transfusion related acute lung injury - past, present and future - am j clin pathol 2008

Am J Clin Pathol 2008;129:287-297 287287 DOI: 10.1309/D3F7BXH466AE3G0P 287

© American Society for Clinical Pathology

Coagulation and Transfusion Medicine / TRANSFUSION-RELATED ACUTE LUNG INJURY

Transfusion-Related Acute Lung Injury

Past, Present, and Future

Tad Cherry, MD,1 Mark Steciuk, MD, PhD,2 Vishnu V.B. Reddy, MD,2 and Marisa B. Marques, MD2

Key Words: Transfusion-related acute lung injury; TRALI; Transfusion reaction; HLA antibodies; Neutrophilic infiltrates

DOI: 10.1309/D3F7BXH466AE3G0P

A b s t r a c t

Noncardiogenic pulmonary edema caused bytransfusion has been observed for almost 60 years.Today, we know this entity as transfusion-related acutelung injury (TRALI). TRALI is an uncommon butpotentially fatal adverse reaction to transfusion ofplasma-containing blood components. It is typified bydyspnea, cough, hypoxemia, and pulmonary edemawithin 6 hours of transfusion. Most commonly, it iscaused by donor HLA antibodies that react withrecipient antigens. It may also be caused bybiologically active compounds accumulated duringstorage of blood products, which are capable ofpriming neutrophils. Without a “gold standard,” thediagnosis of TRALI relies on a high index of suspicionand on excluding other types of transfusion reactions.Although current definitions of TRALI depend onsymptoms, laboratory parameters can aid in thediagnosis and frequently identify the causative donorunit. As our understanding of TRALI deepens, riskreduction or prevention may become possible.

Recently, a 72-year-old man with peripheral vascular dis-ease was admitted to our institution with an occluded rightlower extremity arterial bypass graft and cellulitis of the rightfoot. On the second hospital day, 2 U of fresh frozen plasma(FFP) were ordered to correct an international normalizedratio of 1.73 before surgery.

After transfusion of approximately 100 mL of the firstunit of FFP, the patient became acutely short of breath, hypox-emic, and hypotensive. The transfusion was stopped, and thepatient was given supplemental oxygen. A chest radiographtaken shortly after the onset of symptoms revealed bilateralpulmonary infiltrates. Intubation and mechanical ventilationwere required to maintain adequate oxygenation, and vaso-pressors were needed to maintain adequate perfusion. A CBCcount drawn approximately 1 hour after the onset of symp-toms revealed a WBC count of 7,500/µL (7.5 × 109/L), whichwas markedly decreased from 10,560/µL (10.6 × 109/L) earli-er that day. During the ensuing hours, the patient becameanuric, and after several hours of maximal support, the familydecided against further resuscitative measures. Shortly there-after, the patient became asystolic and was pronounced dead.

Autopsy revealed edematous lungs with a combinedweight of 2,780 g. Histologic examination revealed neu-trophilic aggregates throughout the pulmonary, central nerv-ous system, hepatic, and renal vasculature. Investigation of theimplicated unit of FFP revealed that it was from a multiparousfemale donor with class I and II histocompatibility antibodies.

The Pre-TRALI Era

In 1950, Lanman and colleagues1 described what may bethe first published account of TRALI. To our knowledge, this

288 Am J Clin Pathol 2008;129:287-297288 DOI: 10.1309/D3F7BXH466AE3G0P


Cherry et al / TRANSFUSION-RELATED ACUTE LUNG INJURY

report has thus far gone unnoticed in the TRALI literature.They described an unusual reaction to a transfusion of wholeblood from a 68-year-old donor with chronic lymphocyticleukemia to a 54-year-old man with squamous cell carcinomaof the esophagus. The recipient had been transfused withwhole blood from the same donor 18 days prior to the reac-tion. Immediately after beginning the second transfusion, non-cardiogenic pulmonary edema, evidenced by dyspnea,cyanosis, asthmatic breathing, rales, chills, and fever, devel-oped in the recipient. Within 5 minutes, his total WBC countfell from 18,430/µL (18.4 × 109/L) to 1,700/µL (1.7 × 109/L),and the relative neutrophil count fell to 8% of pretransfusionlevels. The authors speculated that this reaction was anaphy-lactoid and due to transfusion of blood from a leukemic per-son causing WBC margination in the recipient’s lungs.

