Publications by authors named "Pearl Toy"

46 Publications

Complement activation on endothelium initiates antibody-mediated acute lung injury.

J Clin Invest 2020 11;130(11):5909-5923

Department of Medicine, UCSF, San Francisco, California, USA.

Antibodies targeting human leukocyte antigen (HLA)/major histocompatibility complex (MHC) proteins limit successful transplantation and transfusion, and their presence in blood products can cause lethal transfusion-related acute lung injury (TRALI). It is unclear which cell types are bound by these anti-leukocyte antibodies to initiate an immunologic cascade resulting in lung injury. We therefore conditionally removed MHC class I (MHC I) from likely cellular targets in antibody-mediated lung injury. Only the removal of endothelial MHC I reduced lung injury and mortality, related mechanistically to absent endothelial complement fixation and lung platelet retention. Restoration of endothelial MHC I rendered MHC I-deficient mice susceptible to lung injury. Neutrophil responses, including neutrophil extracellular trap (NET) release, were intact in endothelial MHC I-deficient mice, whereas complement depletion reduced both lung injury and NETs. Human pulmonary endothelial cells showed high HLA class I expression, and posttransfusion complement activation was increased in clinical TRALI. These results indicate that the critical source of antigen for anti-leukocyte antibodies is in fact the endothelium, which reframes our understanding of TRALI as a rapid-onset vasculitis. Inhibition of complement activation may have multiple beneficial effects of reducing endothelial injury, platelet retention, and NET release in conditions where antibodies trigger these pathogenic responses.
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http://dx.doi.org/10.1172/JCI138136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7598054PMC
November 2020

Update on transfusion-related acute lung injury.

Authors:
Pearl Toy

Clin Adv Hematol Oncol 2019 Jul;17(7):378-381

University of California San Francisco, San Francisco, California.

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July 2019

An update of the transfusion-related acute lung injury (TRALI) definition.

Transfus Clin Biol 2019 Nov 12;26(4):354-356. Epub 2019 Jun 12.

Department of Pathology, University British Columbia, Vancouver, Canada.

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http://dx.doi.org/10.1016/j.tracli.2019.05.007DOI Listing
November 2019

A consensus redefinition of transfusion-related acute lung injury.

Transfusion 2019 07 16;59(7):2465-2476. Epub 2019 Apr 16.

Department of Pathology, University British Columbia, Vancouver, British Columbia, Canada.

Background: Transfusion-related acute lung injury (TRALI) is a serious complication of blood transfusion and is among the leading causes of transfusion-related morbidity and mortality in most developed countries. In the past decade, the pathophysiology of this potentially life-threatening syndrome has been increasingly elucidated, large cohort studies have identified associated patient conditions and transfusion risk factors, and preventive strategies have been successfully implemented. These new insights provide a rationale for updating the 2004 consensus definition of TRALI.

Study Design And Methods: An international expert panel used the Delphi methodology to develop a redefinition of TRALI by modifying and updating the 2004 definition. Additionally, the panel reviewed issues related to TRALI nomenclature, patient conditions associated with acute respiratory distress syndrome (ARDS) and TRALI, TRALI pathophysiology, and standardization of reporting of TRALI cases.

Results: In the redefinition, the term "possible TRALI" has been dropped. The terminology of TRALI Type I (without an ARDS risk factor) and TRALI Type II (with an ARDS risk factor or with mild existing ARDS) is proposed. Cases with an ARDS risk factor that meet ARDS diagnostic criteria and where respiratory deterioration over the 12 hours before transfusion implicates the risk factor as causative should be classified as ARDS. TRALI remains a clinical diagnosis and does not require detection of cognate white blood cell antibodies.

Conclusions: Clinicians should report all cases of posttransfusion pulmonary edema to the transfusion service so that further investigation can allow for classification of such cases as TRALI (Type I or Type II), ARDS, transfusion-associated circulatory overload (TACO), or TRALI or TACO cannot distinguish or an alternate diagnosis.
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http://dx.doi.org/10.1111/trf.15311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6850655PMC
July 2019

Antibodies associated with TRALI: differences in clinical relevance.

Transfusion 2019 03 13;59(3):1147-1151. Epub 2018 Dec 13.

Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California.

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http://dx.doi.org/10.1111/trf.15094DOI Listing
March 2019

Eradicating hepatitis B virus: The critical role of preventing perinatal transmission.

Biologicals 2017 Nov 2;50:3-19. Epub 2017 Sep 2.

University of California School of Medicine, San Francisco, CA, 94143-0134, United States.

Prevention of hepatitis B virus (HBV) transmission from infected mothers to their newborns is critical to HBV control and eventual eradication. Mother-to-child perinatal transmission causes the highest chronic carrier rate (>85%) with a high rate of subsequent chronic liver disease and hepatocellular carcinoma. This risk is reduced by 90% with HBV vaccine given along with hepatitis B immune globulin (HBIG) starting at birth. New analyses of our data from US trials of HBIG and HBV vaccine in high-risk infants revealed better efficacy with yeast-recombinant vaccine than plasma-derived vaccine, especially in preventing late onset infections, with evidence that vaccine prevented transmission of maternal HBV infection with the glycine to arginine mutation in surface antigen codon 145 (sG145R). Most late infections with sG145R were in vaccine non-responders, suggesting escape from HBIG rather than from vaccine-induced antibody. Our findings also help explain survey results from Taiwan following universal childhood immunization implemented in the mid-1980s. We conclude that current vaccines will remain effective against surface antigen mutants. Anti-viral drugs in high-risk pregnant women, in combination with newborn HBIG and vaccine, show promise for eliminating residual breakthrough neonatal infections, critical to meeting WHO 2030 goals and for eradicating HBV.
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http://dx.doi.org/10.1016/j.biologicals.2017.08.008DOI Listing
November 2017

Differentiating pulmonary transfusion reactions using recipient and transfusion factors.

