Transfusion related acute lung injury - Past, present and future - Am J Clin Pathol 2008

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Published on March 4, 2014

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Transfusion related acute lung injury - Past, present and future

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 Abstract Noncardiogenic pulmonary edema caused by transfusion has been observed for almost 60 years. Today, we know this entity as transfusion-related acute lung injury (TRALI). TRALI is an uncommon but potentially fatal adverse reaction to transfusion of plasma-containing blood components. It is typified by dyspnea, cough, hypoxemia, and pulmonary edema within 6 hours of transfusion. Most commonly, it is caused by donor HLA antibodies that react with recipient antigens. It may also be caused by biologically active compounds accumulated during storage of blood products, which are capable of priming neutrophils. Without a “gold standard,” the diagnosis of TRALI relies on a high index of suspicion and on excluding other types of transfusion reactions. Although current definitions of TRALI depend on symptoms, laboratory parameters can aid in the diagnosis and frequently identify the causative donor unit. As our understanding of TRALI deepens, risk reduction or prevention may become possible. Recently, a 72-year-old man with peripheral vascular disease was admitted to our institution with an occluded right lower extremity arterial bypass graft and cellulitis of the right foot. On the second hospital day, 2 U of fresh frozen plasma (FFP) were ordered to correct an international normalized ratio of 1.73 before surgery. After transfusion of approximately 100 mL of the first unit of FFP, the patient became acutely short of breath, hypoxemic, and hypotensive. The transfusion was stopped, and the patient was given supplemental oxygen. A chest radiograph taken shortly after the onset of symptoms revealed bilateral pulmonary infiltrates. Intubation and mechanical ventilation were required to maintain adequate oxygenation, and vasopressors were needed to maintain adequate perfusion. A CBC count drawn approximately 1 hour after the onset of symptoms revealed a WBC count of 7,500/µL (7.5 × 109/L), which was markedly decreased from 10,560/µL (10.6 × 109/L) earlier that day. During the ensuing hours, the patient became anuric, and after several hours of maximal support, the family decided against further resuscitative measures. Shortly thereafter, the patient became asystolic and was pronounced dead. Autopsy revealed edematous lungs with a combined weight of 2,780 g. Histologic examination revealed neutrophilic aggregates throughout the pulmonary, central nervous system, hepatic, and renal vasculature. Investigation of the implicated unit of FFP revealed that it was from a multiparous female donor with class I and II histocompatibility antibodies. The Pre-TRALI Era In 1950, Lanman and colleagues1 described what may be the first published account of TRALI. To our knowledge, this Am J Clin Pathol 2008;129:287-297 © American Society for Clinical Pathology 287 DOI: 10.1309/D3F7BXH466AE3G0P 287 287

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 whole blood from a 68-year-old donor with chronic lymphocytic leukemia to a 54-year-old man with squamous cell carcinoma of the esophagus. The recipient had been transfused with whole blood from the same donor 18 days prior to the reaction. Immediately after beginning the second transfusion, noncardiogenic pulmonary edema, evidenced by dyspnea, cyanosis, asthmatic breathing, rales, chills, and fever, developed in the recipient. Within 5 minutes, his total WBC count fell 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 pretransfusion levels. The authors speculated that this reaction was anaphylactoid and due to transfusion of blood from a leukemic person causing WBC margination in the recipient’s lungs. One year later, Barnard2 described a connection between transfusion of allogeneic blood and pulmonary compromise. The patient had acute leukemia and sought care because of epistaxis. After having his nose packed, he was given a transfusion of whole blood, “during which acute pulmonary edema developed.”2 Shortly thereafter, a second transfusion commenced, and the patient died. Barnard2 ascribed the pulmonary edema to hypersensitivity, not volume overload. Bittingham3 was able to induce a similar set of symptoms by infusing whole blood with known leukoagglutinins into a healthy volunteer. Approximately 45 minutes after infusion of 50 mL of blood, the test subject began experiencing