- Email: [email protected]
New understandings of post injury coagulation and resuscitation
Accepted Manuscript New Understandings of Post Injury Coagulation and Resuscitation Mitchell Jay Cohen, MD, S. Ariane Christie, MD PII:
S1743-9191(16)30120-0
DOI:
10.1016/j.ijsu.2016.05.037
Reference:
IJSU 2804
To appear in:
International Journal of Surgery
Received Date: 3 May 2016 Accepted Date: 10 May 2016
Please cite this article as: Cohen MJ, Christie SA, New Understandings of Post Injury Coagulation and Resuscitation, International Journal of Surgery (2016), doi: 10.1016/j.ijsu.2016.05.037. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT New Understandings of Post Injury Coagulation and Resuscitation Mitchell Jay Cohen MDa and S. Ariane Christie MDa
a
Department of Surgery, San Francisco General Hospital and the University of California, San Francisco; San
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Francisco, California
Corresponding Author:
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Mitchell Jay Cohen Department of Surgery, Ward 3A
1001 Potrero Avenue, Room 3C-38 Email: [email protected] San Francisco, CA 94110
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Phone: (415) 206-4644
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San Francisco General Hospital
Conflicts of Interest: None Declared
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Grants: Supported by NIH 1UM1 HL10877 (MJC), DOD W911NF-10-1-0384 (MJC)
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ACCEPTED MANUSCRIPT
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New Understandings of Post Injury Coagulation and Resuscitation
ABSTRACT
Coagulopathy following injury is common and it predicts poor outcomes and increased mortality. For many decades, coagulopathy in trauma was considered as an iatrogenic phenomenon, and clinical practice focused on a resuscitation strategy using large volume crystalloid and packed red blood cells. The discovery of Acute
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Traumatic Coagulopathy as a distinct pathophysiologic state coupled with a transition towards balanced product resuscitation has fundamentally changed the paradigm of trauma care and represents one of the most active areas of current research in the field of trauma. In this review, we examine the development and
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current understanding of the mechanisms, implicated mediators, and physiology of Acute Traumatic Coagulopathy, with an emphasis on the role of the activated
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Protein C pathway. We will also review the state of resuscitation practice including the evidence for balanced product administration and the previously underappreciated importance of platelet count and function. Importantly, we highlight ongoing knowledge deficits in traumatic coagulopathy and resuscitation as directions for future investigation in order to facilitate further insight into these rapidly evolving fields.
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1.1 INTRODUCTION: Bleeding is responsible for the vast majority of early trauma deaths. Coagulopathy after trauma is common, affecting one in three severely injured patients, and results in worsened outcomes and increased mortality. Since its discovery, determining the
among the most active areas of trauma research.
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drivers and ideal treatment of acute traumatic coagulopathy (ATC) have been
Initial investigation of ATC centered on characterization of the mechanisms and
mediators of coagulopathy. Extensive translational efforts ensued to biologically
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characterize the coagulation milieu after injury. A second area of inquiry sought to delineate the role of resuscitation in coagulation and patient outcomes.
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Retrospective data suggested that resuscitation protocols which “recreated” whole blood from component products more effectively treated coagulopathy and resulted in improved survival. Initially, efforts focused on balancing administration of plasma and PRBC. However, recent data demonstrate perturbations of platelet count and function following severe injury correlate strongly with adverse outcomes, suggesting that the importance of platelets in traumatic coagulopathy was
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previously under-recognized.
Together, the identification of ATC and the ‘rediscovery’ of balanced blood product ratios brought about a paradigm shift within the trauma community. Changes in resuscitation practice have resulted in improved outcomes and decreased the role of
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damage control. The purpose of this review is to examine the development and current state of the science of acute traumatic coagulopathy and trauma
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resuscitation. We hope to provide insight into this rapidly evolving field and identify ongoing knowledge gaps as areas of opportunity for future scientific study.