Transfusion 2017 07 3;57(7):1684-1690. Epub 2017 May 3.

Blood Systems Research Institute.

Background: It is increasingly recognized that recipient risk factors play a prominent role in possible transfusion-related acute lung injury (pTRALI) and transfusion-associated circulatory overload (TACO). We hypothesized that both transfusion and recipient factors including natriuretic peptides could be used to distinguish TRALI from TACO and pTRALI.

Study Design And Methods: We performed a post hoc analysis of a case-control study of pulmonary transfusion reactions conducted at the University of California at San Francisco and Mayo Clinic, Rochester. We evaluated clinical data and brain natriuretic peptides (BNP) levels drawn after transfusion in patients with TRALI (n = 21), pTRALI (n = 26), TACO (n = 22), and controls (n = 24). Logistic regression and receiver operating characteristics curve analyses were used to determine the accuracy of clinical and biomarker predictors in differentiating TRALI from TACO and pTRALI.

Results: We found that pTRALI and TACO were associated with older age, higher fluid balance, and elevated BNP levels relative to those of controls and TRALI. The following variables were useful in distinguishing cases of pTRALI and TACO from TRALI: age more than 70 years, BNP levels more than 1000 pg/mL, 24-hour fluid balance of more than 3 L, and a lower number of transfused blood components. Using the above variables, our logistic model had a 91% negative predictive value in the differential diagnosis of TRALI.

Conclusions: Models incorporating readily available clinical and biomarker data can be used to differentiate transfusion-related respiratory complications. Additional studies examining recipient risk factors and the likelihood of TRALI may be useful in decision making regarding donor white blood cell antibody testing.
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http://dx.doi.org/10.1111/trf.14118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5758383PMC
July 2017

Proposed revised nomenclature for transfusion-related acute lung injury.

Transfusion 2017 03 26;57(3):709-713. Epub 2016 Dec 26.

Departments of Medicine and Laboratory Medicine, University of California at San Francisco, San Francisco, California.

A decade ago, definitions of "transfusionߚrelated acute lung injury (TRALI)" and "possible TRALI" were standardized for research and clinical diagnosis. Since then, evidence has confirmed that TRALI is often due to transfusion of white blood cell antibodies to at-risk patients, and the term "TRALI, antibody mediated" is appropriate for such cases. Other TRALI cases are non-antibody mediated. Because specific, nonantibody transfusion factors have not yet been confirmed to cause TRALI in humans, the general term "TRALI, non-antibody mediated" is appropriate for such cases. In contrast, evidence is against possible TRALI being due to transfusion with the more likely cause of the acute respiratory distress syndrome (ARDS) being the alternative ARDS risk factor present in these patients. We propose to drop the misleading term "possible TRALI" and to rename this category of cases as "transfused ARDS." These nomenclature updates will more accurately categorize ARDS cases that develop after transfusion.
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http://dx.doi.org/10.1111/trf.13944DOI Listing
March 2017

Reply to concerns regarding dropping the term "possible TRALI".

Transfusion 2016 09;56(9):2394-5

University of California at San Francisco, San Francisco, CA.

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http://dx.doi.org/10.1111/trf.13734DOI Listing
September 2016

A Clinical Trial to Detect Subclinical Transfusion-induced Lung Injury during Surgery.

Anesthesiology 2015 Jul;123(1):126-35

From the Department of Anesthesia and Perioperative Care (J.R.F., M.A.G., J.L., R.B.W.), Department of Laboratory Medicine (P.T.), and Quality Improvement Department (J.T.), University of California, San Francisco, San Francisco, California.

Background: Transfusion-related acute lung injury incidence remains the leading cause of posttransfusion mortality. The etiology may be related to leukocyte antibodies or biologically active compounds in transfused plasma, injuring susceptible recipient's lungs. The authors have hypothesized that transfusion could have less severe effects that are not always appreciated clinically and have shown subtly decreased pulmonary oxygen gas transfer in healthy volunteers after transfusion of fresh and 21-day stored erythrocytes. In this study, the authors tested the same hypothesis in surgical patients.

Methods: Ninety-one patients undergoing elective major spine surgery with anticipated need for erythrocyte transfusion were randomly allocated to receive their first transfusion of erythrocytes as cell salvage (CS), washed stored, or unwashed stored. Clinicians were not blinded to group assignment. Pulmonary gas transfer and mechanics were measured 5 min before and 30 min after erythrocyte transfusion.

Results: The primary outcome variable, gas transfer, as assessed by change of PaO2/FIO2, with erythrocyte transfusion was not significant in any group (mean ± SD; CS: 9 ± 59; washed: 10 ± 26; and unwashed: 15 ± 1) and did not differ among groups (P = 0.92). Pulmonary dead space (VD/VT) decreased with CS transfusion (-0.01 ± 0.04; P = 0.034) but did not change with other erythrocytes; the change from before to after erythrocyte transfusion did not differ among groups (-0.01 to +0.01; P = 0.28).

Conclusions: The authors did not find impaired gas exchange as assessed by PaO2/FIO2 with transfused erythrocytes that did or did not contain nonautologous plasma. This clinical trial did not support the hypothesis of erythrocyte transfusion-induced gas exchange deficit that had been found in healthy volunteers.
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http://dx.doi.org/10.1097/ALN.0000000000000689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4626309PMC
July 2015

Cytokines and clinical predictors in distinguishing pulmonary transfusion reactions.

Transfusion 2015 Aug 23;55(8):1838-46. Epub 2015 Feb 23.

Blood Systems Research Institute and.

Background: Pulmonary transfusion reactions are important complications of blood transfusion, yet differentiating these clinical syndromes is diagnostically challenging. We hypothesized that biologic markers of inflammation could be used in conjunction with clinical predictors to distinguish transfusion-related acute lung injury (TRALI), transfusion-associated circulatory overload (TACO), and possible TRALI.

