Cardenas, Jessica C.; Wade, Charles E.; Holcomb, John B.
The global health burden due to injury has been profoundly understated until recent years. Injury is the third leading cause of death in the United States and is responsible for 10% of deaths worldwide [1▪]. Although recent advances in transfusion practices and prehospital management of trauma patients have improved considerably, hemorrhage remains the leading cause of potentially preventable death following injury and accounts for 40% of trauma-related fatalities [2–6]. Approximately 25% of all seriously injured trauma patients experience severe, excessive, and sustained bleeding associated with impaired blood clotting, a condition referred to as trauma-induced coagulopathy (TIC). Patients with TIC are at five-fold higher risk of death within the first 24 h, have substantially greater transfusion requirements, require longer hospital stays, and are subject to more complications [2–4]. The need for early diagnosis of TIC has changed coagulation testing in the emergency department with increased utilization of viscoelastometry to monitor global hemostatic potential and guide transfusion practices [7,8▪]. However, the increasing prevalence of antiplatelet and anticoagulant therapies in our aging population creates iatrogenic coagulopathy and has complicated the recognition and treatment of TIC. Historical perspectives on mechanisms of TIC focused on consumption or dilution of coagulation factors, hypothermia, and acidosis . Although this ‘lethal triad’ is still a critical component of the pathophysiology of TIC today, research into the mechanisms behind TIC has revealed a more complex and multifactorial cause than previously assumed. This review will focus on the most current findings on mechanisms driving TIC.
There are two recognized types of coagulopathy: TIC and iatrogenic coagulopathy . TIC is the endogenous, pathologic response to physiologic derangement driven by dysregulation of hemostatic pathways secondary to tissue injury and hypoperfusion. Iatrogenic coagulopathy is caused by use of anticoagulants or aggressive resuscitation with asanguineous fluids resulting in hypothermia, acidosis, and hemodilution [5,10]. Coagulopathy is diagnosed using clinical laboratory tests such as the international normalized ratio, the activated partial thromboplastin time, and viscoelastometry. Implementing these tests in the emergency department has substantially improved diagnosis of TIC; however, abnormal laboratory values do not always equate to clinically relevant bleeding. True coagulopathic bleeding is uncontrolled, systemic diffuse hemorrhage, not simply bleeding from injury sites. Distinguishing coagulopathic bleeding observed by physicians at the bedside and coagulopathy as defined by laboratory testing is important to our understanding of TIC; however, there has yet to be a prospective study employing surgeon's declaration of coagulopathy to give a realistic epidemiologic view of the prevalence of TIC. Despite the limitation of a clear definition of TIC, evidence supports a role for platelet dysfunction, endothelial activation, endogenous anticoagulation, fibrinogen modifications, and hyperfibrinolysis in the cause and progression of TIC (Fig. 1). The following review describes the most current state of published knowledge on TIC.
Although platelet count is a well recognized determinant of transfusion requirements and survival in trauma patients, the prevalence of prolonged bleeding despite normal platelet counts in the majority of patients has brought into question the functionality of platelets in response to trauma and massive hemorrhage . First described by Solomon et al., platelet aggregation defects in trauma patients have been confirmed and characterized by several other groups [12–14]. Most recently, Kutcher et al. described the dramatic and persistent platelet dysfunction in trauma patients despite relatively normal platelet counts, and an association between both early and late mortality. Further, these findings showed platelet dysfunction in response to not only adenosine diphosphate (ADP) and arachidonic acid, but also collagen and thrombin receptor-activating peptide, indicating a global dysfunction due to trauma rather than prehospital use of antiplatelet agents . In a swine model of brain injury and hemorrhage, Sillesen et al.[15▪▪] demonstrated pronounced platelet dysfunction as early as 15 min following injury and sustained through 2 h. Interestingly, platelet aggregation was only reduced in response to ADP, not collagen or arachidonic acid, in contrast to the work of Kutcher et al., although this could have been due to differences in activation of human versus swine platelets. Platelet dysfunction was associated with an increase in tissue growth factor-β, suggesting early platelet activation results in a diminished response to further exogenous stimulation. Sillesen et al. [15▪▪] suggested another possible explanation driving selective hypofunction following ADP stimulation could be loss of red blood cell (RBC) volume following hemorrhage. RBCs have recently been recognized to promote platelet aggregation through release of ADP and thromboxane B2. Thus, the observed inverse relationship between platelet aggregation to ADP and both hematocrit and hemoglobin provides interesting new insights into the contribution of other circulating cells during whole blood aggregometry. Alternatively, several studies have reported the debilitating effects of hypothermia, a common consequence of hemorrhage and shock, on platelet function [16,17]. It is thought that hypothermia-induced platelet dysfunction is caused by defects in platelet adhesion rather than activation resulting in insufficient primary hemostasis . However, a recent study by Mohr et al. reported no effect of hypothermia on platelet function in a swine model of trauma. Although swine models provide an anatomically similar model to humans and are important to our understanding of hemorrhagic shock, they may not be the most representative model of platelet function following injury. In contrast to reports demonstrating platelet dysfunction following trauma, a recent study by Windelov et al. reported no association between platelet aggregation and severity of injuries and furthermore that reduced platelet aggregation in exsanguinating patients was most likely due to low platelet counts, not function.