1.2 HISTORY
Prior to the mid-1970’s trauma resuscitation was conducted with whole blood. A combination of blood-banking advances including bloodcomponent separation, improved storage capabilities, and increasing attention to resource allocation resulted in replacement of whole blood with its components [1, 2]. The emergence of viral hepatidities and HIV/AIDS in the 1980’s essentially eliminated whole blood 2
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from the blood supply. At the same time, the canonical understanding of shock was evolving; luminaries such as Carrico and Shires suggested that severely injured patients required augmentation of blood pressure (flow) and oxygen carrying capacity [3]. The trauma community responded by shifting resuscitation to
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administration of large volumes of crystalloid and packed red blood cells (PRBCs)
[4]. Coagulation was not viewed as a critical driver of patient physiology at this time. Rather, coagulopathy in injured patients was considered to be iatrogenic. A vast literature developed in support of the theory of “iatrogenic coagulopathy,”
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describing the role of dilution, hypothermia and acidosis on coagulation [5, 6]. This period, characterized by crystalloid resuscitation and a lack of emphasis on
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coagulation, continued for the remainder of the 20th century until two key findings eventually challenged this landscape.
1.3 ACUTE TRAUMATIC COAGULOPATHY
In 2003, the paradigm of “iatrogenic coagulopathy” in trauma was disrupted when two independent studies demonstrated early coagulopathy in injured patients.
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Derangements of prothrombin time and partial thromboplastin time were found in approximately 30% of trauma patients one hour following injury, before significant resuscitation had been administered. Termed “Acute Traumatic Coagulopathy,” these derangements were described as increasing with injury severity and predicted
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significantly greater mortality [7, 8, 9].
Further investigation sought to characterize the mechanism underlying Acute
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Traumatic Coagulopathy. ATC was observed to occur specifically in injured patients with tissue hypo-perfusion (clinically measured as base deficit). These patients were found to have elevated soluble thrombomodulin, protein C (PC) depletion, and reciprocally elevated activated protein C (aPC), implicating activation of the protein C pathway as mechanistically important to traumatic coagulopathy [10]. Protein C is a serene protease with dual anticoagulant and inflammomodulatory functions which is activated in a mechanism involving thrombin, thrombomodulin and EPCR. Once activated, aPC proteolitically cleaves Factors Va and VIIIa and depletes plasminogen inhibitors [11, 12]. When severe injury is combined with 3
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tissue hypoperfusion (shock), systemic protein C activation results in coagulopathy by both impairing clot formation via factor cleavage, and through de-repression of fibrinolysis by consumption of plasminogen activator inhibitor-1 (PAI-1) leading to unopposed conversion of plasminogen to plasmin by tissue plasminogen activator
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(tPA) [13]. Fibrinolytic activity is further exacerbated by reduced activation of
thrombin-activatable fibrinolysis inhibitor (TAFI) as thrombin is diverted to PC activation [14].
Characterization of Protein C pathway activation as the key mechanistic process
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underlying ATC was established by data from multiple clinical and laboratory
studies. A prospective single-center study of 203 critically-injured trauma patients
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linked early coagulopathy to elevated aPC and subsequent PC depletion within six hours after injury [10]. Protein C depletion was found to predict increased risk of acute lung injury (ALI), ventilator-associated pneumonia (VAP), multi- system organ failure (MOSF), and death. Additional prospective data from 208 patients demonstrated that injured patients with ATC developed hyper-fibrinolysis with decreased levels of PAI-1 and increased levels of tPA and D-dimer [3]. As part of a
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multicenter observational study, 165 critically-injured patients were followed for factor levels and coagulation at serial timepoints. In addition to elevated aPC, deficits in fibrinogen, thrombin, and factors V, VIII, IX, and X were identified as principal drivers of coagulopathy for patients with severe injury and shock [15].
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Another prospective study of 75 trauma patients linked PC depletion with elevated markers of endothelial injury and coagulopathy [16]. In an animal model, antibody-
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mediated protein C inhibition was shown to prevent the development of ATC in response to trauma and hemorrhagic shock [17]. To summarize, ATC is characterized by an endogenous hypocoagulable state and activation of fibrinolysis mediated by activation of the Protein C pathway. It develops early after injury and is biochemically evident prior to, and independent of, the development of significant acidosis, hypothermia, or hemodilution. The development of ATC is associated with hypotension, tissue injury, worsening base deficit, and head injury [3, 7, 18].
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1.4 CURRENT INVESTIGATIONS IN TRAUMATIC COAGULOPATHY Ongoing areas of investigation in ATC include the role of aPC in barrier protection, potential aPC-associated late hypercoagulability, the role of circulating microparticles, and the therapeutic potential of antifibrinolytic agents.
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Cytoprotective functions of aPC may be important in pulmonary capillary
endothelial barrier function. Persistently low PC in critically-injured, mechanicallyventilated patients is associated with pneumonia [19]. The interactions between Protein C, innate and cellular immunity [20], endothelial activation and barrier
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permeability are currently being investigated [21, 22].
