josephson, 2004 A SDP 0 256 8,192 SA SDP 0 NR 1,024 S

Platelet Transfusions:7 Reported HTR in Children

Author, Year Age ABO Pit Type PltABO Saline AHG OutcomeTiter Titer

Conway, 1984 15 A SDP 0 8,192 NR D

Pierce, 1985 2.5 A SDP 0 512 32,000 S

Chow, 1991 18 AS SDP, RDP 0 1,024 NR S

Valbonesi,2000 16 A SDP(dry) 0 >8,000 NR D

Duguld,lgg9 5w A NR 0 NR NR S9d AB NR 0 NR NR S

Angiolillo, 2004 8m A SDP 0 NR NR D

I

I

I

I

I

I

I

I

I

I

I

I

I

I

I

I

I

I

I

I

I

Platelet Transfusion:

Minor ABO Mismatch and Hemolysis

Mair B and Benson K. Transfusion 1998;38:51-55.

. Retrospective review (7 month period) N = 16. Inclusion: Non-group a Auto-BMT ADULTS who received ABO-identical and non-identical SDP in 24 hrs.

. Exclusion: RBC transfusion during the 24 hr period.

. 1 AHTR in 9,000 ABO-mismatched platelet transfusions

I p =0.193 I

Minor ABO Mismatch and Hemolysis:Mitigating Factors

" Antibody Dilution- Antibodiesin plasmaproductare dilutedin

recipientplasmavolume" Issue

-Small-volumerecipientshavelessdilutionalcapacity

-"High-titer" anti-Aor anti-Bmaynot beeffectivelydiluted(e.g.SDPs)

Minor ABO Mismatch andHemolysis: Mitigating Factors

" Antibody Neutralization- Infused donor ABO antibodies are

neutralized by soluble and tissue-expressed ABO substances"Issue

-Some individuals do not havesoluble ABO substances

-ABO mismatched HSCT patients(ABO tissue expression differentfrom RBC expression)

10

Group Number Mean Change Hb 95% CI

ABa-identical 24 -0.50 -0.72-0.29

Plasma- 24 -0.11 -0.36-0.15incompatible

"High Titer" Donors: UK Policy"Platelet recovery of both major and minor ABCincompatible platelet transfusions may be impaired tosome extent, but this is not usually clinically significant. Amore important consideration concerning donor ABCantibodies is the avoidance of acute haemolysis, whichmay occur after ABC-incompatible platelet transfusions,typically with transfusions of high titre anti-A to A 1recipients. This problem has been particularly apparentin small children receiving apheresis platelet

concentrates, which contain large volumes of plasmafrom single donors. Group C platelets should only be

used for group A, Band AB patients if they have beentested and labelled as negative for high titre anti-A andanti-B." Consider anti-A titer "2 128 as "high titer".

www.blood.co.ukfpdfdocs/blood_matters_5.pdf

Critical Titer:

"Dangerous Universal Donor"

. "DangerousUniversalDonor"termed in1923- BloodfromsomeGroup0 donorscaused

AHTR- Required minor crossmatch to be performed

. A critical antibody titer was attempted to bedefined- Methods not standardized

- High prevalence of "dangerous universaldonors" relative to number of passive AHTRs

11

Critical Titer:

"Dangerous Universal Donor"Reference Dafe Titer Medium Prevalence

Rutzky' 1956 64 SalineErvin' 1950 200 Saline 8% anti-A

200 Saline 2% antl-BCra-.;ord" 1952 200 AHG serum 18%anti-AGrove-Rasmussen" 1966 20 AHG serum 40%Gardnerand Tovey" 1954 Strong Saline 8.7% anti-A

oI:ilYSin0.36% anti-B

Grove-Rasmussen" 1953 AHG serumGrove-Rasmussen" 1956

$Saline

Tisdall" 1946 Saline 19.2%Saline -50%

Ebert" 1946 500 Saline 13%A3.5%B

Aubert" 1942 512 Saline 40% A9%B

Larssonet 01.Transfusion 2000;40:902-906.

Significant numbers of a(,heresis-derived group 0 platelet wdt.have "Wgh-titer" IIntl-1\IA,B: intpllcatiollsfor trunsfusloll poUry

Transfusion. 2004;44:805-808C.D. J"'~"w",. N.C. ..,,,/11,. t: v"" D<m'a.-<.ond en 1Ii/(".

N=100 Critical Titer: IgG 01:256 and IgM 01:64

TABLE 1. Ant~AJA,B 19Mand IgG tita.. In group 0SDP.: gel technology

Numb&,.r """'P'"'igiig~""""""""""""""""""""""iiiG'gi;

rn ~

TII""32

...",.25ESI.'''''roo.

