Critical Role of Activated Protein C in Early Coagulopathy and Later Organ Failure, Infection and Death in Trauma Patients

Abstract

Background Recent studies have identified an acute traumatic coagulopathy that is present on admission to the hospital and is independent of iatrogenic causes. We have previously reported that this coagulopathy is due to the association of severe injury and shock and is characterized by a decrease in plasma protein C levels. Whether this early coagulopathy and later propensity to infection, MOF and mortality are associated with the activation of protein C pathway has not been demonstrated and constitutes the aim of this study. Methods and Findings This was a prospective cohort study of 203 major trauma patients. Serial blood samples were drawn on arrival in the ED, and at 6, 12, and 24 hours after admission to the hospital. PT, PTT, Va, VIIIa, PC aPC t-PA and D-Dimer levels were assayed. Comprehensive injury, resuscitation and outcome data were prospectively collected. A total of 203 patients were enrolled. Patients with tissue hypoperfusion and severe traumatic injury showed a strong activation of the protein C which was associated with a coagulopathy characterized by inactivation of the coagulation factors V and VIII and a derepression of the fibrinolysis with high plasma levels of plasminogen activator and high D-dimers. Elevated plasma levels of activated protein C were significantly associated with increased mortality, organ injury, increased blood transfusion requirements, and reduced ICU ventilator-free days. Finally early depletion of protein C after trauma is associated with a propensity to post-traumatic ventilator-associated pneumonia. Conclusions Acute traumatic coagulopathy occurs in the presence of tissue hypoperfusion and severe traumatic injury and is mediated by activation of the protein C pathway. Higher plasma levels of aPC upon admission are predictive of poor clinical outcomes following major trauma. After activation, patients who fail to recover physiologic plasma values of protein C have an increased propensity to later nosocomial lung infection.

The pathogenesis of traumatic coagulopathy

“…In addition, by binding PAI-1 and de-repressing t-PA, it may activate fibrinolysis [3,5,29]. This mechanism is plausible but problematic due to the kinetics of the reactions.…”

“…These processes are reflected in the findings of observational clinical studies that show reduced clotting factor and physiological anticoagulant levels [21][22][23], high thrombin generating capacity [3,4,21,[24][25][26] and reduced platelet counts [27,28] Overall, these data indicate a consumptive coagulopathy. The most depleted coagulation factors are fibrinogen and factor V [22,28], which are likely consumed in part by activated Protein C or free plasmin [29,30], although the relative importance of these proteases in reducing factor levels remains unknown. Thrombin is the key effector molecule in haemostasis; its generation not only converts fibrinogen to fibrin but, like a cytokine, it also activates platelets, leucocytes and endothelium.…”

“…Tissue damage and shock are associated with platelet release of soluble CD40-ligand, a potent immune activator that itself can cause further ECA and platelet activation, and is known to be necessary in order to stabilise thrombi [29]. Immune stimulation, including complement activation, is associated with release of damageassociated molecular patterns (DAMPs), such as mitochondrial DAMPs and histone-complexed DNA [30,31].…”

Clotting Factor XIII and desmopressin improve hemostasis in uncontrolled bleeding

“…More recently, early fibrinolysis, platelet dysfunction, clotting factor inactivation and depletion, were described in acute traumatic coagulopathy [18][19][20] . To approach those multiple conditions, pharmacological agents have been incorporated in the management of coagulopathy 6,7 .…”

Fluid Resuscitation and Massive Transfusion Protocol in Pediatric Trauma

“…Several mechanisms have been proposed to explain the coagulation abnormalities associated with TBI, which show a combination of both hypocoagulable and hypercoagulable states (14). It has also been hypothesized that the trauma causes local release of tissue factor from the injured neurons, which is associated with activation of the protein C pathway, thus triggering the release of anticoagulant mediators (15). Borgman et al (16) found both admission base deficit < 8 and INR > 1.8 to be independently associated with mortality, and proposed that a score based on these predictors of adverse outcome ("BIG" score: base deficit + [2.5 x INR] + [15-GCS score]) may more accurately predict mortality in pediatric trauma patients than scoring systems currently in use.…”