Insights into the association between coagulopathy and inflammation: abnormal clot mechanics are a warning of immunologic dysregulation following major injury

Abstract

Background: Severe injury initiates a complex physiologic response encompassing multiple systems and varies phenotypically between patients. Trauma-induced coagulopathy may be an early warning of a poorly coordinated response at the molecular level, including a deleterious immunologic response and worsening of shock states. The onset of trauma-induced coagulopathy (TIC) may be subtle however. In previous work, we identified an early warning sign of coagulopathy from the admission thromboelastogram, called the MAR ratio. We hypothesized that a low MAR ratio would be associated with specific derangements in the inflammatory response. Methods:In this prospective, observational study, 88 blunt trauma patients admitted to the intensive care unit (ICU) were identified. Concentrations of inflammatory mediators were recorded serially over the course of a week and the MAR ratio was calculated from the admission thromboelastogram. Correlation analysis was used to assess the relationship between MAR and inflammatory mediators. Dynamic network analysis was used to assess coordination of immunologic response.Results: Seventy-nine percent of patients were male and mean age was 37 years (SD 12). The mean ISS was 30.2 (SD 12) and mortality was 7.2%. CRITICAL patients (MAR ratio ≤14.2) had statistically higher shock volumes at three time points in the first day compared to NORMAL patients (MAR ratio >14.2).CRITICAL patients had significant differences in IL-6 (P=0.0065), IL-8 (P=0.0115), IL-10 (P=0.0316) and MCP-1 (P=0.0039) concentrations compared to NORMAL. Differences in degree of expression and discoordination of immune response continued in CRITICAL patients throughout the first day. Conclusions:The admission MAR ratio may be the earliest warning signal of a pathologic inflammatory response associated with hypoperfusion and TIC. A low MAR ratio is an early indication of complicated dysfunction of multiple molecular processes following trauma.

Variations in clot phenotype following injury: The MA-R ratio and fragile clots

“…The measurements obtained from TEG, while helpful, are also reflective of the complexity and interrelated nature of the system that is being measured. Several studies have shown that some TEG results are within normal range despite the patients suffering from clinical coagulopathy 22,23,36 . Conversely, abnormal coagulation laboratory values often do not equate to bleeding 15 .…”

“…Several studies have shown that some TEG results are within normal range despite the patients suffering from clinical coagulopathy. 22,23,36 Conversely, abnormal coagulation laboratory values often do not equate to bleeding. 15 This is particularly true for patients with normal R times and MA, as seen in the current study.…”

Leukocyte activation primes fibrinogen for proteolysis by mitochondrial oxidative stress

“…Several factors contribute to this hypocoagulability, including coagulation factor inhibition, platelet dysfunction, fibrinogen consumption, and hyperfibrino(geno)lysis [ [3] , [4] , [5] , [6] ]. Among those causes, inflammation through endothelial and immune system activation is presumed to be a key initiator that contributes to the underlying mechanism of both sepsis-induced and trauma-induced coagulopathy (TIC) [ [5] , [6] , [7] , [8] , [9] , [10] ].…”

Freeze‐dried plasma: From damage control resuscitation to coronavirus disease 2019 therapy

“…In collaboration with Canadian Blood Services (CBS) and Defense Research and Development Canada, Canadian Forces Health Services is developing FDP from Canadian‐sourced plasma. Hemostatic and immunological properties play important roles in the use of FDP for the treatment of severe trauma and COVID‐19 patients who show changes in both functions despite different underlying mechanisms 14,15 . Numerous studies have revealed bidirectional interactions between the coagulation cascade and systemic inflammatory response following severe traumatic injury 16 .…”

“…Hemostatic and immunological properties play important roles in the use of FDP for the treatment of severe trauma and COVID-19 patients who show changes in both functions despite different underlying mechanisms. 14,15 Numerous studies have revealed bidirectional interactions between the coagulation cascade and systemic inflammatory response following severe traumatic injury. 16 Moreover, there is increasing evidence that a combination of inflammation and hypercoagulable state are the main mechanisms of respiratory failure in patients with COVID-19.…”