In the past, coagulation defects associated with trauma were attributed to triggering of DIC or resuscitative therapy, such as hemodilution. Although DIC and hemodilution still exist in trauma and contribute to hemostastic defects, it is now recognized that trauma incites its unique coagulopathy, which we are just beginning to understand (see review by Chang et al 2016 and Kornblith et al 2019). The pathogenesis of trauma-induced coagulopathy (TIC), which manifests as a bleeding phenotype (such as diffuse bleeding from capillary beds, even in uninvolved tissue), is complex and likely multifactorial, but does require hypoperfusion or shock. Factors contributing to the excessive hemorrhage seen in traumatized patients (particularly in the first 6 to 24 hours) and includes the following (Chang et al 2016, Kornblith et al 2019):

  • Excessive activation of protein C: Too high concentrations or activity of activated protein C will lead to a bleeding phenotype. This is because protein C acts as an anticoagulant (inhibiting the cofactors, FV and FVIII, with the help of free protein S and the endothelial protein C receptor) and as a profibrinolytic (inhibiting plasminogen activator inhibitor-1, PAI-1). There is a strong association between high protein C activity and hypoperfusion, suggesting that the latter is the driving force behind excessive protein C, however the mechanism by which this occurs is unclear. 
  • Acidosis and hypothermia: Both of these conditions are associated with decreased clotting activity ex vivo and in vivo. The rate of tissue factor-initiated thrombin generation ex vivo in human plasma is slower when the test is performed under conditions mimicking hypothermia (27ºC) (Whelihan et al 2014). When using thromboelastometry, hypothermia (27ºC or 30ºC) reduced clot formation with triggers of the intrinsic or extrinsic pathway, whereas clot lysis was reduced (Dirkmann et al 2008, Whelihan et al 2014). Acidosis promoted the hypothermic effect, but had no effect on this assay alone at 37ºC (Dirkmann et al 2008). These ex vivo findings were supported by in vivo observations in human trauma patients using global tests of hemostasis (Lv et al 2018). Similarly, induction of acidosis ex vivo in dog blood with hydrochloric acid (not a true mimic of in vivo acidosis) decreased clot formation but did not alter the PT or APTT (Burton et al 2018). 
  • Endothelial dysfunction: The endothelial system is damaged or becomes dysfunctional in trauma, with the balance tilting towards activation of coagulation. There is also renewed interest on the role of the glycocalyx in coagulopathies, such as that due to trauma. Activating stimuli, including catecholamine release, can induce shedding of anticoagulant moieties, e.g. heparin and chondroitin sulfate, from the endothelial glycocalyx, leading to inhibition of clotting factor activity and excessive hemorrhage.
  • Platelet dysfunction: Platelets in human trauma patients have reduced responsiveness to various agonists, e.g. ADP, in platelet aggregation assays. This has been attributed to “platelet exhaustion”.
  • Fibrinolysis: Enhanced fibrinolysis has been ascribed to increased concentrations of tissue plasminogen activator (released in early stages of trauma as a response to endothelial injury) and urokinase plasminogen activator (in later stages of trauma). This would lead to excessive hemorrhage. Reduced fibrinolysis, which would promote clot formation and organ injury, has also been identified in patients with sepsis and is likely mediated through increased concentrations of PAI-1, such as occurs in endotoxemia in humans. 
  • Deficient fibrinogen: This is a major risk factor for mortality in human patients and affected people may substantially benefit from fibrinogen supplementation (Chang et al 2016).
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