Further, it is estimated that 30–60% of platelet function could be lost because of storage lesions resulting in reduced hemostatic activity of platelets in vivo following transfusion [20,21]. A number of groups are currently exploring cold storage conditions or supplements to storage media that could increase the effectiveness of donor platelets for treating massive hemorrhage [20,22]. Given the profound importance of platelets to controlling hemorrhage, platelet dysfunction following injury and mechanisms causing it remain in question.
Anticoagulant in nature, endothelial cells express many molecules that downregulate thrombin generation, including thrombomodulin, endothelial protein C receptor, and within the glycocalyx layer, chondroitin and heparan sulfate. Our laboratory and others have recently shown that increased plasma levels of sydecan-1, a proteoglycan component of the glycocalyx, are evident, following traumatic injury [23–25]. Shedding of the glycocalyx into the circulation could have an anticoagulating effect as chondroitin sulfate increases the efficiency of thrombomodulin inhibition of thrombin, and heparan sulfate increases the efficiency of thrombin inhibition by antithrombin III [26,27]. Ostrowski and Johansson  described endogenous heparinization in 5% of severely injured trauma patients measured by differences in kaolin versus heparinase thromboelastography (TEG) parameters. These patients sustained more severe injuries, and had greater transfusion requirements, prolonged clotting times, and evidence of endothelial damage. The degree of endogenous heparinization was associated with plasma levels of syndecan-1, suggesting that degradation of the endothelial glycocalyx was causing autoheparinization . Loss of this glycocalyx barrier also increases permeability and vascular leakiness, increasing the likelihood of inflammatory and edematous complications. Recent data in a rat model of hemorrhagic shock showed that the glycocalyx could be restored through resuscitation with fresh frozen plasma (FFP) . This agrees with previous reports [25,30] and provides crucial evidence supporting the beneficial effects of plasma (FFP or liquid) resuscitation on the vascular endothelium. Furthermore, a very recent article by Sillesen et al.[31▪▪] has described improvements in platelet function, fibrinogen levels, and endothelial activation following resuscitation with FFP. In a model of polytrauma and hemorrhagic shock, swine were transfused with either FFP or saline following loss of 40% total blood volume. In the FFP-resuscitated group, platelet aggregation in response to both ADP and arachidonic acid was significantly higher and corresponded to increases in TEG values. The FFP group also had increased plasma fibrinogen and, interestingly, reduced expression of the endothelial activation marker, vascular cell adhesion molecule. In addition to FFP-mediated control of hemodilution and fibrinogen depletion, the authors propose reduced endothelial activation following FFP administration also attenuates trauma-induced platelet dysfunction compared with saline [31▪▪]. This is likely due to reduced systemic activation and adhesion of platelets to damaged endothelium, resulting in more platelets in circulation available for participating in hemostasis. These data further support the use of FFP as an optimal resuscitative fluid to both manage bleeding and restore balance to the coagulation system following injury.
ACTIVATED PROTEIN C
The dual cytoprotective and anticoagulant functions of activated protein C (APC) have become widely recognized to play a critical role in the early response to injury and development of TIC. APC is generated following formation of the thrombin and thrombomodulin complex in the presence of endothelial protein C receptor, which binds and activates protein C. APC signals through protease-activated receptors to stimulate anti-inflammatory and antiapoptotic pathways, and also limits endothelial cell permeability. APC also potently inhibits thrombin generation by inactivating FVa and FVIIIa and is also profibrinolytic as it inhibits plasminogen activator inhibitor (PAI-1), the physiologic inhibitor of tissue-derived and urokinase plasminogen activators (tPA and uPA, respectively) thus promoting plasmin generation. Cohen et al. described the relationship between admission APC levels and coagulopathy, increased transfusion requirements, and mortality. This group also provided evidence in a mouse model of trauma and hemorrhagic shock that inhibition of APC's anticoagulant function was protective against TIC; however, inhibiting both the anticoagulant and cytoprotective signaling function of APC was lethal following shock . These data support a crucial role for APC in mediating TIC and also its importance in tempering the cytotoxic consequences of hypoperfusion and shock.
Jansen et al. demonstrated that trauma is associated with an overall reduction in activity of coagulation factors FII, FVII, FIX, FX, and FXI and that the degree of inactivity is dependent on the severity of shock. Although the loss of FV activity was frankly evident in all patients sampled, it was independent of the degree of hypoperfusion. Furthermore, no difference in FVIII activity was observed. Shock-dependent inactivation of coagulation proteins that are not subject to inactivation by APC and observing the two coagulation proteins (FV and FVIII) that are targeted by APC were either unaffected or independent of shock suggest that although the anticoagulant effects of APC are indisputably important in driving TIC, it cannot be the only inhibitory pathway inactivating essential procoagulants.
