Chapter 13: Trauma-Induced Coagulopathy

Despite advances in emergency medical systems (EMS) and trauma care, deaths from injury have increased in the United States over the last decade.¹ In both the civilian² and military³ settings, uncontrolled hemorrhage is the leading cause of preventable death after injury. In civilian studies, >95% of deaths from hemorrhage occur within the first 24 hours at a median time <3 hours.² Consequently, there is intense interest worldwide in the pathogenesis of trauma induced coagulopathy (TIC), and its early management. While there have been substantial insights, the words of Mario Stefanini in his address to the New York Academy of Medicine in 1954⁴ remain applicable today:

Although transfusion medicine has undergone enormous development over the past 60 years since the challenge issued by Stefanini, important gaps in scientific knowledge persist, and several fundamental issues involving the diagnosis and management of TIC remain controversial. The more we learn about TIC the more we appreciate the contributions of surgical scientists from the past century who had the insight to form the basis of our current understanding of trauma-related bleeding. This chapter will refresh important historical landmarks in our evolution of understanding TIC, synthesize recent investigations into the pathophysiology underlying these processes, and provide a rationale for current diagnostic and resuscitation strategies in these patients.

The evolution of our understanding of the complexities of trauma induced coagulopathy has been, in large part, the result of collaboration between civilian and military teams. The early reports of TIC were generated from military research teams, often including civilian consultants, during major wars. These novel observations would then intensify hemostasis research in civilian centers. Ultimately, the resulting findings improved coagulopathy management in subsequent conflicts, and primed the environment for making new observations. The specific contributions to our understanding of TIC, however, are somewhat difficult to ascertain from World War I through Vietnam because the primary focus was on optimizing shock resuscitation at a time when plasma or whole blood was employed to replace acute blood loss.⁵ Nonetheless, several landmark contributions are well recognized.

In 1916 the US National Research Council formed a subcommittee on traumatic shock that collaborated with the British Medical Research Committee to study wounded soldiers in the front lines of France. Among them was Walton B. Cannon, who was perplexed by the inconsistencies of the prevailing toxin theory of shock. Cannon documented experimentally that stress, that is, epinephrine infusion into animals, provoked hypercoagulability followed by hypocoagulability.⁶ Cannon stated “ … shock is a loss of homeostasis, and without homeostasis the patient does not survive.”⁷ During World War II experts recognized that bottled whole blood would be logistically impractical and enlisted the expertise of Edwin J. Cohen, a biochemist, to deconstruct blood to enable components to be used on the battlefield.⁸ Cohen was successful in purifying albumin as well as preparing plasma. At the onset of World War II, the National Research Council’s Committee on Transfusion recommended that dried plasma—not blood—would be used if combat occurred outside the continental United States because it was easy to prepare and transport; whereas, whole blood had to be typed, cross-matched, and refrigerated. Based on the legendary work of consultant Edward D. Churchill,⁹ who concluded, “wound shock is blood volume loss,” the policy was changed to whole blood administration and implemented in 1943.

During the 1950s civilian investigators recognized impaired coagulation associated with severe injury; the culprits were believed to be fibrinolysis,¹⁰ loss of labile clotting factors,¹¹ disseminated intravascular coagulopathy,¹² and platelet dysfunction.¹³ The labile factor depletion hypothesis was echoed during the Korean War. Scott and Crosby,¹⁴ reported that the prothrombin time (PT) was doubled in combat casualties while platelet count and fibrinogen were increased. Artz and Fitts¹⁵ observed that severely injured soldiers in the Korean conflict required both return of shed blood and crystalloid for optimal survival. The recognition of the high incidence of acute renal failure further stimulated the classical experimental work of Shires et al¹⁶ who demonstrated the accumulation of sodium in hypoxic cells. These studies ultimately lead to the routine practice of initial crystalloid loading for shock resuscitation.¹⁷

During the Vietnam war, crystalloid resuscitation was used in such excess that it lead to iatrogenic lung dysfunction, similar to the civilian description of acute respiratory distress syndrome. The factor depletion component of coagulopathy was proposed by Simmons et al¹⁸ and attributed to a DIC like phenomena. During the 1970s coagulation research in civilian centers began to accelerate; the recurring theme was trauma patients with liver injury bleeding to death despite control of mechanical hemorrhage. From these challenging patients the concept of pre-emptive plasma resuscitation was introduced^19,20; “If the patients remain hypotensive after the second unit of blood—FFP should be administered then and with every fourth unit thereafter” and “fresh whole blood if bleeding persists despite normal PT, PTT, and bleeding times.”²⁰ The bloody viscous cycle, later known as the lethal triad, was introduced in 1981 as it was observed that refractory bleeding was associated with hypothermia, acidosis, and coagulopathy.²¹ The frequent recognition of this scenario lead to the concept of damage control resuscitation in which definitive repair of injuries was delayed in favor of optimizing the patient’s physiologic status.²² Coagulation research during this period was further complicated by the practice of aggressive crystalloid resuscitation targeting supraphysiologic oxygen delivery. This resulted in an epidemic of compartment syndromes and, in retrospect, much of the coagulopathies were generated by overzealous infusion of crystalloid.²³

The first decade of the 21st century represents perhaps the most significant insights into trauma induced coagulopathy in modern history. Progress was unquestionably inspired by the revolutionary concept of the cell-based model of coagulation proposed by Hoffman and Monroe²⁴ who emphasized the fundamental role of platelets as a platform for clotting factor assembly and thrombin generation on damaged endothelium. In 2003, MacLeod et al²⁵ from the University of Miami and Brohi et al from the Royal London Hospital independently reported that 25% of severely injured patients had prolonged clotting times, and this abnormality was independent of fluid administration. Consequently, the London group termed the syndrome, the “acute coagulopathy of trauma” (ACOT).²⁶ Stimulated by his observations of the ACOT, Brohi pursued a trauma research fellowship with Cohen, Pittet, and colleagues in San Francisco. Together, in 2007, this civilian research team provided compelling evidence that activation of protein C was an integral component of ACOT.²⁶ Simultaneous with these provocative civilian findings, the US military analyzed combat casualties in Iraq and concluded that uncontrolled hemorrhage was the predominant source of preventable death.³ Hess et al²⁷ suggested the solution was to replace the lost blood with component therapy that replicated the composition of whole blood, initiating the concept of 1:1:1 (FFP:RBC:platelets). Remarkably in the same year as the protein C hypothesis, Borgman et al²⁸ reported that resuscitation with FFP:RBC approaching 1:1 improved survival. These landmark civilian and military reports prompted a literal explosion of coagulation research. Recognizing the ongoing controversies the Nation Institutes of Health (NIH) responded with a workshop on postinjury hemostasis in 2010, and achieved consensus in renaming this challenge “trauma induced coagulopathy” (TIC).

Cell-Based Model of Hemostasis

Hoffman and Monroe²⁴ enhanced our understanding of the mechanisms of coagulation by shifting from a simple enzymatic cascade to a cell-based paradigm with tightly regulated events (Fig. 13-1). The key concept underlying the paradigm of “cell-mediated hemostasis” is that cells play active roles in regulating and localizing the coagulation reactions. Many cells can participate in hemostasis and thrombosis, but the two critical players are platelets and endothelial cells. This model consists of three overlapping phases: initiation, amplification, and propagation. A breach of the endothelium promotes clot formation via exposed collagen and tissue factor. Collagen localizes platelets via their GP-VI receptor. Circulating von Willibrand factor also binds collagen, and this complex further promotes platelet adherence through their GP-Ib-V-IX receptors, particularly important under high-stress flow. Tissue factor (TF) binds circulating factor VII; the resulting TF/FVIIa complex activates factors IX and X. The initial amount of thrombin generated is insufficient to cleave fibrin, but activates platelets through their PAR 1 and 4 receptors and also activates factors V and VIII. In the ensuing amplification phase, these activated factors form the prothrombinase (Va/Xa) and tenase (VIIIa/IXa) complexes on the surface of platelets. Tenase (VIIIa/IXa) generates sufficient amounts of factor Xa to support thrombin generation through prothrombinase (Va/Xa). These coagulation complexes require phospholipid and calcium for their activity. Prothrombinase and tenase then potentiate the “thrombin burst” in the propagation phase, which cleaves fibrinogen. The resulting fibrin polymerizes and integrates platelets by binding via their GP-IIb-IIIa receptors. This thrombin further generates Va and VIIIa for prothrominase and tenase assembly, and activates XIII which cross-links fibrin to stabilize the evolving clot. Activated platelets release adenosine diphosphate (ADP) and thromboxane A2 (TxA2) that further recruit platelets to form an outer shell to stabilize the clot (Fig. 13-2). The various proteins known to be active in the clotting system are summarized in Table 13-1.

