Challenges in testing for platelet-related adverse events

Challenges in testing for platelet-related adverse eventsJ. Kjeldsen-KraghDepartment of Immunology and Transfusion Medicine, Oslo University Hospital, Oslo, Norway

According to haemovigilance data from many Western

countries, platelet concentrates (PCs) is the type of blood

component most frequently associated with transfusion

reactions [1]. In a prospective study by Heddle et al. adverse

events were reported to occur in up to 31% of platelet

transfusion [2], but more recently, the incidence of trans-

fusions reactions to PCs has been reported to be around 2%

or less [3,4]. Although differences in the reporting practice

make direct comparison between studies difficult, the fre-

quency of adverse reactions to platelets has undoubtedly

decreased considerably during the last two decades. The

most important single cause that can explain this decreased

number of transfusion reactions is various improvements

in production and storage of PCs.

Most platelet-related adverse events are mild and non-

life threatening reactions. More rarely, transfusion of plate-

lets is associated with potentially fatal reactions such as

transfusion-related acute lung injury (TRALI), septicaemia

and severe anaphylactic reactions.

Transfusion-related acute lung injury

TRALI is a rare but serious and potentially fatal transfusion

reaction that usually occurs after transfusion of plasma-

containing blood products such as fresh frozen plasma or

PC. From 2005 through 2009 TRALI was the leading cause

of transfusion-associated death in the United States [5]. The

incidence figures of TRALI vary widely, ranging from 1 of

432 to 1 of 88 000 per units of platelets [6]. The large varia-

tion in incidence rates is probably related to different defi-

nitions of TRALI, different methods of surveillance and

different methods of tabulating the denominator data of

blood products transfused across studies [6]. During the last

decade the awareness of this rare transfusion reaction has

increased considerably. More cases are now being recogni-

sed as TRALI, whereas previously the association with

transfusion was overlooked, and cases were interpreted as

acute lung injury with a different aetiology.

The typical clinical features of TRALI are respiratory dis-

tress, hypotension, hypoxemia, tachycardia, bilateral pul-

monary infiltrates and fever appearing within 6 h after

initiation of the transfusion. Circulatory overload and other

obvious causes of acute lung injury should be ruled out.

Treatment of TRALI patients is mainly supportive and in

mild cases oxygen support is usually sufficient. In more

severe TRALI cases, however, artificial ventilation may be

required. The mortality in the severe cases is in the range of

6–20% [7–9], but patients who survive usually recover

within 48 h.

For decades it has been known that anti-leucocyte anti-

bodies in the blood component are associated with TRALI.

Antibodies against HLA class I and class II antigens have

been implicated as well as neutrophil specific alloantibod-

ies. HLA class I antigens are expressed on all nucleated cells

whereas HLA class II are only constitutively expressed on

monocytes, macrophages, dendritic cells and B cells. For

unknown reasons some antibody specificities (anti-HLA

A2, anti-HLA B12 and anti-HNA3a) seem to be more often

involved with the severe cases than others. In the large

majority of cases it is antibodies present in the blood com-

ponent that are implicated in TRALI, whereas antibodies in

the donor are only rarely a causative factor. In some cases

of TRALI there are neither anti-leucocyte antibodies in the

transfused blood component nor in the patient’s blood. In

these cases it has been suggested that neutrophil priming

lipids, such as lysophosphatidylcholines, released from

platelets or red blood cells during storage, may be a crucial

pathogenic factor [10].

The key cells involved in the pathogenesis are the

neutrophil granulocytes. Alloantibodies reacting with neu-

trophils (anti-HLA class I or anti-HNA antibodies) and ⁄ or

neutrophil priming lipids lower the threshold for activation

of the patient’s neutrophils. Strong neutrophil-reactive

antibodies may be sufficient to induce TRALI in a patient

without any predisposing factors while weak antibodies or

neutrophil-priming lipids may be harmless unless the reci-

pient is severely ill, suffering from a concurrent infection

or inflammatory disease. Under such conditions the

patient’s neutrophils, pulmonary endothelial cells and ⁄ or

platelets may already be primed, and transfusion of a blood

component containing anti-leucocyte antibodies and ⁄ or

neutrophil-priming lipids will further activate the recipi-

ent’s neutrophils. Consequently, these hyper-reactive

neutrophils will be activated intravascularly, they will

become rigid and trapped in the pulmonary capillaries

where they release pro-inflammatory mediators such as

Correspondence: J. Kjeldsen-Kragh, Department of Immunology andTransfusion Medicine, Oslo University Hospital, Oslo, NorwayE-mail: [email protected]

ISBT Science Series (2011) 6, 124–128

STATE OF THE ART 3C-S6 ª 2011 The Author(s).ISBT Science Series ª 2011 International Society of Blood Transfusion

124

CXCL8 (IL8), cytotoxic reactive oxygen species (O2- and

H2O2) and toxic enzymes [11]. The pulmonary endothelium

will be damaged giving rise to increased vascular perme-

ability which in turn will lead to exudation and develop-

ment of non-cardiogenic pulmonary oedema. In the case of

anti-HLA class II antibodies, recent studies suggest that the

antibodies bind to and stimulate monocytes to release pro-

inflammatory cytokines, which in turn activate the

patient’s neutrophils [12].

