Case Investigation -- Severe Transfusion Reaction


This is a 48 year-old female who developed fever (37.0C to 38.1C), hypotension (128/60 to 100/50) and severe respiratory distress requiring ventilation support after transfusion of 5 units FFP, which resolved within 48 hours of onset. The patient's course, the chest x-ray finding, and the presence of anti-HLA antibody matching with recipient HLA in the transfused FFP were consistent with transfusion-related acute lung injury (TRALI). Diagnosis of TRALI was made out of exclusion of other causes of respiratory insufficiency, such as volume overload, bronchospasm due to allergic reaction, or bacterial pneumonia, all of which did not match with the whole picture of this case.


Transfusion-related acute lung injury (TRALI) is a noncardiogenic bilateral pulmonary edema developed during or shortly after transfusion, causing severe respiratory insufficiency, clinically indistinguishable from adult respiratory distress syndrome (ARDS) secondary to other causes (1,2).


Popovsky et al. reported that the incidence of TRALI was 1 in 5000 (0.02%) plasma-containing transfusions in 1985, when blood banks in the United States were converting to red blood cell product containing much less plasma than before 1985 (1). The number of reported TRALI cases, however, has increased significantly since then. A total of fewer than 40 TRALI cases had been reported in the English literature until 1985, but additional 130 cases have been published between 1986 and 2000 (3). Clarke et al. reported that 46 cases of 14,602 random donor platelets transfusion was associated with severe respiratory reactions (4), and the incidence of TRALI in this report was 1 in 317 (0.34%), 17 times higher than the previous report by Popovsky (1). It is believed that TRALI might be significantly underdiagnosed, partly due to low level of awareness of TRALI among physicians and that the true incidence of TRALI is unknown (3,5). In most of the TRALI cases, the minimum volume of plasma contained in the implicated blood product is more than 60 ml, but the smaller quantities of plasma, such as in cryoprecipitate, were reported to cause TRALI (6)

Clinical symptoms and diagnosis

The symptoms of TRALI include respiratory insufficiency and distress, severe hypoxia (O2 saturation 50-70%), tachycardia, chill, fever (1-2 C increase), and hypotension usually within 1-2 hours posttransfusion (1,7). The chest x-ray typically shows "white-out" by interstitial and alveolar infiltration pattern (1). There is no specific marker for TRALI, and diagnosis should be made after ruling out differential diagnosis (1). Exclusion of other causes of respiratory failure and pulmonary edema secondary to transfusion, such as bronchospasm due to allergic reaction, volume overload, and bacterial contamination are essential (1). In contrast to volume overload, central venous pressure and pulmonary wedge pressure should be normal in TRALI. In addition, the demonstration of lymphocytotoxic, HLA, or neurtophil-specific antibodies in donor or recipient serum is strongly supportive of diagnosis of TRALI.

Pathogenesis and etiology

Although the precise pathogenesis of TRALI remains unknown, multiple mechanisms have been proposed. Most often, anti-HLA class I and anti-neutrophil antibodies from plasma containing blood products are passively transfused to a recipient. Less frequent is the recipient antibody reacting to the white blood cells in the transfused blood product. Popovsky et al. reported the presence of such antibodies in 89% of 36 TRALI cases (1). Most of donors are multiparous women. The subsequent antibody-antigen reaction in the recipient activates complement, and C5a produced during complement activation promotes neutrophil aggregation, margination, and sequestration in pulmonary microvasculature (8,9). The influx of neutrophils into the lung damages and increases permeability of the pulmonary microvasculature, leading to pulmonary edema. Brittingham reported in 1957 that the transfusion of 50 ml blood containing leukoagglutinins caused hypoxia, pulmonary edema, hypotention and fever in a healthy recipient (10), and this study suggested the pivotal role of passive transfer of leukoagglutinins in the development of TRALI. The development of TRALI was demonstrated using an ex-vivo rabbit lung model (11) In this model, the infusion of complement, anti-C5b antibody and 5b-positive neutrophils caused acute lung injury with severe lung edema within 3-6 hours after infusion, which was compatible with TRALI presentation in human. In 2001, the first prospective, randomized double-blind, crossover study of TRALI was published (12). In this study, 105 intensive care unit patients, judged to need at least 2 units of plasma, were randomly assigned to receive plasma from either multiparous donors or from donors with no history of transfusion or pregnancy, and they found that plasma transfusion from multiparous donors was associated with significantly lower oxygen saturation and higher TNF-a concentrations than transfusion of control plasma. It has been suggested that TNF-a released from activated neutrophils is associated with the injury of lung capillary endothelium in ARDS (13).