Impaired Clot Formation (Part I)

Activated Protein C

The activated protein C (APC) pathway attenuates coagulation activation, serving as a critical anticoagulant restraint on the multiple physiologic processes that promote clot formation. Independent of these anticoagulant properties, APC has been shown to have multiple cytoprotective effects as well, acting as an anti-inflammatory agent and preventing endothelial barrier leakage.²⁹ By these two mechanisms, the APC pathway serves to maintain vascular flow by preventing excessive thrombosis, and also protects cells from damage associated with inflammatory insults, such as sepsis and trauma. Once activated, APC achieves its primary anticoagulant function through proteolytic cleavage of activated factors Va and VIIIa, the major drivers of thrombin formation.³⁰ Activation of protein C is achieved via thrombin-mediated cleavage.³¹ Following injury, thrombin binds to upregulated thrombomodulin activating the endothelial receptor for protein C (ERPC) culminating in the release of protein C (Fig. 13-3). Thrombomodulin can increase this activity by 20,000-fold.³² Thrombomodulin is a transmembrane protein that is found predominantly on the surface of endothelial cells, and in heavy concentration in microvasculature.³³ Protein S also increases activated protein C complex adherence to the phospholipid membrane, further enabling the more efficient inactivation of factor Va.³⁴ Recently Mann et al have shown that meizothrombin released from stored RBC can also bind to thrombomodulin and activate protein C.³⁵

As previously mentioned, data from the San Francisco general group suggested that APC has a central role in pathogenesis of TIC. The hypothesis is that this event is related to an evolved but maladaptive response to severe injury. In the setting of severe trauma and tissue hypoperfusion, an excess of protective anti-inflammatory APC is released in an attempt to prevent local microvascular thrombosis and mitigate cellular dysfunction. This view is supported by data from a trauma cohort demonstrating that poor outcomes associated with increased levels of inflammatory histones are abrogated by simultaneous increases in endogenous APC, implying a protective effect of APC in the setting of widespread inflammation.³⁶

Autoheparinization from Glycocalyx Degradation

Shortly after the proposed role of APC in TIC, Johansson et al³⁷ from Copenhagen added evidence implicating endothelial glycocalyx degradation, emphasizing the endotheliopathy component of TIC. The vascular endothelium comprises a single layer of cells that line blood vessels and lymphatics in every organ, covering a surface area of 4000–7000 m² with a weight of 1 kg.³⁸ The luminal surface of the endothelial cells is covered by a 0.2–1.0 μm thick negatively charged carbohydrate-rich surface layer, the endothelial glycocalyx, that represents a large structure in the vascular system by containing a fixed noncirculating plasma volume of approximately 1 L in adults, corresponding to one-third of the vascular plasma volume.³⁸ The glycocalyx is an antiadhesive and anticoagulant structure that protects endothelial cells and maintains vascular barrier function.³⁹ It is bound to the underlying endothelial cells through various backbone molecules of proteoglycans (the most abundant are syndecan-1 and glypican) and glycoprotein. The proteoglycans have long glycosaminoglycan side-chains comprised mainly of heparan sulfate that has heparin-like functions.³⁹ Glycocalyx damage can range from discrete disturbances in the composition of the most luminal layer to degradation with loss of the entire glycocalyx. Upon shedding, the glycocalyx glycosaminoglycans retain their anticoagulant (heparin-like) activity and promote measurable hypocoagulability in the circulating blood through endogenous auto-heparinization.³⁹ Rehm et al⁴⁰ provided the first evidence of acute destruction of the endothelial glycocalyx in patients undergoing vascular surgery associated with ischemia/reperfusion injury. This study reported that syndecan-1 and heparan sulphate levels increased after ischemia/reperfusion injury during vascular surgery and that this increase correlated to shedding of glycocalyx as detected by electron microscopy. Despite 40- to 60-fold increases in syndecan-1 postischemia, the levels of the classical endothelial adhesion molecules ICAM-1 and VCAM-1 did not change, emphasizing the occurrence of selective glycocalyx disruption. Johansson et al⁴¹ translated these observations to trauma when his group demonstrated reversibility of prolonged clotting time by heparinase-TEG in critically injured trauma patients. These patients had syndecan-1 levels four-fold higher than noncoagulopathic patients in this study in addition to a higher injury severity and transfusion requirements.

DIC and Consumptive Coagulopathy

The role of disseminated intravascular coagulopathy (DIC) in depleting circulating clotting factors resulting in impaired thrombin generation remains debated.⁴² Theoretically the distinction is that DIC occurs within the vessel lumen; whereas, consumption occurs from disrupted endothelium exposing tissue factor bearing calls and collagen. Most investigators do not believe DIC is a dominant mechanism in TIC, but acknowledge its potential contribution. The innate immune response to injury has been implicated in the genesis of DIC, particularly with the release of damage-associated molecule patterns (DAMPS). But beyond increased tissue factor expression on monocytes and microparticles, the mechanism remains unclear. Among those with procoagulant implications are HMBG₁, histone DNA complexes⁴³, and polyphosphates.⁴⁴ Additionally, neutrophils are believed to contribute to a procoagulant state via degranulation of elastase, which can act as an indiscriminate protease.⁴⁵ Finally, with extensive tissue disruption, there is undoubtedly some element of coagulation factor consumption to achieve hemostasis.

Hypothermia and Acidosis

Hypothermia and acidosis are no longer considered the primary drivers of TIC, but they can become secondary events that complicate the management of coagulopathy. In vitro⁴⁶ and in vivo⁴⁷ work suggests that hypothermia affects hemostasis when the temperature is below 33°C. Below this temperature, hypothermia inhibits the initiation phase of clotting. This would be anticipated as most of the coagulation enzymes are slowed by hypothermia. Thus while moderate hypothermia delays the onset of thrombin generation, the total amount of thrombin generation is unaffected.^46,47 The effect of hypothermia on platelet function is contradictory due to limitation in the ability to replicated platelet function under physiologic conditions.⁴⁸ Some studies indicate enhanced platelet activation (priming) and aggregation,^49,50 while others indicate decreased adhesion and aggregations.⁴⁶ Profound hypothermia has been long recognized for promoting hepatic sequestration of platelets, but the clinical relevance outside of cardiac surgery is minimal, as a temperature below 30°C is needed for this phenomenon.

Metabolic acidosis has a more profound effect on TIC than hypothermia at clinically relevant levels.^47,51 A reduction of pH from 7.4 to 7.0 has been shown in vitro to reduce FVIIa activity by 90%, prothrombin complex (Xa/Va) activity by 70%, and FVIIa-TF complex activity by 55%.⁵² In vitro work has confirmed a pronounced inhibition of the propagation phase of thrombin generation at a pH of 7.1, resulting in a marked reduction in clot strength.⁴⁷ These studies also suggest this degree of acidosis increases fibrinogen degradation two-fold. While impaired platelet aggregation and adhesion at a pH of less than 7 has been appreciated for decades, more recently the mechanism has been elucidated and associated to the store-operated calcium entry (SOCE) channels. Perhaps more worrisome, the correction of pH with bicarbonate⁴⁷ or tris-hydroxymethylaminomethane (THAM)⁵³ does not restore platelet function. This may have implications for the optimal timing of platelet transfusion in the critically injured patient.