One year later, Barnard2 described a connection betweentransfusion of allogeneic blood and pulmonary compromise.The patient had acute leukemia and sought care because ofepistaxis. After having his nose packed, he was given a trans-fusion of whole blood, “during which acute pulmonary edemadeveloped.”2 Shortly thereafter, a second transfusion com-menced, and the patient died. Barnard2 ascribed the pul-monary edema to hypersensitivity, not volume overload.Bittingham3 was able to induce a similar set of symptoms byinfusing whole blood with known leukoagglutinins into ahealthy volunteer. Approximately 45 minutes after infusion of50 mL of blood, the test subject began experiencing fever,chills, tachypnea, dyspnea, cyanosis, hypotension, andleukopenia followed by leukocytosis. By the next day, thepatient’s symptoms had resolved.

Years later, Phillips and Fleischner4 described the firstseries of cases in which pulmonary edema, thought not to beattributable to volume overload, developed in patients whohad received transfusions. The first patient was a 23-year-oldparturient who was given 500 mL of whole blood for anemia.Fifteen minutes into the transfusion, a cough developed, andher chest radiograph revealed bilateral pulmonary edema.Aggressive diuresis was carried out, but the pulmonary edemashowed only mild initial improvement. By the third day, theedema had resolved. In 2 other patients, fever and cyanosisdeveloped after they received whole blood, and they werenoted to have pulmonary edema that resolved within 1 to 5days. Phillips and Fleischner4 postulated that the pulmonaryedema was due to “incompatibility of undetermined nature.”

In 1968, Ward et al5 described the case of a 19-year-oldman with melena in whom a shaking chill and fever developedduring infusion of a third unit of blood. Although pulmonaryedema was diagnosed radiographically, circulatory overloadwas dismissed based on the patient’s orthostatic symptoms.He was diagnosed with a pulmonary hypersensitivity reaction,and leukoagglutinins were later found in his serum. Ward6

added 3 similar cases to the literature in 1970.

Thompson et al7 contributed to the literature in 1971 withthe report of 2 cases of pulmonary edema attributable to wholeblood in normovolemic patients. In both patients, chills, fever,dyspnea, cough, tachycardia, and hypotension developedabruptly, but the pulmonary edema resolved quickly duringthe ensuing days. Further investigation into these reactionsrevealed erythrocyte incompatibility was not the culprit, andcultures from donor and recipient blood samples were nega-tive. Instead, antibodies from donor serum reacting with recip-ient leukocytes were found in both cases. Extensive testing ofthe antibody from the first donor revealed a specificity “thatwas probably not directly related to the human leukocyte anti-gens (HLA) A locus, the neutrophil antigens NA1, NB1, NC1,or the 5a-5b locus.”7 In both cases, the donors were multi-parous women.

A “New” Disease

Numerous case reports of pulmonary reactions due totransfusions were published after the initial description byLanman et al.1 Anaphylactoid,1 hypersensitivity,2,8 unknownincompatibility,4 allergic,8,9 and noncardiogenic pulmonaryedema10 are some of the terms used to describe this pattern ofpulmonary deterioration following transfusion of blood prod-ucts. In 1983, Popovsky et al11 recognized a pattern of acutepulmonary compromise in a series of 5 patients and termed ittransfusion-related acute lung injury (TRALI). All patientshad received whole blood or packed RBCs (PRBCs). Analysisof the recipient samples and donor units revealed lymphocy-totoxic antibodies in the latter. HLA antibodies against recip-ient antigens were found in 3 of 5 cases.11 Based on the totalnumber of patients and units transfused during the observedperiod, they estimated an incidence of TRALI of 0.02% perunit transfused and 0.16% per recipient.11 Although rare,TRALI has become the leading cause of transfusion-relateddeaths reported to the US Food and Drug Administration(FDA) since 2004 (J.C. Goldsmith, written communication,May 4, 2007).