The identification of PC depletion in patients with ATC suggests that the aPC
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pathway may also play a mechanistic role in hypercoagulability and
thromboembolic complications after injury [16, 23, 24]. A vast literature has described thrombotic complications after trauma and shock and multiple investigators have reported greater risk of thromboembolic complications in patients with initial coagulopathy [25], but no study has demonstrated hypercoagulability specifically associated with Protein C. Despite this, the transition
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from hypocoaguability to hypercoaguability occurs rapidly and remains an important area of characterization.
Emerging research suggests that microparticles may be an additional mechanism influencing ATC. Tissue injury causes release of thrombin-rich microparticles, which
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at the local level likely contribute to hemostasis. If released systemically, preliminary studies suggest these particles may lead to a disseminated intravascular
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coagulation-like coagulopathy. One prospective observational study of 180 trauma patients identified elevated levels of endothelial-, erythrocyte-, and leukocytederived microparticles in the circulation of traumatically injured patients compared with non-injured controls [26]. Patients with coagulopathy had lower levels of platelet-derived microparticles and tissue factor-positive microparticles than noncoagulopathic patients. A small study of 16 brain-injured patients also identified elevated levels of microparticles compared with controls [27]. Further characterization of the mechanism and implications of circulating microparticles on ATC is needed. 5
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Evidence of hyperfibrinolysis in severe trauma has led to investigation of the role of antifibrinolytic therapy in the treatment of ATC. The Clinical Randomization of an Antifibrinolytic in Significant Hemorrhage (CRASH-2) trial demonstrated a 1.5% mortality reduction in patients administered tranexamic acid (TXA) compared to
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placebo. However, enrollment criteria included any patients with or at risk for
significant hemorrhage without specific coagulation criteria and the data was sparse from multiple centers that likely did not conform to modern trauma care practice. Of note, despite the overall mortality difference, there was actually increased mortality
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in patients who received TXA three or more hours after injury and there was no
difference in product administration between groups despite a purported decrease
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in death from bleeding [28]. A subsequent study of 896 patients demonstrated that patients receiving TXA had reduced mortality compared to non-treated patients; this mortality difference was greater for patients requiring massive transfusion [29]. While many have incorporated empiric TXA administration into practice, the data are not yet mature enough to recommend routine use[30]. Fortunately additional prospective studies with higher-quality data are currently ongoing to answer this
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important patient care and scientific issue.
1.5 PLATELET FUNCTION
Platelets play a more important role in both hemostasis and inflammation than
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previously recognized [31]. While thrombocytopenia is relatively rare in injured populations, platelet count is inversely related to poor outcomes after injury [32]. In
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389 severely-injured patients, a nearly linear relationship was identified between decreasing platelet number and mortality. Specifically, this study demonstrated a 17% decrease in 6-hour mortality and a 0.7 unit decrease in blood utilization for every 50,000 increase in platelet count. Of particular note, the relationship with increased mortality persisted within a normal platelet range at which most practitioners would not previously have considered patients to be at risk for deleterious effects of thrombocytopenia. In another cohort of 1292 patients, relatively lower initial platelet counts were strongly associated with hemorrhagic and CNS mortality, even when counts were within the canonically normal range 6
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(228+90)[33]. Additionally, platelet count decreased substantially between admission and subsequent time points.
Despite interest in the correlation between platelet count and outcomes, until
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recently there was little data regarding platelet function in injured patients. In 2001, Jacoby et al used flow cytometry and a light aggrogremetry PFA 100 platelet
analyzer to assess platelet activation after injury. The platelet analyzer functions by measuring occlusion of a porous membrane after platelet activation. The authors
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reported significantly impaired platelet function in 6 non-survivors compared to 94 survivors. In a separate analysis closure was prolonged in 22 patients with head
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injury at 24-hours despite normal platelet function at admission. Additionally, flow cytometry demonstrated elevation of all three platelet activation parameters (Pselectin, GpIIb-IIIa and platelet microparticles) in trauma patients compared to uninjured controls [34]. However, no association was found between platelet function and other outcomes.
