Traumatized triad of complementopathy, endotheliopathy, and coagulopathy ˗ Impact on clinical outcomes in severe polytrauma patients

Abstract

Complementopathy, endotheliopathy, and coagulopathy following a traumatic injury are key pathophysiological mechanisms potentially associated with multiple-organ failure (MOF) and mortality. However, the heterogeneity in the responses of complementopathy, endotheliopathy, and coagulopathy to trauma, the nature and extent of their interplay, and their relationship to clinical outcomes remain unclear. Fifty-four poly-trauma patients were enrolled and divided into three subgroups based on their ISS. Biomarkers in blood plasma reflecting complement activation, endothelial damage, and coagulopathy were measured starting from admission to the emergency department and at 3, 6, 12, 24, and 120 hours after admission. Comparative analyses showed that severely injured patients (ISS>24) were associated with longer days on mechanical ventilation, in the intensive care unit and hospital stays, and a higher incidence of hyperglycemia, bacteremia, respiratory failure and pneumonia compared to mildly (ISS<16) or moderately (ISS=16-24) injured patients. In this trauma cohort, complement was activated early, primarily through the alternative complement pathway. As measured in blood plasma, severely injured patients had significantly higher levels of complement activation products (C3a, C5a, C5b-9, and Bb), endothelial damage markers (syndecan-1, sTM, sVEGFr1, and hcDNA), and fibrinolytic markers (D-dimer and LY30) compared to less severely injured patients. Severely injured patients also had significantly lower thrombin generation (ETP and peak) and lower levels of coagulation factors (I, V, VIII, IX, protein C) than less severely injured patients. Complement activation correlated with endothelial damage and hypocoagulopathy. Logistic regression analyses revealed that Bb >1.57 μg/ml, syndecan-1 >66.6 ng/ml or D-dimer >6 mg/L at admission were associated with a higher risk of MOF/mortality. After adjusting for ISS, each increase of the triadic score defined above (Bb>1.57 µg/ml/Syndecan-1>66.6 ng/ml/D-dimer>6.0mg/L) was associated with a 6-fold higher in the odds ratio of MOF/death [OR: 6.83 (1.04-44.96, P=0.046], and a 4-fold greater in the odds of infectious complications [OR: 4.12 (1.04-16.36), P=0.044]. These findings provide preliminary evidence of two human injury response endotypes (traumatized triad and non-traumatized triad) that align with clinical trajectory, suggesting a potential endotype defined by a high triadic score. Patients with this endotype may be considered for timely intervention to create a pro-survival/organ-protective phenotype and improve clinical outcomes.

Immunopathological Alterations after Blast Injury and Hemorrhage in a Swine Model of Prolonged Damage Control Resuscitation

“…The pathological alterations of heart and brain were positively associated with blood levels of C3a (survivors vs. non-survivor: 401 vs. 2007 ng/mL) and HMGB1 (survivors vs. non-survivor: 57 vs. 1794 ng/mL) at 1 h post-BI, suggesting that early complement activation and HMGB1 release may represent the mechanism underlying the development of myocarditis and encephalitis in non-survivor. These findings are in agreement with our previous reports that demonstrated: (1) early systemic complement activation and HMGB1 release positively correlated with clinical outcomes in combat casualties [ 18 , 19 ] and civilian trauma patients [ 10 , 16 , 20 ]; (2) BI+HS triggered systemic and local complement activation and systemic HMGB1 release, induced brain injury, and increased mortality in rats, whereas treatment with nomacopan (a C5 inhibitor) or CX-01 (an HMGB1 inhibitor) alleviated this phenomenon [ 18 , 19 ]; (3) HS + voluven resulted in myocarditis and mortality that correlated to systemic and cardiac terminal complement activation (TCA) and plasma levels of TNF-α in swine (unpublished data); and (4) polytrauma + HS-induced myocarditis, encephalitis (unpublished data), and mortality paralleled with systemic and tissue TCA, metabolic acidosis and hypocalcemia in swine, while C1 inhibitor administration ameliorated this phenomenon [ 31 ]. Therefore, stratification of disease-associated phenotypes/endotypes in BI+HS may have value for prognostic, predictive, and personalized medicine.…”