fever, chills, tachypnea, dyspnea, cyanosis, hypotension, and leukopenia followed by leukocytosis. By the next day, the patient’s symptoms had resolved. Years later, Phillips and Fleischner4 described the first series of cases in which pulmonary edema, thought not to be attributable to volume overload, developed in patients who had received transfusions. The first patient was a 23-year-old parturient who was given 500 mL of whole blood for anemia. Fifteen minutes into the transfusion, a cough developed, and her chest radiograph revealed bilateral pulmonary edema. Aggressive diuresis was carried out, but the pulmonary edema showed only mild initial improvement. By the third day, the edema had resolved. In 2 other patients, fever and cyanosis developed after they received whole blood, and they were noted to have pulmonary edema that resolved within 1 to 5 days. Phillips and Fleischner4 postulated that the pulmonary edema was due to “incompatibility of undetermined nature.” In 1968, Ward et al5 described the case of a 19-year-old man with melena in whom a shaking chill and fever developed during infusion of a third unit of blood. Although pulmonary edema was diagnosed radiographically, circulatory overload was 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. 288 288 Am J Clin Pathol 2008;129:287-297 DOI: 10.1309/D3F7BXH466AE3G0P Thompson et al7 contributed to the literature in 1971 with the report of 2 cases of pulmonary edema attributable to whole blood in normovolemic patients. In both patients, chills, fever, dyspnea, cough, tachycardia, and hypotension developed abruptly, but the pulmonary edema resolved quickly during the ensuing days. Further investigation into these reactions revealed erythrocyte incompatibility was not the culprit, and cultures from donor and recipient blood samples were negative. Instead, antibodies from donor serum reacting with recipient leukocytes were found in both cases. Extensive testing of the antibody from the first donor revealed a specificity “that was probably not directly related to the human leukocyte antigens (HLA) A locus, the neutrophil antigens NA1, NB1, NC1, or the 5a-5b locus.”7 In both cases, the donors were multiparous women. A “New” Disease Numerous case reports of pulmonary reactions due to transfusions were published after the initial description by Lanman et al.1 Anaphylactoid,1 hypersensitivity,2,8 unknown incompatibility,4 allergic,8,9 and noncardiogenic pulmonary edema10 are some of the terms used to describe this pattern of pulmonary deterioration following transfusion of blood products. In 1983, Popovsky et al11 recognized a pattern of acute pulmonary compromise in a series of 5 patients and termed it transfusion-related acute lung injury (TRALI). All patients had received whole blood or packed RBCs (PRBCs). Analysis of the recipient samples and donor units revealed lymphocytotoxic antibodies in the latter. HLA antibodies against recipient antigens were found in 3 of 5 cases.11 Based on the total number of patients and units transfused during the observed period, they estimated an incidence of TRALI of 0.02% per unit transfused and 0.16% per recipient.11 Although rare, TRALI has become the leading cause of transfusion-related deaths 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 and Moore12 identified 36 patients with acute respiratory distress occurring within 4 hours of transfusion from 22,292 patients who had received 194,715 units. In 89% of the cases, granulocyte 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 led the authors to believe that passive transfer of antibodies is associated with the occurrence of TRALI and likely a factor in its pathogenesis.12 A similar incidence of 0.02% per unit transfused and 0.16% per patient transfused was demonstrated in this study. Of the 36 patients, 2 died, resulting in a 6% mortality risk.12 In the reports by Popovsky et al11 and Popovsky and © American Society for Clinical Pathology