Inspired by these findings, our group studied platelet function in 101 severely-
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injured trauma patients on arrival and then serially to 120 hours using impedance aggregrometry. A battery of agonists were selected to test the primary mechanisms of platelet function: adenosine diphosphate (ADP) via P2 receptors, thrombin receptor activating peptide 6 (TRAP) via PAR receptors, arachidonic acid (AA) via
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the cyclo-oxygenase pathway, and collagen via GpIa-IIa and GpVI receptors. While no patient had thrombocytopenia upon arrival, 46% of patients had impaired
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platelet function to at least one agonist at admission and 91.1% had impaired function during the first 120 hours of hospitalization [35]. Impaired admission platelet function to AA, collagen, and TRAP were predictive of death. An Austrian group separately reported platelet hypo-responsiveness in patients after injury, with decreased platelet function to ADP and TRAP more frequent in non-survivors than in patients who survived their injuries [36]. Additional thrombelastograph platelet mapping data from the Denver group demonstrated that severely injured trauma patients had impaired median ADP and AA stimulation after trauma as
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compared to healthy human volunteers [37]. As in other cohorts, impaired platelet function correlated with severity of injury.
1.6 CHANGES IN RESUSCITATION
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Beginning in the early 2000s, retrospective data from the US military campaigns in Afghanistan and Iraq suggested that injured warfighters who received a balanced ratio of packed red blood cells to plasma were more likely to survive [38].
Subsequent retrospective studies in civilian populations showed similar benefits
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using a 1:1:1 ratio of PRBCs, FFP and platelets [39, 40]. Rapidly, the resuscitation paradigm shifted away from utilizing large volume crystalloid towards balanced
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blood product resuscitation.
However, despite this general change in practice, no prospective or randomized trial had established the benefit of balanced hemostatic resuscitation raising the concern that the retrospective results were possibly attributable to survival bias [41]. Two trials were conducted to address this concern. The Prospective, Observational, Multicenter, Major Trauma Transfusion study (PROMMTT) was a prospective
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observational trial of 1245 patients which ultimately confirmed reduced 6-hour mortality in injured patients who received increased plasma to PRBC ratios [42]. The Pragmatic, Randomized Optimal Platelet and Plasma Ratios trial (PROPPR) was a prospective trial which randomized severely-injured patients to resuscitation
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using a 1:1:1 vs 1:1:2 PRBC to FFP to platelet ratio. This trial ultimately failed to demonstrate a difference between resuscitation groups for 24 hour and 28 day
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mortality [43]. The lack of difference may have been attributable to poor separation between treatment groups; pre-randomization transfusion was not accounted for and patients who died or came off protocol early did not have time to receive the intervention. Ultimately, the ideal transfusion ratio of PRBC to FFP to platelets remains unknown. However, there is clear consensus that balanced resuscitation with the goal of recreating whole blood from components while limiting crystalloid has become the standard of care.
1.7 CONCLUSION 8
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In summary, over the past 15 years there has been significant change in the understanding and treatment of coagulopathy in critically injured patients. Acute traumatic coagulopathy has been identified as independent from iatrogenic and resuscitation-associated etiologies of coagulopathy. It has been characterized as
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hypocoagulable state arising in the setting of tissue injury and hypoperfusion and is mediated by activation of the Protein C pathway, resulting in retarded clot
formation and hyperfibrinolysis. However, activated Protein C is likely only one of multiple implicated pathways, which underscores the importance of ongoing
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investigation of other mediators of coagulopathy. Platelet count and function are now understood to be critical players in post-injury physiology and are closely
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linked with outcomes. Resuscitation practice has also undergone evolution to a current model of balanced product transfusion. Mechanistic understanding underlying the efficacy of hemostatic resuscitation remains uncertain and may be attributable either to reversal of coagulopathy or to correction of endotheliopathy. The relative contribution of coagulation versus inflammation on ATC has yet to be determined. Current and ongoing research efforts include further characterization
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of the effects of aPC pathway, the role of other components and mechanisms in traumatic coagulopathy, and determination of optimal transfusion ratios and platelet targets for optimal resuscitation of the severely injured patient.
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•
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• •
Development and current understanding of the mechanisms, implicated mediators, and physiology of Acute Traumatic Coagulopathy Role of the activated Protein C pathway. Resuscitation practice, including the evidence for balanced product administration, importance of platelet count and function. ongoing knowledge deficits in traumatic coagulopathy and resuscitation as directions for future investigation.
