Poster Board III-126
Transfusion related acute lung injury (TRALI) is the leading cause of transfusion related deaths in the United States. The incidence of TRALI is estimated at 1 in 5000 transfusions and can occur with all blood products, however it is most common with transfused platelets. TRALI is associated with rapid onset of non-cardiogenic pulmonary edema, generally within a few hours of a transfusion. The resulting respiratory distress is often severe enough to require mechanical ventilation, up to 70% of patients in some case studies, and mortality rates associated with TRALI are high. While the etiology of TRALI is still not fully defined, donor anti-HLA class I and II antibodies have been reported in transfused blood products responsible for episodes of TRALI. An experimental system for inducing TRALI in mice has recently been described that depends on a single intravenous injection of a monoclonal antibody against MHC-I (mAB 34-1-2S against H2Kd). Here, experimental animals develop tachypnea, pulmonary edema, and capillary leak within minutes of the injection. Lungs, harvested from animals at two hours following challenge, were found to exhibit profuse fibrin deposition within the lungs which was prominent both in perivascular regions and along alveolar walls. Given the copious fibrin deposition associated with the challenge, we hypothesized that thrombin activation and intra- and extra-vascular fibrin deposition exacerbates disease pathologies associated with TRALI. To test this concept, we first challenged animals genetically altered to carry low levels of prothrombin (∼10% of normal) with this model of TRALI. Low prothrombin mice were consistently more tolerant than wildtype mice of the challenge with mAB 34-1-2S based both on overall appearance and activity after initial injection and low prothrombin mice rarely progressed to moribundity. Complementary studies of fibrinogen-deficient and -sufficient animals suggest that mice lacking coagulation function were also tolerant of the TRALI challenge, suggesting that fibrin deposition aggravates pathology. Lungs harvested from cohorts of control and fibrinogen-null mice at either two or four hours after antibody injection revealed significantly higher pulmonary edema in fibrinogen-sufficient relative to fibrinogen-null animals based on wet-to-dry ratios. To further elucidate the mechanisms coupling fibrin(ogen) to TRALI pathobiology, comparative studies were done of mice expressing a mutant form of fibrinogen (Fibγ390-396A) that retains full clotting function, but lacks the binding motif for the leukocyte integrin receptor, Mac-1. These mice also exhibited diminished pulmonary edema in comparison to controls, suggesting that fibrin-coupled inflammatory processes may drive lung disease. Taken together, these studies suggest that strategies to limit the hemostatic pathways or uncouple fibrin from secondary inflammatory events might be advantageous in the clinical management of TRALI.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.