Hemodilution

Hemodiution is no longer considered the dominant mechanism for TIC, but overzealous crystalloid resuscitation can exaggerate an existing coagulopathy. Reduced levels of coagulation proteins have been documented in healthy volunteers after administration of crystalloids, colloids, and stored RBCs,⁵⁴ and remains a fundamental rationale for permissive hypotensive resuscitation (see Chapter 12). Interestingly, acute hemodilution to 50% in vitro does not impair clot formation,⁵⁵ but this magnitude of hemodilution enhances the sensitivity to tPA due to the dilution of endogenous antifibrinolytics.⁵⁶

In sum, impaired clot formation is central in the pathogenesis of TIC, but the mechanism is complex and time dependent, and can be exacerbated by hypothermia, acidosis, factor consumption, and hemodilution (Fig. 13-4).

Phenotypes of TIC

With the multiple mechanisms that drive TIC, it is not surprising that patients manifest coagulopathy for different reasons, and thus, represent unique phenotypes of coagulopathy warranting patient specific management. Trauma is a combination of tissue injury and shock, and no two patients have an identical injury mechanism and degree of shock. These variables in combination with genetic variability, preexisting medical conditions, and age-related changes in coagulation make every trauma patient unique when they arrive at the emergency department. In the early description of TIC, two components were proposed: (1) impaired blood clot formation (hypocoagulation) and (2) increased clot degradation (hyperfibrinolysis).²⁶ These two processes appear to be mechanistically unique based on principal component analyses, which also implicate a third mechanistic variant of coagulopathy.^56,57 To make it more complicated, the extremes of the phenotypes can be pathologic. Recently it has been identified that trauma patients can present with a spectrum of fibrinolysis within 12 hours of injury and those patients on either extreme with excessive or impaired fibrinolysis have increased mortality (Fig. 13-5).⁵⁸

Stafford’s review on fibrinolysis and hemostasis in 1964⁵⁹ established a logical understanding for why coagulation becomes pathologic: “a general assumption has developed that clotting is not episodic but a continuous process which is normally never allowed to progress to a physical end point.” In the previous section we stressed that APC and the gylcocalyx serve physiologic functions to localize thrombin generated clot, and that fibrinolysis serves a physiologic role to control clot burden. The recurring theme of biologic systems becomes apparent in TIC that coagulation is a balance and preventing the extremes should be the resuscitation goal.

Dysregulation of Fibrinolysis (Part II)

Hyperfibrinolysis

Although proposed in 1948,¹⁰ during the 1960s a number of investigators emphasized that fibrinolysis was a physiologic process to counter balance thrombosis and was occurring perpetually.^60,61,62 Fibrinolysis is the active degradation of polymerized fibrin through the lysine avid binding protease plasmin.⁶³ The conversion of plasminogen to plasmin is accomplished by proteolytic cleavage by one of its activators (tissue plasminogen activator/tPA or urine-type plasminogen activator/uPA). Plasmin activity is highly dependent on its local environment, and its proenzyme plasminogen binds numerous receptors indicating the process occurs on cell surfaces and not in circulation.⁶⁴ The regional distribution of specialized endothelial cells contributory to the fibrinolytic system is reflective of the importance of localizing this process.⁶⁵ The primary driver of intravascular fibrinolysis, tPA, is released from precapillary arteriole and postvenular endothelial cells; uPA is considered a secondary source derived from epithelial cells but its relative importance is likely tissue specific. Release of tPA into the circulation results in complex formation with its most abundant serine protease inhibitor, plasminogen activator inhibitor 1 (PAI-1), and secondary inhibitors such as C-1 inhibitor. These tPA complexes are cleared by the liver.^66,67 There are a number of additional proteins present in plasma that either inhibit tPA directly, inhibit plasmin, or impair plasmin access to fibrin (Fig. 13-6). These proteins are normally in relatively high abundance in the plasma including α-2 antiplasmin (α-2AP), α-2 macroglobulin, α-1 antitrypsin, and histidine rich glycoprotein.⁶⁸ In addition there are potent inhibitors integrated into the fibrin clot, including α-2AP and thrombin-activatable fibrinolysis inhibitor (TAFI), which are directly released from platelets to ensure a tight regulation of the system. TAFI cleaves lysine binding sites on fibrinogen, inhibiting plasminogen and tPA binding. Plasma can buffer the effects of tPA in vivo,⁵⁶ and in vitro exogenous tPA mixed in whole blood of healthy volunteers requires supraphysiologic concentrations to reproduce hyperfibrinolysis.⁶⁹ While fibrinolysis is constitutively occurring at a microvascular level to maintain vascular patency, pathologic systemic hyperfibrinolysis is the result of not only an increase in circulating tPA, but also a reduction of its circulating inhibitors.

Interest in fibrinolysis as a component of TIC was stimulated by the proposal of Brohi et al²⁶ who suggested activated protein C degraded PAI-1. However, recognition of systemic fibrinolysis following injury did not occur until the widespread use of viscoelastic assays. Recent clinical studies indicate that systemic hyperfibrinolysis occurs in 2–5% of critically injured patient and 10–15% of those requiring a massive transfusion.^{59,69,70,71,72} In our experience, the highest rate of hyperfibrinolysis in trauma occurs in those undergoing ED resuscitative. Currently, the only established mechanistic factor for hyperfibrinolysis is inadequate tissue perfusion, suggested by a number of retrospective studies^{59,69,70,71,72} and further strengthened by the fact that the patients in the CRASH II trial who benefited from antifibrinolytics had a systolic blood pressure less than 75 mm Hg.⁷³ Supporting this observation is that blood taken from patients who have nontraumatic cardiac arrest have a high prevalence of hyperfibrinolysis.⁷⁴ Shock may also generate metabolic disturbances that enhance fibrinolysis. For example, taurocholic acid increases fibrinolysis in vitro and is markedly elevated following shock.⁷⁵ Recent animal work indicates that tPA levels increase substantially in animals undergoing hemorrhagic shock, while tissue injury does not increase systemic tPA levels.⁷⁶

Fibrinolysis Shutdown

The mortality rate of injured patients with impaired fibrinolysis (shutdown) has been reported to be nearly four times greater than patients with a physiologic level of fibrinolysis.⁷³ Death is primarily attributable to organ failure. The term fibrinolysis shutdown was first used in 1969⁷⁷ in a review describing the effects of electroplexy, myocardial infarction, and elective surgery on fibrinolysis. Animal work prior to this time suggested microemboli in visceral small vessels leads to irreversible shock that was later found to be survivable with a profibrinolytic.⁷⁸ Hardaway further translated these findings to humans and implicated trauma and shock in producing microvascular occlusion.⁷⁹ Confusion arises as the nomenclature of describing impaired removal of vascular thrombi is often referred to as either the syndrome of disseminated intravascular coagulation (DIC) or pathologic impairment of fibrinolysis (shutdown). As mentioned previously, some investigators consider DIC to have two distinct phenotypes; that is, hyperfibrinolysis and fibrinolysis shutdown,⁴² which is somewhat difficult to reconcile as diffuse intravascular thrombus should not exist in the presence of systemic hyperfibrinolysis.

It is well known that trauma patients are prone to thrombotic events. The prevalence has been reported to approach 60% when screening for postinjury venous thrombosis.⁸⁰ There is evidence for thrombosis in the pulmonary vasculature in nearly one in four seriously injured patients within 48 hours of their injury.⁸¹ Furthermore, microvascular clot has been implicated in organ dysfunction.^82,83 Therefore, it is intuitive that maintaining adequate fibrinolysis to clear the microvasculature of excessive fibrin deposition would be beneficial.

Acute lung injury models using mustard gas have implicated PAI-1 in addition to other antifibrinolytics (α-2AP and TAFI) as culprits in progression to pulmonary failure.⁸² Fibrinolysis inhibition is more common after trauma than hyperfibrinolysis. In 1991, Enderson et al described that the majority of multisystem trauma patients in their study had elevated d-dimers but low fibrinolysic activity.⁸⁴ Subsequently, Raza et al⁸⁵ showed minimal fibrinolysis activity measured by rotational thromboelastometry (ROTEM) and high plasmin-antiplasmin (PAP) complexes in 57% of their patients. The circulating half-life of PAP is 12 hours. Most recently we demonstrated that 65% of severely injured patients had suppressed fibrinolytic activity measured by TEG.⁶⁰

In sum, enhanced clot degradation (hyperfibrinolysis) (Fig. 13-6) can be a major component of TIC, but the incidence is relatively low and the underlying mechanisms remain unclear. On the other hand, impaired fibrinolysis (shutdown) is present in the majority of severely injured patients and may result in microvascular occlusion and organ dysfunction.

