Historically, trauma mortality has been defined by a trimodal temporal distribution.² The first phase comprises patients with nonsurvivable injury. These injuries result in uncontrollable and nearly instantaneous exsanguinations or catastrophic brain injury. The second phase on the spectrum encompasses the patients who succumb to early hospital death as a result of ongoing, uncorrected hemorrhagic shock or severe brain injury. The late phase of the model defines patients who have had reversible hemorrhage, either by surgical or interventional control, and manageable and correctable coagulopathy, but whose late course is complicated by inflammatory dysfunction and infection stemming from the initial traumatic insult.

The commonest contributor to immediate death after trauma, in both military and civilian settings, remains uncontrolled hemorrhage.³ Seventy-five percent of early deaths, recognized above as phases one and two of the defined model, are due to uncontrolled hemorrhage, but late deaths tend to occur secondary to sepsis and related multiorgan failure to which early bleeding and coagulopathy contribute.⁴, ⁵, ⁶

Recent data have called the classic trimodal distribution into question because it seems that trauma deaths now fall largely within the first two phases.⁷, ⁸ The trimodal distribution is no longer valid because mortality rates are actually increased in the initial hours following the traumatic event, not evenly distributed among three phases. In reality what occurs is a large peak of early deaths, those seen in the first 6 to 12 hours, followed by a tail of later deaths.⁴, ⁹ Several centers even describe an earlier peak, one that occurs within the first 6 hours after injury. Large urban centers agree that few hemorrhagic deaths occur after 24 hours, and fewer patients die of multiorgan failure and sepsis than originally described in the trimodal model¹⁰, ¹¹, ¹² (FIGURE 128.1).

Traditionally, bleeding after trauma was thought to be caused by surgical bleeding, which was then exacerbated by iatrogenic coagulopathy.¹³ This mantra of iatrogenic coagulopathy has been altered and is no longer believed to be the singular cause of continued bleeding once surgical causes have been controlled.¹⁴ Coagulopathy after trauma is now primarily caused by the injury and shock and can be compounded by the lethal combination of dilution, hypothermia, and acidosis and additional iatrogenic influences.¹⁵, ¹⁶

In the past, trauma resuscitation included large volume crystalloid and cold blood product administration, which contributed to dilution and hypothermia. Surgery was expected to control hemorrhage but contributed further to the coagulopathy by worsening the hypothermia and perpetuating the acidosis. Considerable literature exists documenting the detrimental effects of hypothermia, acidosis, and dilution on coagulation and bleeding.¹⁷ From this initial understanding, trauma and resuscitative efforts have evolved to combat these significant players of the downward spiral of coagulopathy and death.

Important to the evolution of the understanding of coagulopathy is the observation that trauma patients with life-threatening injuries who have not received large volume fluid resuscitation still arrive to the hospital coagulopathic. Several groups have explored these observations and coined the term, acute traumatic coagulopathy, or ATC.¹⁴, ¹⁸, ¹⁹, ²⁰ ATC occurs in approximately 25% to 35% of trauma patients nearly immediately after severe trauma and shock, occurs prior to and independent of iatrogenic causes, and remains a primary determinant of poor outcome after severe injury.¹⁸, ¹⁹, ²¹

While the traditional causes of the “lethal triad” of coagulopathy have been known and studied for some time, trauma practitioners have also described a coagulopathy that is independent of acidosis, dilution, and hypothermia. This coagulopathy, termed ATC, appears concurrently in works by Brohi et al.¹⁹ and Macleod et al.¹⁸ in 2003. Brohi et al. reported that one fourth of his study population demonstrated evidence of coagulopathy within 75 minutes of hospital arrival, without having received significant resuscitation volume or suffering acidosis or hypothermia. Patients afflicted with this newly described coagulopathy were four times more likely to die than those with a normal coagulation profile.²² Macleod et al. also demonstrated the relationship of ATC to concurrent tissue injury and shock. ATC is clearly exacerbated and affected by hypothermia, acidosis, and dilutional causes, but it is equally clear that it is a separate entity.