In an effort to confirm their initial findings, Popovsky andMoore12 identified 36 patients with acute respiratory distressoccurring within 4 hours of transfusion from 22,292 patientswho had received 194,715 units. In 89% of the cases, granu-locyte antibodies were detected in the serum of the donors.Lymphocytotoxic antibodies were found in 72% of the cases.The lack of antibodies in recipients’ pretransfusion serum ledthe authors to believe that passive transfer of antibodies isassociated with the occurrence of TRALI and likely a factor inits pathogenesis.12 A similar incidence of 0.02% per unit trans-fused and 0.16% per patient transfused was demonstrated inthis study. Of the 36 patients, 2 died, resulting in a 6% mortal-ity risk.12 In the reports by Popovsky et al11 and Popovsky and



Moore,12 whole blood, PRBCs, and FFP led to the developmentof TRALI. All blood components have now been implicated inTRALI, including whole blood–derived platelets,13 apheresisplatelets,14 cryoprecipitate,15 granulocytes,16 stem cells,17

immune globulin concentrates,18 and even autologous RBCs.19

Seeger and colleagues20 reproduced this antibody-medi-ated lung injury in an animal model. Isolated rabbit lungs wereperfused with plasma containing anti-5b antibody, 5b-positivehuman granulocytes, and rabbit plasma as a complementsource. Significant increases in pulmonary arterial pressureand vascular permeability occurred 3 to 6 hours following theinfusion. When the experiments were repeated without 1 ofthe 3 components, no pulmonary edema occurred.20 By usingrat lungs, Sachs et al21 demonstrated pulmonary edema with-out the addition of complement. Human neutrophil antigen(HNA)-2a monoclonal antibodies (mAb) and neutrophils witha high density of the equivalent antigen were added to the per-fusate of isolated rat lungs, and an increase in vascular perme-ability was observed. In a separate experiment, the addition offormyl-Met-Leu-Phe, a component of bacterial cell walls,accelerated the increase in vascular permeability.21

In an effort to further understand the pathogenesis ofTRALI, Looney and colleagues22 developed an in vivo mousemodel. Passive transfusion of a major histocompatibility com-plex (MHC)-I mAb (H2Kd) to cognate mice produced increas-es in excess lung water, vascular and epithelial permeability toprotein, and decreased alveolar fluid clearance. Severe pul-monary sequestration of neutrophils and peripheral neutrope-nia were also observed.22 In a separate experiment, mice werefirst treated with Gr-1 mAb to selectively induce neutropenia.When the animals were challenged with MHC-I mAb, ALIfailed to develop. Next, FcRγ–/– mice were challenged withMHC-I mAb and did not experience ALI. Recognizing thatFcγRI and FcγRIII are also present on lymphocytes, mono-cytes, mast cells, and dendritic cells, the authors injected wild-type neutrophils into the FcRγ–/– mice and challenged themwith MHC-I mAb.22 Untreated mice showed no evidence ofALI, whereas mice transfused with wild-type neutrophilschallenged with MHC-I mAb did. Histologic examinationrevealed the presence of the mAb in the microvasculature ofthe lungs, kidneys, and liver, suggesting that neutrophils weretrapped in various organs besides the pulmonary vasculature.The authors concluded that “neutrophils and their Fcγ recep-tors were essential to the pathogenesis of ALI in this mousemodel of TRALI.”22

Popovsky and Moore12 were unable to identify granulo-cyte antibodies in 11% of their patients with TRALI. Sillimanand colleagues23 studied 10 patients with TRALI whose unitdonors did not have significant titers of HLA antibodies andonly half expressed weakly positive granulocyte-specific anti-bodies. However, they observed that all patients with TRALIhad significant underlying medical conditions (eg, infection,

recent surgery, massive transfusion, or cytokine administra-tion) and hypothesized that 2 events are necessary to induceTRALI.23 Thus, predisposing clinical factors would primeneutrophils and are necessary but not sufficient to causeTRALI. The second insult would be the transfusion or, morespecifically, biologically active lipids that accumulate duringstorage of cellular components.23 Subsequently, Silliman etal14,24 identified lysophosphatidylcholine as a component ofthese biologically active lipids and showed that it can primeneutrophils. In 2003, the same investigators prospectivelydetermined that the lipid-priming activity was higher in unitsof whole blood platelets implicated in TRALI than in controlunits.25 In a case report of recurrent TRALI, Win and col-leagues26 also noted that biologically active lipids may havehad a role in the second TRALI event.