Coagulation and Transfusion Medicine / REVIEW ARTICLE Moore,12 whole blood, PRBCs, and FFP led to the development of TRALI. All blood components have now been implicated in TRALI, including whole blood–derived platelets,13 apheresis platelets,14 cryoprecipitate,15 granulocytes,16 stem cells,17 immune globulin concentrates,18 and even autologous RBCs.19 Seeger and colleagues20 reproduced this antibody-mediated lung injury in an animal model. Isolated rabbit lungs were perfused with plasma containing anti-5b antibody, 5b-positive human granulocytes, and rabbit plasma as a complement source. Significant increases in pulmonary arterial pressure and vascular permeability occurred 3 to 6 hours following the infusion. When the experiments were repeated without 1 of the 3 components, no pulmonary edema occurred.20 By using rat lungs, Sachs et al21 demonstrated pulmonary edema without the addition of complement. Human neutrophil antigen (HNA)-2a monoclonal antibodies (mAb) and neutrophils with a high density of the equivalent antigen were added to the perfusate of isolated rat lungs, and an increase in vascular permeability was observed. In a separate experiment, the addition of formyl-Met-Leu-Phe, a component of bacterial cell walls, accelerated the increase in vascular permeability.21 In an effort to further understand the pathogenesis of TRALI, Looney and colleagues22 developed an in vivo mouse model. Passive transfusion of a major histocompatibility complex (MHC)-I mAb (H2Kd) to cognate mice produced increases in excess lung water, vascular and epithelial permeability to protein, and decreased alveolar fluid clearance. Severe pulmonary sequestration of neutrophils and peripheral neutropenia were also observed.22 In a separate experiment, mice were first treated with Gr-1 mAb to selectively induce neutropenia. When the animals were challenged with MHC-I mAb, ALI failed to develop. Next, FcRγ–/– mice were challenged with MHC-I mAb and did not experience ALI. Recognizing that FcγRI and FcγRIII are also present on lymphocytes, monocytes, mast cells, and dendritic cells, the authors injected wildtype neutrophils into the FcRγ–/– mice and challenged them with MHC-I mAb.22 Untreated mice showed no evidence of ALI, whereas mice transfused with wild-type neutrophils challenged with MHC-I mAb did. Histologic examination revealed the presence of the mAb in the microvasculature of the lungs, kidneys, and liver, suggesting that neutrophils were trapped in various organs besides the pulmonary vasculature. The authors concluded that “neutrophils and their Fcγ receptors were essential to the pathogenesis of ALI in this mouse model of TRALI.”22 Popovsky and Moore12 were unable to identify granulocyte antibodies in 11% of their patients with TRALI. Silliman and colleagues23 studied 10 patients with TRALI whose unit donors did not have significant titers of HLA antibodies and only half expressed weakly positive granulocyte-specific antibodies. However, they observed that all patients with TRALI had significant underlying medical conditions (eg, infection, recent surgery, massive transfusion, or cytokine administration) and hypothesized that 2 events are necessary to induce TRALI.23 Thus, predisposing clinical factors would prime neutrophils and are necessary but not sufficient to cause TRALI. The second insult would be the transfusion or, more specifically, biologically active lipids that accumulate during storage of cellular components.23 Subsequently, Silliman et al14,24 identified lysophosphatidylcholine as a component of these biologically active lipids and showed that it can prime neutrophils. In 2003, the same investigators prospectively determined that the lipid-priming activity was higher in units of whole blood platelets implicated in TRALI than in control units.25 In a case report of recurrent TRALI, Win and colleagues26 also noted that biologically active lipids may have had a role in the second TRALI event. Silliman and colleagues27 reproduced TRALI with biologically active lipids in animal models. In keeping with the 2insult model, the authors first pretreated rats with endotoxin. The rat lungs were then isolated, ventilated, and perfused with saline, 5% fresh human plasma, plasma from stored blood from the day of isolation, plasma from stored blood from the day of outdate, lipid extracts from day of outdated plasma, or purified lysophosphatidylcholine.27 Rat lungs pretreated with endotoxin and perfused with day-of-outdate plasma developed ALI. Significant pulmonary edema was also seen in the endotoxin-pretreated lungs perfused with lipid extracts from dayof-outdate plasma and lysophosphatidylcholine.27 A similar study in rats with plasma from whole blood–derived and apheresis platelets was done by Silliman et al.28 Again, plasma from both sources collected at day 5 induced ALI in endotoxin-pretreated rats, but plasma from day 0 did not.28 In a retrospective case control study, Khan et al29 identified the CD40 ligand (CD40L) as a cofactor in the development of TRALI. Soluble CD40L levels were 76% higher in implicated platelet concentrates than in nonimplicated units.29 The highest levels were found in apheresis products. The authors also found that CD40L accumulates during the storage of PRBCs and whole blood.29 Furthermore, CD40L increased in the posttransfusion plasma of 8 of 12 patients with TRALI compared with pretransfusion levels. These findings suggested an association among soluble CD40L in platelet 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 acute respiratory distress. Transfusion-associated circulatory overload (TACO) is chief among these entities. Reports of the incidence of TACO vary from less than 1% to 11% in critically ill Am J Clin Pathol 2008;129:287-297 © American Society for Clinical Pathology 289 DOI: 10.1309/D3F7BXH466AE3G0P 289 289