In order to understand ATC, one must be well versed in the function of protein C, which is the main mediator of ATC.²², ²³ Protein C is a serine protease. After minor tissue injury, it is
cleaved to its active form via the complexing of thrombin, thrombomodulin, and the endothelial protein C receptor (EPCR).²⁴, ²⁵, ²⁶ In patients without severe injury who are not coagulopathic, this pathway will downregulate itself from the inherent elevation in thrombin levels that occur after tissue injury. However, in patients with ATC, there is a pathologic response. Protein C is activated to the point of being acutely depleted. Thereafter, this event leads to global inactivation of factors V and VIII and yields an increase in tissue-type plasminogen activator and D-dimer.²² Factors V and VIII are the main cofactors for thrombin and factor X activation, respectively. This derangement, stemming from the depletion of activated protein C (APC), which prohibits thrombin production, is the cornerstone of ATC.

ATC is characterized by prolonged prothrombin time (PT) and/or activated partial thromboplastin time, despite normal and appropriate thrombin production prior to injury.²⁷ As tissue injury progresses at the molecular level, there is a congruent reduction in thrombin in patients who have increasing levels of APC. In the face of tissue injury and hemorrhagic shock, the decrease in thrombin production and the subsequent resultant increase in fibrinolysis cause a proportional coagulopathy that defines ATC.²², ²⁸ While thrombocytopenia and hypofibrinogenemia are clear contributors to hemorrhage and have been separately studied, ATC occurs even in patients with normal fibrinogen levels and platelet counts.²²

It is not well understood why thrombin depletion is seen following severe traumatic injury and shock. It seems counterintuitive because mild tissue injury is known to cause an elevation in thrombin production, which is in contrast to the abrupt decrease seen in the severely injured patient.²⁹ It is believed that ATC is initiated with tissue injury, which exposes tissue factor, thereby inducing the coagulation cascade.¹⁴ In patients who are not in shock, exposure of tissue factor leads to production of thrombin, fibrin deposition, and clot formation. However, in the severely injured patient, hypoperfusion secondary to hemorrhagic shock causes increased expression of thrombomodulin and EPCR on the endothelium while simultaneously activating and then depleting protein C.³⁰ Further augmentation of the coagulopathy of severe injury is the result of decreased activation of the thrombin-activatable fibrinolysis inhibitor, which depletes plasminogen activator inhibitor-1.²², ³¹ Thrombomodulin complexes with thrombin, diverting the normal cleavage of fibrinogen toward the APC and the consequent inhibitory effect on thrombin formation as described above.³²

One protective mechanism to injury is the elaboration of thrombus formation at the site of injury. For reasons still being elucidated, patients in severe shock from trauma develop an exaggerated response of protein C, which prevents local thrombus formation. These complicated mechanistic relationships between injury, shock, and ATC are important avenues of research.

While there are numerous proteins involved in the generation of the traumatic response, protein C is one that is responsible for mediating the late cytoprotective response to injury.³³, ³⁴, ³⁵ Protein C activation is a primary instigator of ATC. Poorly regulated protein C activation, which occurs during the acute traumatic injury or hemorrhagic shock, will eventually deplete the natural baseline levels of protein C that the body otherwise, in physiologic normalcy, depends upon to fight infection and thrombotic complication. This is because, in addition to its anticoagulant effects, protein C has been shown to be cytoprotective and anti-inflammatory.³⁶, ³⁷ This mechanism is derived via its signaling through protease-activated receptor-1 and EPCR.³⁸ Cytoprotective effects of APC can be appreciated when observing their role in the pulmonary system. In patients with persistently low levels of protein C, such as those seen in the trauma population, there is a decrease in capillary endothelial barrier function. This decrease in barrier function, which is thought to be modulated in part by protein C, leads to higher rates of ventilator-associated pneumonia.³⁰, ³⁹, ⁴⁰ There is evidence that similar cytoprotective and anti-inflammatory effects of APC also exist in acute kidney injury.⁴¹

It seems that the phenomenon of early protein C activation, perpetuation of ATC, and eventual depletion of usable protein C may in fact represent one link of hemorrhagic shock to later inflammatory complications seen in the trauma population. The initial APC has an overall detrimental effect of contributing to coagulopathy. Additionally, while inflammatory modulation is helpful in combating the initial stress of injury and shock, the depletion of protein C is further detrimental because it occurs at a time when the patient requires an ongoing stress response and is at risk for thrombotic, inflammatory, and infectious sequelae.
This conundrum may drive investigation to further characterize and modulate these mechanisms in severely injured patients.⁴²