Silliman and colleagues27 reproduced TRALI with bio-logically active lipids in animal models. In keeping with the 2-insult model, the authors first pretreated rats with endotoxin.The rat lungs were then isolated, ventilated, and perfused withsaline, 5% fresh human plasma, plasma from stored bloodfrom the day of isolation, plasma from stored blood from theday of outdate, lipid extracts from day of outdated plasma, orpurified lysophosphatidylcholine.27 Rat lungs pretreated withendotoxin and perfused with day-of-outdate plasma developedALI. Significant pulmonary edema was also seen in the endo-toxin-pretreated lungs perfused with lipid extracts from day-of-outdate plasma and lysophosphatidylcholine.27 A similarstudy in rats with plasma from whole blood–derived andapheresis platelets was done by Silliman et al.28 Again, plas-ma from both sources collected at day 5 induced ALI in endo-toxin-pretreated rats, but plasma from day 0 did not.28

In a retrospective case control study, Khan et al29 identi-fied the CD40 ligand (CD40L) as a cofactor in the develop-ment of TRALI. Soluble CD40L levels were 76% higher inimplicated platelet concentrates than in nonimplicated units.29

The highest levels were found in apheresis products. Theauthors also found that CD40L accumulates during the stor-age of PRBCs and whole blood.29 Furthermore, CD40Lincreased in the posttransfusion plasma of 8 of 12 patientswith TRALI compared with pretransfusion levels. These find-ings suggested an association among soluble CD40L inplatelet concentrates, activation of the innate immune system,and development of TRALI.29

Differentiating TRALI

Because transfusions typically are given to sick patients,it is important to consider all entities that might cause acuterespiratory distress. Transfusion-associated circulatory over-load (TACO) is chief among these entities. Reports of the inci-dence of TACO vary from less than 1% to 11% in critically ill

Coagulation and Transfusion Medicine / REVIEW ARTICLE




medical patients.30,31 Mortality from TACO has been estimat-ed from 3.6%30 to 20%.31 Clinically, patients with TACO havetachypnea, dyspnea, cyanosis, tachycardia, and hyperten-sion.32 They also have signs of circulatory overload, such asjugular venous distension and an elevated pulmonary arteryocclusion pressure.32 Such signs may be present before theinitiation of transfusion, and review of the patient’s intake andoutput will likely add evidence for the diagnosis.33 TACO usu-ally responds to diuresis and ventilatory support.34

Respiratory distress is a major symptom in anaphylactictransfusion reactions as well. These typically include tachyp-nea, cyanosis, and wheezing.35 Hypotension is also frequentlya component.35 Theses symptoms typically arise from laryn-geal and bronchial edema instead of interstitial pulmonaryinvolvement.35 Skin manifestations include urticaria, erythe-ma, and edema of the face and trunk.35 Bacterial contaminationof transfused blood products should also be considered in apatient with respiratory distress. Sepsis usually manifests ashypotension, fever, and even circulatory collapse, often accom-panied by respiratory distress.32 Culture of the blood bag is cru-cial in the evaluation. Finally, an acute hemolytic transfusionreaction must also be considered and ruled out because thesigns and symptoms may include respiratory distress.

Suspecting and Diagnosing TRALI

A high index of suspicion is necessary to accurately iden-tify TRALI. In a look-back study of patients who receivedblood components from a donor implicated in TRALI, Kopkoet al36 determined that TRALI was underrecognized andunderreported. Anyone experiencing dyspnea, hypoxemia,pulmonary edema, hypotension, and fever temporally relatedto transfusion should be suspected of having TRALI. To aid inthe diagnosis and management of TRALI, the hospital trans-fusion service should be notified immediately wheneverTRALI is suspected.

In their original article, Popovsky et al11 studied patientsin whom unexplained pulmonary edema developed followingtransfusions. Later, they added respiratory distress, hypox-emia, and hypotension in the absence of volume overload orunderlying pulmonary disease, occurring usually within 1 to 2hours of transfusion of plasma-containing products.12

Silliman et al25 defined TRALI as follows: (1) respiratoryinsufficiency (tachypnea, shortness of breath, increased workof breathing, and cyanosis) accompanied by significant oxy-gen desaturation as the predominant presenting symptom; (2)respiratory compromise that required immediate intervention;(3) onset of symptoms temporally related to transfusion (with-in 4 hours; most occurring within 10 to 30 minutes); and (4)no other clinical cause (eg, volume overload, allergic manifes-tation, or sepsis) evident for the pulmonary compromise.