Cherry et al / TRANSFUSION-RELATED ACUTE LUNG INJURY medical patients.30,31 Mortality from TACO has been estimated from 3.6%30 to 20%.31 Clinically, patients with TACO have tachypnea, dyspnea, cyanosis, tachycardia, and hypertension.32 They also have signs of circulatory overload, such as jugular venous distension and an elevated pulmonary artery occlusion pressure.32 Such signs may be present before the initiation of transfusion, and review of the patient’s intake and output will likely add evidence for the diagnosis.33 TACO usually responds to diuresis and ventilatory support.34 Respiratory distress is a major symptom in anaphylactic transfusion reactions as well. These typically include tachypnea, cyanosis, and wheezing.35 Hypotension is also frequently a component.35 Theses symptoms typically arise from laryngeal and bronchial edema instead of interstitial pulmonary involvement.35 Skin manifestations include urticaria, erythema, and edema of the face and trunk.35 Bacterial contamination of transfused blood products should also be considered in a patient with respiratory distress. Sepsis usually manifests as hypotension, fever, and even circulatory collapse, often accompanied by respiratory distress.32 Culture of the blood bag is crucial in the evaluation. Finally, an acute hemolytic transfusion reaction must also be considered and ruled out because the signs and symptoms may include respiratory distress. Suspecting and Diagnosing TRALI A high index of suspicion is necessary to accurately identify TRALI. In a look-back study of patients who received blood components from a donor implicated in TRALI, Kopko et al36 determined that TRALI was underrecognized and underreported. Anyone experiencing dyspnea, hypoxemia, pulmonary edema, hypotension, and fever temporally related to transfusion should be suspected of having TRALI. To aid in the diagnosis and management of TRALI, the hospital transfusion service should be notified immediately whenever TRALI is suspected. In their original article, Popovsky et al11 studied patients in whom unexplained pulmonary edema developed following transfusions. Later, they added respiratory distress, hypoxemia, and hypotension in the absence of volume overload or underlying pulmonary disease, occurring usually within 1 to 2 hours of transfusion of plasma-containing products.12 Silliman et al25 defined TRALI as follows: (1) respiratory insufficiency (tachypnea, shortness of breath, increased work of breathing, and cyanosis) accompanied by significant oxygen desaturation as the predominant presenting symptom; (2) respiratory compromise that required immediate intervention; (3) onset of symptoms temporally related to transfusion (within 4 hours; most occurring within 10 to 30 minutes); and (4) no other clinical cause (eg, volume overload, allergic manifestation, or sepsis) evident for the pulmonary compromise. 290 290 Am J Clin Pathol 2008;129:287-297 DOI: 10.1309/D3F7BXH466AE3G0P Several definitions of TRALI have been published in the United States and abroad ❚Table 1❚.37-40 The American-European Consensus Conference (AECC) definition differs most notably in its inclusion of possible TRALI cases.39 It is noteworthy that the National Heart, Lung, and Blood Institute and the AECC definitions are based solely on clinical symptoms. Therefore, careful observation of the patient is crucial in diagnosing TRALI. The use of brain natriuretic peptide (BNP) levels has recently been postulated as a laboratory adjunct in the differentiation of TRALI from TACO. BNP is a polypeptide released by the ventricles and atria in response to volume or pressure overload.41 A study by Maisel et al42 showed that BNP levels “were more accurate than any historical or physical findings or laboratory values in identifying congestive heart failure as the cause of dyspnea.” In a case reported by Burgher et al,41 a patient suspected of having TRALI was diagnosed with TACO based on normal pretransfusion BNP and elevated posttransfusion BNP levels. Further work has confirmed