Summary Background Systemic hyperfibrinolysis is a lethal phenotype of trauma-induced coagulopathy. Its pathogenesis is poorly understood. Recent studies have support a central role of platelets in hemostasis and in fibrinolysis regulation, implying that platelet impairment is integral to the development of postinjury systemic hyperfibrinolysis. Objective The objective of this study was to identify if platelet function is associated with blood clot sensitivity to fibrinolysis. We hypothesize that platelet impairment of the ADP pathway correlates with fibrinolysis sensitivity in trauma patients. Methods A prospective observational study of patients meeting the criteria for the highest level of activation at an urban trauma center was performed. Viscoelastic parameters associated with platelet function (maximum amplitude [MA]) were measured with native thrombelastography (TEG), and TEG platelet mapping of the ADP pathway (ADP-MA). The contribution of fibrinogen to clotting was measured with TEG (angle) and the TEG functional fibrinogen (FF) assay (FF-MA). Another TEG assay containing tissue-type plasminogen activator (t-PA) (75 ng mL−1) was used to assess clot sensitivity to an exogenous fibrinolytic stimulus by use of the TEG lysis at 30 min (LY30) variable. Multivariate linear regression was used to identify which TEG variable correlated with t-PA-LY30 (quantification of fibrinolysis sensitivity). Results Fifty-eight trauma patients were included in the analysis, with a median injury severity score of 17 and a base deficit of 6 mEq L−1. TEG parameters that significantly predicted t-PA-LY30 were related to platelet function (ADP-MA, P = 0.001; MA, P < 0.001) but not to fibrinogen (FF-MA, P = 0.773; angle, P = 0.083). Clinical predictors of platelet ADP impairment included calcium level (P = 0.001), base deficit (P = 0.001), and injury severity (P = 0.001). Results and Conclusions Platelet impairment of the ADP pathway is associated with increased sensitivity to t-PA. ADP pathway inhibition in platelets may be an early step in the pathogenesis of systemic hyperfibrinolysis.

Background We developed a hemorrhagic shock animal model to replicate an urban prehospital setting where resuscitation fluids are limited to assess the effect of saline versus plasma in coagulopathic patients. An in vitro model of whole blood dilution with saline exacerbated tPA mediated fibrinolysis, while plasma dilution did not change fibrinolysis. We hypothesize that shock induced hyperfibrinolysis can be attenuated by resuscitation with plasma while exacerbated by saline. Methods Sprague Dawley rats were hemorrhaged to a mean arterial pressure (MAP) of 25 mmHg and maintained in shock for 30 minutes. Animals were resuscitated with either normal saline (NS) or platelet free plasma (PFP) with a 10% total blood volume bolus, followed by an additional 5 minutes of resuscitation with NS to increase blood pressure to a MAP of 30 mmHg. Animals were observed for 15 minutes for assessment of hemodynamic response and survival. Blood samples were analyzed with thrombelastography (TEG) paired with protein analysis. Results The median percent of total blood volume shed per group were similar (NS 52.5% vs PFP 55.7 p=0.065). Survival was 50% in NS compared to 100% in PFP. The change in LY30 and tPA levels from baseline to shock was similar between groups (LY30 PFP10 IQR 4.3 to 11.2, NS 4.5 IQR 4.1 to 14.2 p=1.00; tPA PFP 16.6 ng/ml IQR 13.7–27.8, NS 22.4 IQR 20.1 to 25.5 p=0.240). After resuscitation, the median change in LY30 was greater in the NS group (13.5 IQR 3.5 to 19.9) compared to PFP (−4.9 % IQR −9.22 to 0.25 p=0.004) but tPA levels did not significantly change (NS 1.4 IQR-6.2 to 7.1 vs PFP 1.7 IQR-5.2 to 6.8 p=0.699). Conclusions Systemic hyperfibrinolysis is driven by hypoperfusion and associated with increased levels of tPA. Plasma is a superior resuscitation fluid to normal saline in a prehospital model of severe hemorrhagic shock as it attenuates hyperfibrinolysis and improves systemic perfusion.

Background Post-injury hyperfibrinolysis (HF), defined as LY30 ≥3% on rapid thrombelastography (rTEG), is associated with high mortality and large utilization of blood products. We observed that some cases of HF are reversible and are associated with patients who respond to hemostatic resuscitation; whereas, other cases of severe HF appear to be associated with these patients’ inevitable demise. We therefore sought to define this unsurvivable subtype of hyperfibrinolysis as a recognizable rTEG tracing pattern. Methods We queried our trauma registry for patients who either died or spent at least one day in the ICU, received at least one unit of PRBCs, and had an admission rTEG. Within this group of 572 patients, we identified 42 pairs of non-survivors and survivors who matched on age, sex, injury mechanism and NISS. We inspected the rTEG tracings to ascertain if any pattern was found exclusively within the non-surviving group and applied these findings to the cohort of 572 patients to assess the predictive value for mortality. Results Within the matched group 17% of patients developed HF. Within the HF subgroup, a unique rTEG pattern was present in 14 HF patients who died and in none of the survivors. This pattern was a “diamond-shaped” tracing with a short time to maximum amplitude (TMA) of ≤14 min and complete lysis before the LY30 point. Applying these criteria to the 572 unmatched patients, this pattern had a 100% positive predictive value for mortality. Conclusions Patients displaying the “black diamond” pattern on their admission rTEG are at higher risk for mortality. Given the volume of blood products and other resources that these patients consume, this TEG pattern may represent an objective criterion to discontinue efforts at hemostatic resuscitation.