Platelet Dysfunction (Part III)

Platelet Role in Hemostasis

Platelets are anucleated cells fragments from megakaryocyte (MK). Maturation of platelets occurs in two phases.⁸⁶ The first phase is MK maturation in the bone marrow that takes several days. In the second phase mature MKs grow pedicles that project into the sinusoids of bone marrow blood vessels and fragment into circulation as platelets, a process that only requires several hours. The circulating count of platelets in normal subjects is around 250,000/mcL with a half-life of 9 days, representing a turnover rate of 35,000 platelets per day.

Successful hemostasis requires the rapid accumulation of platelets to occlude the site of blood extravasation (Fig. 13-7). In animal models, platelets can seal a small wound in ~30 seconds, and within minutes form a fibrin rich core.⁸⁷ Contracted platelets free of fibrin have decreased permeability. This work suggests that activated platelets serve as the primary sealant with fibrin acting as a secondary stabilization of the platelet plug. In addition, platelets form a complex around fibrin clots that provides a unique microenvironment that is both prothrombotic and antifibrinolytic.^88,89 Therefore platelets have multiple roles in initiating and maintaining hemostasis. This interplay of platelet auto and paracrine signaling from release of granules and the local environment optimize clot formation and resist degradation.

Effects of Trauma on Platelet Dysfunction

Endogenous activators of platelets have been well characterized in both the arterial and venous system with a focus on collagen and thrombin that work in conjunction with platelet released ADP and thromboxane. However, the precise roles of these platelet activation pathways during TIC are not well defined. Interestingly, the TIC patient is more likely to display platelet dysfunction as opposed to platelet consumption.^90,91 Platelet dysfunction occurs early after injury, and has been documented with isolated traumatic brain injury.⁹² In the context of TIC, the molecular definitions of the desensitized, stunned, inactive, postactivated, dysfunctional, degranulated, or exhausted platelets are still emerging. For example, damage associated molecular pattern molecules (DAMPs) have been shown to bind the toll-like four receptor of platelets and promote coagulopathy.⁹³ Circulating platelets may experience combinations or sequential exposures of agonists to trigger modes of activation as indicated by shape change, degranulation, and receptor expression, activation or shedding.

Traditional Laboratory Tests

Lack of an accurate tool to identify and track coagulopathy remains a major limitation surrounding both postinjury hemostatic derangements and empiric blood component replacement therapy. Traditional laboratory tests of coagulation function, such as PT and PTT, were designed originally for the assessment of coagulation function with isolated factor deficiencies in hemophiliacs, and are based on the interaction of the coagulation factors in isolation. To date, the performance characteristics of these tests in the trauma patient remain unproven. Furthermore, a prohibitive amount of time (30–45 minutes) is required to conduct these assays. Because both the PT and PTT are performed on platelet-poor plasma, they are sensitive only to the earliest initiation of clot formation (estimated to represent 5% of the thrombin generation during clot formation) and do not incorporate platelet function. Finally, these tests are performed in an artificial environment, irrespective of the patient’s core body temperature and pH. Measurements of individual clotting factors and related proteins, such as protein C, are both costly and time consuming. Diagnosis of fibrinolysis is also problematic. The euglobulin lysis time is a complex and time-consuming procedure that can take more than 180 minutes, reduces some of the inhibitors, and does not include platelets that regulate fibrinolysis. Other techniques suggested to identify hyperfibrinolysis, such as plasmin–antiplasmin complex, fibrin monomers, and d-dimers, are only reflective of the footprint of fibrinolysis; that is, they do not represent the patient’s current systemic fibrinolytic activity. Thus, partitioning the components of a patient’s blood and testing them independently in an artificial environment that requires a lengthy assay time is not clinically optimal to manage coagulopathy in the critically injured patient.

Viscoelastic Hemostatic Assays

In response to the shortcomings of conventional measurements of coagulopathy, point-of-care, viscoelastic hemostatic assays are emerging as the standard of care for both the diagnosis and treatment of postinjury coagulopathy in many trauma centers throughout the world. Viscoelastic assays quantify whole blood clot formation and degradation based on the resistance created by liquid blood solidifying and degrading after reaching maximum strength. The time and rate to achieve output of the device correlate with coagulation factor status, fibrinogen function, platelet function, and quantify fibrinolysis. Interpretation of the two most clinically employed viscoelastic assays is described in the following discussion.

Thrombelastography (TEG)

The various components of the thrombelastography (TEG) tracing are depicted in Figure 13-8, and the viscoelastic output measured by TEG is summarized in Table 13-2. The rapid TEG is designed to provide the quickest results by using both extrinsic (tissue factor) and intrinsic (kaolin) pathway activators. The down side of maximizing clot initiation is the resulting amplification of the coagulation system, which may mask more subtle changes in coagulation particularly in the hypercoagulable setting or when quantifying fibrinolysis. Kaolin activation is used for the later indications. A native TEG is performed without activators after recalcifcation. The reaction time (R, minutes) is defined as the time elapsed from the initiation of the test to the point where the onset of clotting provides enough resistance to produce a 2-mm amplitude reading on the TEG tracing.⁹⁴ Of note, in the R-TEG assay (discussed below), due to the acceleration of clotting initiation, the R time is represented by a TEG-derived activated clotting time (TEG-ACT). The R time and TEG-ACT are most representative of the initiation phase of clotting due to enzymatic factors. A prolonged R time or TEG-ACT is diagnostic of hypocoagulability; whereas shortened times suggest hypercoagulability. The alpha-angle (α, degrees) is the angle formed by the slope of a tangent line traced from the R to the time required to reach 20-mm amplitude (k time) measured in degrees. Alpha-angle represents the rate at which the clot strengthens and is most representative of thrombin’s cleavage of available fibrinogen into fibrin. The maximum amplitude (MA, mm) is the point at which clot strength reaches its maximum on the TEG tracing, and reflects the end result of maximal platelet–fibrin interaction and is often used to guide platelet transfusions. The LY30 variable represents the percent of clot degradation 30 minutes after the clot reaches MA, and is used to quantify fibrinolysis. The functional fibrinogen (FF-TEG) assay is a more specific method to quantify fibrinogen levels, and is performed by using a monoclonal antibody to glycoprotein IIb-IIIa to eliminate the contribution of platelets to clot strength.⁹⁵ One of the limitations of the viscoelastic assay is the generation of abundant thrombin which masks the effects of antiplatelet therapy or potential platelet dysfunction by activating platelets via the robust protease activating receptors (PAR) 1 and 4. In order to quantify platelet dysfunction, a platelet mapping assay (PM-TEG) relies on heparin to eliminate thrombin activation and employs reptilase and FXIII to cross-link fibrin and, thus, eliminate the fibrin contribution to clot strength. The contribution of the P2Y12 or thromboxane receptors to clot formation are measured by the addition of adenosine diphosphate (ADP) or arachidonic acid (AA) respectively. There are additional TEG variables that are not routinely used clinically which also provide information on clot strength and fibrinolysis that are, at this time, mostly used in experimental work.

Rotational Thromboelastometry (ROTEM)

Rotational thromboelastometry (ROTEM) is the other commonly employed viscoelastic assay,⁹⁶ and is based on the same fundamental principles as TEG. Consequently, the graphical output appears similar to that obtained with TEG (Fig. 13-9). In the TEG system, the sample cup oscillates and a pin on a torsion wire is suspended in the blood sample. In the ROTEM system, the sample cup remains fixed while the pin oscillates. ROTEM and TEG provide essentially the same information on clot formation kinetics and strength (Table 13-2). EXTEM is activated with tissue factor (external) and INTEM with ellagic acid (internal). FIBTEM is a modified EXTEM with the added platelet inhibitor cytoclasin D to provide an estimate of functional fibrinogen,⁹⁷ and APTEM is a modified EXTEM with the addition of TXA to guide antifibrinolytic therapy. The NATEM is recalcified without activators. Another assay, approved in Europe, is ECATEM using the viper venom ecarin (prothrombin activator) to measure the effect of direct thrombin inhibitors. Because of differences in operating characteristics, the results of ROTEM and TEG are not interchangeable. Furthermore, the two tests use different nomenclature to describe the same variables although the sensitivity of TEG and ROTEM variables to detect coagulopathy is comparable.⁹⁸ Limits of agreement between TEG and ROTEM variables from multiple institutions has been reported. But newer generation TEG and ROTEM devices, currently undergoing clinical validation for FDA approval, are operator independent and, thus, will provide more consistent output.

