2009 Ten Years of Hemovigilance Reports of Transfusion-r

7/27/2019 2009 Ten Years of Hemovigilance Reports of Transfusion-r

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T R A N S F U S I O N P R A C T I C E

Ten years of hemovigilance reports of transfusion-related acute

lung injury in the United Kingdom and the impact of preferential

use of male donor plasma

Catherine E. Chapman, Dorothy Stainsby, Hilary Jones, Elizabeth Love, Edwin Massey, Nay Win,

Cristina Navarrete, Geoff Lucas, Neil Soni, Cliff Morgan, Louise Choo, Hannah Cohen, and

Lorna M. Williamson on behalf of the Serious Hazards of Transfusion Steering Group

BACKGROUND AND METHODS: From 1996 through

2006, 195 cases were reported as transfusion-related

acute lung injury (TRALI) to the Serious Hazards ofTransfusion scheme and from 1999 onward classified

by probability, using clinical features and HLA and/or

HNA typing. From late 2003, the National Blood Service

provided 80 to 90 percent of fresh-frozen plasma (FFP)

and plasma for platelet (PLT) pools from male donors.

RESULTS: Forty-nine percent of reports were highly

likely/probable TRALI, and 51 percent possible/unlikely.

Of 96 investigations, donor antibodies recognizing

recipient antigens were found in 73 cases (65%), with

HLA Class I in 25 of those (40%), HLA Class II anti-

bodies in 38 (62%), and granulocyte antibodies in 12

(17%). A review in 2003 revealed that the TRALI risk/component was 6.9 times higher for FFP and 8.2 times

higher for PLTs than for red blood cells, and that in

donors of implicated FFP/PLTs, white blood cell anti-

bodies were found 3.6 times more often than by chance

(p 0.0001), with all implicated donors being female.

Provision of male plasma was associated with a reduc-

tion in TRALI reports from 36 in 2003 to 23 in each of

2004 and 2005 and 10 in 2006. Highly likely/probable

cases reduced from 23 in 2003 to 10, 6, and 4 in the 3

subsequent years, with cases implicating FFP or PLTs

falling from 16 to 9, 3, and 1 respectively.

CONCLUSIONS: The risk of highly likely/probable

TRALI due to FFP has fallen from 15.5 per million units

issued during 1999 through 2004 to 3.2 per million

during 2005 through 2006 (p = 0.0079) and from 14.0

per million to 5.8 per million for PLTs.

N

ow that the risk of transfusion-transmitted

viral infection has reached extremely low

levels, transfusion-related acute lung injury

(TRALI) has emerged as one of the most

serious complications of transfusion. In reports to the

Food and Drug Administration (FDA), TRALI moved from

the third commonest causeof transfusion-related death in

1997 through 2002 to the commonest in 2003.1 Although

single case reports which were probably TRALI have been

published since the 1950s, the syndrome was character-

ized and named only in the past 2 decades. 2 The accepted

features of TRALI are acute dyspnea with hypoxia and new

or worsening pulmonary infiltrates arising during or

within a few hours of a transfusion of plasma, cellular

blood components, or immunoglobulin.3 Immediate and

ABBREVIATIONS: BC(s) = buffy coat(s); CSP = cryosupernatant;

NBS = National Blood Service; SHOT = Serious Hazards of

Transfusion; SSP(s) = sequence-specific primer(s);

TACO = transfusion-associated circulatory overload;

TTP = thrombotic thrombocytopenic purpura; vCJD = variant

Creutzfeldt-Jakob disease.

From the NHS Blood and Transplant, Newcastle, Manchester,

Bristol, Tooting, Colindale, and Cambridge; Serious Hazards of

Transfusion, Manchester; Chelsea and Westminster NHS Trust,

Royal Brompton NHS Trust, Medical Research Council Clinical

Trials Unit, and University College London Hospitals NHSFoundation Trust, London; and the Department of Haematol-

ogy, University of Cambridge, Cambridge, UK.

Address reprint requests to: Dr Catherine Chapman, NHS

Blood and Transplant, Holland Drive, Barrack Road, Newcastle

Upon Tyne NE2 4NQ, UK; e-mail: catherine.chapman@

nhsbt.nhs.uk.

This study was funded by the UK Blood Services.

Received for publication February 3, 2008; revision

received August 10, 2008; and accepted August 25, 2008.

doi: 10.1111/j.1537-2995.2008.01948.x

TRANSFUSION 2009;49:440-452.

440 TRANSFUSION Volume 49, March 2009


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specific diagnosis of TRALI at the bedside is not possible,

since the clinical features of TRALI are also seen in acute

lung injury arising from other causes such as sepsis,

trauma, and shock. Some of the features also overlap with

transfusion-associated circulatory overload (TACO), but

this is not always recognized acutely. The Canadian Con-

sensus Conference on TRALI in 2004 therefore describedclinical criteria defining both TRALI and possible

TRALI,4 depending on whether there were other factors

that may have caused acute lung injury.

Although neither of these proposed definitions

depends on results of any laboratory investigations of

donor or patient, the original case series describing TRALI

noted that in nearly 90 percent of cases, either HLA- or

neutrophil-specific antibodies could be detected in the

plasma of one or more implicated donors and that most

antibody-positive donors were multiparous women.2 The

importance of the presence of the corresponding antigen

in the recipient was also noted.5 It has since been pro-

posed that the antibody/antigen interaction triggers a

series of inflammatory responses involving neutrophils,

monocytes, cytokines, and complement, culminating in

pulmonary endothelial damage leading to an increase in

pulmonary vascular permeability and rapid development

of a protein-rich pulmonary exudate.3,6 It is now well

accepted that exposure to white blood cell (WBC) anti-

bodies is one important cause of TRALI. However, all

reported case series contain a proportion of cases in

which no WBC antibodies can be demonstrated in either

donor or patient. A further mechanism to explain

antibody-negative TRALI has therefore been proposed, in

which a lipid promoter of neutrophil activation is pro-duced during storage of cellular blood components.7,8 This

neutrophil priming activity has also been described in

theplasma of some TRALI cases, leading to theproposal of

two-hit model of TRALI pathogenesis, with the underly-

ing illness being the first event and infusion of the lipid

priming activity the second.9 However, since HLA anti-

bodies have caused TRALI in two healthy volunteers with

no predisposing factors,10,11 a thresholdmodel allowing for

a single major or multiple minor hits provides a more

unified theory that links all the available clinical and

experimental observations.6

The UK hemovigilance scheme Serious Hazards ofTransfusion (SHOT) was established in 199612 and from

the outset included TRALI among the complications to be

reported. The case definition, like the Consensus Confer-

ence proposal, has no absolute requirement for positive

donor or patient serology. It remained unchanged from

1996 till 2005, thus allowing the effect of risk reduction

steps to be monitored, with only the time limit for onset of

symptoms being reduced from 24 to 6 hours after trans-

fusion in 2006. In 2003, based on observations and recom-

mendations from SHOT, the National Blood Service (NBS)

carried out an option appraisal on steps which could be

taken to reduce TRALI risk. This led to a strategy to use

plasma from male donors for the production of fresh-

frozen plasma (FFP) and for suspension of buffy coat

(BC)-derived pooled platelets (PLTs), both strategies to be

adopted as far as was operationally possible. No specific

steps were taken at that time to reduce risk from apheresis

PLTs. This report describes the clinical and serologic fea-tures of TRALI cases reported to SHOT from 1996 through

2006, including the impact of the policy of preferentially

using plasma from male donors.