“…TH-related tissue injury and ischemia, and initial TH-associated therapeutic interventions (e.g., blood transfusion, volume resuscitation, surgical damage control, instrumentation), instantly and massively activate innate immunity, such as damage-associated molecular patterns [DAMPs; e.g., high mobility group box 1 protein (HMGB1)] and complement cascade (ComC), which represents a crucial driver of inflammation-mediated multiorgan dysfunction syndrome (MODS) and mortality [ 6 , 7 , 8 , 9 ]. Growing evidence from our studies and those of others illustrates that early excessive release of HMGB1 and activation of ComC represent a key mechanism regulating the development of inflammation-mediated MODS in civilian and military trauma patients [ 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ], rat models of BI [ 14 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 ], BI+HS [ 18 , 19 ], and swine models of HS [ 21 , 25 , 29 , 30 , 31 , 32 ]. Recently, we have further shown that early administration of nomacopan, a complement inhibitor [ 19 ] and CX-01, an HMGB1 inhibitor [ 18 ], attenuate morbidity and mortality 24 h after injury in a rat model of blast injury (BI) and HS.…”

“…We also provided preliminary evidence for a potential endotype within trauma patients defined by the triad of complementopathy, endotheliopathy, and coagulopathy, which may serve as a distinguishing prognostic and diagnostic indicator for multiple-organ failure (MOF)/death and a potential therapeutic target for clinical trauma patients [ 10 ]. A recent report on closed-head injury caused by dynamic acceleration combined with two levels of HS in mature Yucatan pigs showed diffuse axonal injury, blood-brain barrier breach, and systemic and local inflammation in the brain tissue [ 33 ].…”

Complement as a vital nexus of the pathobiological connectome for acute respiratory distress syndrome: An emerging therapeutic target

“…Furthermore, other clinical data also elucidated that early eHMGB1 release after severe trauma in patients was associated with post-traumatic complement terminal pathway (CTP) activation and tissue hypoperfusion (204). Consistent with these findings, our recent studies have shown that (1) ComC activation (C3a, C5a, C5b-9, Bb) post-trauma positively correlated with plasma levels of eHMGB1 (205) and histone-complexed DNA fragments (hcDNA) in trauma patients ( 206); (2) blocking C5 by nomacopan reduced the release of eHMGB1 (206), whereas HMGB1 inhibition by CX-01 also reversed ComC activation in a rat model of traumatic hemorrhage-induced ALI (205); and (3) CTP inhibition by DAF reduced expression of HMGB1, RAGE, NF-kB, cytokines (IL-6, IL-12, IL-13, IL-18, GRO KC) and caspase-1, and HMGB1 nuclear translocation in blast-induced ALI in rats (207). Altogether, these findings indicate synergistic crosstalk between the ComC and DAMPs that markedly amplifies pro-inflammatory responses and may contribute to ALI.…”

Impact of immunopathy and coagulopathy on multi-organ failure and mortality in a lethal porcine model of uncontrolled hemorrhagic shock

“…We have noted the activation of complement and coagulation cascades and their interaction, impacting outcomes in preclinical animal models of traumatic hemorrhage [18,19] and clinical trauma patients [20]. Furthermore, our recent findings have shown that the synergistic effects of the traumatic triad (complementopathy, endotheliopathy, and coagulopathy) occurred early after trauma, contributed to poor clinical outcomes (MOF/death), and led to infectious complications; therefore, the triadic intercommunication model is proposed [21]. Additionally, biomarkers such as Bb, syndecan-1, and D-dimer are reliable early predictive biomarkers of clinical outcomes [21].…”