Additional factors that contribute to the ATC are reductions in natural anticoagulants, such as antithrombin and protein S.⁴³, ⁴⁴, ⁴⁵, ⁴⁶ Pharmaceutical hemostatic agents include recombinant factor VIIa (rFVIIa), prothrombin complex concentrate (PCC), and several antifibrinolytics. These hemostatic pharmaceutical adjuncts are used, at times off label, in patients with traumatic coagulopathy. rFVIIa (NovoSeven; Novo Nordisk A/S: Bagsvaerd, Denmark) can be used for rapid correction of coagulopathy induced by Coumadin and may also have a role in the correction of ATC secondary to the association of exposed tissue factor.⁴⁷ There have been two randomized controlled trials using rFVIIa in traumatic hemorrhage, demonstrating a moderate reduction in total units transfused, but no mortality benefit.⁴⁸, ⁴⁹ In addition to reduction in packed red blood cells (pRBCs) and plasma requirements, these studies demonstrated a decreased incidence of multiorgan failure and acute respiratory distress syndrome, which may be attributed to the molecular control of ATC, protein C, and other unknown contributors. While thromboembolic events are thought to be a consequence of factor VII use, these events occurred with similar frequency in the trauma groups receiving rFVIIa and the control group.⁴⁹, ⁵⁰, ⁵¹, ⁵² Interestingly, a subset of patients will see no correction of their PT despite receiving rFVIIa. These patients have a significantly higher 24-hour and 30-day mortality and are considered nonresponders to this agent.⁵³, ⁵⁴

It has also been demonstrated that rFVIIa is impaired by acidosis; “nonresponders” in some studies demonstrate a lower mean pH than those patients who achieved hemostasis with rFVIIa.⁵⁵, ⁵⁶ It is widely understood that the role of rFVIIa in trauma patients has decreased for two reasons: The randomized studies showed no survival benefit, and the iatrogenic resuscitation injury of excessive crystalloid and unbalanced plasma and RBC transfusion is less frequent than in previous years.

PCC was originally developed for hemorrhagic complications of hemophilia B and is rich in factors II, VII, IX, X, and there are several different formulations in use.⁵⁷ It also has a significant role in warfarin reversal because of its composition of vitamin K-dependent clotting factors.⁵⁸ There may be increased thromboembolic risk associated with its use, but this has not been well substantiated.⁵⁹, ⁶⁰ Fries et al. in 2006 corrected coagulopathy in the porcine model with the use of PCC. This model showed that clot formation was enhanced, blood loss decreased, and mortality improved with administration of PCC in uncontrolled hemorrhage.⁶¹ While the indications for use after injury in humans have not been completely delineated, the porcine model and observational study through clinical application are provocative.⁶¹, ⁶², ⁶³

ATC has a well-definable antifibrinolytic component, so it is reasonable to use antifibrinolytic agents as adjuncts in the correction of traumatic hemorrhage. Tranexamic acid (TXA) is an antifibrinolytic that targets the lysine binding pocket of plasminogen and has been shown to significantly improve survival after trauma.⁶⁴, ⁶⁵, ⁶⁶, ⁶⁷ Fibrinolysis is well documented in the trauma patient by the thromboelastogram, indicating a swifter than expected breakdown in clot formation.

In 2010, Shakur et al. published the CRASH-2 study, which randomized trauma patients to receive TXA versus placebo. Allcause mortality was decreased from 16% in placebo to 14.5% in the treatment group, with the risk of death from bleeding significantly reduced and no reported safety issues.⁶⁷ Approximately, 50% of the patients randomized in the study were not transfused any blood products. Unfortunately, when TXA was given more than 3 hours after injury, death rates were increased.⁶⁵, ⁶⁶, ⁶⁷ These data influenced others to carefully examine the use of TXA in the trauma population.

It is now known that a prolonged Ly30 on thromboelastography in a patient in hemorrhagic shock corresponds to a severe state of fibrinolysis and increased mortality.⁶⁴ Higher doses of TXA may lower seizure threshold, and this requires further investigation in trauma patients.⁶⁷, ⁶⁸ Aminocaproic acid, which has not been extensively evaluated in traumatic hemorrhage, is a similar lysine-based plasminogen binding inhibitor. This agent has been shown to decrease hemorrhage during elective surgery.⁶⁵ Its application to the acutely hemorrhaging trauma patient is an interesting avenue of research.