However, though approximately 1-2 % of blood donors have HLA-specific antibodies, the incidence of TRALI is much less than that. Also, 5-15% of TRALI cases were reported to have no such antibodies in either patients or donors (3). A nonantibody-mediated model of TRALI has been proposed by Silliman and his colleagues (14). The bioactive lipid, lysophophatidylcholine or related compounds, which accumulates during storage of blood products, was identified as a neutrophil-priming agent, which enhances activation of respiratory burst of neutrophils and causes TRALI. In this study, the half of TRALI patients were not exposed to leukoagglutinins, in contrary to the previous report by Popovsky, who reported leukoagglutinins as an etiologic factor in 89% TRALI patients (1). They proposed a "two-hit" model, in which the first hit is a recipient's predisposing condition such as sepsis and the second hit is a donor factor, which includes specific antibodies, or another factor such as cytokine or bioactive lipid in stored blood products (14). By utilizing isolated, perfused rat lung model, it was shown that TRALI could be reproducible by plasma and lipids from stored packed red blood cells or platelets (15,16).

Treatment and Prevention

Treatment of TRALI is largely supportive, and O2 supplementation is needed in almost all cases. Intubations and mechanical ventilation might be necessary for severe hypoxemia. Administration of corticosteroids has been proposed for TRALI, but its benefit has been unproven. The course of TRALI is typically transient, and most of TRALI patients would regain the pulmonary function within 2 to 4 days (1). The mortality rate is less than 10% with supportive measures (5).

Prevention of TRALI in the recipient side is difficult because there is no profile known for recipients at risk of developing TRALI or no specific diagnostic markers for TRALI. Therefore, the measures are focused on the prevention of exposure of potential blood products to donors. Although there is no consensus, Popovsky et al. proposed the following (7):

  1. Donors who have been implicated in TRALI should be permanently deferred or subsequent donations should be limited to the production of frozen-deglycerolized or washed red blood cells.
  2. Multiparous donors should be prospectively identified and their blood should be screened for HLA and neutrophil antibodies or diverted for uses other than whole blood, fresh frozen plasma or single-donor apheresis platelets.


  1. Popovsky MA, Moore SB. Diagnostic and pathogenetic considerations in transfusion-related acute lung injury. Transfusion 1985;25:573-7.
  2. Carilli AD, Ramanamurty MV, Chang YS, Shin D, Sethi V. Noncardiogenic pulmonary edema following blood transfusion. Chest. 1978;74(3):310-2.
  3. Popovsky MA, Transfusion-Related Acute Lung Injury (TRALI). In: Popovsky MA. Editor. Transfusion Reactions. 2nd ed. AABB Press; 2001. p.155-170
  4. Clarke G, Podlosky L, Petrie L, Boshkov L. Severe respiratory reactions to random donor platelets: An incidence and nested case-control study (abstract). Blood 1994;84(Suppl 1):465a
  5. Brecher M. editor. AABB Technical Manual. 14th ed. AABB Press; 2002.
  6. Reese EP Jr, McCullough JJ, Craddock PR. An adverse pulmonary reaction to cryoprecipitate in a hemophiliac. Transfusion. 1975 Nov-Dec;15(6):583-8.
  7. Popovsky MA, Chaplin HC Jr, Moore SB. Transfusion-related acute lung injury: a neglected, serious complication of hemotherapy. Transfusion. 1992;32(6):589-92.
  8. Jacob HS, Craddock PR, Hammerschmidt DE, Moldow CF. Complement-induced granulocyte aggregation: an unsuspected mechanism of disease. N Engl J Med. 1980;302(14):789-94.
  9. Hammerschmidt DE, Jacob HS. Adverse pulmonary reactions to transfusion. Adv Intern Med. 1982;27:511-30.
  10. Brittingham TE. Immunologic studies of leukocytes. Vox Sang 1957;2:242-8
  11. Seeger W, Schneider U, Kreusler B, von Witzleben E, Walmrath D, Grimminger F, Neppert J. Reproduction of transfusion-related acute lung injury in an ex vivo lung model. Blood. 1990;76(7):1438-44
  12. Palfi M, Berg S, Ernerudh J, Berlin G. A randomized controlled trial of transfusion-related acute lung injury: is plasma from multiparous blood donors dangerous? Transfusion. 2001;41(3):317-22.
  13. Tracey KJ, Lowry SF, Cerami A.Cachetin/TNF-alpha in septic shock and septic adult respiratory distress syndrome. Am Rev Respir Dis. 1988;138(6):1377-9.
  14. Silliman CC, Paterson AJ, Dickey WO, et al. The association of biologically active lipids with the development of transfusion-related acute lung injury: a retrospective study. Transfusion. 1997;37(7):719-26.
  15. Silliman CC, Voelkel NF, Allard JD, et al. Plasma and lipids from stored packed red blood cells cause acute lung injury in an animal model. J Clin Invest. 1998;101(7):1458-67.
  16. Silliman CC, Bjornsen AJ, Wyman TH, et al. Plasma and lipids from stored platelets cause acute lung injury in an animal model. Transfusion. 2003;43(5):633-40.

Contributed by Kenichi Tamama, MD, PhD, Mark Fung, MD, PhD, and Ileana Lopez-Plaza, MD

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