MATERIALS AND METHODS

SHOT reporting

The scope of SHOT encompasses all labile blood compo-

nents issued by the four UK Blood Transfusion Services

(NBS supplying England and North Wales; Welsh Blood

Service, supplying the rest of Wales; Scottish National

Blood Transfusion Service; and Northern Ireland Blood

Transfusion Service). NBS supplies 83 percent of blood

components in theUK. Adverse reactionsto FFP pathogen

inactivated by either solvent/detergent (S/D) or methyl-

ene blue are also included.When SHOT was established in

1996, letters were sent to consultant hematologists and

blood bank managers in all UK hospitals taking part in the

national quality assessment scheme blood group serology

exercises, inviting participation in hemovigilance. The

reporting system involves hospital transfusion staff sub-

mitting an initial report summarizing each case, followed

by a detailed questionnaire specific for the complication

reported. Investigation of the case is the responsibility of

the reporting hospital and the blood service, which sup-plied the components, with laboratory results made avail-

able to SHOT on completion. From 1997 through 2003,

hospitals were also invited to either submit an annual

no eligible cases observed to SHOT or to confirm the

number and type of cases reported throughout the year.

Linking of reports and confirmation of participation was

aided from 2003 onward by the allocation of a confidential

identity number for each hospital. Until 2006, participa-

tion in SHOT was voluntary, but endorsed by the Depart-

ment of Health Better Blood Transfusion initiative.

Participation in SHOT was between 80 and 90 percent of

all UK hospitals for the period covered by this article. For2006, SHOT reports were received via the new mandatory

electronic reporting system SABRE run by the Medicines

and Healthcare Regulatory Agency, the competent author-

ity designated under the UK Blood Safety and Quality

Regulations.13 SHOT publishes annual reports in paper

form and on the internet (http://www.shotuk.org). The

reports from 1996 until 2001 covered 12-month periods

from October 1 to September 30, but in 2001, a decision

was taken to move to calendar year reporting. The report

for 2001 to 2002 therefore covers 15 months, with calendar

year reports from 2003 onward. The data presented in this

HEMOVIGILANCE REPORTS OF TRALI

Volume 49, March 2009 TRANSFUSION 441
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article are compiled from TRALI reports encompassing

the period October 1, 1996, through December 31, 2006.

Case definition and investigation

From 1996 to 2005, TRALI cases were defined by SHOT as

acute dyspnea with hypoxia and bilateral pulmonary

infiltrates occurring during or in the 24 hours after trans-

fusion, with no other apparent cause, with no require-

ment for any specific serologic findings. The 24-hour time

period was chosen because in 1996, there was insufficient

evidence that a shorter time period would capture all

TRALI cases. In 2006, based on previous findings and the

recommendations of the Canadian Consensus Confer-

ence,4 SHOT reduced the time limit for onset of symptoms

after transfusion from 24 to 6 hours.

Suspected cases were referred to UK Blood Services

laboratories for investigation. In the early years of SHOT

reporting, the extent of each investigation was variable

across the UK, but from 1999 onward the majority ofpatients and implicated donors were investigated forWBC

antibodies as described below. In the NBS, a standard pro-

tocol was introduced in 2002, in which the first step was a

discussion between the hospital clinician and one of three

specialist NBS consultants, including an intensive therapy

specialist from 2003 onward. When investigation was con-

sidered appropriate, donors were recalled to give fresh

samples, because these had been shown to give less non-

specific reactivity in lymphocyte and granulocyte immun-

ofluorescence assays than frozen and thawed archived

samples. All female donors and previously transfused

males to whom the patient had been exposed were inves-tigated for WBC antibodies. Untransfused male donors

were investigated only if all other donors gave negative

results and if the patient had no other identified cause for

the respiratory symptoms. From 2002, all patients were

also tested for WBC antibodies, except those who died

acutely. Ifspecific HLAor HNAantibodieswerefound inan

implicated donor or patient, the relevant patient or donor

HLA or HNA genotypes/phenotypes were determined to

establish whether the cognate antigen was present.

In 1999, SHOT introduced a system to assess the like-

lihood of the reported cases actually being TRALI. This

was based on clinical context, in particular fluid balance

charts and features of cardiogenic pulmonary edema, the

presence of other risk factors for acute lung injury and

donor/patient WBC serology. After review by two clini-

cians from the SHOT team, including an intensivist from

2003 onward, cases were allocated into one of four groups:

Highly likely: no other cause identified for the symp-

toms AND positive serology (defined below);

Probable: either positive serology as defined below

but with other causes for symptoms also present OR

no other causes present, but with either absent or

incomplete serology;

Possible: clinical picture compatible with TRALI, no

other cause present, but results of patient and donor

investigation negative as defined below; . . .

Unlikely: another cause of symptoms present AND

results of patient and donor investigation negative as

defined below.

The definition of positive serology used throughout this

article is the presence of donor WBC antibodies that cor-

responded with one or more recipient antigens and/or a

positive WBC crossmatch between donor and recipient.

Donor WBC antibodies which did not recognize cognate

antigen(s) in the recipient were not considered relevant,

unless recipient samples were not available for typing or

crossmatch, for example, because the patient had died.

The definition of an implicated component is the

component transfused from a donor with positive serol-

ogy. In cases of probable TRALI without positive serology,

the type of component implicated could be allocated only

in cases receiving one component type in the 24 hoursbefore theTRALI episode. For cases with no positive serol-

ogy receiving multiple types of components, it was not

possible to identify an implicated component.