Several definitions of TRALI have been published in theUnited States and abroad ❚Table 1❚.37-40 The American-EuropeanConsensus Conference (AECC) definition differs most notablyin its inclusion of possible TRALI cases.39 It is noteworthy thatthe National Heart, Lung, and Blood Institute and the AECC def-initions are based solely on clinical symptoms. Therefore, care-ful observation of the patient is crucial in diagnosing TRALI.

The use of brain natriuretic peptide (BNP) levels hasrecently been postulated as a laboratory adjunct in the differ-entiation of TRALI from TACO. BNP is a polypeptidereleased by the ventricles and atria in response to volume orpressure overload.41 A study by Maisel et al42 showed thatBNP levels “were more accurate than any historical or physi-cal findings or laboratory values in identifying congestiveheart failure as the cause of dyspnea.” In a case reported byBurgher et al,41 a patient suspected of having TRALI wasdiagnosed with TACO based on normal pretransfusion BNPand elevated posttransfusion BNP levels. Further work hasconfirmed the usefulness of BNP in predicting TACO. Zhou etal43 demonstrated 81% sensitivity, 89% specificity, 89% posi-tive predictive value, 81% negative predictive value, and 87%accuracy of BNP in diagnosing TACO.

Atrial natriuretic peptide is another major peptide that hasbeen postulated as a superior marker for TACO because of itsrapid release into the blood following atrial stretch and itsshorter half-life of 2 to 4 minutes.44 Currently, however, atrialnatriuretic peptide testing is not widely available.

Despite availability of testing, BNP levels in the setting ofsuspected TRALI have not been extensively studied. One casereport demonstrated a normal posttransfusion BNP level in apatient with fatal TRALI.45 When interpreting BNP levels, it isimportant to compare posttransfusion with pretransfusion lev-els. Because BNP can be accurately measured on refrigeratedsamples, comparison is easily done with previously collectedblood samples. Although a normal BNP level may exclude

❚Table 1❚Current Criteria for the Diagnosis of TRALI

American-European Consensus Conference Definition of ALI39

Acute onsetBilateral pulmonary infiltrates evident on chest radiographHypoxemia, defined as PaO2/FIO2 ≤300No evidence of left atrial hypertension (ie, no congestive heart

failure; or PAOP ≤18, if available)National Heart, Lung, and Blood Institute Definition of TRALI40

No ALI before transfusionSigns or symptoms of TRALI during or within 6 hours of transfusionIn patients with an alternative ALI risk factor, TRALI is still possible.Massive transfusion should not exclude the possibility of TRALI.

European Haemovigilance Network Definition of TRALI37

Respiratory distress during or within 6 hours of transfusionNo signs of circulatory overloadRadiographic evidence of bilateral pulmonary infiltrates

ALI, acute lung injury; FIO2, fraction of inspired oxygen; PAOP, pulmonary arteryocclusion pressure; TRALI, transfusion-related ALI.



TACO and posttransfusion increases in the BNP level favorTACO, the role of BNP in TRALI remains to be determined.

Other laboratory parameters may also be useful.Transient, acute neutropenia has been reported by manyauthors,1,3,46-48 and the CBC count is a readily available, inex-pensive tool to increase the likelihood of identifying TRALI.Analysis of the pulmonary edema protein content can aid inthe exclusion of circulatory overload.31,49,50 A ratio of 0.75 ormore between the protein in the edema fluid and the plasma isconsistent with increased permeability, whereas a ratio of 0.65or less is characteristic of hydrostatic edema.51 If the suspect-ed case of TRALI proves fatal, gross examination of the lungswill likely reveal diffuse edema, and microscopic examinationwill identify an increased number of leukocytes in themicrovasculature and alveolar spaces ❚Image 1❚.52 Finally, theage of suspected blood products should also be determinedbecause cytokines and lipids accumulate during storage.27-28

Treating TRALI

The mainstay of treatment for TRALI remains supportivecare. If the suspected blood product is still being transfused, itshould be discontinued immediately.53 In the original seriesstudied by Popovsky and Moore,12 all 36 patients requiredsupplemental oxygen and 72% required mechanical ventila-tion. In 81% of patients, complete recovery occurred within96 hours. Only 17% had persistent hypoxia and pulmonaryinfiltrates up to 7 days.12 Although an optimal ventilationstrategy for TRALI has not been specifically studied, smallertidal volumes and optimization of positive end-expiratorypressure seem to improve outcome in ALI.54