During the last decade several transfusion centres have

implemented preventive measures to reduce the risk of

TRALI, such as limiting the collection of plasma or single

donor platelets to male donors, or female donors without a

history of pregnancy, or to donors who have been shown

not to have anti-leucocyte antibodies [13]. Another

approach to reduce the risk of TRALI is to use solvent deter-

gent-treated pooled plasma (SD plasma), which is devoid of

anti-leucocyte antibodies [14] instead of fresh frozen

plasma (FFP). This transfusion practice has been used in

Norway for nearly two decades and during this period not a

single case of TRALI after transfusion of SD plasma has been

reported to the Norwegian haemovigilance system [15].

Although TRALI is a clinical diagnosis, laboratory inves-

tigations are required to explore whether any of the donors

of the suspected blood components have anti-leucocyte

antibodies. The laboratory case workup varies considerably

from centre to centre [16]. The lymphocytotoxicity test,

enzyme-linked immunosorbent assay (ELISA), flow cytom-

etry and bead array assays are techniques that are fre-

quently used to identify anti-HLA antibodies [17]. The

granulocyte immunoflourescence test (by flow cytometry

and ⁄ or microscopy), granulocyte agglutination test (GAT)

and monoclonal antibody immobilization of granulocyte

antigen (MAIGA) test are used for the detection of antibod-

ies against granulocytes [17]. There are numerous chal-

lenges for the laboratory examining TRALI cases. Ideally, at

least two different methods for antibody identification

should be used, as some methods are more reliable for iden-

tification of certain antibody specificities. As an example,

GAT is the best method for identification of anti-HNA-3a,

which is known to be involved in many of the most severe

cases of TRALI [17].

The analyses are labour-intensive and in many cases

there are a number of blood donors under suspicion. If the

patient had received two units of PCs produced from buffy

coats (PC-BCs) a total of 8–10 donors should be investi-

gated, but obtaining a new blood sample from all 8 to 10

implicated donors can be difficult.

How should we interpret the results if anti-leucocyte

antibodies are detected in one of the donors? Does this

mean that we have a laboratory confirmation of the diagno-

sis? Not necessarily, because anti-HLA antibodies can be

detected in 25% of female donors [18,19]. Thus, the

presence of anti-HLA antibodies may just be a coincidence

and these antibodies will do no harm in the recipient unless

the patient’s neutrophils carry the cognate antigen. Like-

wise, anti-HNA-1a will not cause TRALI if the recipient is

HNA-1a negative. Hence, a laboratory confirmation of the

diagnosis will require a sample from the patient, from which

neutrophils and monocytes can be isolated and tested

against plasma samples from the donors. Since the patient’s

neutrophils must be fresh in order to make the cross

matches with the donors’ plasma, it is quite often logisti-

cally difficult to obtain a sample from the patient once all of

the samples from the donors have eventually been collected.

Consequently, this important test is often not carried out.

What consequences should be drawn from the analyses

for anti-leucocyte antibodies? Both the AABB bulletin [20]

and the Canadian Consensus Panel [6] recommended that a

donor implicated in a TRALI case, where the donor has

antibodies against leucocyte antigens of the recipient,

should be deferred from future donations (or have their

donations restricted to the further manufacture of washed

or frozen deglycerolized red cells). Despite these recom-

mendations a recent survey has demonstrated that the

donor management policies vary considerable in the United

Stated [16]. If anti-leucocyte antibodies cannot be detected

in plasma from the implicated donors deferral should not

be necessary.

Transfusion transmitted infections

The transmission of viruses is a risk that is not only

restricted to transfusion of PCs but is associated with all

blood products that have not been subjected to pathogen

reduction treatment. In the Western countries the risk of

viral transmission is very low and will not be further dis-

cussed in the present paper. Transmission of bacteria, how-

ever, is a significant risk associated with platelet

transfusions and transfusion-associated septicaemia repre-

sents a considerable proportion of transfusion-associated

fatalities [13].