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•
S1743-9191(16)30120-0
DOI:
10.1016/j.ijsu.2016.05.037
Reference:
IJSU 2804
To appear in:
International Journal of Surgery
Received Date: 3 May 2016 Accepted Date: 10 May 2016
Please cite this article as: Cohen MJ, Christie SA, New Understandings of Post Injury Coagulation and Resuscitation, International Journal of Surgery (2016), doi: 10.1016/j.ijsu.2016.05.037. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT New Understandings of Post Injury Coagulation and Resuscitation Mitchell Jay Cohen MDa and S. Ariane Christie MDa
a
Department of Surgery, San Francisco General Hospital and the University of California, San Francisco; San
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Francisco, California
Corresponding Author:
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Mitchell Jay Cohen Department of Surgery, Ward 3A
1001 Potrero Avenue, Room 3C-38 Email: [email protected] San Francisco, CA 94110
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Phone: (415) 206-4644
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San Francisco General Hospital
Conflicts of Interest: None Declared
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Grants: Supported by NIH 1UM1 HL10877 (MJC), DOD W911NF-10-1-0384 (MJC)
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New Understandings of Post Injury Coagulation and Resuscitation
ABSTRACT
Coagulopathy following injury is common and it predicts poor outcomes and increased mortality. For many decades, coagulopathy in trauma was considered as an iatrogenic phenomenon, and clinical practice focused on a resuscitation strategy using large volume crystalloid and packed red blood cells. The discovery of Acute
TE D
Traumatic Coagulopathy as a distinct pathophysiologic state coupled with a transition towards balanced product resuscitation has fundamentally changed the paradigm of trauma care and represents one of the most active areas of current research in the field of trauma. In this review, we examine the development and
EP
current understanding of the mechanisms, implicated mediators, and physiology of Acute Traumatic Coagulopathy, with an emphasis on the role of the activated
AC C
Protein C pathway. We will also review the state of resuscitation practice including the evidence for balanced product administration and the previously underappreciated importance of platelet count and function. Importantly, we highlight ongoing knowledge deficits in traumatic coagulopathy and resuscitation as directions for future investigation in order to facilitate further insight into these rapidly evolving fields.
1
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1.1 INTRODUCTION: Bleeding is responsible for the vast majority of early trauma deaths. Coagulopathy after trauma is common, affecting one in three severely injured patients, and results in worsened outcomes and increased mortality. Since its discovery, determining the
among the most active areas of trauma research.
RI PT
drivers and ideal treatment of acute traumatic coagulopathy (ATC) have been
Initial investigation of ATC centered on characterization of the mechanisms and
mediators of coagulopathy. Extensive translational efforts ensued to biologically
SC
characterize the coagulation milieu after injury. A second area of inquiry sought to delineate the role of resuscitation in coagulation and patient outcomes.
M AN U
Retrospective data suggested that resuscitation protocols which “recreated” whole blood from component products more effectively treated coagulopathy and resulted in improved survival. Initially, efforts focused on balancing administration of plasma and PRBC. However, recent data demonstrate perturbations of platelet count and function following severe injury correlate strongly with adverse outcomes, suggesting that the importance of platelets in traumatic coagulopathy was
TE D
previously under-recognized.
Together, the identification of ATC and the ‘rediscovery’ of balanced blood product ratios brought about a paradigm shift within the trauma community. Changes in resuscitation practice have resulted in improved outcomes and decreased the role of
EP
damage control. The purpose of this review is to examine the development and current state of the science of acute traumatic coagulopathy and trauma
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resuscitation. We hope to provide insight into this rapidly evolving field and identify ongoing knowledge gaps as areas of opportunity for future scientific study.
1.2 HISTORY
Prior to the mid-1970’s trauma resuscitation was conducted with whole blood. A combination of blood-banking advances including bloodcomponent separation, improved storage capabilities, and increasing attention to resource allocation resulted in replacement of whole blood with its components [1, 2]. The emergence of viral hepatidities and HIV/AIDS in the 1980’s essentially eliminated whole blood 2
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from the blood supply. At the same time, the canonical understanding of shock was evolving; luminaries such as Carrico and Shires suggested that severely injured patients required augmentation of blood pressure (flow) and oxygen carrying capacity [3]. The trauma community responded by shifting resuscitation to
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administration of large volumes of crystalloid and packed red blood cells (PRBCs)
[4]. Coagulation was not viewed as a critical driver of patient physiology at this time. Rather, coagulopathy in injured patients was considered to be iatrogenic. A vast literature developed in support of the theory of “iatrogenic coagulopathy,”
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describing the role of dilution, hypothermia and acidosis on coagulation [5, 6]. This period, characterized by crystalloid resuscitation and a lack of emphasis on
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coagulation, continued for the remainder of the 20th century until two key findings eventually challenged this landscape.