Proper diagnosis of TRALI and exclusion of TACO arealso important. Although examples of successful treatment ofTRALI with diuretics exist,5,11 Levy et al55 caution againsttheir routine use. Likewise, although various reports describecorticosteroids used in TRALI,7,10,11 there exists no random-ized, controlled study to support their need.56 Fluid replace-ment is crucial to treat the hypotension and respiratory signsas evidenced by the example of immediate improvement inoxygenation and hemodynamics observed after administrationof large volumes of 5% albumin.57

Investigating TRALI

Although the diagnosis of TRALI relies on clinical symp-toms and the exclusion of other causes, a thorough laboratoryinvestigation will help support the diagnosis. Any investiga-tion into suspected TRALI should begin with immediate noti-fication of the hospital transfusion service, which will ensureproper evaluation and follow-up ❚Table 2❚. The FDA requires

prompt reporting of all transfusion-related deaths and encour-ages voluntary reporting of complications of transfusions.

Complete assessment requires specimens from the recip-ient, all blood components transfused within the preceding 6hours, and the corresponding donor(s). The AECC suggeststesting the donor(s) for HLA class I and II and HNA antibod-ies and determining their specificity, if positive.39 Donorsimplicated in TRALI are those with antibodies specific for arecipient antigen or causing a positive WBC crossmatch.39

Although neutrophil priming activity has also been postulatedin TRALI,14,21 the AECC recognized the lack of widespreadavailability for testing and recommended it only for researchsettings.39 Because numerous studies have found that theimplicated unit was from a multiparous woman,7,12,58 serolog-ic investigation of cases in which multiple transfusions weregiven in the preceding 6 hours should begin with units fromsuch donors.

Predicting TRALI

Although any blood component can cause TRALI, plas-ma-rich units are more likely to be the culprits.31 In addition,Silliman et al25 found that patients with hematologic malig-nancies and those requiring coronary bypass surgery are atparticular risk.

Donor factors may also predict the possibility of develop-ing TRALI. Since 1971, multiple previous pregnancies in thedonor have been considered a risk factor for inducingTRALI.7 Densmore et al59 showed that the prevalence of HLAsensitization is directly related to parity: 15% of womenreporting 1 to 2 pregnancies and 26% of women with 3 ormore. However, transfusion of HLA antibodies into patientswith corresponding antigens typically does not result inTRALI.59,60 Palfi and colleagues58 conducted the first ran-domized, controlled trial of TRALI and multiparous donors.They identified 100 critically ill patients who needed transfu-sion of 2 U of FFP and gave each one a unit from a nulliparousand a unit from a multiparous donor. Patients were random-ized to receive the nulliparous or the multiparous unit first, atleast 4 hours apart. Hemodynamics, cytokine levels, andPaO2/fraction of inspired oxygen (FIO2) ratio were measured.Although only 1 case of TRALI was diagnosed, a small butstatistically significant decrease in the PaO2/FIO2 ratiooccurred after transfusion of the multiparous units.58

Preventing TRALI

Transfusion of any blood component poses a risk fordeveloping TRALI. Consistent, evidence-based transfusionguidelines will likely decrease the number of transfusions





and the risk of associated morbidity and mortality.61-63 In alandmark study, Hebert and colleagues64 compared arestrictive RBC transfusion strategy with a liberal one, withgoal hemoglobin levels of 7 to 9 g/dL (70-90 g/L) and 10 to12 g/dL (100-120 g/L), respectively, in patients admitted tocritical care units. The overall 30-day mortality between the2 groups was not significantly different. Subgroup analysisrevealed that patients in the restrictive group who wereyounger than 55 years and patients who were less severelyill had lower 30-day mortality rates. These data suggest thata restrictive RBC transfusion strategy is at least as effectiveas a liberal one and that for certain subsets of patients it mayprovide benefit.64

The use of plasma in the United States rose 70% from1991 to 2001.67 Indeed, transfusion of plasma in the UnitedStates far exceeds that in Europe.65 Most commonly, plasmais used to correct coagulopathy in bleeding patients or patientsbeing prepared for invasive procedures. However, an extensivereview by Segal and Dzik66 concluded that there are insuffi-cient data to support the assumption that abnormal laboratoryresults are predictive of bleeding in patients undergoing inva-sive procedures. To assess the impact of FFP on the correctionof mild coagulation abnormalities, Abdel-Wahab and col-leagues67 prospectively examined coagulation screening testresults before and after transfusion. The international normal-ized ratio normalized in only 0.8% of the patients anddecreased to at least halfway toward normalization in only15%. Adoption of plasma transfusion strategies based on theseand other studies would undoubtedly reduce the amount ofFFP transfused in the United States.