Other relevant categories of reporting to SHOT over

this time period were acute febrile or anaphylactic reac-

tions without chest X-ray changes, but TACO was not

reportable. This has been included as a separate category

from 2008.

Laboratory methods

Screening for HLA Class I antibodies was done usingthe microlymphocytotoxicity test14 and enzyme-linked

immunosorbent assay (ELISA; GTI Quik Screen, ELISA

system) assaysto detectthe presenceof cytotoxicand non-

cytotoxic HLA Class I antibodies respectively. Investiga-

tions for HLA Class II-specific antibodies by ELISA (GTI

Quik Screen) were introduced in December 2001. One

Lambda LABScreen replaced the ELISAand microlympho-

cytotoxicity test in 2005. The cutoff to determine a positive

result was twice the value of the negative control. Samples

were initially screened by Lab Screen mixed and if positive,

antibody identification was performed using panel-

reactive antibodyClassI or Class II identification andmorerecently (since 2006) single antigen beads. If HLA-specific

antibodies were identified in a donor sample, HLA Class I

or Class II DNA typing of the patient was performed by

using a polymerase chain reaction (PCR)-based assay

employing sequence-specific primers (SSPs).15

HNA antibody screening was performed using

the granulocyte immunofluorescence test, lymphocyte

immunofluorescence test, and granulocyte chemilumi-

nescence test using cells obtained from a panel of

HNA-1a, -1b, -1c, -2a, and -3a and HLA Class Ityped

donors.16-18We have found the granulocyte chemilumines-

CHAPMAN ET AL.



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cence test to be comparable to the granulocyte agglutina-

tion test in the detection of HNA-3a antibodies and more

sensitive than the granulocyte agglutination test in detect-

ing other HNA antibody specificities. If specific HLA- or

HNA-specific antibodies were found in an implicated

donor or patient, the relevant patient or donor HLA or

HNA genotypes/phenotypes were determined to establishwhether the cognate antigen was present.

HLA Class I or Class II DNA typing was performed by

using a PCR-based assay employing SSPs,15while serologic

and PCR-SSP techniques were used to determine the HNA

genotypes.19,20 In cases in which nonspecific HLA or

granulocyte antibodies were detected, and if material was

available, a flow cytometric crossmatch (granulocyte

immunofluorescence test/lymphocyte immunofluores-

cence test) was undertaken using donor serum and

cells obtained from ethylenediaminetetraacetate-

anticoagulated patient samples within 24 hours of

venesection.

Specifications of blood component,

implementation of male FFP and pooled S/D FFP,

and suspension of PLT pools in male plasma

All blood components (red blood cells [RBCs], PLTs, FFP)

were leukoreduced to EU specification from late 1999

onward. Across the period of this report, more than 95

percent of all RBC units were suspended in additive solu-

tion (AS; saline, mannitol, glucose, adenine) with less than

30 mL of plasma. The remainder were plasma reduced to

approximately 100 mL of plasma. In April 2004, as a

variant Creutzfeldt-Jakob disease (vCJD) risk reductionstep, all donors previously transfused in the UK from 1980

onward were excluded from donation.

Following SHOT observations up to 2002 to 2003,

showingthat there was an excess against expected ofTRALI

cases associated with FFP or PLTs from HLA antibody

positive female donors, the NBS conducted an option

appraisal to consider ways of minimizing TRALI risk. Since

new donor questions were being introduced regarding

West Nile virus and severe acute respiratory syndrome, it

was agreed that no additional questions would be asked

regarding previous pregnancy or transfusion. As a result of

theoptionappraisal,the NBSintroducedin October 2003apolicy to use male plasma for manufacture of FFP as far as

was operationally possible. This policy did not involve any

additional donor questioning or loss of any donors from

either whole bloodor apheresiscollections,since plasma is

not collected by the latter method. Fractionation of UK

plasma was discontinued in 1999 because of vCJD, so all

plasma from non-FFP donations is discarded.

Blood collection staff marked whole blood donations

M or F at the donor session, and on return to the

processing center the male donations marked M were

directed for FFP production. To maintain supply continu-

ity, FFPfromfemale donorsheldin NBSor hospitalfreezers

was not withdrawn. The production of 100 percent of FFP

units from male donors was limited by the requirement to

meet thenational quality standardfor FFPof 0.7 IU permL

of Factor VIII in more than 75 percent of units tested.13

Whole blood units held at 4C overnight before processing

do not meet this requirement, so plasma had to be sepa-rated and frozen on the day of collection. Therefore, the

proportion of FFP that can be manufactured from male

donors has consistently been between 80 and 90 percent

since implementation (NBS quality monitoring data).

In 2004, there were two further changes to FFP provi-

sion, to reduce vCJD risk. First, pooled S/D FFP (Octaplas,

Octapharma, Vienna, Austria) was recommended by the

Department of Health for plasma exchange procedures for

thrombotic thrombocytopenic purpura (TTP). Octaplas

has been licensed in the UK since the mid-1990s, but only

two hospitals used it for all patients across the time period

of this report. In 2002, a survey of 29 representative

hospitals estimated that FFP use for TTP amounted to

approximately 11 percent of total issues (Wells A, EASTR

study, unpublished data), and in 2006 through 2007, Octa-

plas use was 42,000 units (each of 200 mL), amounting to

14 percent of total FFP.

Second, single-unit FFP for children was imported

from the United States; this was all from male donors and

was virus-inactivated by methylene blue/light treatment

once in the United Kingdom. This amounted to approxi-

mately 5 percent of total demand.

As part of the 2003 TRALI review, NBS also considered

ways to reduce the risk from PLT concentrates, which

were provided from both apheresis (40% of supply) andBC-derived PLT pools (60% of supply). The standard NBS

method for production of PLT pools requires separation of

BC from whole blood donations within 8 hours of collec-

tion. After overnight hold at 22C, four BCs are suspended

in a unit of plasma from one of the four BC donors and

respun and filtered to produce a pool of leukoreduced

PLTs. From October 2003, processing centers were asked

to ensure that, as far as was logistically possible, the resus-

pending plasma would be derived from a male donor

(Donor 1). Studies on the resulting components esti-

mated that the contribution of plasma to the final PLT

pool was approximately 225 mL from Donor 1 and 25 mLfrom each of the other three donors. As with FFP, the pro-

portion of PLT pools that can be suspended in male

plasma was limited by the requirements to separate the

BC on the day of collection and has varied between 80

and 90 percent of all PLT pools manufactured since

implementation. No specific steps were taken to reduce

the risk from apheresis PLTs.