Clinical Implementation of Viscoelastic Hemostatic Assays

A recent prospective randomized trial has shown that viscoelastic assays are superior compared to PT/INR, aPTT, platelet count, and fibrinogen level for the management of TIC.⁹⁹ Furthermore, a retrospective cohort study indicated that viscoelastic assays are better than a fixed ratio (1:1:1) strategy.¹⁰⁰ TEG is also capable of detecting hypercoagulability (increased MA), whereas the PT and aPTT do not.¹⁰¹ Perhaps the greatest advantage of viscoelastic assays is to individualize management of patients based on their phenotype of TIC. Considering the diverse mechanisms driving TIC (Figs. 13-3 and 13-6), severely injured patients manifest unique patterns of TIC.^57,58 Patients with predominately impaired thrombin generation have a prolonged R and low MA. Depressed MA has been associated with an increased risk of bleeding and mortality.^102,103,104 The ROTEM A5 (5 minutes after clot initiation) and A10 have also been accurate in early identification of patient with advanced TIC.^105,106 The hyperfibrinolytic phenotype has also been identified with TEG using the LY30 parameter and associated with high mortality.^70,71,72 New devices using microfluiditics on surfaces replicated injured endothelium and shear stress may further refine patient specific transfusion needs.¹⁰⁷

Blood Components

Red Blood Cells Transfusion

Red blood cell (RBC) transfusion is lifesaving in the setting of critical anemia associated with hemorrhagic shock. However, the optimal target hematocrit during resuscitation remains unknown (see Chapter 12). Elimination of oxygen debt involves optimization of oxygen delivery, which is the product of cardiac output and arterial oxygen content. The arterial oxygen content, in turn, is dependent primarily on the hemoglobin concentration and oxygen saturation. During resuscitation, a balance must occur between the competing goals of maximal oxygen content (hematocrit = 100%) and minimal blood viscosity (hematocrit = 0%). Furthermore, beyond a role in oxygen delivery, erythrocytes are integral to hemostasis via their involvement in platelet function as well as thrombin generation. The hematocrit is thus relevant to hemorrhagic shock as it relates to both oxygen availability and hemostatic integrity. As the hematocrit rises, platelets are displaced laterally toward the vessel wall, placing them in contact with the injured endothelium; this phenomenon is referred to as margination. Platelet adhesion via margination appears optimal at a hematocrit of 40%.¹⁰⁸ Erythrocytes are also involved in the biochemical and functional responsiveness of activated platelets. Furthermore, RBCs participate in thrombin generation through exposure of procoagulant phospholipids and generation of meizothrombin.³⁵ Interestingly, animal studies suggest that a decrease of the platelet count of 50,000 is compensated for by a 10% increase in hematocrit.¹⁰⁹ At this point we continue to target a hemoglobin >10 g during hemorrhage control.¹¹⁰

Plasma Transfusion

As discussed previously, the role of preemptive plasma transfusion was introduced in the late 1970s to manage coagulopathy associated with major liver injuries.^19,20 Several decades later Borgman et al²⁸ evaluated the military data and identified that a high ratio of plasma to red blood cells (RBC) has a survival advantage. This report prompted ongoing debate in civilian setting in regards to the optimal ratio of empiric ratios of plasma to RBC.¹¹¹ Plasma is obtained via whole blood centrifugation or apheresis. Despite plasma’s acellular composition, this blood product contains hundreds of biologically active proteins that have marked variability between individuals.¹¹² While blood banks have minimal requirements for concentrations of certain coagulation factors, it is becoming clear that not all plasma is the same. AB plasma is the universal donor, but it is limited in supply as less than 2% of the population qualify as donors. Appreciation of the calcium binding capacity of transfused plasma is essential to prevent iatrogenic hypocalcaemia which exacerbates coagulopathy. Pooled plasma with pathogen reduction, such as OCTAPLAS and UNIPLAS, may find a role into early plasma resuscitation in trauma patients as they have a more standardized composition and do not require the calcium-chelating anticoagulant citrate.¹¹³

Plasma containing the highest concentration of coagulation factors is referred to as fresh frozen plasma (FFP) that represents plasma frozen at –18°C within 8 hours of blood draw. Alternatively, plasma can be frozen within 24 hours and called FP24, which has a small reduction in coagulation factors. Frozen plasmas require 20–40 minutes to dethaw prior to transfusion by convention devices. For this reason many trauma centers have pre-thawed plasma available in the ED. Thawed FFP is required to be transfused within 24 hours or relabeled becomes relabeled as thawed plasma. Thawed plasma can be stored at 4°C for up to 5 days, and can still be useful in the setting of trauma resuscitations. Thawed plasma retains many functioning proteins but is depleted of the more labile factors V, VII, and VIII.¹¹⁴ In plasma resuscitation, it is important to appreciate that patients are receiving more than just coagulation factors. Plasma contains abundant proteins with diverse regulatory functions related to inflammation, coagulation, and fibrinolysis, in addition to being an effective colloid. The levels of these proteins have high variability person to person and between sexes.¹¹² Plasma first resuscitation in animal models has been shown to repair the endothelium,¹¹⁵ improve platelet function,¹¹⁶ and attenuate fibrinolysis.⁵⁶ While it remains a challenge to transfuse plasma in the prehospital setting at the moment,¹¹⁷ lyophilized plasma is currently licensed in France and Germany, and are being developed for FDA approval in the United States. Historically the problem with these products in WW II was hepatitis B, but now it is hepatitis C.

Cryoprecipitate/Fibrinogen Replacement

Fibrinogen levels are decreased early after injury in coagulopathic trauma patients (<1.5 g/L in 15%, <1.0 g/L in 5%, and <0.5 g/L in 2%). Although plasma units contain fibrinogen, its low concentration requires a large volume of transfusion; hence, cryoprecipitate has remained the main source of fibrinogen supplementaion in the United States. Cryoprecipitate also contains factor VIII, von Willebrand factor, fibronectin, factor XIII, and platelet microparticles, in addition to the fibrinogen. Recently, European experience has suggested that the use of recombinant fibrinogen concentrate is effective in the management of TIC. Each 10 unit pool or fibrinogen contains approximately 5 g of fibrinogen or a median 500 mg per unit. Most trauma centers administer fibrinogen dosed by 10 unit pools (1 fibrinogen “pack” = 10 pooled units). A 10 pooled unit of fibrinogen transfusion is expected to increase fibrinogen by 0.5–0.9 g/L; however, dose response may vary in the setting of ongoing bleeding and may require redosing. Several retrospective studies in trauma patients, civilian and military, suggest that more aggressive use of fibrinogen replacement improves outcome.^118,119,120 Consensus guidelines recommend a fibrinogen threshold of >1.5–2.0 g/L for transfusing for hemostasis.¹²¹ Recent studies using a viscoelastic assay to administer cryoprecipitate as part of a goal-directed transfusion strategy use the alpha angle or FF assay of TEG or FIBTEM of ROTEM as a trigger for transfusion. Randomized clinical trials are underway to evaluate the impact of empiric cryoprecipitate administration on outcomes in patients requiring massive transfusion, as well as prehospital administration of cryoprecipitate. Label indications for recombinant fibrinogen concentrate use in Europe allow for its use both in congenital and acquired coagulopathies (such as TIC); however, in the United States, its use is restricted to congenital coagulopathies. Cryoprecipitate has been removed from most blood banks in Europe due to transfusion-related infectious concerns given that transfusion of one dose (or “pack”) of cryoprecipitate exposes the patient to 10 random donors; hence, the surge in use of fibrinogen concentrate in Europe. To date, retrospective reviews of the use of fibrinogen concentrate in trauma patients suggest it has been associated with reduced blood product requirement, but no conclusions can be drawn on the impact on mortality.