Prophylactic platelet transfusion in thrombocytopenicpatients has been a mainstay of therapy for many decades.Historically, a platelet count of 20 × 103/µL (20 × 109/L) wasused as the trigger prompting platelet transfusion in patients inclinically stable condition.68 Research in the last decade hasindicated that a transfusion trigger of 10 × 103/µL (10 × 109/L)does not result in an increased risk of bleeding or RBC trans-fusion but does result in a reduction in the number of platelettransfusions.69,70 More recently, the need for prophylacticplatelet transfusions has been questioned. Wandt and col-leagues71 examined a therapeutic transfusion strategy inpatients following autologous peripheral stem cell transplanta-tion. Platelet transfusions were given only for relevant bleed-ing. Only 19% of patients experienced minor or moderatebleeding, and none had severe or life-threatening bleedingepisodes. Compared with historic control subjects, the numberof platelet transfusions was reduced by half.71 Clearly, adher-ence to lower platelet transfusion thresholds and reservingthem for treatment of clinical bleeding can reduce the numberof patient exposures.

Patients requiring surgery are one of the largest groups ofconsumers of blood products. Multiple strategies have beendevised to reduce the number of transfusions required duringthe perioperative period. In the weeks leading up to surgery,Goodnough and Shander72 suggest a thorough review of apatient’s preoperative CBC count to diagnose any anemiathat might be present and initiate appropriate therapy earlyenough to correct the anemia. They also advocate carefulmanagement of anticoagulation in the perioperative period,including discontinuation of antiplatelet agents that patients

A B

❚❚Image 1❚❚ A complete autopsy was performed on a patient who died with the clinical diagnosis of transfusion-related acutelung injury. The most significant finding was pulmonary edema (combined lung weight of 2,780 g) (A) with neutrophilicaggregates in the pulmonary vasculature (B, H&E, ×180).



might be taking.72 Administration of erythropoietin preoper-atively has also been shown to decrease allogeneic transfu-sion requirements in certain populations.73 Intraoperatively,reductions in transfusion rates of plasma and platelets are alsoattainable. The use of antifibrinolytic drugs can decreasetransfusion requirements in a variety of surgical procedures,74

as can the avoidance of intraoperative hypothermia.75 Theretransfusion of postoperatively shed blood has also receivedattention, and it is effective for reducing the number of allo-geneic transfusions in total hip and knee arthroplasty.76

Despite maximal efforts to reduce the number of transfu-sions, patients will continue to require them for specific con-ditions. When transfusion of plasma is indicated, exclusion of


C D

E F

❚❚Image 1❚❚ Also, marked congestion of most tissues, sludging of RBCs, and neutrophilic collections were found in the liversinusoids (C, H&E, ×180), myocardium, glomeruli, and central nervous system.Several meningeal blood vessels of frontallobes and hippocampus contained RBCs and leukocytes (D, H&E, ×50; E, H&E, ×50), and pontine blood vessels had denseneutrophilic aggregates (F, H&E, ×180). Several small lacunar infarcts of the pons were noted (not shown).

❚Table 2❚Investigation of Suspected TRALI*

Discontinue transfusionNotify hospital transfusion serviceRepeat ABO typing and crossmatchObtain CBC count, levels of ABG, blood cultures, and chest radiographReturn all component bags recently transfusedTest donor and recipient for HLA class I and II antibodies and human

neutrophil antigen–specific antibodies (antihuman globulin complement–dependent cytotoxicity or flow cytometry)

Determine specificity, if antibodies detectedPerform donor-recipient WBC crossmatchDetermine parity of donor(s)Determine age of unit(s) transfusedTest for neutrophil-priming activity when available in research settings