The other three UK Blood Services (together compris-

ing approximately 17% of component manufacture) also

moved toward exclusion of female plasma from FFP and

PLTs as far as possible during 2004.




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RESULTS

Overview of cases

Between 1996 and 2006 inclusive, 224 initial reports of

suspected TRALI cases were received by SHOT. Of these,

23 were subsequently withdrawn, typically because the

reporting clinician considered another cause for thesymptoms as more likely. In addition, six questionnaires

were not returned, leaving 195 cases which met the TRALI

case definition and that were analyzed further. As shown

in Fig. 1, reports of TRALI to SHOT increased year on year

from 9 cases in 1996 to 1997 to a peak of 36 cases in 2003

and decreased thereafter.

The probability of each case actually being TRALI was

assessed in all 156 cases reported from 1999 onward, as

defined above. Overall 51 cases were assessed as highly

likely and 25 cases as probable (therefore, 76 cases, or 49%

highly likely/probable), with 42 cases considered possible

and 38 cases unlikely to be TRALI (80 cases, or 51%

possible/unlikely).

Sex and age were reported for 193 of the 195 cases,

with 88 (46%) being male and 105 (54%) female. There was

a slightly greater percentage of males amongst the highly

likely/probable cases (53%) when compared with cases

considered possible/unlikely (40%). The ages ranged from

26 days to 83 years with a median age of 56 years. Twenty

cases (9.7%) were children under the age of 18.

As shown in Fig. 2, the most frequent clinical special-

ties represented in the 195 TRALI cases were hematology

and oncology combined (36%) and surgery (36%). Eigh-

teen cases had had cardiac surgery (10%), of whom 12

were considered highly likely/probable. Nine cases (5%)were associated with the use of FFP to reverse warfarin

and an additional 9 (5%) with plasma exchange with FFP

for TTP.

Clinical features and outcomes

By definition, all patients had acute dyspnea, hypoxia, and

bilateral pulmonary infiltrates, with fever and hypoten-

sion seen in 37 and 52 percent of cases, respectively. There

was no difference in the incidence of these secondary fea-

tures between highly likely/probable cases and those clas-

sified as possible/unlikely. Up to and including 2005, theTRALI definition used by SHOT permitted the inclusion of

cases where onset was up to 24 hours after transfusion

(changed to 6 hr for 2006). Timing was reported in 151

cases during these years, with 139 cases (92%) occurring

either during or within 6 hours of transfusion, 7 (5%)

between 6 and 12 hours, and 5 (3%) between 12 and 24

hours. The corresponding figures for the 67 highly likely/

probable cases between 1999 and 2005 where time of

onset was reported were 63 (94%), 4 (6%), and none,

respectively. Overall, 143 of 195 cases (73%) required

admission to intensive therapy units or were already on an

intensive therapy unit when thereactionoccurred, with 88

(45%) requiring mechanical ventilation.

A total of 40 deaths (21%) occurred in patients

meeting the TRALI case definition and in whom TRALI

was considered at least a contributory factor. The corre-

sponding figures for highly likely/probable and possible/

unlikelyTRALI, from 1999 to 2006, were15 of 76 (19%) and

17 of 80 (21%), respectively. As with total reports, TRALI

deaths rose year on year to a peak of 9 deaths in 2003(Fig. 1). The number of deaths per year fell thereafter in

line with total cases to 1 in 2006, but the fatality rate has

not varied significantly over time. Since SHOT began in

1996, TRALI has been implicated in more deaths than any

other category of adverse event, with a total of 109

transfusion-associated deaths from all causes recorded in

3763 SHOT reports (2.9%), 40 of which were at least

possibly due to TRALI.

In addition to the fatalities, 10 cases (5%) were

reported as having suffered some long-term morbidity

after the TRALI episode, for example, due to concomitant

0

5

10

15

20

25

30

35

40

1996 1997 1998 1999 2000 2001 2003 2004 2005 2006

Fig. 1. All reports of TRALI ( ; n = 195) and deaths ( ; n = 40)

from 1996 through 2006 inclusive. Reporting years from 1996

until 2000 each cover 12 months from October 1 until Sep-

tember 30; 2001 covers 15 months from October 1, 2001, to

December 31, 2002; 2003 and subsequently cover calendar

years.

TRALI reports analyzed by reason for transfusion

1996-2006 n = 195

35.9%

35.9%

4.6%

4.1%

4.6%

6.2%

6.7% 2.1%

Hematology/oncology

Surgery

Medical

Coagulation correction

Sepsis

Plasma exchange

Obstetrics/gynecology

Liver biopsy

Fig. 2. Reported reasons for transfusion of blood componentsin TRALI cases.

CHAPMAN ET AL.



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myocardial infarction or residual pulmonary impairment.

The remaining 145 patients (74%) made a full recovery or

died of an unrelated cause.

Laboratory investigations

The level of investigation of cases of suspected TRALI has

improved and developed over the SHOT reporting period.

Between 1996 and 1999, when there was no national labo-

ratory protocol, 43 of 57 (75%) cases were either not inves-tigated at all or the investigations were incomplete or

inconclusive. The NBS introduced a national testing pro-

tocol during 1999, and from 2000 (the first full year the

protocol was in place) to 2006 inclusive, 96 of 138 (70%)

cases had complete donor investigations for antibodies

considered relevant to the TRALI episode. As shown in

Table 1, donor antibodies recognizing a cognate antigen

in the patient were found in 62 of 96 completely investi-

gated cases (65%), of which 12 matched an HLA Class I

antigen, 25 matched an HLA Class II antigen, and 13

matched both HLA Class I and Class II antigens, meaning

that concordant HLA Class II antibodies were found

overall in 61 percent of antibody-positive cases.

Granulocyte-specific antibodies recognizing a cognate

patient antigen were found in 9 cases, and antibodies

reacting with patient granulocytes and lymphocytes

without a clear specificity in 3 cases. In the remaining 34

cases (35%), no donor antibodies were detected.

Concordant donor WBC antibodies were identified in

73 cases reported between 1996 and 2006. As shown in

Table 2, the most common antibody specificities wereHLA Class II antigens DR52 and DR4 being found alone or

in combination with other antibodies in 13 (18%) and 12

(16%) cases, respectively. The most frequent concordant

HLA Class I antibody specificity was HLA-A2, being iden-

tified, alone or in combination in 10 cases (13%). In 18

cases (24%), more than one concordant antibody was

found. Concordant granulocyte antibodies were found

less often and the most frequent specificity was HNA-1a (5

cases). A single case involved HNA-3a antibodies. All

donors found to have concordant WBC antibodies were

female, with none attributed to a transfused male.