Platelet Transfusion

Before the development of platelet concentrates in the second half of the 20th century, platelets were administered through whole blood transfusion. When blood component therapy became the standard, transfusion of platelets focused on treating thrombocytopenia; in trauma this was often the result of dilution from crystalloid and RBC transfusion. But platelet dysfunction has been shown to occur following injury despite platelet numbers exceeding these traditional threshold levels.^71,72,73 The strategy of early transfusion of hemostatic blood components has improved outcomes after injury; however, whether this is due to the early administration of platelets or of plasma is difficult to distinguish. Perkins et al¹²² reported that platelet administration was independently associated with survival in combat casualties. In a review of civilian trauma patients requiring transfusion of ≥5 RBC units in 24 hours, Brasel et al¹²³ reported that a higher ratio of platelets:RBC (≥1:2) units was independently associated with improved 30-day survival among patients with TBI, while a higher ratio of plasma:RBC (≥1:2) units was independently associated with improved 30-day survival only in non-TBI patients. On the other hand, more recent data suggest presumptive platelet administration does not improve outcome for patients with blunt TBI.¹²⁴ Holcomb et al¹²⁵ reported that in civilian trauma patients transfused ≥10 RBC units in 24 hours, using a time-dependent analysis of survival, a higher plasma:platelet:RBC unit ratio (≥1:1:2) was associated with improved survival, compared to lower ratios. However, survival was not significantly different between patients with lower plasma but higher platelet to RBC unit ratio and higher plasma but lower platelet to RBC unit ratio. A drawback of these retrospective studies is that the collinearity between plasma and platelet ratios obscures the relative contribution of each component to patient outcomes. This is further compounded by the fact that all platelet concentrates are suspended in plasma; for apheresis platelets, each unit contains one unit of plasma. The recent multicenter randomized control trial PROPPR (pragmatic randomized optimal platelet and plasma ratios) to assess the impact on survival of 1:1 versus 1:2 FFP:RBC did not show a benefit for a higher ratio of PLT:RBC.¹²⁶ Perhaps one of the reasons for conflicting results is the timing of platelet administration. Previous experimental work indicates that platelets given to acidotic animals are irreversibly impaired.⁵³ Finally, to add to the confusion, there is evidence that cold stored platelets may be superior for reversing coagulopathy.¹²⁷

Warm Fresh Whole Blood

After the introduction of whole blood fractionation into blood components for clinical use in the late 1970s, several civilian trauma centers continued to transfuse warm fresh whole blood for severely injured patients with a refractory coagulopathy.²⁰ This concept was resurrected in the recent military conflict in Iraq, where plasma and platelets where not immediately available.¹²⁸ The concept of fresh whole blood transfusion is becoming the international standard for far forward care,¹²⁹ and the reported experience suggests it warrants reconsideration in the civilian setting.

Hemostasis Adjuncts

Prothrombin Complex Concentrate

Prothrombin complex concentrate (PCC) contains the vitamin K-dependent coagulation factors II, VII, IX, and X, as well as the anticoagulants protein C and protein S. As such, its main indication is for rapid reversal of the anticoagulant effects of warfarin in bleeding patients. Importantly, PCC provides these factors in a concentrated form as compared to FFP (approximately 50 mL vs 300 mL, respectively). The efficacy of PCC for urgent reversal of warfarin reversal in the perioperative period has been well documented,¹³⁰ and use in this setting has been recommended by expert panels in the United States and Europe. The role of PCC in the bleeding patient not on anticoagulants continues to be studied. Bruce and Nokes¹³¹ reported favorable outcomes following PCC administration for uncontrolled hemorrhage following cardiac surgery, exclusive of warfarin use. Several animal studies of hemodilutional coagulopathy have reported superior achievement of hemostatic resuscitation using PCC as compared to FFP.¹³² Although the reduced time and volume necessary to achieve coagulation factor replacement are appealing, transfusion of PCC likely carries the same immunomodulatory risks as those of FFP and the product is expensive. Controlled trials in injured patients are necessary to define recommendations.¹³³

Recombinant Factor VIIa

Treatment of postinjury coagulopathy with supraphysiologic doses of recombinant factor VIIa (rVIIa) is believed to amplify coagulation through generation of a thrombin burst in the presence of both tissue factor and functional platelets, and in the absence of either hypothermia or acidosis. Due to continued concerns over efficacy, thrombotic risk and cost, two parallel randomized controlled trials, one of penetrating and one of blunt trauma patients, were conducted among 32 international institutions (exclusive of the United States) from 2003 to 2004.¹³⁴ Eligibility criteria was transfusion of ≥6 U RBC in 4 hours. Subjects were randomized to receive either placebo or three doses of rVIIa, 200, 100, and 100 μg/kg, with the first dose given after the eighth unit of RBC transfused. A reduction in RBC transfusion requirement for both blunt (median 7.0 vs 7.5) and penetrating (3.9 vs 4.2) groups was observed among those alive 48 hours after the first dose of the study drug. However, these relatively small differences were eliminated when the analysis was expanded to include patients who had died within the first 48 hours of injury. In another multicenter trial of rVIIa in trauma, including the United States, there was also no evidence of significant clinical benefit.¹³⁵ Thus, the role for rVIIa in trauma care is considered very limited. If rVIIa therapy is contemplated, several pharmacokinetic properties of the drug warrant consideration. The activity of rVIIa is both pH and temperature dependent, with a 60% decrement at a pH of 7.20 and a 20% decrement at a temperature less than 34°C.⁵² Furthermore, physiologic concentrations of calcium, fibrinogen, and platelets are required, such that replacement of these clotting factors is essential prior to rVIIa administration. Dosages range from 50 to 200 mcg/kg, with redosing recommended for continued coagulopathy beyond the half-life of 2 hours.

Factor XIIIa

Factor XIII acts to stabilize the fibrin clot once formed, and a relationship between XIII concentration and maximal clot firmness has been demonstrated experimentally.¹³⁶ Early depletion of the limited endogenous XIII stores has been documented following major hemorrhage, and is believed to contribute to coagulopath.¹³⁷ Although prospective data are lacking, rXIIIa should be considered for postinjury coagulopathy that is refractory to conventional factor replacement therapy. As discussed previously, cryoprecipitate is abundant in factor XIII.

Antifibrinolytics

The role of antifbrinolytics in trauma remains controversial, and has been fueled by the recognition that the majority of severely injured patients manifest fibrinolysis shutdown.⁵⁹ Antifibrinolytic agents include the lysine analogue inhibitors of plasminogen binding to fibrin, aminocaproic acid (Amicar) (dosing = 150 mg/kg followed by 15 mg/h) and tranexamic acid (dosing 10 mg/kg, followed by 1 mg/kg h), as well as the direct plasmin inhibitor aprotinin (dosing 280 mg, followed by 70 mg/h). In addition to its effect on plasmin, aprotinin also inhibits kallikrein, factor XIIa, and trypsin. Aprotinin, however, is not currently approved in the United States due to increased mortality in a randomized trial during cardiac surgery.¹³⁸ The Crash II trail suggested improvement in survival with tranexamic acid,⁷³ but this trial has many limitations,¹³⁹ particularly when applied to care at US level I trauma centers. Furthermore, there is compelling investigative work suggesting indiscriminate use of antifibrinolytics can have adverse effects.¹⁴⁰ Retrospective studies in civilian centers in the United States have failed to identify a survival advantage,¹⁴¹ and at least one suggested increased mortality.¹⁴² On the other hand, inhibiting plasminogen activation may have benefits beyond coagulation considering the diverse cellular receptors for plasminogen.⁶⁴ There are a number of ongoing randomized trials evaluating the efficacy of tranexamic acid in trauma patients that will be completed over the next several years which will better define the role of antifibrinolytics in trauma.