Study Design And Methods: In a nested case-control study performed at the University of California at San Francisco and Mayo Clinic, Rochester, we evaluated clinical data and blood samples drawn before and after transfusion in patients with TRALI (n = 70), possible TRALI (n = 48), TACO (n = 29), and controls (n = 147). Cytokines measured included granulocyte-macrophage-colony-stimulating factor, interleukin (IL)-6, IL-8, IL-10, and tumor necrosis factor-α. Logistic regression and receiver operating characteristics curve analyses were used to determine the accuracy of clinical predictors and laboratory markers in differentiating TACO, TRALI, and possible TRALI.

Results: Before and after transfusion, IL-6 and IL-8 were elevated in patients with TRALI and possible TRALI relative to controls, and IL-10 was elevated in patients with TACO and possible TRALI relative to that of TRALI and controls. For all pulmonary transfusion reactions, the combination of clinical variables and cytokine measurements displayed optimal diagnostic performance, and the model comparing TACO and TRALI correctly classified 92% of cases relative to expert panel diagnoses.

Conclusions: Before transfusion, there is evidence of systemic inflammation in patients who develop TRALI and possible TRALI but not TACO. A predictive model incorporating readily available clinical and cytokine data effectively differentiated transfusion-related respiratory complications such as TRALI and TACO.
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http://dx.doi.org/10.1111/trf.13021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4536135PMC
August 2015

Male-predominant plasma transfusion strategy for preventing transfusion-related acute lung injury: a systematic review.

Crit Care Med 2015 Jan;43(1):205-25

1Multidisciplinary Epidemiology and Translational Research in Intensive Care (M.E.T.R.I.C.), Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN. 2Harvard School of Public Health, Boston, MA. 3University Witten-Herdecke, Witten, Germany. 4Cliniques Universitaires Saint-Luc, Universite' Catholique de Louvain, Bruxelles, Belgium. 5School of Public Health, Imperial College, London, United Kingdom. 6Division of Neurosurgery, Dalhousie University, Halifax, Canada. 7Division of Preventive Medicine, Mayo Clinic, Rochester, MN. 8Department of Laboratory Medicine, University of California at San Francisco, San Francisco, CA.

Objectives: To assess 1) the effectiveness of male-predominant plasma transfusion strategy for preventing transfusion-related acute lung injury and related mortality; and 2) whether this effect varies across different patient subgroups.

Design: Systematic Review and meta-analysis: Data were identified by querying MEDLINE and EMBASE (including proceedings of major conferences on blood transfusions), searching the Internet for hemovigilance reports, reviewing reference lists of eligible articles and contacting experts in the field. Eligible were all studies reporting transfusion-related acute lung injury incidence, all-cause mortality (primary outcomes), hospital length of stay, time to extubation, PaO2/FIO2-ratio or blood pressure changes (secondary outcomes) in recipients of plasma transfusions containing relatively more plasma from individuals at low risk of carrying leukocyte-antibodies ("male plasma") than those receiving comparator plasma ("control plasma"). No limits were placed on study design, population or language. The only exclusion criteria were non-human subjects and lack of control group. Prespecified study quality indicators (including risk of bias assessment) and potential effect modifiers were tested using Cochran's Q Test. Final analyses using random-effects models and I2 to assess heterogeneity were performed in the subset of studies judged to provide the best evidence and separately for significantly different subgroups using STATA 12.1 (StataCorp, College Station, TX).

Setting: As per primary studies.

Patients/subjects: As per primary studies.

Interventions: As per primary studies (generally: exposure to plasma containing relatively more male plasma than comparator plasma).

Measurements And Main Results: From a total of 850 retrieved records, we identified 45 eligible studies. For transfusion-related acute lung injury incidence, final analysis was restricted to 13 cohort studies and one randomized controlled trial in which transfusion-related acute lung injury cases only involved plasma transfusions. Risk of transfusion-related acute lung injury and mortality in plasma recipients exposed to men when compared with control plasma were 0.27 (95% CI, 0.20-0.38; p < 0.001; I = 0%; n = 14; 286 events) and 0.89 (95% CI, 0.80-1.00; p = 0.04; I = 79%; n = 7; 5, 710 events), respectively. No other significant interactions were found. Secondary outcomes showed similar results but were less reported and the studies were more heterogeneous. Sensitivity analyses did not alter the results. There was no evidence of publication bias.

Discussion: More than 800 million people in 17 countries are subject to male-predominant plasma transfusion policy and at least three more countries are planning or considering adoption of this strategy. On the basis of most observational data, judged to be of high quality, male-predominant plasma transfusion strategy reduces plasma-related transfusion-related acute lung injury incidence and possibly mortality. There was no evidence that the effect differs across patient subgroups, but power to detect such differences was low.
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http://dx.doi.org/10.1097/CCM.0000000000000675DOI Listing
January 2015

Recipient clinical risk factors predominate in possible transfusion-related acute lung injury.

Transfusion 2015 May 8;55(5):947-52. Epub 2014 Dec 8.

Department of Medicine, University of California at San Francisco, San Francisco, California.

Background: Possible transfusion-related acute lung injury (pTRALI) cases by definition have a clear temporal relationship to an alternative recipient risk factor for acute respiratory distress syndrome (ARDS). We questioned whether transfusion factors are important for the development of pTRALI.

Study Design And Methods: In this nested case-control study, we prospectively identified 145 consecutive patients with pTRALI and randomly selected 163 transfused controls over a 4-year period at the University of California at San Francisco and the Mayo Clinic (Rochester, Minnesota).