TABLE 1. Numbers of donors with antibodies matching a patient antigen in 96 TRALI cases with completeinvestigations between 2000 and 2006

Year

HLA Class

Granulocyte Granulocyte and lymphocyte NegativeI II* I and II*

2000 to 2001 3 0 0 1 0 22001 to 2002 5 4 2 3 2 5

2003 1 11 4 4 1 92004 2 7 3 0 0 42005 1 2 3 0 0 102006 0 1 1 1 0 4

Total, number (%) 12 (19) 25 (41) 13 (21) 9 (14) 3 (5) 34

The percentages shown are in relation to the 62 cases where matching donor antibodies were detected.* HLA Class II antibody testing was introduced in 2001.

TABLE 2. Donor antibody specificities in 73 cases with concordant antibodies investigated between 1996and 2006

HLA Class

Granulocyte Granulocyte and lymphocyte TotalI II I and II

17 25 13 13 5 73A2 4 DR1 2 A2 + DR52 2 HNA1a 5 All nonspecific, positive

crossmatch onlyNS 8 DR4 4 A2 + DR4 1 HNA3a 1A24 and B7 1 DR8 1 A2 + DR4 + DR11 1 NS 7Bw6 1 DR11 1 A2 + DR4 + B13 + DR53 1B18 1 DR13 1 A2 + DR15 1

B8 2 DR17 1 A11 + DR4 1DR52 7 A11 + DR14 1DR53 1 A24 + DR52 1DR52 + DR10 1 A29 + B12 + DR53 1DR52 + DQ9 1 NS + DR7 1DR4 + DQ8 1 B57 + DR4 1

DR4 + DR7 2 B57 + DR4 + DR53 1DR7 + DR9 1NS 1




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Of 195 cases analyzed from 1996 to 2006, HLA anti-

bodies were found in the patient in 30 cases (15%) and

granulocyte antibodies in 1. Eighty-four patients werenegative for the presence of both HLA and granulocyte

antibodies and 81 cases did not have reported results.

Antibody concordance with donor antigens was not fully

assessed in most patients with WBC antibodies and was

established in only three patients (2 male, 1 female), all

with HLA antibodies. However, all 3 cases occurred after

the introduction of universal leukoreduction, and the rel-

evance of patient antibody to the development of TRALI is

considered doubtful, especially as two of these cases also

had donors with HLA antibodies, with one donors anti-

bodies matching three HLA antigens in the patient. The

third antibody-positive patient also had cardiac failureand a large positive fluid balance and was categorized as

unlikely to be TRALI.

Two TRALI cases were reported in which the only

demonstrableWBC incompatibility was between 2 donors

in the same PLT pool of4 donors. The firstcaseoccurred in

1996, before universal leukoreduction and involved a

donor with a strong HLA antibody in the plasma that

reacted with the lymphocytes of another donor in the

pool. The patient was negative for the presence of concor-

dant antigens. The second case, which has been previ-

ously published,21 involved a donor with HNA-1a

antibodies and two other donors in the

same leukoreduced PLT pool who were

HNA-1apositive. The patient was

HNA-1anegative and all donors were

negative by serum crossmatch with the

patients WBCs.

Implicated components and their

relationship to positive donor

serology

In 2003, a review of all TRALI reports

to date was carried out to assess the

relative risk of TRALI from different

blood components and the relationship

between implicated components and

positive donor serology. As shown in

Table 3, the risk/component for all

TRALI case reports from 1996 through

2003 was 6.86 times higher for FFP/cryosupernatant

(CSP) than for RBCs (95% confidence interval [CI], 4.2-

11.2) and 8.16 times higher for PLTs than for RBCs (95%CI, 4.91-13.37). These values show significance, unlike the

relative risk from cryoprecipitate, which was 1.76 (95% CI,

0.42-7.32). Next, 74 cases that had been fully investigated

between 1998 and 2003 were analyzed to see whether they

had had a greater than expected exposure to an antibody-

positive donor. The expected figure was based on a pre-

vious study that demonstrated HLA antibodies in 1 in 7

female donors22 and assumed a median exposure to 3

donors per transfusion episode, from which it can be cal-

culated that 20 percent of all transfusion episodes would

include an antibody-positive female donor by chance.

This analysis (Table 4) showed that in TRALI cases whereRBCs had been implicated, exposure to an antibody-

positive female donor was no greater than expected

(p 0.08). In contrast, transfusions where FFP or PLTs

were implicated in a TRALI episode had a much greater

than expected exposure to an antibody-positive female

donor (p 0.0001). In cases where the sex of the

antibody-positive donor was reported to SHOT, all were

female, as were those with antibodies either concordant

with the patients antigens or with a positive crossmatch.

These findings led to a decision by the NBS to source

FFP from male donors, in whom the incidence of HLA and

TABLE 3. Relative risk of TRALI from different blood components, based on the 93 cases from 1996 through2003 in which an implicated component could be identified

Category RBCs Cryoprecipitate FFP/CSP PLTs

TRALI cases in which component implicated 33 2 31 27Components issued (103) 18,370 634 2,515 1,842Risk/component issued* 1:556,000 1:317,000 1:81,000 1:68,000

Relative risk compared to RBCs (95% CI) 1.76 (0.42-7.32) 6.86 (4.2-11.2) 8.16 (4.91-13.37)* To the nearest thousand. Significant since 95 percent CI does not contain 1.

TABLE 4. Relationship between implicated component, serology, anddonor gender in 74 fully investigated cases of TRALI 1998 through

2003

Category RBCs FFP/PLTs

All cases 18 56Cases with antibody positive donor,

whether or not matching patient antigen

6 44

Proportion of all cases in which exposureto antibody-positive donor expected*

0.2 0.2

Proportion of all cases in which exposureto antibody-positive donorobserved (95% CI)

0.33 (0.12-0.55) 0.79 (0.68-0.89)

Sex of antibody-positive donors 3/3 female 34/34 femaleSex of donors with antibodies matching

patient antigens/positive crossmatch2/2 female 29/29 female

* Based on McLennan et al.22

p 0.08. p 0.0001. In other cases, donor sex not notified from investigating laboratory.

CHAPMAN ET AL.



8/13

HNA antibodies is low,22 and to suspend BC-derived PLT

pools in male plasma, as far as regulatory and operational

considerations permitted. This was implemented from

October 2003 onward; to maintain supplies, FFP from

female donors was not withdrawn from storage either in

blood centers or hospital blood banks.