the usefulness of BNP in predicting TACO. Zhou et al43 demonstrated 81% sensitivity, 89% specificity, 89% positive predictive value, 81% negative predictive value, and 87% accuracy of BNP in diagnosing TACO. Atrial natriuretic peptide is another major peptide that has been postulated as a superior marker for TACO because of its rapid release into the blood following atrial stretch and its shorter half-life of 2 to 4 minutes.44 Currently, however, atrial natriuretic peptide testing is not widely available. Despite availability of testing, BNP levels in the setting of suspected TRALI have not been extensively studied. One case report demonstrated a normal posttransfusion BNP level in a patient with fatal TRALI.45 When interpreting BNP levels, it is important to compare posttransfusion with pretransfusion levels. Because BNP can be accurately measured on refrigerated samples, comparison is easily done with previously collected blood 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 onset Bilateral pulmonary infiltrates evident on chest radiograph Hypoxemia, defined as PaO2/FIO2 ≤300 No 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 transfusion Signs or symptoms of TRALI during or within 6 hours of transfusion In 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 transfusion No signs of circulatory overload Radiographic evidence of bilateral pulmonary infiltrates ALI, acute lung injury; FIO2, fraction of inspired oxygen; PAOP, pulmonary artery occlusion pressure; TRALI, transfusion-related ALI. © American Society for Clinical Pathology

Coagulation and Transfusion Medicine / REVIEW ARTICLE TACO and posttransfusion increases in the BNP level favor TACO, the role of BNP in TRALI remains to be determined. Other laboratory parameters may also be useful. Transient, acute neutropenia has been reported by many authors,1,3,46-48 and the CBC count is a readily available, inexpensive tool to increase the likelihood of identifying TRALI. Analysis of the pulmonary edema protein content can aid in the exclusion of circulatory overload.31,49,50 A ratio of 0.75 or more between the protein in the edema fluid and the plasma is consistent with increased permeability, whereas a ratio of 0.65 or less is characteristic of hydrostatic edema.51 If the suspected case of TRALI proves fatal, gross examination of the lungs will likely reveal diffuse edema, and microscopic examination will identify an increased number of leukocytes in the microvasculature and alveolar spaces ❚Image 1❚.52 Finally, the age of suspected blood products should also be determined because cytokines and lipids accumulate during storage.27-28 prompt reporting of all transfusion-related deaths and encourages voluntary reporting of complications of transfusions. Complete assessment requires specimens from the recipient, all blood components transfused within the preceding 6 hours, and the corresponding donor(s). The AECC suggests testing the donor(s) for HLA class I and II and HNA antibodies and determining their specificity, if positive.39 Donors implicated in TRALI are those with antibodies specific for a recipient antigen or causing a positive WBC crossmatch.39 Although neutrophil priming activity has also been postulated in TRALI,14,21 the AECC recognized the lack of widespread availability for testing and recommended it only for research settings.39 Because numerous studies have found that the implicated unit was from a multiparous woman,7,12,58 serologic investigation of cases in which multiple transfusions were given in the preceding 6 hours should begin with units from such donors. Treating TRALI Predicting TRALI The mainstay of treatment for TRALI remains supportive care. If the suspected blood product is still being transfused, it should be discontinued immediately.53 In the original series studied by Popovsky and Moore,12 all 36 patients required supplemental oxygen and 72% required mechanical ventilation. In 81% of patients, complete recovery occurred within 96 hours. Only 17% had persistent hypoxia and pulmonary infiltrates up to 7 days.12 Although an optimal ventilation strategy for TRALI has not been specifically studied, smaller tidal volumes and optimization of positive end-expiratory pressure seem to improve outcome in ALI.54 Proper diagnosis of TRALI and exclusion of TACO are also important. Although examples of successful treatment of TRALI with diuretics exist,5,11 Levy et al55 caution against their routine use. Likewise, although various reports describe corticosteroids used in TRALI,7,10,11 there exists no randomized, controlled study to support their need.56 