Results: For pTRALI, we found evidence against transfusion being important: receipt of plasma from female donors (odds ratio [OR], 0.82; 95% confidence interval [CI], 0.29-2.3; p = 0.70), total number of units transfused (OR, 0.99; 95% CI, 0.89-1.10; p = 0.86), and number of red blood cell and whole blood units transfused (OR, 0.78; 95% CI, 0.59-1.03; p = 0.079). In contrast, we found that risk for pTRALI was associated with additional recipient factors: chronic alcohol abuse (OR, 12.5; 95% CI, 2.8-55; p < 0.001), current smoker (OR, 4.2; 95% CI, 1.67-10.8; p = 0.0024), shock before transfusion (OR, 4.6; 95% CI, 2.0-10.7; p < 0.001), and positive fluid balance before transfusion (OR, 1.32/L; 95% CI, 1.20-1.44; p < 0.001).

Conclusion: Recipient risk factors for ARDS rather than transfusion risk factors predominate in pTRALI.
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http://dx.doi.org/10.1111/trf.12954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4428945PMC
May 2015

Prospective study on the clinical course and outcomes in transfusion-related acute lung injury*.

Crit Care Med 2014 Jul;42(7):1676-87

1Department of Medicine, University of California San Francisco, San Francisco, CA. 2Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA. 3Blood Systems Research Institute, San Francisco, CA. 4Department of Medicine, Mayo Clinic, Rochester, MN. 5Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, CA. 6Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA. 7Department of Anesthesia, Mayo Clinic, Rochester, MN. 8Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN. 9American Red Cross Neutrophil Reference Laboratory, St. Paul, MN. 10Blood Centers of the Pacific, San Francisco, CA.

Objective: Transfusion-related acute lung injury is the leading cause of transfusion-related mortality. A prospective study using electronic surveillance was conducted at two academic medical centers in the United States with the objective to define the clinical course and outcomes in transfusion-related acute lung injury cases.

Design: Prospective case study with controls.

Setting: University of California, San Francisco and Mayo Clinic, Rochester.

Patients: We prospectively enrolled 89 patients with transfusion-related acute lung injury, 164 transfused controls, and 145 patients with possible transfusion-related acute lung injury.

Interventions: None.

Measurements And Main Results: Patients with transfusion-related acute lung injury had fever, tachycardia, tachypnea, hypotension, and prolonged hypoxemia compared with controls. Of the patients with transfusion-related acute lung injury, 29 of 37 patients (78%) required initiation of mechanical ventilation and 13 of 53 (25%) required initiation of vasopressors. Patients with transfusion-related acute lung injury and possible transfusion-related acute lung injury had an increased duration of mechanical ventilation and increased days in the ICU and hospital compared with controls. There were 15 of 89 patients with transfusion-related acute lung injury (17%) who died, whereas 61 of 145 patients with possible transfusion-related acute lung injury (42%) died and 7 of 164 of controls (4%) died. Patients with transfusion-related acute lung injury had evidence of more systemic inflammation with increases in circulating neutrophils and a decrease in platelets compared with controls. Patients with transfusion-related acute lung injury and possible transfusion-related acute lung injury also had a statistically significant increase in plasma interleukin-8, interleukin-10, and interleukin-1 receptor antagonist posttransfusion compared with controls.

Conclusions: In conclusion, transfusion-related acute lung injury produced a condition resembling the systemic inflammatory response syndrome and was associated with substantial in-hospital morbidity and mortality in patients with transfusion-related acute lung injury compared with transfused controls. Patients with possible transfusion-related acute lung injury had even higher in-hospital morbidity and mortality, suggesting that clinical outcomes in this group are mainly influenced by the underlying acute lung injury risk factor(s).
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http://dx.doi.org/10.1097/CCM.0000000000000323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4284060PMC
July 2014

Risk factors and outcomes in transfusion-associated circulatory overload.

Am J Med 2013 Apr 26;126(4):357.e29-38. Epub 2013 Jan 26.

Department of Laboratory Medicine, University of California, San Francisco, CA 94118, USA.

Background: Transfusion-associated circulatory overload is characterized by new respiratory distress and hydrostatic pulmonary edema within 6 hours after blood transfusion, but its risk factors and outcomes are poorly characterized.

Methods: Using a case control design, we enrolled 83 patients with severe transfusion-associated circulatory overload identified by active surveillance for hypoxemia and 163 transfused controls at the University of California, San Francisco (UCSF) and Mayo Clinic (Rochester, Minn) hospitals. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using multivariable logistic regression, and survival and length of stay were analyzed using proportional hazard models.

Results: Transfusion-associated circulatory overload was associated with chronic renal failure (OR 27.0; 95% CI, 5.2-143), a past history of heart failure (OR 6.6; 95% CI, 2.1-21), hemorrhagic shock (OR 113; 95% CI, 14.1-903), number of blood products transfused (OR 1.11 per unit; 95% CI, 1.01-1.22), and fluid balance per hour (OR 9.4 per liter; 95% CI, 3.1-28). Patients with transfusion-associated circulatory overload had significantly increased in-hospital mortality (hazard ratio 3.20; 95% CI, 1.23-8.10) after controlling for Acute Physiology and Chronic Health Evaluation-II (APACHE-II) score, and longer hospital and intensive care unit lengths of stay.

Conclusions: The risk of transfusion-associated circulatory overload increases with the number of blood products administered and a positive fluid balance, and in patients with pre-existing heart failure and chronic renal failure. These data, if replicated, could be used to construct predictive algorithms for transfusion-associated circulatory overload, and subsequent modifications of transfusion practice might prevent morbidity and mortality associated with this complication.
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http://dx.doi.org/10.1016/j.amjmed.2012.08.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3652681PMC
April 2013

Lot-to-lot variability in HLA antibody screening using a multiplexed bead-based assay.

Transfusion 2013 Sep 10;53(9):1940-7. Epub 2013 Jan 10.