Many blood banks have implemented pathogen reduc-

tion technology to reduce the risk of septicaemia in recipi-

ents of PCs. Without this technology the frequency of PCs

contaminated with bacteria varies from 0Æ03% [21] to 0Æ7%

[22].

The risk of bacterial contamination of PCs can be mini-

mized by strictly adhering to a chain of procedures that

involves: (1) carefully interviewing the blood donors to

exclude donors with possible bacteraemia, (2) careful disin-

fection of the donors’ skin before venipuncture, (3) usage of

a diversion pouch for collection of the first 30 ml of blood

that may contain a skin plug, (4) sampling 10 ml of each

PC the day after blood collection for an automatic bacterial

culture systems, (5) visual inspection of each unit before

Testing for platelet-related adverse events 125

� 2011 The Author(s).ISBT Science Series � 2011 International Society of Blood Transfusion, ISBT Science Series (2011) 6, 124–128

the PC is issued for transfusion and discarding all PCs with-

out swirling, and finally (6) emphasizing for the donor the

importance of reporting to the blood bank if he or she gets

ill within a few days after donation.

If a patient develops a febrile reaction and bacterial con-

tamination of the PC is suspected, it is essential that sam-

ples are collected from the patient for blood cultures and

that the transfusion set and the platelet storage container is

examined for bacterial contamination. However, the later

part often gives rise to problems because the transfusion set

and the platelet storage container have not been kept ster-

ile. In order to conclude that the patient’s transfusion reac-

tion is caused by bacterial contamination of the PC, the

same bacterial strain found in the remains of the PC should

also be present in the patient’s blood.

Allergic transfusion reactions

Allergic transfusion reactions (ATRs) are the most fre-

quently reported adverse event in transfusion [23]. PCs are

involved in around 1 ⁄ 3 of these types of reactions, and

together with plasma, PCs are associated with the more

severe reactions [24], suggesting that blood components

containing large amounts of plasma may be associated with

more severe allergic transfusion reactions. Accordingly,

replacement of plasma in the PCs with various platelet

additive solutions have been shown to significantly

reduced the frequency of allergic transfusion reactions

[25,26].

In most cases, ATRs are associated with IgE or IgG anti-

bodies in the recipient’s serum reacting with drugs, chemi-

cals (e.g. ethylene oxide) or allotypic serum proteins in the

transfused blood. Although life-threatening reactions can

occur in patients with IgA deficiency and anti-IgA due to

previous immunization, anti-IgA is in fact only rarely the

cause of allergic transfusion reactions. Complement-

derived anaphylatoxins (C3a and C5a), cytokines, chemo-

kines (such as CCL5 or RANTES), bradykinin, histamine and

other biological response modifiers may accumulate in the

blood component during storage, and these substances

have also been implicated in ATRs [24,27].

Measurement of tryptase, an enzyme released to serum

during mast cells activation, is used at some centres as a

diagnostic marker for anaphylaxis [28]. Checking the reci-

pient’s serum for anti-IgA is usually also a part of the labo-

ratory case workup. However, as the causes of allergic

transfusion reactions are vast, the reason for an allergic

adverse event usually remains unknown.

Febrile non-haemolytic transfusion reactions

Febrile non-haemolytic transfusion reaction (FNHTR) is

suspected if the patient gets a fever (a rise of body

temperature of more than 1�C) and complains of chills, rig-

ors, and ⁄ or cold sensations, during or shortly after transfu-

sion of a PC, and there are no other obvious explanations

for these symptoms. The temperature increase, however,

may be masked by antipyretics. With symptomatic treat-

ment the patients usually recover rather quickly.

FNHTR is seen more often after platelet than plasma or

red cells transfusions. Before the implementation of univer-

sal leucoreduction of PCs, FNHTR was associated with

around 1 ⁄ 3 of platelet transfusions [2]. Since pre-storage

leucoreduction has been universally adopted there has been

a significant reduction of the frequency of FNHTR [29,30].

Recent studies suggest that the frequency of FNHTR can be

further reduced by implementing pathogen reduction tech-

nology [4,31].

The pathophysiology of FNHTR is complex and only

partly known. Although it is well-known that a large num-

ber of biological response modifiers such as sCD154

(sCD40L), IL-1b, TNFa, CXCL4 (PF4), CXCL8 (IL-8), IL-6,

CCL3 (MCP-1), complement activation products, and many

others, accumulate in the PCs during storage [32,33], the

clinical role of each of these is not clarified. After imple-

mentation of pre-storage leucoreduction of PCs, those sub-

stances primarily produced by leucocytes are probably not

of any clinical importance.

Most laboratory investigations of FNHTR have been car-

ried out in a research context, and because of the multitude

of agents that have been suggested to be involved there is

no consensus regarding which analyses should be included

in a routine laboratory case workup for FNHTR.

