Complement Activation Associated with Transfusion Related Acute Lung Injury (TRALI).
Authors: Ambruso Daniel R. , Giclas Patsy , Silliman Christopher C. , Kelher Marguerite , Geier Steve 
Published: April 2020

Abstract
Introduction: TRALI is acute lung injury occurring during or within hours of a blood transfusion. The etiology is thought to be infusion of leukocyte antibodies or neutrophil priming and activation caused by biologically active lipids in blood components. We report a TRALI reaction associated with fresh frozen plasma (FFP) and activation of complement in both the unit of FFP and the patient at the time of the reaction.
Case History: A 59 year old male with factor XI was admitted to the hospital with hematochezia and given 3 units of FFP. During infusion of the third unit, he developed dyspnea and cyanosis requiring ventilator and O2 support. A chest x-ray showed bilateral diffuse pulmonary infiltrates, CVP was 3 mm Hg, and an echocardiogram was normal. The symptoms resolved in 3 days.
Methods: Samples from donors and/or units were screened for the presence of HLA antibodies by ELISA and lymphocytotoxicity and antibodies detected were typed for HLA specificity and antibody class. Reactivity was determined by flow crossmatch. Serologic and molecular HLA typing was completed on donor and patient samples. Priming activity of the implicated FFP, fresh plasma from donor and recipient, and plasma from controls was completed against freshly isolated neutrophils from the three sources. Significant activity was defined as &gt;1.5 times the fMLP stimulated superoxide anion (O2−) production. C3aLE, C4aLE, SC5b-9, and Bb were determined by standard techniques.
Results: HLA antibodies were only detected in the third unit of FFP. Samples from this unit and the donor exhibited HLA Class I and II reactivity by ELISA but not lymphocytotoxicity. Flow crossmatch cells demonstrated Class II, IgG reactivity of donor serum against recipient DR11, 13. No autologous reactivity was demonstrated. The FFP unit primed the fMLP response in donor, recipient and control neutrophils 2.6, 3.1, and 3.4 fold above baseline. Testing of donor, recipient and control plasma obtained 3 months after the reaction showed no priming against the same battery of cells (priming ratio 0.8–1.3). C4aLE (105%, control range 24–176%); C3aLE (476%, control range 21–180%); and Bb (351%, control range 31–169%) were elevated in recipient samples obtained during the TRALI reaction and SC5b-9 was at the high end of normal (164%, control 0–200%). These returned to normal after the reaction. Strikingly, evidence of complement activation was seen in the FFP unit (C4aLE 214%, C3aLE 402%, C5b-9 213%) but not in subsequent samples from the donor.
Conclusion: These studies document a TRALI reaction with symptoms expressed during the administration of FFP. One unit exhibited HLA Class I and II antibodies, the latter of which bound to the recipient’s cells. Priming activity was seen with plasma from the implicated unit, not in subsequent samples from the donor. Laboratory studies document activation of complement in the FFP infused but not donor samples. Plasma from the recipient at the time of the reaction also exhibit activation of complement which became normal after the TRALI resolved. Infusion of the FFP with activated complement capable of priming neutrophils may have induced pulmonary leukostasis and TRALI quite distinct from any subsequent effect of antibodies. Although the cause of FFP complement activation is not defined, these results suggest alternative mechanisms involving complement may be responsible for HLA antibody-associated TRALI.