Department of Laboratory Medicine and Pathology, Department of Biomedical Statistics & Informatics, Department of Anesthesiology, Division of Transfusion Medicine, Mayo Clinic, Rochester, Minnesota; Westat, Inc., Rockville, Maryland; One Lambda, Inc., Canoga Park, California; Deparment of Laboratory Medicine, University of California at San Francisco, Blood Systems Research Institute, San Francisco, California.

Background: Identifying antibodies to HLA (anti-HLA) by solid-phase assays is used to screen blood donors to mitigate transfusion-related acute lung injury risk. Various cutoffs for detection assays have been proposed in the literature; however, these do not take into consideration lot-to-lot variability of commercially available assays.

Study Design And Methods: Samples from 93 nontransfused males were tested using five different lots of a multiplex bead-based anti-HLA detection kit. A subset of 17 samples was tested on 5 days using a single lot. An additional 96 samples from donations with varied anti-HLA levels were tested using kits from two different lots. Results were reported as a normalized background (NBG) ratio.

Results: For the 93 nontransfused donors, NBG values generated using the reference lot were significantly higher than those obtained with three of the four comparator lots. However, for the 96 samples with low-, moderate-, and higher-level anti-HLA, Class I (CL-I) values were 1.4 times lower and Class II (CL-II) values were 1.2 times lower using the reference versus comparator lot. For CL-I antibodies the between-lot standard deviation (SD) was 1.36 (95% confidence interval [CI], 1.19-1.60), while the between-day SD was 1.27 (95% CI, 1.08-1.52). Similarly, for CL-II antibodies the between-lot SD was 0.81 (95% CI, 0.70-0.95), while the between-day SD was 0.50 (95% CI, 0.43-0.60).

Conclusions: There is interlot variability in the tested HLA detection assay as well as significant bias between lots. It may be reasonable to develop a new cutoff when a new lot is obtained.
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http://dx.doi.org/10.1111/trf.12064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3626740PMC
September 2013

Electronic health record surveillance algorithms facilitate the detection of transfusion-related pulmonary complications.

Transfusion 2013 Jun 31;53(6):1205-16. Epub 2012 Aug 31.

Mayo Clinic, Rochester, Minnesota 55905, USA.

Background: Transfusion-related acute lung injury (TRALI) and transfusion-associated circulatory overload (TACO) are leading causes of transfusion-related mortality. Notably, poor syndrome recognition and underreporting likely result in an underestimate of their true attributable burden. We aimed to develop accurate electronic health record-based screening algorithms for improved detection of TRALI/transfused acute lung injury (ALI) and TACO.

Study Design And Methods: This was a retrospective observational study. The study cohort, identified from a previous National Institutes of Health-sponsored prospective investigation, included 223 transfused patients with TRALI, transfused ALI, TACO, or complication-free controls. Optimal case detection algorithms were identified using classification and regression tree (CART) analyses. Algorithm performance was evaluated with sensitivities, specificities, likelihood ratios, and overall misclassification rates.

Results: For TRALI/transfused ALI detection, CART analysis achieved a sensitivity and specificity of 83.9% (95% confidence interval [CI], 74.4%-90.4%) and 89.7% (95% CI, 80.3%-95.2%), respectively. For TACO, the sensitivity and specificity were 86.5% (95% CI, 73.6%-94.0%) and 92.3% (95% CI, 83.4%-96.8%), respectively. Reduced PaO2 /FiO2 ratios and the acquisition of posttransfusion chest radiographs were the primary determinants of case versus control status for both syndromes. Of true-positive cases identified using the screening algorithms (TRALI/transfused ALI, n = 78; TACO, n = 45), only 11 (14.1%) and five (11.1%) were reported to the blood bank by physicians, respectively.

Conclusions: Electronic screening algorithms have shown good sensitivity and specificity for identifying patients with TRALI/transfused ALI and TACO at our institution. This supports the notion that active electronic surveillance may improve case identification, thereby providing a more accurate understanding of TRALI/transfused ALI and TACO epidemiology.
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http://dx.doi.org/10.1111/j.1537-2995.2012.03886.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4839484PMC
June 2013

Two septic transfusion reactions presenting as transfusion-related acute lung injury from a split plateletpheresis unit.

Crit Care Med 2012 Aug;40(8):2488-91

Department of Anesthesia & Perioperative Care, University of California, San Francisco, CA, USA.

Objectives: We report two simultaneous cases of Staphylococcus aureus sepsis initially consistent with and diagnosed as transfusion-related acute lung injury. The sepsis in both cases resulted from transfusion of two split products from a single contaminated plateletpheresis unit. In each case, the platelets were given along with numerous other blood products during posterior spine surgery. The discussion includes presentation, clinical course, diagnosis, and similarities between sepsis and transfusion-related acute lung injury. The cases and discussion highlight the importance of considering sepsis as part of the differential for any patient believed to have transfusion-related acute lung injury with clinical features of sepsis.

Data Sources: Data were collected from the patients' electronic medical records and the hospital laboratory medicine database.

Conclusions: Our cases highlight the importance of vigilant investigation in patients suspected of transfusion-related acute lung injury, as septic transfusions are easily missed and may mimic or coexist with transfusion-related acute lung injury. Sepsis should be strongly considered whenever clinical features such as hypotension, leucopenia, and fever are noted in patients with suspected transfusion-related acute lung injury. In comparison to patients receiving red blood cells or plasma, platelet transfusion recipients are at a greater risk for sepsis from a contaminated unit. Patients developing sepsis from a contaminated blood product may meet the clinical definition of transfusion-related acute lung injury. In such cases, if the clinical syndrome is attributed solely to transfusion-related acute lung injury and bacterial sepsis is not suspected, the correct diagnosis may be missed or delayed. Consequently, appropriate treatment for sepsis would also be delayed or not provided and likely result in increased morbidity and mortality.
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http://dx.doi.org/10.1097/CCM.0b013e3182544f85DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3733455PMC
August 2012

Transfusion reactions: newer concepts on the pathophysiology, incidence, treatment, and prevention of transfusion-related acute lung injury.