As shown in Table 5, this policy has been associatedwith a gradual reduction in the total number of TRALI

cases reported. Strikingly, the risk of highly likely/

probable TRALI attributed to FFP associated with an

antibody-positive donor fell dramatically, particularly

after the washout period for female FFP still in storage.

Despite some continued FFP production from female

donors, there were no concordant antibody-positive cases

attributed to FFP in 2005 or 2006, although antibody-

negative TRALI after FFP was occasionally reported. The

reduction in the number of cases attributed to PLTs was

less dramatic because no risk reduction steps have been

put in place for apheresis PLTs. Four cases attributed to

antibody-positive female plasma in BC-derived PLTs

occurred in 2004 and 2005 but none has occurred in 2006.

As shown in Table 6, the risk of highly likely/probable

TRALI associated with FFP and PLTs has reduced consid-

erably between the two time periods before and after themale plasma policy was fully in place, dropping from

15.5 to 3.2 per million components issued for FFP/CSP

(p = 0.0079) and from 14 to 5.8 per million components

issued for PLTs (p = 0.068). No such reduction was seen for

RBCs, where the male : female mix was unchanged, while

for cryoprecipitate, the risk appears to have doubled.

DISCUSSION

The case definition of TRALI used throughout 9 of the 10

years spanned by this SHOT series was defined in 1996

and remains valid and broadly consistent with the defini-tion proposed by the Canadian Consensus Conference on

TRALI in 2004.4 TRALI is defined entirely on clinical

grounds and neither the SHOT definition nor that pro-

posed by the Consensus Conference requires positive

serology in the donor/patient. Since there may be mul-

tiple etiologies of TRALI, it would be too restrictive in the

current state of knowledge to require the presence of WBC

antibodies in donor or patient to define a TRALI case. Two

differences between the SHOT and Consensus Confer-

ence definitions merit discussion. First, up to and includ-

ing 2005, the SHOT definition allowed TRALI to be

diagnosed up to 24 hours after commencement of trans-

fusion, compared to 6 hours as proposed by the Canadian

Consensus Conference. However, only 8 percent of the

SHOT series developed after 6 hours (and only 6% of the

highly likely/probable cases) so a 6-hour time limit now

seems reasonable and was adopted by SHOT from 2006.

TABLE 5. Changes to the profile of TRALI casesreported to SHOT 2003 through 2006

Category 2003 2004 2005 2006

TRALI cases analyzed 36 23 23 10Highly likely 20 10 3 2Probable 2 3 3 1Possible 6 4 3 4Unlikely 8 6 14 3

Implicated componentFFP 8 6 1 1PLTs 8 4 2 1RBCs 1 3 2 3FFP plus other 3 0 0 4Cryoprecipitate 1 0 1 1

Positive donor serologyFFP 8 6 0 0PLTs 8 3 3 1RBCs 1 3 2 2FFP plus other 2 0 0 0

Cryoprecipitate 1 0 1 1

TABLE 6. Risk of highly likely and probable cases of TRALI before and after introduction of male plasma forFFP and PLT pools*

Categroy 1999-2004 2004-2006

RBCs issued (103) 13,411 4,745Cases implicating RBCs 9 5Cases/106 RBCs issued (frequency) 0.67 (1:1,490,000) 1.1 (1:949,000)FFP/CSP issued (103) 1,874 634

Cases implicating FFP/CSP 29 2Cases/106 FFP/CSP issued (frequency) 15.5 (1:65,000) 3.2 (1:317,000)PLTs issued (103) 1,265 518Cases implicating PLTs 18 3Cases/106 PLTs issued (frequency) 14 (1:71,000) 5.8 (1:173,000)||Cryoprecipitate issued (103) 465 209

Cases implicating cryoprecipitate 2 2Cases/106 cryoprecipitate issued (frequency) 4.3 (1:232,000) 9.6 (1:104,000)

The denominators are units of each component issued by UK Blood Services for the respective time periods.

Frequency calculated to nearest thousand. p = 0.79. p = 0.0079.|| p = 0.068. p = 0.79.




9/13

Second, there are some differences in the way the likeli-

hood of the cases being TRALI is assessed. In 1999, SHOT

introduced a likelihood scale based on both clinical fea-

tures and serologic findings, such that cases with positive

donor or patient serology would fall into the probable or

highly likely categories. The Canadian Consensus Confer-

ence proposes separate definitions for TRALI and pos-sible TRALI, but both are based entirely on clinical

findings. Since there is scientific consensus that an inter-

action between donor HLA or HNA antibodies and the

corresponding antigen in the recipient can cause TRALI,

we believe that it is entirely legitimate to use serologic

findings as part of the assessment of whether posttrans-

fusion pulmonary symptoms are likely to be due to TRALI

or not. Since the workup of suspected TRALI cases pro-

posed by the Consensus Conference includes testing of

donors for HLA and HNA antibodies, it seems illogical not

to use those results to reach a final conclusion as to the

nature of the case. Our definitions resulted in 49 percent

of cases thereafter being classified as highly likely or prob-

able, the remaining 51 percent being considered possible

or unlikely. Secondary clinical features such as hypoten-

sion and fever were unhelpful in differentiating highly

likely TRALI from less clear cut cases. This is not surpris-

ing, since the final steps in the pathogenesis of TRALI are

likely to involve the same proinflammatory cytokines

leading to a final common pathway of pulmonary damage

shared by other causes of acute lung injury such as sepsis

and trauma.

Some of the low-likelihood cases in whom TRALI

could not be excluded may have been TACO, which was

until recently not included as a category in the SHOTscheme. TACO may be difficult to differentiate from TRALI

at the bedside without invasive monitoring and even more

difficult after the event by case note review. Unless

patients are in intensive care units, definitive diagnosis

of TACO by measurement of pulmonary capillary

wedge pressure is unlikely to be performed. The use of

noninvasive markers of left-sided cardiac strain such

as B-natriuretic peptide offers new possibilities to differ-

entiate TACO and TRALI.23

There are limitations in using hemovigilance data

spanning 10 years to generate figures for TRALI incidence.