Fluid replacement is crucial to treat the hypotension and respiratory signs as evidenced by the example of immediate improvement in oxygenation and hemodynamics observed after administration of large volumes of 5% albumin.57 Although any blood component can cause TRALI, plasma-rich units are more likely to be the culprits.31 In addition, Silliman et al25 found that patients with hematologic malignancies and those requiring coronary bypass surgery are at particular risk. Donor factors may also predict the possibility of developing TRALI. Since 1971, multiple previous pregnancies in the donor have been considered a risk factor for inducing TRALI.7 Densmore et al59 showed that the prevalence of HLA sensitization is directly related to parity: 15% of women reporting 1 to 2 pregnancies and 26% of women with 3 or more. However, transfusion of HLA antibodies into patients with corresponding antigens typically does not result in TRALI.59,60 Palfi and colleagues58 conducted the first randomized, controlled trial of TRALI and multiparous donors. They identified 100 critically ill patients who needed transfusion of 2 U of FFP and gave each one a unit from a nulliparous and a unit from a multiparous donor. Patients were randomized to receive the nulliparous or the multiparous unit first, at least 4 hours apart. Hemodynamics, cytokine levels, and PaO2/fraction of inspired oxygen (FIO2) ratio were measured. Although only 1 case of TRALI was diagnosed, a small but statistically significant decrease in the PaO2/FIO2 ratio occurred after transfusion of the multiparous units.58 Investigating TRALI Although the diagnosis of TRALI relies on clinical symptoms and the exclusion of other causes, a thorough laboratory investigation will help support the diagnosis. Any investigation into suspected TRALI should begin with immediate notification of the hospital transfusion service, which will ensure proper evaluation and follow-up ❚Table 2❚. The FDA requires Preventing TRALI Transfusion of any blood component poses a risk for developing TRALI. Consistent, evidence-based transfusion guidelines will likely decrease the number of transfusions Am J Clin Pathol 2008;129:287-297 © American Society for Clinical Pathology 291 DOI: 10.1309/D3F7BXH466AE3G0P 291 291

Cherry et al / TRANSFUSION-RELATED ACUTE LUNG INJURY A B ❚Image 1❚ A complete autopsy was performed on a patient who died with the clinical diagnosis of transfusion-related acute ❚ lung injury. The most significant finding was pulmonary edema (combined lung weight of 2,780 g) (A) with neutrophilic aggregates in the pulmonary vasculature (B, H&E, ×180). and the risk of associated morbidity and mortality.61-63 In a landmark study, Hebert and colleagues64 compared a restrictive RBC transfusion strategy with a liberal one, with goal hemoglobin levels of 7 to 9 g/dL (70-90 g/L) and 10 to 12 g/dL (100-120 g/L), respectively, in patients admitted to critical care units. The overall 30-day mortality between the 2 groups was not significantly different. Subgroup analysis revealed that patients in the restrictive group who were younger than 55 years and patients who were less severely ill had lower 30-day mortality rates. These data suggest that a restrictive RBC transfusion strategy is at least as effective as a liberal one and that for certain subsets of patients it may provide benefit.64 The use of plasma in the United States rose 70% from 1991 to 2001.67 Indeed, transfusion of plasma in the United States far exceeds that in Europe.65 Most commonly, plasma is used to correct coagulopathy in bleeding patients or patients being prepared for invasive procedures. However, an extensive review by Segal and Dzik66 concluded that there are insufficient data to support the assumption that abnormal laboratory results are predictive of bleeding in patients undergoing invasive procedures. To assess the impact of FFP on the correction of mild coagulation abnormalities, Abdel-Wahab and colleagues67 prospectively examined coagulation screening test results before and after transfusion. The international normalized ratio normalized in only 0.8% of the patients and decreased to at least halfway toward normalization in only 15%. Adoption of plasma transfusion strategies based on these and other studies would undoubtedly reduce the amount of FFP transfused in the United States. 