Crit Care Clin 2012 Jul;28(3):363-72, v

Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143-0130, USA.

Transfusion-related acute lung injury (TRALI) is the leading cause of transfusion-related mortality. TRALI presents as acute lung injury (ALI) within 6 hours after blood product transfusion. Diagnosing TRALI requires a high index of suspicion, and the exclusion of circulatory overload or other causes of ALI. The pathophysiology of TRALI is incompletely understood, but in part involves transfusion of certain anti-neutrophil antibodies, anti-HLA antibodies, or other bioactive substances, into susceptible recipients. Recent studies have identified both recipient and transfusion risk factors for the development of TRALI. This article describes these TRALI risk factors, as well as diagnosis, treatment and prevention strategies.
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http://dx.doi.org/10.1016/j.ccc.2012.04.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3380279PMC
July 2012

Platelets induce neutrophil extracellular traps in transfusion-related acute lung injury.

J Clin Invest 2012 Jul 11;122(7):2661-71. Epub 2012 Jun 11.

Cardiovascular Research Institute, UCSF, San Francisco, CA, USA

There is emerging evidence that platelets are major contributors to inflammatory processes through intimate associations with innate immune cells. Here, we report that activated platelets induce the formation of neutrophil extracellular traps (NETs) in transfusion-related acute lung injury (TRALI), which is the leading cause of death after transfusion therapy. NETs are composed of decondensed chromatin decorated with granular proteins that function to trap extracellular pathogens; their formation requires the activation of neutrophils and release of their DNA in a process that may or may not result in neutrophil death. In a mouse model of TRALI that is neutrophil and platelet dependent, NETs appeared in the lung microvasculature and NET components increased in the plasma. We detected NETs in the lungs and plasma of human TRALI and in the plasma of patients with acute lung injury. In the experimental TRALI model, targeting platelet activation with either aspirin or a glycoprotein IIb/IIIa inhibitor decreased NET formation and lung injury. We then directly targeted NET components with a histone blocking antibody and DNase1, both of which protected mice from TRALI. These data suggest that NETs contribute to lung endothelial injury and that targeting NET formation may be a promising new direction for the treatment of acute lung injury.
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http://dx.doi.org/10.1172/JCI61303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3386815PMC
July 2012

Fresh and stored red blood cell transfusion equivalently induce subclinical pulmonary gas exchange deficit in normal humans.

Anesth Analg 2012 Mar 19;114(3):511-9. Epub 2012 Jan 19.

Department of Anesthesia & Perioperative Care, University of California, San Francisco, Box 0648, San Francisco, CA 94143-0648, USA.

Background: Transfusion can cause severe acute lung injury, although most transfusions do not seem to induce complications. We tested the hypothesis that transfusion can cause mild pulmonary dysfunction that has not been noticed clinically and is not sufficiently severe to fit the definition of transfusion-related acute lung injury.

Methods: We studied 35 healthy, normal volunteers who donated 1 U of blood 4 weeks and another 3 weeks before 2 study days separated by 1 week. On study days, 2 U of blood were withdrawn while maintaining isovolemia, followed by transfusion with either the volunteer's autologous fresh red blood cells (RBCs) removed 2 hours earlier or their autologous stored RBCs (random order). The following week, each volunteer was studied again, transfused with the RBCs of the other storage duration. The primary outcome variable was the change in alveolar to arterial difference in oxygen partial pressure (AaDo(2)) from before to 60 minutes after transfusion with fresh or older RBCs.

Results: Fresh RBCs and RBCs stored for 24.5 days equally (P = 0.85) caused an increase of AaDo(2) (fresh: 2.8 mm Hg [95% confidence interval: 0.8-4.8; P = 0.007]; stored: 3.0 mm Hg [1.4-4.7; P = 0.0006]). Concentrations of all measured cytokines, except for interleukin-10 (P = 0.15), were less in stored leukoreduced (LR) than stored non-LR packed RBCs; however, vascular endothelial growth factor was the only measured in vivo cytokine that increased more after transfusion with LR than non-LR stored packed RBCs. Vascular endothelial growth factor was the only cytokine tested with in vivo concentrations that correlated with AaDo(2).

Conclusion: RBC transfusion causes subtle pulmonary dysfunction, as evidenced by impaired gas exchange for oxygen, supporting our hypothesis that lung impairment after transfusion includes a wide spectrum of physiologic derangements and may not require an existing state of altered physiology. These data do not support the hypothesis that transfusion of RBCs stored for >21 days is more injurious than that of fresh RBCs.
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http://dx.doi.org/10.1213/ANE.0b013e318241fcd5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3927839PMC
March 2012

Transfusion-related acute lung injury: incidence and risk factors.

Blood 2012 Feb 23;119(7):1757-67. Epub 2011 Nov 23.

Department of Laboratory Medicine, Box 0451, University of California–San Francisco, San Francisco, CA 94143-0451, USA.