There is still likely to be a considerable degree of underre-porting of all types of events to hemovigilance systems,

but overreporting may also occur. We saw a sharp increase

in low-likelihood cases in 2005, perhaps because of

greater awareness of the condition. Blood safety and

hemovigilance have been given a much higher hospital

profile in recent years. Given that approximately 3 million

components are issued annually by UK Blood Services,the

incidence of TRALI case reports per unit issued based on

SHOT data would be in the range of 1 case per 100,000

components. However, figures for TRALI incidence in

published case series vary widely, dependingon the inten-

sity of surveillance, the range and type of components

included, and whether the study was local or national.3,4

The incidence as estimated by SHOT figure appears to be

at the low end of the reported range, although consistent

with other hemovigilance series from Quebec.24,25

Our series covers the full age range of transfused

patients, including a 2-year-old who developed TRALIafter receiving an HLA and HNA antibodypositive PLT

concentrate.26 A previous nested case-control study has

suggested an excess risk associated with cardiac surgery

and hematologic malignancy.27 However, when calculated

against FFP and PLT usage in the UK (Wells A, Llewelyn C,

Casbard A, Johnson T, Ballard S, Buck J, Malfroy M,

Murphy M,Williamson LM, unpublished), our data do not

suggest a hugely increased risk in these groups of patients.

The mortality in our series was 21 percent overall,

which is at the high end of the 5 to 25 percent range in

reported series.3 This may be because of inclusion of cases

in the SHOT series in which TRALI was thought to have

been only a contributory factor to the death. There was no

significant difference in mortality between highly likely/

probable cases and those considered possible/unlikely.

Denominator data for the number of patients or transfu-

sion episodes represented by these figures are not readily

available.

By 2003, clear differences in risk had emerged for dif-

ferent blood components, particularly when only highly

likely/probable TRALI cases are considered. Exposure to

FFP has also been noted as an independent risk factor for

TRALI in two recent series of intensive care patients from

the Mayo Clinic.28,29 Interestingly, the risks from FFP and

PLTs were not significantly different, so it does not appearthat the presence of intact PLTs or their microparticles

generated additional factors such as lipid-priming activ-

ity, which gave PLTs a higher risk than plasma alone. We

did not see any differences in incidence between pooled

and apheresis PLTs, probably because 75 percent of the

plasma in pooled BC-derived PLTs comes from a single

donor.

We agree with an earlier study that all steps must be

taken in TRALI case investigations to establish whether or

not donor WBC antibody corresponds with the patient,

either by patient genotyping or by a direct crossmatch,23

since there have been studies demonstrating a 13 to 17percent incidence of HLA antibodies in female donors.22,30

We have also confirmed earlier reports of concordant HLA

Class II antibodies as a possible cause of TRALI. 31,32 The

antibody specificities found in reported TRALI cases most

frequently were HLA-A2, -DR4, and -DR52. All these anti-

gens occur relatively commonly in the UK population but

antigen frequency does not appear to be the only factor

influencing whether the corresponding antibody is impli-

cated in TRALI. HLA-A2 antigen frequency is approxi-

mately 50 percent in the UK and HLA-A2 concordant

antibody was identified in 14 percent SHOT cases with

CHAPMAN ET AL.



10/13

concordant antibody. HLA-A1, however, is also relatively

common in the UK with an antigen frequency of approxi-

mately 30 percent, but we did not identify a single case of

TRALI with concordant HLA-A1 antibody in our series.

One of the most striking findings in this series was the

association between positive donor serology, sex, and type

of implicated component in cases investigated between1999 and 2003. It might have been expected that, before

they were excluded from donation in 2004, previously

transfused male donors would have accounted for some

of the cases, but this did not prove to be the case. This may

be related or explained to the observation that HLA (and

possibly HNA) antibodies induced by transfusion are of

low affinity (mostly immunoglobulin M) and tend to be

transient, compared with those induced by pregnancy.33

The strong association between female FFP, WBC

antibodies, and TRALI has also been noted in a recent

series from the United States,34 in which 19 of 25 TRALI/

possible TRALI cases due to FFP were associated with an

antibody-positive female donor, compared with 5 of 10

RBC cases. In the only prospective randomized trial to

have been carried out in TRALI, infusion of plasma from

parous females resulted in significantly greater changes in

oxygen saturation than control plasma, with one frank

TRALI case.35 However, although the implicated donor

had granulocyte antibodies, crossmatch with the patient

was negative. The finding of antibody-positive TRALI after

cryoprecipitate and RBC transfusion in this and other

series34 confirms other evidence36 that exposure to only a

small volume of antibody-positive plasma can cause

TRALI.

Unusually, the TRALI series reported by Silliman andcoworkers in 200325 reported antibody positivity in a

donor in only 3.6 percent of cases, with a high percentage

of cases in hematology patients receiving PLTs. Because

components in that study were not leukoreduced, it may

be that a high proportion of reactions were due to inter-

actions between donorWBCs and patient HLA antibodies,

which occur in 20 to 40 percent of multitransfused hema-

tology patients receiving nonleukoreduced blood compo-

nents.37 Unfortunately, patients were not investigated for

WBC antibodies in the series by Silliman and colleagues.

In addition, the diagnostic criteria listed for definition of

TRALI in the series of Silliman and colleagues did notinclude a requirement for bilateral infiltrates on chest

X-ray, in contrast to the SHOT and Canadian Consensus

Conference definitions. Only 3 of 90 (3%) of their reported

cases required mechanical ventilation and only 1 patient

(1%) died, due to a concomitant myocardial infarct. These

compare with mechanical ventilation initiated or con-

tinued in 47 percent of TRALI cases and an overall

transfusion-related mortality of 21 percent in our series of

hemovigilance reports. It seems that the series by Silliman

andcolleagues included a much largerproportion of cases

with less severe respiratory reactions.

The cause of posttransfusion respiratory symptoms in

our antibody-negative cases remains unknown. Many

reported cases had additional risk factors for acute lung

injury and some may have had a degree of TACO. In addi-

tion, the donors may have had HLA or HNA antibodies

belowthe limit of detection, other as yetundefined types of

WBC antibodies may have been responsible, or there mayhave been another cause altogether. Some cases before

2001 could have been due to HLA Class II antibodies.

It has been reported that cellular blood components

accumulate lipid-derived neutrophil priming material

during storage,7,8 although the frequency with which the

concentration of such material becomes capable of trig-

gering a TRALI reaction remains undefined. It is interest-

ing to note that lipid priming material has not been

identified in FFP. In one series, TRALI due to PLTs was

associated with PLT storage time;25 unfortunately we

have not recorded the age of implicated cellular compo-

nents in our series. Since, by definition, an implicated

component cannot be identified in antibody-negative

cases transfused with more than one type of component,

it would be difficult to correlate components of a par-

ticular age with TRALI cases reported to hemovigilance

systems.