292 292 Am J Clin Pathol 2008;129:287-297 DOI: 10.1309/D3F7BXH466AE3G0P Prophylactic platelet transfusion in thrombocytopenic patients has been a mainstay of therapy for many decades. Historically, a platelet count of 20 × 103/µL (20 × 109/L) was used as the trigger prompting platelet transfusion in patients in clinically stable condition.68 Research in the last decade has indicated that a transfusion trigger of 10 × 103/µL (10 × 109/L) does not result in an increased risk of bleeding or RBC transfusion but does result in a reduction in the number of platelet transfusions.69,70 More recently, the need for prophylactic platelet transfusions has been questioned. Wandt and colleagues71 examined a therapeutic transfusion strategy in patients following autologous peripheral stem cell transplantation. Platelet transfusions were given only for relevant bleeding. Only 19% of patients experienced minor or moderate bleeding, and none had severe or life-threatening bleeding episodes. Compared with historic control subjects, the number of platelet transfusions was reduced by half.71 Clearly, adherence to lower platelet transfusion thresholds and reserving them for treatment of clinical bleeding can reduce the number of patient exposures. Patients requiring surgery are one of the largest groups of consumers of blood products. Multiple strategies have been devised to reduce the number of transfusions required during the perioperative period. In the weeks leading up to surgery, Goodnough and Shander72 suggest a thorough review of a patient’s preoperative CBC count to diagnose any anemia that might be present and initiate appropriate therapy early enough to correct the anemia. They also advocate careful management of anticoagulation in the perioperative period, including discontinuation of antiplatelet agents that patients © American Society for Clinical Pathology

Coagulation and Transfusion Medicine / REVIEW ARTICLE C D E F ❚Image 1❚ Also, marked congestion of most tissues, sludging of RBCs, and neutrophilic collections were found in the liver ❚ sinusoids (C, H&E, ×180), myocardium, glomeruli, and central nervous system.Several meningeal blood vessels of frontal lobes and hippocampus contained RBCs and leukocytes (D, H&E, ×50; E, H&E, ×50), and pontine blood vessels had dense neutrophilic aggregates (F, H&E, ×180). Several small lacunar infarcts of the pons were noted (not shown). might be taking.72 Administration of erythropoietin preoperatively has also been shown to decrease allogeneic transfusion requirements in certain populations.73 Intraoperatively, reductions in transfusion rates of plasma and platelets are also attainable. The use of antifibrinolytic drugs can decrease transfusion requirements in a variety of surgical procedures,74 as can the avoidance of intraoperative hypothermia.75 The retransfusion of postoperatively shed blood has also received attention, and it is effective for reducing the number of allogeneic transfusions in total hip and knee arthroplasty.76 Despite maximal efforts to reduce the number of transfusions, patients will continue to require them for specific conditions. When transfusion of plasma is indicated, exclusion of ❚Table 2❚ Investigation of Suspected TRALI* Discontinue transfusion Notify hospital transfusion service Repeat ABO typing and crossmatch Obtain CBC count, levels of ABG, blood cultures, and chest radiograph Return all component bags recently transfused Test 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 detected Perform donor-recipient WBC crossmatch Determine parity of donor(s) Determine age of unit(s) transfused Test 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 Am J Clin Pathol 2008;129:287-297 © American Society for Clinical Pathology 293 DOI: 10.1309/D3F7BXH466AE3G0P 293 293

Cherry et al / TRANSFUSION-RELATED ACUTE LUNG INJURY units from multiparous women has been shown to decrease the incidence of TRALI.77 If there is a choice, different preparations of plasma also seem to differ in their risk of causing TRALI. Sinnott et al78 compared the presence of HLA antibodies in single-donor FFP units with pooled, solvent detergent–treated plasma. Antibodies were detected in 9% of FFP units but in none of the solvent detergent–treated units.78 Although the latter units may test negative for HLA antibodies, performing FDA-mandated look-back investigations on pooled components is time-consuming, cumbersome, and costly. Therefore, this product is no longer available in the United States. The 2004 consensus conference suggested that TRALI-implicated donors with demonstrable antibodies be deferred from future donations.40 In 2006 the AABB adopted the following recommendations to decrease the incidence of TRALI79: (1) Blood collecting facilities should implement interventions to minimize the preparation of high plasma volume components from donors known to have or