1.3 ACUTE TRAUMATIC COAGULOPATHY
In 2003, the paradigm of “iatrogenic coagulopathy” in trauma was disrupted when two independent studies demonstrated early coagulopathy in injured patients.
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Derangements of prothrombin time and partial thromboplastin time were found in approximately 30% of trauma patients one hour following injury, before significant resuscitation had been administered. Termed “Acute Traumatic Coagulopathy,” these derangements were described as increasing with injury severity and predicted
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significantly greater mortality [7, 8, 9].
Further investigation sought to characterize the mechanism underlying Acute
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Traumatic Coagulopathy. ATC was observed to occur specifically in injured patients with tissue hypo-perfusion (clinically measured as base deficit). These patients were found to have elevated soluble thrombomodulin, protein C (PC) depletion, and reciprocally elevated activated protein C (aPC), implicating activation of the protein C pathway as mechanistically important to traumatic coagulopathy [10]. Protein C is a serene protease with dual anticoagulant and inflammomodulatory functions which is activated in a mechanism involving thrombin, thrombomodulin and EPCR. Once activated, aPC proteolitically cleaves Factors Va and VIIIa and depletes plasminogen inhibitors [11, 12]. When severe injury is combined with 3
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tissue hypoperfusion (shock), systemic protein C activation results in coagulopathy by both impairing clot formation via factor cleavage, and through de-repression of fibrinolysis by consumption of plasminogen activator inhibitor-1 (PAI-1) leading to unopposed conversion of plasminogen to plasmin by tissue plasminogen activator
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(tPA) [13]. Fibrinolytic activity is further exacerbated by reduced activation of
thrombin-activatable fibrinolysis inhibitor (TAFI) as thrombin is diverted to PC activation [14].
Characterization of Protein C pathway activation as the key mechanistic process
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underlying ATC was established by data from multiple clinical and laboratory
studies. A prospective single-center study of 203 critically-injured trauma patients
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linked early coagulopathy to elevated aPC and subsequent PC depletion within six hours after injury [10]. Protein C depletion was found to predict increased risk of acute lung injury (ALI), ventilator-associated pneumonia (VAP), multi- system organ failure (MOSF), and death. Additional prospective data from 208 patients demonstrated that injured patients with ATC developed hyper-fibrinolysis with decreased levels of PAI-1 and increased levels of tPA and D-dimer [3]. As part of a
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multicenter observational study, 165 critically-injured patients were followed for factor levels and coagulation at serial timepoints. In addition to elevated aPC, deficits in fibrinogen, thrombin, and factors V, VIII, IX, and X were identified as principal drivers of coagulopathy for patients with severe injury and shock [15].
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Another prospective study of 75 trauma patients linked PC depletion with elevated markers of endothelial injury and coagulopathy [16]. In an animal model, antibody-
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mediated protein C inhibition was shown to prevent the development of ATC in response to trauma and hemorrhagic shock [17]. To summarize, ATC is characterized by an endogenous hypocoagulable state and activation of fibrinolysis mediated by activation of the Protein C pathway. It develops early after injury and is biochemically evident prior to, and independent of, the development of significant acidosis, hypothermia, or hemodilution. The development of ATC is associated with hypotension, tissue injury, worsening base deficit, and head injury [3, 7, 18].
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1.4 CURRENT INVESTIGATIONS IN TRAUMATIC COAGULOPATHY Ongoing areas of investigation in ATC include the role of aPC in barrier protection, potential aPC-associated late hypercoagulability, the role of circulating microparticles, and the therapeutic potential of antifibrinolytic agents.
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Cytoprotective functions of aPC may be important in pulmonary capillary
endothelial barrier function. Persistently low PC in critically-injured, mechanicallyventilated patients is associated with pneumonia [19]. The interactions between Protein C, innate and cellular immunity [20], endothelial activation and barrier
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permeability are currently being investigated [21, 22].