Although the implementation of preferentially male

plasma seems a rather crude approach, it proved simple

and low cost to implement, aided by other changes to the

UK blood supply. Because UK plasma had been excluded

from fractionation since 1999, there was no program of

collection of plasma by apheresis, with all FFP being

manufactured from whole blood donations. Thus male

FFP could be implemented without loss of any donorsand without the need to discuss the policy with the

company undertaking fractionation. Donors were already

aware that plasma from most donations was discarded

and we have not specifically communicated the male

plasma policy to them. Similarly, the decision to suspend

most BC-derived PLT pools in male plasma could be

implemented relatively easily.

The steps we have taken have been associated with a

reduction in highly likely/probable TRALI. All antibody-

positive cases associated with FFPand PLTs continue to be

due to female donors, either because of female FFP still in

storage freezers during 2004 or because of the ongoingneed to use female donors for 10 to 20 percent of FFP/PLT

production. Highly likely/probable TRALI due to FFP has

now virtually disappeared, In contrast, highly likely/

probable cases due to RBCs have not changed over the

same 4-year period. The risk from cryoprecipitate seems

to have increased slightly. Although numbers are small,

this could be due to enriching of cryoprecipitate

production with the female donors not used for FFP.

Inone sense,this reduction wasas expected,sinceour

definition of highly likely/probableTRALI was usually met

by donor WBC antibodies matching a recipient antigen.




11/13

Occasional antibody-negativecases dueto FFP continueto

be seen, however. It should also be considered whether the

reduction in reports of FFP-related cases could be due to

clinicians assuming that FFP no longer causesTRALI. This

cannot be excluded, but the reporting of cases which can

be tracked to a female donor suggests some continuing

awareness of FFP-relatedTRALI. In 2005, there wasa sharpincrease in possible/unlikely TRALI. These are cases in

which antibodies have not been detected, with complex

clinical histories, and since antibody-negative TRALI

cannot be totally excluded, they will continue to be classi-

fied as possible/unlikely. Currentsteps to reduce antibody-

positive TRALI would not be expected to have any impact

on the incidence of such cases.

It has not proved possible, within the NBS, to

produce either 100 percent male FFP or plasma for PLT

pools, because of current UK processing requirements

which mean that FFP and BCs have to be manufactured

on the same day the blood is collected. Other European

countries (Ireland, Netherlands, France) have partially or

totally adopted the 20C overnight hold method of

component production, in which whole blood donations

are held at a controlled 20C until separation into com-

ponents the next day. This method produces RBCs, PLTs,

and FFP of excellent quality,38 and steps are being taken

to introduce it into the UK to provide 100 percent male

FFP and cryoprecipitate. An alternative strategy to

increase availability of male FFP would be acceptance of

Day 1 FFP, as used in Canada.39 The use of manufactur-

ing strategies to reduce TRALI risk from FFP has now

been recommended by the AABB,40 although not yet

mandated by the FDA. This parallels the situation inEurope, where some blood services are moving voluntar-

ily toward greater use of male FFP, without it yet being an

EU regulatory requirement.

The use of S/D FFP was considered as an alternative

to the male FFP approach. Countries that have both heavy

or universal use of S/D FFP and an established hemo-

vigilance system (Norway, Ireland, Belgium) have not

reported any TRALI cases.41 The safe profile of S/D FFP

with respect to TRALI has been attributed to dilution of

donations containing high-titer HLA or HNA antibodies

in the pool of 500 to 1000 donors, and such antibodies

cannot be detected in the final product by current tech-niques.42 However, this is an expensive product compared

with standard FFP and is currently recommended in the

UK only for TTP and uncommon congenital coagulation

factor deficiencies where no concentrate is available.43

Some of the reduction in TRALI due to FFP which we saw

after 2004 could be attributed to the use of S/D FFP for

TTP, which now amounts to 14 percent of total FFP usage.

However, the risk calculation shown in Table 6 takes

reduced FFP use into account.

A further key step in minimizing TRALI risk from FFP

is appropriate prescribing. FFP and PLT use in the UK has

remained virtually unchanged across the 10 years of this

study. For example, UK guidelines for FFP recommend

prothrombin complex concentrates for warfarin reversal

in life-threatening situations and vitamin K otherwise,44

yet 5 percent of patients in this series developed TRALI

after FFP given to reverse warfarin. A systematic review of

FFP trials concluded that no definite evidence for benefitof FFP has been shown in high quality trials in any clinical

setting.45 This is not to say that FFP is of no value, but that

there needs to be much stronger evidence supporting its

use. The relationship between abnormal coagulation,

bleeding, and the role of FFP in preventing or treating

hemorrhage remains uncertain,46,47 andfurther studies are

required to define this.

Finally, further steps will be necessary to further

reduce TRALI resulting from PLT transfusion. One possi-

bility is the use of a PLT AS to replace most of the plasma.

Several solutions are licensed in Europe, but none yet in

the United States. PLT AS could be adopted in the manu-

facture of pooled BC PLTs to replace the unit of plasma

currently used. Although 100 mL of plasma is required in

the final product, this would comprise 25 mL from each

of the four donors, so the risk from WBC antibodies

should be reduced to that of a RBC unit or of a PLT pool

suspended largely in male plasma. However, since TRALI

may occur after exposure to as little as 30 mL of plasma,

as is seen in RBCs in AS or in cryoprecipitate, this would

probably not eliminate the risk totally. For apheresis

single-donor PLTs, the remaining 100 mL of plasma

would come from a single donor, enough to trigger a

clinically significant TRALI reaction. An alternative strat-

egy would be to screen current apheresis donors for HLAand HNA antibodies, but this would result in loss of 7 to

10 percent of donors. A compromise position would be to

preferentially recruit men for plateletpheresis or screen

female prospective apheresis donors. However, even this

may be seen as excessively cautious, since reported

TRALI is rare compared to the percentage of donors with

WBC antibodies. Perhaps a more refined approach would

be to exclude donors with high-titer antibodies or those

with specificities commonly associated with TRALI. No

approach is ideal, but it is reassuring that, 15 years after

risk reduction was recommended,48 we are at last begin-

ning to tackle one of the leading causes of transfusion-related mortality.

ACKNOWLEDGMENTS

The authors are as alwaysgrateful to all hospital staffwho partici-

pate inSHOTandwho reportedTRALIcases; tothe staffin UKH&I

laboratories for performing the HLA and HNA investigations; to

Prof. M. Mythenfor clinicalreview of somecasesreferredto SHOT;

toNeil Beckmanforproductiondataon useofmaleplasma;and to

Rebecca Cardigan and the staff of the NBS Component Develop-

ment Laboratory for calculations of plasma in PLT pools.

CHAPMAN ET AL.



12/13

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CHAPMAN ET AL.


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