Resuscitation Strategies for TIC

Predicting Massive Transfusion

Massive transfusions require a predetermined plan to rapidly deliver blood products to the exsanguinating patients. One of the major challenges in trauma resuscitation is correctly identifying patient at risk of massive transfusion. Several scoring strategies have been proposed to rank a patients risk of life-threatening hemorrhage. Many of these score use a combination of physiologic measurements, laboratory values and physical findings. The trauma associated severe hemorrhage (TASH) score was developed from a regression analysis that identified seven independent predictors of massive transfusion in trauma patients based on retrospective data.¹⁴³ The score takes into consideration the patient’s systolic blood pressure, hemoglobin, FAST examination, pelvic/long-bone fracture, gender and base deficit. The TASH score has a range from 0 to 28 making it somewhat complex to calculate. The assessment of blood consumption (ABC) score was proposed and was developed as a minimalist score not requiring laboratory values to predict massive transfusions.¹⁴⁴ The ABC score incorporates four variables that are simplified by dichotomous point scoring, rather than ordinal grouping as used in TASH. These include a positive FAST, penetrating mechanism, heart rate >120 beats per minute and systolic BP <90 mm Hg. In consideration of these scoring systems, the timing of when a decision can be made to activate a massive transfusion is critical. The optimal goal is early communication to the blood bank of the urgent need of a large volume of blood products. The majority of the scoring systems have a high negative predictive value but universally lack a strong positive predictive value, which is likely best determined at this time by experience.¹⁴⁵ Our current massive transfusion protocol emphasizing goal-directed approach is shown in Figure 13-10.

Hypotensive Crystalloid Resuscitation

Permissive hypotension was proposed as a deliberate tolerance of lower arterial pressures in the face of uncontrolled hemorrhagic shock in order to minimize further bleeding. This strategy is based on the notion that decreasing perfusion pressure will maximize the body’s natural mechanisms for hemostasis, such as arteriolar vasoconstriction, increased blood viscosity, and in situ thrombus formation (see Chapter 12). In the first large-scale trial, Bickell et al¹⁴⁶ randomized patients in hemorrhagic shock (systolic blood pressure (SBP) <90 mm Hg) who had sustained penetrating torso trauma to either crystalloid resuscitation or no resuscitation prior to operative intervention. Mean SBP was significantly decreased on arrival for the delayed resuscitation group as compared to the immediate resuscitation group (72 mm Hg vs 79 mm Hg, respectively, p = 0.02) with a corresponding increase in survival (70% vs 62%, respectively, p = 0.04). A subsequent subgroup analysis, however, indicated that these benefits were limited to patients who had cardiac injury with tamponade. Furthermore, prehospital crystalloid resuscitation in severely injured patients with sustained hypotension appears to be beneficial. Brown et al. demonstrated a survival benefit with increased crystalloid use in blunt injured trauma patients with prehospital hypotension.¹⁴⁷ Most recently, Schreiber et al¹⁴⁸ demonstrated a survival advantage using limited crystalloid resuscitation in the prehospital setting in a prospective phase II trial. The study randomized patients with a SBP <70 mm Hg to a controlled resuscitation of 250 cc boluses of crystalloid compared repeated to maintain SBP >70 mm Hg or palpable radial pulse compared to standard care of 2 L. In blunt injury, mortality was reduced from 18% in the standard of care group to 3% in the controlled resuscitation group, while with penetrating trauma there was no difference in survival. In considering the dominant factors for TIC, hypotension is associated with impaired thrombin generation as well as hyperfibrinolysis. Overzealous crystalloid dilution dilutes whole blood and results in the depletion of the critical balance of regulatory proteins.⁵⁶ Perhaps the optimal compromise is prehospital small volume plasma resuscitation fluid, which would maintain the correct balance of regulatory factors.¹⁴⁹

Goal Directed Management of TIC

While there is no debate in the United States that early plasma resuscitation is warranted for the severely injured patient at risk, there is substantial debate as how to best deliver the optimal quantity of plasma and platelets; that is, fixed ratios or point of care guided resuscitation with clinical assays. A large multicenter prospective observational multicenter major trauma transfusion (PROMMTT) trial suggested the beneficial effects of early plasma administration during trauma resuscitation, and indicated platelets were given late.² These findings were then translated into a multicenter randomized control trial PROPPR (pragmatic randomized optimal platelet and plasma ratios) to assess the impact on survival of 1:1 versus 1:2.¹²⁶ The PROPPR study also included a different platelet:RBC transfusion target which confounded the results. The important finding from this study was that the ratios did not make a difference in the primary study endpoints 24 hours or 30-day mortality. But there have been no randomized trials to address the important issue of fixed ratio versus goal directed management, although a retrospective cohort evaluation suggested that TEG driven resuscitation is superior.¹⁰⁰ Our current TEG-driven protocol¹⁰⁰ is outlined in Figure 13-10. In the injured patient considered at risk of TIC, a citrated rapid TEG is performed, 1 g of calcium chloride is administered followed by transfusion of two units of FP24 and four units of RBC. Subsequent blood products are delivered based on the initial rapid TEG output, and serial TEG-directed transfusions are continued until hemostasis is achieved.

Novel Resuscitation Fluids to Mitigate TIC

New resuscitation fluids are continually being developed and tested. The most recent to fail was hypertonic saline that was ultimately found to enhance coagulopathy. The most recent promising solution is adenosine lidocaine magnesium (ALM). Originally designed for cardioplegia in cardiothoracic surgery based on an induced hibernation state for myocytes, ALM has now been shown to attenuate TIC in experimental models of postinjury shock.¹⁵⁰

Antiplatelet Therapy

Antiplatelet therapy, which consists predominantly of acetylsalicyclic acid (ASA) and clopidogrel (P2Y12 inhibitors), have revolutionized the care of patients with atherosclerotic cardiovascular disease. Although via independent mechanisms, both ASA and clopidogrel irreversibly inhibit platelet aggregation. The average lifespan of a platelet is roughly 9 days, and platelet function recovers gradually following cessation of antiplatelet agents, as the bone marrow generates approximately 30,000 platelets per day. Data comparing the incidence of ICH between patients using antiplatelet therapy and controls are sparse. However, several matched case series of head-injured patients have indicated an increased severity of hemorrhage, as well as mortality, among patients using antiplatelet therapy as compared to controls.^151,152 These reports are limited primarily by confounding comorbidity, as patients using antiplatelet therapies tend to be sicker. Despite an apparent increased morbidity associated with preinjury antiplatelet agents among head-injured patients, little data exist to support routine platelet transfusion in this setting.¹²⁴ Prospective, randomized data are warranted, preferably incorporating serial platelet functional assessment. These studies are particularly timely as both the elderly demographic and prevalence of antiplatelet therapy are increasing exponentially. Interestingly, the deleterious effects of antiplatelet therapy do not appear to extend to the non-head-injured trauma patient. In a recent report, no mortality difference was noted for patients using antiplatelet therapies as compared to controls among a cohort of trauma patients with no evidence of ICH.¹⁵³

Warfarin

Warfarin is an oral anticoagulant that inhibits synthesis of the vitamin K-dependent clotting factors II, VII, IX, and X, as well as the anticoagulant protein C and protein S. It is the most common drug prescribed to achieve chronic anticoagulation. Several studies have documented an increased likelihood of traumatic ICH, as well as severity of injury and mortality, among trauma patients using warfarin as compared to nonanticoagulated patient. Importantly, the increased likelihood of adverse outcomes is observed only among patients who have achieved therapeutic anticoagulation (INR >2).¹⁵⁴ Rapid identification of patients on therapeutic warfarin and at risk for traumatic ICH is paramount to minimize hemorrhage progression with resultant irreversible neurologic consequences. Most authors advocate empiric transfusion of FFP prior to laboratory documentation of therapeutic anticoagulation. In such patients, arguing that the morbidity of a delay in reversal of patients with a supratherapeutic INR outweighs that of unnecessary factor administration to patients with a subtherapeutic INR. Although up to one-half of trauma patients on warfarin present with a subtherapeutic INR,¹⁵⁵ the morbidity of an expanding ICH renders this argument reasonable. However, a striking amount of variability exists among trauma surgeons as to the INR above which reversal of anticoagulation should be implemented, the rapidity with which the PT is normalized, or the target INR following reversal. As mentioned previously, reversal of warfarin-induced anticoagulation using PCC may be particularly beneficial in patients at high risk for cardiopulmonary complications secondary to the large-volume plasma administration to correct the INR.^{130,131,132,133} The risk of warfarin anticoagulation in the non-head-injured trauma patient is less clear. A recent study of blunt injured patients age ≥60 years who sustained trauma to the abdomen or thorax, in the absence of intracranial injury, had no difference in outcome.¹⁵³