Transfusion-related acute lung injury (TRALI) is the leading cause of transfusion-related mortality. To determine TRALI incidence by prospective, active surveillance and to identify risk factors by a case-control study, 2 academic medical centers enrolled 89 cases and 164 transfused controls. Recipient risk factors identified by multivariate analysis were higher IL-8 levels, liver surgery, chronic alcohol abuse, shock, higher peak airway pressure while being mechanically ventilated, current smoking, and positive fluid balance. Transfusion risk factors were receipt of plasma or whole blood from female donors (odds ratio = 4.5, 95% confidence interval [CI], 1.85-11.2, P = .001), volume of HLA class II antibody with normalized background ratio more than 27.5 (OR = 1.92/100 mL, 95% CI, 1.08-3.4, P = .03), and volume of anti-human neutrophil antigen positive by granulocyte immunofluoresence test (OR = 1.71/100 mL, 95% CI, 1.18-2.5, P = .004). Little or no risk was associated with older red blood cell units, noncognate or weak cognate class II antibody, or class I antibody. Reduced transfusion of plasma from female donors was concurrent with reduced TRALI incidence: 2.57 (95% CI, 1.72-3.86) in 2006 versus 0.81 (95% CI, 0.44-1.49) in 2009 per 10 000 transfused units (P = .002). The identified risk factors provide potential targets for reducing residual TRALI.
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http://dx.doi.org/10.1182/blood-2011-08-370932DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3286351PMC
February 2012

High oxygen partial pressure decreases anemia-induced heart rate increase equivalent to transfusion.

Anesthesiology 2011 Sep;115(3):492-8

Department of Anesthesia and Perioperative Care, University of California, San Francisco, California 94143-0648, USA.

Background: Anemia is associated with morbidity and mortality and frequently leads to transfusion of erythrocytes. The authors sought to directly compare the effect of high inspired oxygen fraction versus transfusion of erythrocytes on the anemia-induced increased heart rate (HR) in humans undergoing experimental acute isovolemic anemia.

Methods: The authors combined HR data from healthy subjects undergoing experimental isovolemic anemia in seven studies performed by the group. HR changes associated with breathing 100% oxygen by nonrebreathing facemask versus transfusion of erythrocytes at their nadir hemoglobin concentration of 5 g/dl were examined. Data were analyzed using a mixed-effects model.

Results: HR had an inverse linear relationship to hemoglobin concentration with a mean increase of 3.9 beats per min per gram of hemoglobin (beats/min/g hemoglobin) decrease (95% CI, 3.7-4.1 beats/min/g hemoglobin), P < 0.0001. Return of autologous erythrocytes significantly decreased HR by 5.3 beats/min/g hemoglobin (95% CI, 3.8-6.8 beats/min/g hemoglobin) increase, P < 0.0001. HR at nadir hemoglobin of 5.6 g/dl (95% CI, 5.5-5.7 g/dl) when breathing air (91.4 beats/min; 95% CI, 87.6-95.2 beats/min) was reduced by breathing 100% oxygen (83.0 beats/min; 95% CI, 79.0-87.0 beats/min), P < 0.0001. The HR at hemoglobin 5.6 g/dl when breathing oxygen was equivalent to the HR at hemoglobin 8.9 g/dl when breathing air.

Conclusions: High arterial oxygen partial pressure reverses the heart rate response to anemia, probably because of its usability rather than its effect on total oxygen content. The benefit of high arterial oxygen partial pressure has significant potential clinical implications for the acute treatment of anemia and results of transfusion trials.
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http://dx.doi.org/10.1097/ALN.0b013e31822a22beDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3166888PMC
September 2011

Transfusion-related acute lung injury after transfusion of maternal blood: a case-control study.

Spine (Phila Pa 1976) 2010 Nov;35(23):E1322-7

Department of Laboratory Medicine, School of Medicine, University of California San Francisco, San Francisco, CA 94143, USA.

Study Design: This is a single-center retrospective case-control study of 7 transfusion-related acute lung injury (TRALI) cases and 28 controls in the pediatric spinal surgery population.

Objective: To determine the association between maternal transfusion and risk of TRALI in pediatric spinal surgery patients.

Summary Of Background Data: Previous studies support a "2-hit" model for the pathogenesis of TRALI-activation and sequestration of neutrophils in the pulmonary vasculature followed by transfusion of a biologic response modifier such as antileukocyte antibodies. Maternal donation of blood products is a potential risk factor for TRALI because of the development of antileukocyte antibodies during pregnancy. Until now there have been no studies specifically addressing the risk of TRALI following maternal transfusions.

Methods: This is a retrospective case-control study of 7 TRALI cases with 4 controls per case, matched by strata for volume of plasma transfused. All cases identified by the Transfusion Biology and Medicine Specialized Center of Clinically Oriented Research with a TRALI diagnosis were eligible for inclusion. Electronic medical records and operative notes were reviewed to obtain demographic data, diagnosis, surgical approach, and number of spine levels for each operation.

Results: An increased prevalence of maternal blood transfusion was found among the TRALI cases compared with the control cases: 43% (3 of 7) versus 7% (2 of 28), P = 0.044. There were otherwise no statistical differences between the groups, including age, gender, surgical approach, number of spinal levels, or type of blood product transfused.

Conclusion: Pediatric patients undergoing spinal surgery may be at increased risk for the development of TRALI following the transfusion of maternal blood products. Accordingly, we recommend that directed donation of maternal blood products should be avoided in this population. This study also found that TRALI may be underrecognized and underreported to the transfusion service.
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http://dx.doi.org/10.1097/BRS.0b013e3181e3dad2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2964398PMC
November 2010

Microarray kit analysis of cytokines in blood product units and segments.

Transfusion 2009 Nov 22;49(11):2269-75. Epub 2009 Jun 22.

Department of Laboratory Medicine, and the Cardiovascular Research Institute, University of California at San Francisco, San Francisco, California 94143-0648, USA.

Background: Cytokine concentrations in transfused blood components are of interest for some clinical trials. It is not always possible to process samples of transfused components quickly after their administration. Additionally, it is not practical to sample material in an acceptable manner from many bags of components before transfusion, and after transfusion, the only representative remaining fluid of the component may be that in the "segment," because the bag may have been completely transfused. Multiplex array technology allows rapid simultaneous testing of multiple analytes in small-volume samples. This technology was used to measure white blood cell (WBC) cytokine levels in blood products to determine 1) whether concentrations in segments correlate with those in the main bag and, thus, whether segments could be used for estimation of the concentrations in the transfused component and 2) whether concentrations after sample storage at 4 degrees C for 24 hours do not differ from concentrations before storage, thus allowing for processing within 24 hours, rather than immediately after transfusion.