be at risk for leukocyte alloimmunization. (2) Blood transfusion facilities should work toward implementing appropriate evidence-based hemotherapy practices to minimize unnecessary transfusion. (3) Blood collection and blood transfusion facilities should monitor the incidence of reported TRALI and TRALI-related mortality. Strategies to minimize the risk of transfusing biologically active lipids and cytokines have also been presented. Because these substances accumulate in cellular components during storage,14,24 the use of PRBCs less than 14 days old24 and platelet concentrates less than 2 days old14 would mitigate the effects of these compounds. However, given current requirements regarding serologic and bacterial detection testing, providing platelets less than 2 days old is impractical, if A not impossible, in a clinical setting. Washing of cellular components reduces neutrophil priming activity and biologically active substances80 but has negative effects on shelf life.81 Prestorage leukocyte reduction may reduce the risk of TRALI by limiting complement-mediated processes, which have been shown to be a contributor to TRALI in a rat model.20 What Is to Come? We hope the near future will produce more answers about the pathogenesis and prevention of TRALI. Large, prospective studies of the incidence of TRALI might provide more data about which patients are most at risk and which donors are most likely associated with TRALI. From there, various prevention strategies could be prospectively implemented to test their efficacy. In addition, donor management could be honed to exclude donors whose blood is most likely to cause TRALI, while allowing others with less risk to continue contributing to the already small donor pool. Screening for HLA and HNA antibodies may eventually become feasible, but cost and interpretation of results must be taken into consideration before widespread implementation. Finally, as Wallis82 suggested, the question of whether the lungs are the only affected organ is still open. During the autopsy of the patient who died of TRALI described in the introduction, we identified microvascular neutrophil infiltration in various organs besides the lungs (Image 1) and ❚Image 2❚. Although the pulmonary vasculature is the first capillary bed encountered by transfusions, the effects of TRALI may indeed be systemic, and further study to elucidate these effects is warranted. B ❚Image 2❚ Myeloperoxidase (MPO) stain confirmed that most of the cells in the microvasculature of the lungs and pons were ❚ neutrophilic/MPO+ collections (A, ×180; B, ×100). 294 294 Am J Clin Pathol 2008;129:287-297 DOI: 10.1309/D3F7BXH466AE3G0P © American Society for Clinical Pathology

Coagulation and Transfusion Medicine / REVIEW ARTICLE Conclusion TRALI is a rare but serious complication of transfusion therapy. Since the first description, a great deal of insight has been gained into its pathogenesis, yet many questions remain unanswered. There is clear evidence that passively transfused antibodies have a role in many cases of TRALI. However, the case for a role for biologically active lipids as causative agents continues to mount. Whether these 2 causes are separate entities or represent different points along the same continuum is unknown. Rapid recognition when cases of TRALI occur remains vital to the further understanding and proper treatment of this complication. Notification of the transfusion service is crucial to ensure that a proper investigation is carried out and, if necessary, the case reported to regulatory authorities. Perhaps with a broader and more detailed understanding into the pathogenesis of TRALI, at-risk donors and recipients can be identified and measures taken to lessen the recipient’s risk. From the Departments of 1Anesthesiology and 2Pathology, Division of Laboratory Medicine, University of Alabama at Birmingham. Address reprint requests to Dr Cherry: Dept of Anesthesiology, JT 964; 619 19th St S, Birmingham, AL 35249-6810. References 1. Lanman JT, Bierman HR, Byron RL Jr. Transfusion of leukemic leukocytes in man: hematologic and physiologic changes. Blood. 1950;5:1099-1113. 2. Barnard RD. Indiscriminate transfusion: a critique of case reports illustrating hypersensitivity reactions. N Y State J Med. 1951;51:2399-2402. 3. Bittingham TE. Immunologic studies on leukocytes. Vox Sang. 1957;2:242-248. 4. Phillips E, Fleischner FG. Pulmonary edema in the course of a blood transfusion without overloading the circulation. Dis Chest. 1966;50:619-623. 5. Ward HN, Lipscomb TS, Cawley LP. 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