The role of anti-platelet antibodies inplatelet-related adverse events

The presence of anti-platelet alloantibodies is a well-known

cause of refractoriness to platelet transfusions. Such anti-

bodies can also be present in donors who have previously

been immunized through pregnancy or transfusion. How-

ever, most centres do not screen their platelet donors for

anti-platelet antibodies, and therefore PCs containing

anti-platelet antibodies can be transfused to patients. If the

PC is given prophylactically, one will probably only

notice an unsatisfactory post-transfusion platelet incre-

ment, but if given to a bleeding patient severe thrombocy-

topenia may occur [34], which may further increase the

patient’s bleeding.

Apart from causing thrombocytopenia, most anti-plate-

let antibodies are usually considered as clinically silent.

However, both anti-HLA antibodies [35] and platelet spe-

cific antibodies [34,36,37] have been associated with aller-

gic reactions [34,35,37] and FNHTR [34,36].

How often are anti-platelet antibodies transfused to

patients? We know that approximately 25% of female

126 J. Kjeldsen-Kragh


donors are HLA-immunized [18,19] and if around half of

the donors are females we can expect that anti-HLA anti-

bodies are present in more than 10% of the collected units.

The number of donors with platelet specific antibodies is

much smaller. Assuming that half of the female donors

have a history of a previous pregnancy, that 2% are

HPA-1a negative and that 10% of these women develop

anti-HPA-1a [38], then not more than 1 of 2000 PCs will

contain anti-HPA-1a if produced by platelet apheresis.

Moreover, due to the recent years’ focus on the association

between anti-HLA-antibodies and TRALI, many centres

have changed their policy and defer all female platelet

apheresis donors with histories of prior pregnancies. Thus,

for those centres, the number of apheresis PCs containing

anti-platelet antibodies will not represent a major problem.

How is the situation at centres that primarily produce

PC-BC? Female donors with a history of prior pregnancies

are not excluded from whole blood donations and many of

these buffy coats will be used for production of PCs. Given

this scenario we can expect that anti-HLA antibodies will

be present in up to 40% of the PC-BC and anti-HPA-1a in

one of 500 PCs. There is an apparent discrepancy between

this high number of PC-BCs containing anti-HLA antibod-

ies and how often transfusion of PC-BCs are associated with

TRALI. There may be two reasons for this discrepancy. First,

the volume of plasma from one HLA-immunized donor in a

PC-BC is less than 20 ml and this volume is probably too

small to elicit a case of full-blown TRALI. Secondly, in

many cases anti-HLA class I antibodies from one donor will

bind to HLA class I molecules expressed on platelets from

one or more of the other donors. This will also be the case

when anti-HPA-1a is present in one of the buffy coats.

What will the consequences be if antibodies from one

donor bind to platelets of one or more of the other donors

in a PC-BC? First, it is conceivable that antibody-sensitized

platelets will have reduced survival after transfusion,

resulting in suboptimal post-transfusion platelet increment.

Second, the antibodies by themselves may affect platelet

function. Both anti-HLA and anti-HPA-1a antibodies can

activate platelets [39–41] and anti-HPA-1a has been shown

to induce release of the chemokine CCL5 (RANTES) from

platelets [40], a pro-inflammatory chemokine that has been

implicated in allergic transfusion reactions [42]. Thus,

when anti-platelet antibodies are present in PC-BCs, it is

possible that during storage these antibodies can increase

the concentration of platelet-derived cytokines and chemo-

kines in the PC-BC to levels that clinically will result in

adverse events when the PCs are transfused. At our hospital

we have recently had a case of full blown FNHTR in associ-

ation with transfusion of a 3-day old PC produced from

four buffy coats, where the laboratory case workup

revealed that one of the donors had high level of anti-

HPA-1a. It is, however, not known how often adverse

events related to transfusion of PC-BCs are associated with

the presence of anti-platelet antibodies in the PC.

Conclusion

Platelet-related adverse events are a significant challenge

in transfusion medicine. Core features of the pathophysiol-

ogy of TRALI have been disclosed and there is an increasing

consensus regarding preventive measures, laboratory case

workup and donor management policies. The pathophysiol-

ogy of ATR and FNHTR is multifaceted and complex and

this is an impediment for standardization of laboratory

examinations of such cases. Although anti-platelet anti-

bodies usually are clinically silent, apart from causing

thrombocytopenia, they may be of clinical importance in

some cases where transfusion of PC-BCs are associated with

adverse events.

Disclosures

The author declares that there are no potential conflicts of

interest.

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Challenges in testing for platelet-related adverse events