Burney et al. [35▪▪] provided a potential new mechanism for inactivation of coagulation factors independent of inhibition by endogenous anticoagulants. These data revealed alterations in the fibrin αC-subdomain which is crucially important for the lateral aggregation of fibrin during polymerization, resulting in disrupted fibrin mesh assembly and compromised clot strength [35▪▪]. This alteration was reportedly due to oxidative modification of a methionine residue on this subdomain. Such oxidative damage could occur in the context of diseases in which oxidative stress is prevalent, such as hemorrhagic shock due to traumatic injury. Reactive oxygen species are released by leukocytes, platelets and endothelial cells following inflammatory signals, injury, and tissue hypoperfusion [36,37]. The sudden and substantial increase in circulating reactive oxygen species could have a profound effect on hemostatic potential in vivo. Importantly, other coagulation proteins such as PAI-1, protein C, and thrombomodulin are reportedly susceptible to oxidative regulation [38–41]. Although the consequences of such interactions are currently hypothetical, these data provide interesting and compelling evidence that oxidative modifications of coagulation proteins secondary to shock could contribute to TIC.
Hyperfibrinolysis is a recently described and particularly deadly phenomenon. Severe hyperfibrinolysis diagnosed by viscoelastometry affects only a small subset of trauma patients; however, it is associated with severe injuries, profound shock, and an extremely high risk of mortality [42,43]. In a study from our group, patients considered hyperfibrinolytic by TEG (>7.5% lysis at 30 min) had a mortality rate of 76%, compared with 9% in patients without hyperfibrinolysis . Studies from our laboratory and others have defined TEG LY30% of at least three as the point at which the risk of mortality increases and therefore pharmacologic intervention strategies should be initiated [42,43]. The epidemiology and overall effect of hyperfibrinolysis were described by Raza et al.[44▪], showing that the vast majority of patients exhibit some degree of fibrinolysis, and that 5% of patients develop severe hyperfibrinolysis. This was not due to hypothermia or iatrogenic complications, suggesting that this condition is a distinct disease entity and contributor to TIC. Fibrinolysis is controlled by plasmin that is generated following activation of plasminogen by tPA and uPA. Plasmin degrades fibrin clots by cleaving cross-linked fibrin, a process that is inhibited by PAI-1, which inactivates tPA and uPA [45–47]. A recent study from our laboratory demonstrated the importance of the tPA : PAI-1 complex in hyperfibrinolysis. These data showed that severe hyperfibrinolysis was driven by plasmin generation secondary to excessive increases in tPA circulation in the absence of concomitant increases in PAI-1 [48▪]. This is in agreement with the previous literature and also the role of APC inhibition of PAI-1 linking trauma-induced hyperfibrinolysis with the activation of the protein C system . Recent data by Dirkmann et al. reported the effects of acidosis and hypothermia, two physiologic states common following injury, shock, and hypoperfusion on fibrinolysis. They showed that tPA-induced fibrinolysis in vitro was enhanced under acidotic conditions but blunted under hypothermic conditions . This finding supports the rapid reversal of acidosis via adequate resuscitation. It also has important implications for the treatment of hypothermia as these data suggest that quickly stabilizing patients to normothermic conditions could exacerbate fibrinolysis.
The potential role for thrombin-activatable fibrinolysis inhibitor (TAFI) has recently been reported. TAFI is activated by thrombin and downregulates fibrinolysis by removing carboxy-terminal lysine residues on fibrin that are essential binding sites for plasminogen and tPA. Lustenberger et al.[50▪] recently demonstrated the natural history of circulating TAFI activity and antigen levels in trauma patients over time. Interestingly, compared with noncoagulopathic counterparts, patients with TIC had significantly reduced TAFI activity upon admission and out to 8 days later; however, there was no difference in TAFI antigen levels. Admission TAFI activity was inversely correlated with units of RBCs and plasma transfused within 24 h [50▪]. Although this was performed in a small cohort (n = 26), these data suggest that inefficient thrombin generation could mediate downstream deficient TAFI activation and thus inhibition of fibrinolysis. Given the lethality of hyperfibrinolysis and its role in exacerbating TIC, a greater focus on molecular mechanisms driving this phenotype could result in improved diagnostic sensitivity and pharmaceutical interventions.
Current data on the mechanisms promoting TIC highlight the interplay between the components of the coagulation pathway and how dysregulation of one component can have detrimental effects on another, creating a vicious cycle. Therefore, it is critical to establish the timeline of events that precipitate early coagulation dysregulation to minimize exacerbation, magnitude, and duration of TIC and subsequent excessive hemorrhage. There is an urgent need for high-quality data with mechanistic information to improve not only early survival of hemorrhagic shock following TIC, but also long-term, sustained outcomes following recovery from traumatic injury.
Funding was provided by the National Institutes of Health (T32GM008792 to J.C.C.), The State of Texas Emerging Technology Fund and The University of Texas Health Science Center's Center for Translational Injury Research. The authors would like to thank Dr Elaheh Rahbar for her assistance generating illustrations.
Support for this work was provided by the NIGMS T32GM008792, The State of Texas Emerging Technology Fund and The University of Texas Health Science Center's Center for Translational Injury Research.
Conflicts of interest
The authors declare no conflicts of interest.
REFERENCES AND RECOMMENDED READING
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