Prevalence of "high titer" donors: 30 -40%

Out-of-Group PlateletTransfusion: Other Concerns

. Platelet Refractoriness- HealJM et al. Eur J Haem 1993, Ann Hemato/1993,

B/ood 1987

. Immune Complex Formation- Heal JMet al. VoxSang 1996;71:205-211.- Heal JM et al. Br J HaemaoJ 1993; 85:566-572.

. Increased Morbidity and Mortality in AcuteLeukemia and BMT Patients- Heal JM et al. Am J Hemato/1994; 45:189-190.

- Benjamin RJ et al. Transfusion 1999; 36:1273-1274.. Stem Cell Transplant Population- Limited studies on safety and efficacy out-of-group

platelet transfusions

What 'V(Jllid Karl Lalld.teinrr do? The ABO blood grollP and stem celltrallsplallt.tion

JM ",,". JL U""'d'. GL ,,,;n,p" ,nd N nlnn,''''''

IBone Marrow Transplantation 2005;36:747-755

Table 3 Suggested approach [0 transfusion ther"l'Y in stem cell

transplaut recipients and oU.er patieuts receiving multiple transfusions

Trausfuse outy leukored...'Cd blood componL..[.Transfuse mlly ABO identicat blood eomponCDts

Whell 'hi, is nol possible ""'nuseof ABC) IIollidemiealll'nll'pL"''', or~Iorta~cs of ABO blood group identical comp",'cn"

Use red cell and platdet transfusions Jacking ,",Iuble AOO anligento which the recipient has antibody (usually group 0 red cell, andp"'lcletsjRemove supernatau, p"ISma containin~ antibody '0 recipient ordonor ABO anligL"TIsbefore tralL,fusion. by washing orc'ClltrifngntionExcept wilen ""rious shortages occur, do not trJnsfuse ABOnonidentical componenls merdy for purj)<"es of blood bankh"enlnrY control (ie. to pre"nt ",a'tage)

12

What would Karl Laudsreioer do? The ABO blood group aud srelU ..IItrun,plantation

J" H""', JL u"","', GLPhillip",,'"N ","ml..,'

IBone Marrow Transplantation 2005;36:747-755Table 4 Safest "an,ru,i,m, in ABO nonidentical stem celllmo'plants

Platelet Transfusion:

Minor ABO Mismatch and Hemolysis

Possible Preventive Measures- AvoidABa-mismatched platelet

transfusionsLimited general platelet supplyLimited Band AB products

- Avoid transfusing group a platelets tonon-groupa recipients

Limited platelet supplyGroup 0 donors are prevalent andencouraged to donate

Platelet Transfusion:

Minor ABO Mismatch and Hemolysis. Possible Preventive Measures

- Avoid transfusing ABO-mismatched platelettransfusions to children and neonates. Limited platelet supply

- Volume-reduce ABO-mismatched platelets.Lossofsomeplateletsinprocessing, Delayinplatelettransfusion

- Screen group 0 donors/products for high titer anti-A. 'Critical' titer difficult to define. Increased fiscal cost

. Requires time and technical resources

13

D"nor 11£'-;1';'.711 Trw"luJied Truos.fo",ed Tr.01/itsedRBC plolelN' p/tmll"!

cr.,"p,",,:'P"""

0 0 0 0 0A A A A AU B B B BAn AB An AU AU0 il.. B, AU Washed 0 Washed 0 AUA 0,11 Washed 0 Washed 0 AUA AU Wash.'<!A Washed A AUB O,A Washed 0 Wasbed 0 AUII All Washed II Wushed B AnAll 0 Wasbed 0 W,oshed 0 ABAn A Wu,bcd A Wa,bed A AUAU B Wa,hed U W..,hcd B AB

Platelet Transfusion:Minor ABO Mismatch and Hemolysis

- Screen group a donors/products for high titeranti-A

. "Critical" titer difficult to define

. Increased fiscal cost

.Requires time and technical resources

- Pre-pooled RDPs.Potential to improve platelet supply

. Increase supply from group A whole blood donors

. Dilutes a "high titer" unit among 5-6 other units

. Exposes to multiple donors (HLA alloimmunization)

Summary

. Minor ABa mismatched platelet transfusioncan result in severe hemolytic reactions

. High-titer group a SDP products appear tobe of greatest risk

. Consider vulnerable populations- Children and neonates

- Stem cell transplant patients

14

Summary

. Prevention strategies include:-Avoid transfusing group 0 platelets to non-

group 0 recipients, if possible- Volume reduce group 0 platelets designated

for non-group 0 recipients- Titer group 0 units and avoid transfusing

those with high titer-Increase awareness about group 0 platelets

and HTR

. Pre-pooled RDPs

15