Direct Thrombin and FXa Inhibitors

Chronic anticoagulation has changed substantially in the United States since the introduction of the oral direct thrombin inhibitor dabigatran (Pradaxa) in 2010.¹⁵⁶ Subsequently the FDA has approved two oral factors Xa (FXa) inhibitors, rivaroxaban (Xarelto) and apixaban (Eliquis), and no doubt others are on the horizon. Dabigatran binds to free and clot-bound thrombin, preventing the conversion of fibrinogen to fibrin and platelet aggregation via the PAR receptors. Peak plasma levels occur in 1–2 hours. Clearance is predominantly renal, with a half-life of 14–17 hours. And 20% is metabolized in the liver. Laboratory assessment of the anticoagulation effects are problematic. PT, PTT, and TT are flat dose-response, that is, useful for screening only. Rapid TEG results are somewhat erratic, but trends appear to correlate with circulating drug levels.¹⁵⁷ Eacrin clotting time (ECT) has a dose-response to dabigatran in therapeutic ranges, but is not currently available in most hospitals. ROTEM is anticipated to have a channel to accomplish this testing soon. Reversal has been challenging until recently, and hemodialysis was recommended for emergent settings. The only promising reversal agent has been factor eight inhibitor bypass (FEIBA).¹⁵⁸ But a new antibody fragment, idarucizumab, appears to be clinically effective.¹⁵⁹ Rivaroxaban reversibly binds the active site of FXa, preventing the formation of thrombin and subsequent fibrinogen cleavage.¹⁶⁰ The plasma half-life is 2–4 hours. Clearance is 66% renal and 33% hepatic; the half-life is 5–9 hours.¹⁵⁶ As expected, the most accurate assay for circulating levels is the antiFXa assay. PT is prolonged in a linear fashion, but is variable depending on the test reagents. The response to PTT is nonlinear, and the reliability of TEG remains unclear.¹⁶¹ There are no validated reversal agents for rivaroxaban, but FEIBA appears to be the most effective.¹⁵⁶ Dialysis is not useful because rivaroxaban is highly protein bound. Experimental work indicates a recombinant human FXa molecule, andexanet, may be useful. Apixaban is another competitive inhibitor of FXa.¹⁵⁶ Peak circulating levels are achieved in 3–4 hours; clearance is 50% renal and 50% hepatic. At this point, there are insufficient data to recommend testing and reversal agents, but similarities to rivaroxaban are aniticipated.

Hypercoagulability

Venous Thromboembolism

The incidence of proximal lower extremity deep venous thrombosis (DVT) in injured patients without preventive measures has been reported at 18–32%, and the risk of significant pulmonary embolism (PE) from 0.3–2%.¹⁶² These figures are confounded by the fact that surveillance duplex will identify a higher incidence of asymptomatic DVT, but postinjury PE occurs in the absence of DVT in the majority of patients.¹⁶² Furthermore, asymptomatic PE has been identified in >25% of severely injured patients on admission chest CT scanning,¹⁶³ yet early symptomatic PE has been associated with extremity trauma but not thoracic injuries.¹⁶⁴ Consequently, it is not surprising that the prevention of postinjury VTE remains controversial, underscoring the critical need to understand the pathophysiology and fundamental mechanisms to design effective preventive strategies.

Virchows Triad and Beyond

A century ago, Cannon⁶ recognized that the initial response to severe trauma is hypercoagulability, quickly followed by hypocoagulability. Severely injured patients who survive their injury then transition to a hypercoagulable state as early as 24 hours following injury.¹⁶⁵ In fact, patients presenting with advanced TIC requiring a massive transfusion are at the greatest risk for VTE in the SICU. The etiology of this hypercoagulability is likely multifactorial, involving endothelial injury, circulatory stasis, platelet activation, hyperfibrinogenemia, decreased levels of endogenous anticoagulants, and impaired fibrinolysis. Furie and Furie¹⁶⁶ emphasize the role of the endothelium in maintaining blood flow via the generation of anticoagulants, nitric oxide, prostacyclin, and receptor expression. But even intact endothelium, when activated, can provoke thrombus formation. Furthermore, circulating leukocytes and microparticles can express tissue factor. Obesity¹⁶⁷ and traumatic brain injury¹⁶⁸ are independent risk factors for postinjury VTE, although the responsible mechanisms remain speculative.

Diagnosis of Hypercoagulability

The diagnosis and, thus, treatment of hypercoagulability following injury has been limited by the lack of accurate laboratory testing addressing the pathogenesis. Degradation products of fibrin; that is, d-dimer (Fig. 13-11), are not useful in the acutely injured patient because these products merely indicate that a clot has been formed conventional tests, such as the aPTT and PT/INR are neither able to diagnose hypercoagulability nor delineate the relative contributions of enzymatic and platelet components. Previous trials investigating the benefit of various mechanical and pharmacoprophylactic regimens among injured patients have neither documented hypercoagulability nor monitored the efficacy of prophylaxis. Furthermore, current guidelines do not address the contribution of platelets or fibrinogen to hypercoagulability. Severely injured patients develop inflammation driven hyperfibrinogenemia within days of injury,¹⁶⁹ and there is a growing body of evidence that has implicated platelet activation in the development and propagation of VTE.¹⁷⁰ Our work indicates that platelet hyperactivity contributes substantially to hypercoagulability beyond 48 years of injury.¹⁷¹ Antiplatelet therapy may have additional effects on attenuating hypercoagulability.¹⁷² Finally, there is recent evidence documenting fibrinolysis shutdown in severely injured patients.^59,173 In light of these limitations, it is not surprising that most VTEs among trauma patients occur because of prophylaxis failure rather than failure to provide prophylaxis. In a recent comprehensive international analysis of medical and surgical ICUs, the current rate of DVT is 7.7% and PE 1.3%.¹⁷⁴

Viscoelastic hemostatic assays may provide a breakthrough in managing hypercoagulability. A TEG shortened R time, increased alpha angle, and enhanced MA are indicative of hypercoagulability (Fig. 13-12). Our group documented a strong correlation between hypercoagulability as evidenced by the aforementioned TEG parameters and subsequent VTE.⁶⁷ In the face of standard chemoprophylaxis, 60% of patients displayed evidence of hypercoagulability. Furthermore TEG and ROTEM can distinguish platelet versus fibrinogen contribution to clot formation as well as calibrate fibrinolysis shutdown.¹⁵⁴ We have recently documented that resistant to tPA (fibrinolysis shutdown) is a risk factor for postinjury VTE, and have developed a tPA sensitivity assay. Despite the theoretical advantages of TEG-driven chemoprophylaxis protocols, prospective data remain sparse.

Prevention of Venous Thromboembolism

Early use of preventive measures is critical to prevent postinjury VTE, but identifying the high-risk population has been difficult. The two most widely used scores, risk assessment profile (RAP) and trauma embolic scoring system (TESS), miss a third of the patients who develop VTE.¹⁷⁵ Paradoxically, patients presenting with advanced TIC requiring a massive transfusion are at the greatest risk for subsequent VTE. Mechanical compression devices should be applied as soon as possible in all seriously injured patients. Heparin remains the cornerstone of pharmacologic VTE prophylaxis, and lower molecular weight heparin (LMWH) is superior to unfractionated heparin.¹⁷⁶ Furthermore, weight-based LMWH or anti-factor Xa guided dosing appears to be advantageous.¹⁷⁷ The most controversial issue is timing with central nervous system injury.^178,179 The current debate is 48 versus 72 hours in those patients without progressive intracranial hemorrhage. We currently believe aspirin should be routinely added at 72 hours in patients at high risk of VTE, and dose according to platelet mapping targeting arachidonic acid receptor inhibition at >80%. Statin therapy may also become routine in the SICU for VTE prophylaxis,^180,181 to attenuate tPA resistance. The role of inferior vena cava filters remain controversial, and at best these devices have a limited role.¹⁸²

In sum, the management of postinjury VTE remains a challenge. We currently believe TEG or ROTEM driven protocols should be employed, and the combination of a LMWH, aspirin, and a statin is the optimal benefit:risk strategy.