ABG, arterial blood gases; TRALI, transfusion-related acute lung injury.* Based, in part, on American-European Consensus Conference recommendations.39




units from multiparous women has been shown to decreasethe incidence of TRALI.77 If there is a choice, different prepa-rations of plasma also seem to differ in their risk of causingTRALI. Sinnott et al78 compared the presence of HLA anti-bodies in single-donor FFP units with pooled, solvent deter-gent–treated plasma. Antibodies were detected in 9% of FFPunits but in none of the solvent detergent–treated units.78

Although the latter units may test negative for HLA antibod-ies, performing FDA-mandated look-back investigations onpooled components is time-consuming, cumbersome, andcostly. Therefore, this product is no longer available in theUnited States. The 2004 consensus conference suggested thatTRALI-implicated donors with demonstrable antibodies bedeferred from future donations.40

In 2006 the AABB adopted the following recommenda-tions to decrease the incidence of TRALI79: (1) Blood collect-ing facilities should implement interventions to minimize thepreparation of high plasma volume components from donorsknown to have or be at risk for leukocyte alloimmunization. (2)Blood transfusion facilities should work toward implementingappropriate evidence-based hemotherapy practices to minimizeunnecessary transfusion. (3) Blood collection and blood trans-fusion facilities should monitor the incidence of reportedTRALI and TRALI-related mortality.

Strategies to minimize the risk of transfusing biological-ly active lipids and cytokines have also been presented.Because these substances accumulate in cellular componentsduring storage,14,24 the use of PRBCs less than 14 days old24

and platelet concentrates less than 2 days old14 would mitigatethe effects of these compounds. However, given currentrequirements regarding serologic and bacterial detection test-ing, providing platelets less than 2 days old is impractical, if

not impossible, in a clinical setting. Washing of cellular com-ponents reduces neutrophil priming activity and biologicallyactive substances80 but has negative effects on shelf life.81

Prestorage leukocyte reduction may reduce the risk of TRALIby limiting complement-mediated processes, which have beenshown to be a contributor to TRALI in a rat model.20

What Is to Come?

We hope the near future will produce more answersabout the pathogenesis and prevention of TRALI. Large,prospective studies of the incidence of TRALI might providemore data about which patients are most at risk and whichdonors are most likely associated with TRALI. From there,various prevention strategies could be prospectively imple-mented to test their efficacy. In addition, donor managementcould be honed to exclude donors whose blood is most like-ly to cause TRALI, while allowing others with less risk tocontinue contributing to the already small donor pool.Screening for HLA and HNA antibodies may eventuallybecome feasible, but cost and interpretation of results must betaken into consideration before widespread implementation.Finally, as Wallis82 suggested, the question of whether thelungs are the only affected organ is still open. During theautopsy of the patient who died of TRALI described in theintroduction, we identified microvascular neutrophil infiltra-tion in various organs besides the lungs (Image 1) and ❚Image

2❚. Although the pulmonary vasculature is the first capillarybed encountered by transfusions, the effects of TRALI mayindeed be systemic, and further study to elucidate theseeffects is warranted.

A B

❚❚Image 2❚❚ Myeloperoxidase (MPO) stain confirmed that most of the cells in the microvasculature of the lungs and pons wereneutrophilic/MPO+ collections (A, ×180; B, ×100).



Conclusion

TRALI is a rare but serious complication of transfusiontherapy. Since the first description, a great deal of insight hasbeen gained into its pathogenesis, yet many questions remainunanswered. There is clear evidence that passively transfusedantibodies have a role in many cases of TRALI. However, thecase for a role for biologically active lipids as causative agentscontinues to mount. Whether these 2 causes are separate enti-ties or represent different points along the same continuum isunknown. Rapid recognition when cases of TRALI occurremains vital to the further understanding and proper treat-ment of this complication. Notification of the transfusion serv-ice is crucial to ensure that a proper investigation is carried outand, if necessary, the case reported to regulatory authorities.Perhaps with a broader and more detailed understanding intothe pathogenesis of TRALI, at-risk donors and recipients canbe identified and measures taken to lessen the recipient’s risk.

From the Departments of 1Anesthesiology and 2Pathology,Division of Laboratory Medicine, University of Alabama atBirmingham.

Address reprint requests to Dr Cherry: Dept of Anesthesiology,JT 964; 619 19th St S, Birmingham, AL 35249-6810.

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