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 (PC) levels. Whether this early coagulopathy and later propensity to infection, multiple organ failure and mortality are associated with the activation of PC 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 emergency department, 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 PC 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 PC were significantly associated with increased mortality, organ injury, increased blood transfusion requirements, and reduced ICU ventilator-free days. Finally early depletion of PC after trauma is associated with a propensity to posttraumatic 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 PC pathway. Higher plasma levels of aPC upon admission are predictive of poor clinical outcomes after major trauma. After activation, patients who fail to recover physiologic plasma values of PC have an increased propensity to later nosocomial lung infection.

Figure 1. A combination of tissue injury and shock result in coagulopathy in trauma patients

Patients were divided into groups using previously described definitions of injury severity based on Injury Severity Score and Shock based on Base Deficit. This resulted in 4 groups; minimal injury, no shock (ISS<15 BD<6); minimal injury, shock (ISS>15 BD >6); severe injury, no shock (ISS>15 BD<6); and severe injury and shock (ISS >15, BD >6). Prothrombin time (PT) and partial thromboplastin time (PTT) were assayed. Patients with severe injury and shock had elevated PT (Panel A) and PTT (Panel B). All p<.05 by Kruskall Wallis rank test.

Figure 2. Tissue injury and shock result in a systemic activation of protein C pathway associated with coagulopathy in trauma patients

Patients were divided into groups using previously described definitions of injury severity based on Injury Severity Score and Shock based on Base Deficit. This resulted in 4 groups; minimal injury, no shock (ISS<15 BD<6); minimal injury, shock (ISS>15 BD >6); severe injury, no shock (ISS>15 BD<6); and severe injury and shock (ISS >15, BD >6). Plasma levels of activated protein C (aPC) and protein C (PC) were assayed, as described in the Methods. Patients with severe injury and shock had elevation of plasma levels of aPC (Panel A) and a concomitant decrease in levels of PC (Panel B). aPC levels were then divided into quartiles. Patients with the highest quartile of plasma levels of aPC had elevated PT (Panel C) and PTT (Panel D). All p<.05 by Kruskall Wallis rank test.

Figure 3. Systemic Activation of the protein C pathway is associated with the inactivation of factors Va and VIIIa and derepression of fibrinolysis in trauma patients

Patients were divided into quartiles based on plasma levels of activated protein C. Patients with the highest activation of protein C in the plasma (highest quartile) had a coagulopathy caused by deactivation of factor Va (Panel A) and factor VIIIa (Panel B). In addition, patients with the highest plasma level of aPC had a derepression of the fibrinolysis, as evidenced by elevated tPA and d-Dimers (Panel C&D).

Figure 4. Protein C depletion is associated with an increased incidence of nosocomial lung infection in trauma patients

Patients were divided in three groups based on changes in plasma levels of protein C during the first 24h after trauma. In one group of patients there was a significant increase in the plasma levels of protein C zymogen within 12 hours after trauma. The rest of the patients who had a decrease in the plasma levels of proten C zymogen were divided into two groups characterized either by a moderate decrease of plasma levels of PC with recovery or by a significant decrease in plasma levels of PC without recovery during the first 24 hours after trauma. Patients who decreased their plasma levels of PC without any recovery had a 2.7 times increase in nosocomial lung infection than those we show some recovery of the plasma levels of PC between 12 and 24 hours after trauma (OR 2.7 CI 1.05 −6.8 p = .04).