Study Design And Methods: WBC cytokines were measured in the supernatant from bags and segments of leukoreduced red blood cells (RBCs), nonleukoreduced whole blood, and leukoreduced plateletphereses using a human cytokine array kit (ProteoPlex, Novagen).

Results: Cytokine concentrations in RBCs and whole blood or plateletphereses stored at 4 degrees C did not differ between bag and segment samples (all p > 0.05). There was no evidence of systematic differences between segment and bag concentrations. Cytokine concentrations in samples from plateletphereses did not change within 24 hours storage at 4 degrees C.

Conclusion: Samples from either bag or segment can be used to study cytokine concentrations in groups of blood products. Cytokine concentrations in plateletphereses appear to be stable for at least 24 hours of storage at 4 degrees C and, thus, samples stored with those conditions may be used to estimate the cytokine concentrations of the component at the time of transfusion.
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http://dx.doi.org/10.1111/j.1537-2995.2009.02274.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2783862PMC
November 2009

Cost minimization analysis of preoperative erythropoietin vs autologous and allogeneic blood donation in total joint arthroplasty.

J Arthroplasty 2010 Jan 3;25(1):93-6. Epub 2008 Dec 3.

Department of Orthopedic Surgery, University of California San Francisco, San Francisco, California 94143, USA.

Autologous blood donation and erythropoietin (EPO) have been shown to be effective in reducing allogeneic blood transfusion, but the cost-effectiveness of these interventions remains unclear. A cost minimization analysis was performed, comparing the total costs of allogeneic blood transfusion strategy and autologous and allogeneic blood transfusion strategy for 161 primary total hip arthroplasty (THA) and 195 total knee arthroplasty (TKA) patients. An EPO cost minimization model was constructed using a previously published algorithm for blood management after total joint arthroplasty. The least costly strategy was autologous blood donation in combination with allogeneic blood for THA and TKA patients at $856 and $892 per patient, respectively. The most costly strategy was allogeneic only at $1769 and $1352 per THA and TKA patient, respectively. The EPO strategy model predicted costs similar to the autologous and allogeneic. A strategy that combines autologous blood donation with EPO for patients who cannot donate autologous blood may provide the greatest cost savings and minimize allogeneic blood transfusion.
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http://dx.doi.org/10.1016/j.arth.2008.10.005DOI Listing
January 2010

Computer-generated automatic alerts of respiratory distress after blood transfusion.

J Am Med Inform Assoc 2008 May-Jun;15(3):383-5. Epub 2008 Feb 28.

College of Medicine, University of Cincinnati, Cincinnati, OH, USA.

Transfusion-related acute lung injury (TRALI), the leading cause of transfusion-related death, is underreported by clinicians. For TRALI research, a clinician-independent, computerized system has been developed to detect patients with acute respiratory distress posttransfusion. A computer system generates an alert when a blood gas result indicated a PaO2:FiO2 ratio below 300, within twelve hours of blood issued from the blood bank for a patient. The system was prospectively compared to conventional daily rounds in intensive care units (ICUs). We found that ICU rounds detected 9 of 14 patients (64%), while the computer system detected 13 of 14 patients (93%), p = 0.125. ICU rounds took two to three hours per day, while the computer system took one to one and one-half hours per day of investigator time. In conclusion, an automatic computer alert system was more efficient, and was as effective as conventional daily ICU rounds, in detecting patients with posttransfusion acute respiratory distress.
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http://dx.doi.org/10.1197/jamia.M2538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2410003PMC
June 2008

TRALI--definition, mechanisms, incidence and clinical relevance.

Best Pract Res Clin Anaesthesiol 2007 Jun;21(2):183-93

University of California San Francisco, San Francisco, CA 94143-0100, USA.

Transfusion-related acute lung injury (TRALI) is defined as new acute lung injury (ALI) that occurs during or within six hours of transfusion, not explained by another ALl risk factor. Transfusion of part of one unit of any blood product can cause TRALI. The mechanism may include factors in unit(s) of blood, such as antibody and biologic response modifiers. In addition, yet to be described factors in a patient's illness may predispose to the condition. The current incidence is estimated to be 1 in 5000 units. Patients present with acute dyspnea, or froth in the endotracheal tube in intubated patients. Hypertension, hypotension, acute leukopenia have been described. Management is similar to that for ALI and is predominantly supportive. When TRALI is suspected, Blood banks should be notified to quarantine other components from the same donation. No special blood product is required for subsequent transfusion of a patient who has developed TRALI.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2767181PMC
http://dx.doi.org/10.1016/j.bpa.2007.01.003DOI Listing
June 2007

Transfusion-related acute lung injury: a case-control pilot study of risk factors.

Am J Clin Pathol 2007 Jul;128(1):128-34

Department of Laboratory Medicine, University of California San Francisco, CA 94143, USA.

Transfusion-related acute lung injury (TRALI) is the leading cause of mortality from transfusion therapy. Recipient, donor, and blood product risk factors may have important roles in the occurrence of TRALI. A case-control pilot study of 6 TRALI cases in which HLA-antibody concordance was found and 20 control subjects was conducted to evaluate recipient and donor predictors of TRALI. By using stratified exact logistic regression, characteristics of the recipients, donors, and blood products were analyzed and the results reported as odds ratios. The risk for TRALI was increased per unit of whole blood transfused (odds ratio, 3.0 per unit; P = .0098). A larger prospective case-control study is underway to determine recipient, donor, and blood product risk factors associated with TRALI.
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http://dx.doi.org/10.1309/HC4PVY24NJXMQ884DOI Listing
July 2007