Author(s):
Ivan Rodriguez; Ernest Moore; Peggy Knudson; Peter Moore; Trevor Nydam; Elizabeth Pomfret; Russel Tracy; Steven Wisniewski; Fredric Pieracci; James Morrissey ; Angela Sauaia; Hunter Moore

Background:

Pneumonia (PNA) is associated with high morbidity and costs in the intensive care unit (ICU) and its early identification is key for optimal outcomes, but early biomarkers are lacking. Recent studies suggest that fibrinolysis resistance (FR) after major abdominal surgery is linked to a 3-fold increased risk of infection, consistent with animal models in which plasmin (driver of fibrinolysis) modulates immune response.

Hypothesis:

FR within 48 hours postinjury is associated with an increased risk of PNA.

Methods:

Patients enrolled in a randomized controlled trial for hemorrhagic shock were evaluated for FR.  FR was quantified by thrombelastography with exogenous tissue plasminogen activator (tPA-TEG) at 24 and 48 hours post injury and measuring LY30 (%). A receiver-operating characteristics curve (ROC) analysis was used to identify an inflection point (Youden Index) for increased risk of PNA. PNA was based on a clinical diagnosis requiring treatment >48 hours postinjury. The cutoff was then validated in a cohort of ICU patients at risk for venous thromboembolism (VTE).  Multivariable logistic regression was used to control for confounders. Proteomics was used to assess for altered immune response between groups.

Results:

In the bleeding cohort, 125 patients were enrolled in which 49 had tPA-TEGs at 24 and 48 hours (median ISS= 27, 7% PNA).  A composite tPA-TEG LY30 £ 4% at 24 and 48 hours was found to be the optimal cutoff for increased risk of PNA.  This cohort with persistent tPA resistance had a 7-fold increased rate of PNA (4% vs 28% p=0.048, Figure 1: A). In the ICU cohort, 88 had tPA-TEG at 24 and 48 hours post ICU admission (median ISS=28, 6% PNA).  The tPA-TEG LY30£ 4% was associated with a 10-fold increased rate of PNA (19 vs 1.5% p=0.002, Figure 1: B). In patients with traumatic brain injury, the same association was found (33% vs 3.2% p=0.006). Adjusting for confounders, the tPA-TEG persisted as a significant risk factor for PNA (adjusted OR=35.7, 95%CI 1.9-682, p=0.018). Proteomics identified increased MHC class I polypeptide A(P=0.006) and SERPINA3 (P=0.018) in the tPA resistant cohort, with decreased expression of mannose binding lectin protein C (P=0.018).

Conclusions:

FR quantified by tPA-TEG within 48 hours of ICU admission is associated with an increased risk of PNA in bleeding patients and those at risk for VTE. Prospective validation of the tPA-TEG LY30 optimal cutoff for PNA and further investigation into whether endogenous FR is a cause of an altered immune response related to MHC I and complement or an epiphenomenon for postinjury PNA are needed.