Trauma Induces Intravascular Hemolysis, Exacerbated by Red Blood Cell Transfusion and Associated With Disrupted Arginine–nitric Oxide Metabolism

Abstract

Background: Severe injury can provoke systemic processes that lead to organ dysfunction, and hemolysis of both native and transfused red blood cells (RBCs) may contribute. Hemolysis can release erythrocyte proteins, such as hemoglobin and arginase-1, the latter with the potential to disrupt arginine metabolism and limit physiologic NO production. We aimed to quantify hemolysis and arginine metabolism in trauma patients and measure association with injury severity, transfusions, and outcomes. Methods: Blood was collected from injured patients at a level I trauma center enrolled in the COMBAT (Control of Major Bleeding After Trauma) trial. Proteomics and metabolomics were performed on plasma fractions through liquid chromatography coupled with mass spectrometry. Abundances of erythrocyte proteins comprising a hemolytic profile as well as haptoglobin, l-arginine, ornithine, and l-citrulline (NO surrogate marker) were analyzed at different timepoints and correlated with transfusions and adverse outcomes. Results: More critically injured patients, nonsurvivors, and those with longer ventilator requirement had higher levels of hemolysis markers with reduced l-arginine and l-citrulline. In logistic regression, elevated hemolysis markers, reduced l-arginine, and reduced l-citrulline were significantly associated with these adverse outcomes. An increased number of blood transfusions were significantly associated with elevated hemolysis markers and reduced l-arginine and l-citrulline independently of New Injury Severity Score and arterial base excess. Conclusions: Severe injury induces intravascular hemolysis, which may mediate postinjury organ dysfunction. In addition to native RBCs, transfused RBCs can lyse and may exacerbate trauma-induced hemolysis. Arginase-1 released from RBCs may contribute to the depletion of l-arginine and the subsequent reduction in the NO necessary to maintain organ perfusion.

A metabolomic and proteomic analysis of pathologic hypercoagulability in traumatic brain injury patients after dura violation

“…In addition to increased lipolysis metabolites, our data revealed decreases in citrulline, arginine, and proline metabolites, which has been described in previous TBI metabolomic investigations 44 . These same changes have been observed in critically injured patients and those in hemorrhagic shock 37 and linked to adverse clinical outcomes 45 . These reductions in arginine ultimately lead to reduction in nitric oxide necessary to maintain cerebral perfusion.…”

“…44 These same changes have been observed in critically injured patients and those in hemorrhagic shock 37 and linked to adverse clinical outcomes. 45 These reductions in arginine ultimately lead to reduction in nitric oxide necessary to maintain cerebral perfusion. Further, ornithine, a crucial part of the arginine and nitric oxide pathway, was significantly decreased in TBI patients after dura violation, as seen in previous TBI literature.…”

Cell-Free Hemoglobin in the Pathophysiology of Trauma: A Scoping Review

“…We know from clinical studies that major trauma is associated with endogenous hemolysis and that markers of hemolysis before transfusion correlate with physiologic markers of injury severity, and poor outcomes (6,8). Clinical studies also demonstrated that large-volume transfusion (> 5 L) is associated with a BUN = blood urea nitrogen, Cr = creatinine, NGAL = neutrophil gelatinase-associated lipocalin, NO = nitric oxide, SCD = sickle cell disease.…”

Omics markers of platelet transfusion in trauma patients

“…43 Implementation of omics technologies in the field of coagulopathy of trauma has generated a wealth of data corroborating well-established literature on coagulation and fibrinolytic cascades as a balancing act between proteases and protease-inhibitor systems, 5 and providing for the first time structural molecular evidence of fibrinolytic products beyond clinically accepted markers of fibrin breakdown such as d-dimers. 26 However, despite extensive omics characterization of PLT products 32,[44][45][46][47][48] as they are stored in the blood bank, as well as the signatures associated with the onset and severity of trauma-associated thrombo-inflammatory comorbidities, 4,13,15,16,24,25,46,[49][50][51][52][53] no study to date has focused on the molecular impact of PLT transfusion on the circulating proteome and metabolome of severely injured patients.…”