Proteomics of Coagulopathy Following Injury Reveals Limitations of Using Laboratory Assessment to Define Trauma-Induced Coagulopathy to Predict Massive Transfusion

Abstract

Objective: Trauma-induced coagulopathy (TIC) is provoked by multiple mechanisms and is perceived to be one driver of massive transfusions (MT). Single laboratory values using prothrombin time (INR) or thrombelastography (TEG) are used to clinically define this complex process. We used a proteomics approach to test whether current definitions of TIC (INR, TEG, or clinical judgment) are sufficient to capture the majority of protein changes associated with MT. Methods: Eight level I trauma centers contributed blood samples from patients available early after injury. TIC was defined as INR >1.5 (INR-TIC), TEG maximum amplitude <50 mm (TEG-TIC), or clinical judgment (Clin-TIC) by the trauma surgeon. MT was defined as >10 units of red blood cells in 24 hours or >4 units RBC/hour during the first 4 hours. SomaLogic proteomic analysis of 1305 proteins was performed. Pathways associated with proteins dysregulated in patients with each TIC definition and MT were identified. Results: Patients (n = 211) had a mean injury severity score of 24, with a MT and mortality rate of 22% and 12%, respectively. We identified 578 SOMAscan analytes dysregulated among MT patients, of which INR-TIC, TEG-TIC, and Clin-TIC patients showed dysregulation only in 25%, 3%, and 4% of these, respectively. TIC definitions jointly failed to show changes in 73% of the protein levels associated with MT, and failed to identify 26% of patients that received a massive transfusion. INR-TIC and TEG-TIC patients showed dysregulation of proteins significantly associated with complement activity. Proteins dysregulated in Clin-TIC or massive transfusion patients were not significantly associated with any pathway. Conclusion: These data indicate there are unexplored opportunities to identify patients at risk for massive bleeding. Only a small subset of proteins that are dysregulated in patients receiving MT are statistically significantly dysregulated among patients whose TIC is defined based solely on laboratory measurements or clinical assessment.

Rapid clearing CT-001 restored hemostasis in mice with coagulopathy induced by activated protein C

“…Some of the transitions can occur within hours after injury 11 . The viscoelastic hemostatic assay 19–21 and TGA 22 have been applied to detect this unpredictable transition; however, more reliable methods to monitor the transition from hypocoagulability to hypercoagulability remain to be established 23 . Therefore, along with the current treatment regimen, it is desirable to have a therapeutic agent that could provide patients with additional prohemostatic activity for treating blood loss while having low thrombogenicity risk by being quickly cleared.…”

“…11 The viscoelastic hemostatic assay [19][20][21] and TGA 22 have been applied to detect this unpredictable transition; however, more reliable methods to monitor the transition from hypocoagulability to hypercoagulability remain to be established. 23 Therefore, along with the current treatment regimen, it is desirable to have a therapeutic agent that could provide patients with additional prohemostatic activity for treating blood loss while having low thrombogenicity risk by being quickly cleared. CT-001, through two newly engineered amino acids in the γ-carboxyglutamic acid domain to provide enhanced clotting activity and 4 N-glycosylation sites expressing desialylated glycans for rapid removal by hepatocytes, 12 may represent such a needed treatment.…”

The pathophysiology of pelvic ring injuries: a review

“…However, most of the conventional coagulation tests were developed to monitor anticoagulant therapy, and therefore reflect a crude and artificial in vitro assessment of coagulation [ 21 , 41 , 42 ]. The pure reliance on in vitro coagulation tests (which are performed at a normal pH and a temperature of 37 °C) does not reflect the “true” in vivo coagulopathy in hypothermic and acidotic trauma patients [ 16 ].…”

“…These significant limitations of conventional laboratory tests are mitigated by modern “point of care” coagulation assays, using thromboelastography (TEG) or rotational thromboelastometry (ROTEM) [ 39 , 42 – 44 ]. These modalities are performed quickly at the bedside, and thus represent a “real-time” assessment of coagulation in the bleeding trauma patient.…”

Omics markers of platelet transfusion in trauma patients

“…[11][12][13][14][15][16][17] Our group, for example, has extensively characterized the impact of T/HS on the circulating proteomes and metabolomes of patients and pre-clinical animal models, including rodents, swines, and non-human primate. [11][12][13][14][15][16][17] Omics investigations have not only documented the dysregulation of proteolytic cascades (and inhibition thereof) that underlie proper clot formation and stability, 4,[18][19][20][21][22][23][24][25] but also generated direct structural evidence on fibrin clot formation and stability as regulated by canonical and non-canonical transglutaminase activities (e.g., factor XIII). 26 Altogether, omics studies in the literature have identified molecular markers of mortality, 27 and coagulopathy, 4,28 to the extent this phenomenon is-at least in part-driven by platelet mitochondrial activity, 29 and dysregulation thereof secondary to acidosis following hypoxemia and hypoxia-induced mitochondrial dysfunction, 30,31 Translationally, we identified molecular signatures of trauma that are linked to the onset and severity of coagulopathy, as determined via correlation of metabolomics 28 and proteomics 4 data to measurement from viscoelastic assays.…”