The identification of PC depletion in patients with ATC suggests that the aPC
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pathway may also play a mechanistic role in hypercoagulability and
thromboembolic complications after injury [16, 23, 24]. A vast literature has described thrombotic complications after trauma and shock and multiple investigators have reported greater risk of thromboembolic complications in patients with initial coagulopathy [25], but no study has demonstrated hypercoagulability specifically associated with Protein C. Despite this, the transition
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from hypocoaguability to hypercoaguability occurs rapidly and remains an important area of characterization.
Emerging research suggests that microparticles may be an additional mechanism influencing ATC. Tissue injury causes release of thrombin-rich microparticles, which
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at the local level likely contribute to hemostasis. If released systemically, preliminary studies suggest these particles may lead to a disseminated intravascular
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coagulation-like coagulopathy. One prospective observational study of 180 trauma patients identified elevated levels of endothelial-, erythrocyte-, and leukocytederived microparticles in the circulation of traumatically injured patients compared with non-injured controls [26]. Patients with coagulopathy had lower levels of platelet-derived microparticles and tissue factor-positive microparticles than noncoagulopathic patients. A small study of 16 brain-injured patients also identified elevated levels of microparticles compared with controls [27]. Further characterization of the mechanism and implications of circulating microparticles on ATC is needed. 5
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Evidence of hyperfibrinolysis in severe trauma has led to investigation of the role of antifibrinolytic therapy in the treatment of ATC. The Clinical Randomization of an Antifibrinolytic in Significant Hemorrhage (CRASH-2) trial demonstrated a 1.5% mortality reduction in patients administered tranexamic acid (TXA) compared to
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placebo. However, enrollment criteria included any patients with or at risk for
significant hemorrhage without specific coagulation criteria and the data was sparse from multiple centers that likely did not conform to modern trauma care practice. Of note, despite the overall mortality difference, there was actually increased mortality
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in patients who received TXA three or more hours after injury and there was no
difference in product administration between groups despite a purported decrease
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in death from bleeding [28]. A subsequent study of 896 patients demonstrated that patients receiving TXA had reduced mortality compared to non-treated patients; this mortality difference was greater for patients requiring massive transfusion [29]. While many have incorporated empiric TXA administration into practice, the data are not yet mature enough to recommend routine use[30]. Fortunately additional prospective studies with higher-quality data are currently ongoing to answer this
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important patient care and scientific issue.
1.5 PLATELET FUNCTION
Platelets play a more important role in both hemostasis and inflammation than
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previously recognized [31]. While thrombocytopenia is relatively rare in injured populations, platelet count is inversely related to poor outcomes after injury [32]. In
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389 severely-injured patients, a nearly linear relationship was identified between decreasing platelet number and mortality. Specifically, this study demonstrated a 17% decrease in 6-hour mortality and a 0.7 unit decrease in blood utilization for every 50,000 increase in platelet count. Of particular note, the relationship with increased mortality persisted within a normal platelet range at which most practitioners would not previously have considered patients to be at risk for deleterious effects of thrombocytopenia. In another cohort of 1292 patients, relatively lower initial platelet counts were strongly associated with hemorrhagic and CNS mortality, even when counts were within the canonically normal range 6
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(228+90)[33]. Additionally, platelet count decreased substantially between admission and subsequent time points.
Despite interest in the correlation between platelet count and outcomes, until
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recently there was little data regarding platelet function in injured patients. In 2001, Jacoby et al used flow cytometry and a light aggrogremetry PFA 100 platelet
analyzer to assess platelet activation after injury. The platelet analyzer functions by measuring occlusion of a porous membrane after platelet activation. The authors
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reported significantly impaired platelet function in 6 non-survivors compared to 94 survivors. In a separate analysis closure was prolonged in 22 patients with head
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injury at 24-hours despite normal platelet function at admission. Additionally, flow cytometry demonstrated elevation of all three platelet activation parameters (Pselectin, GpIIb-IIIa and platelet microparticles) in trauma patients compared to uninjured controls [34]. However, no association was found between platelet function and other outcomes.
Inspired by these findings, our group studied platelet function in 101 severely-
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injured trauma patients on arrival and then serially to 120 hours using impedance aggregrometry. A battery of agonists were selected to test the primary mechanisms of platelet function: adenosine diphosphate (ADP) via P2 receptors, thrombin receptor activating peptide 6 (TRAP) via PAR receptors, arachidonic acid (AA) via
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the cyclo-oxygenase pathway, and collagen via GpIa-IIa and GpVI receptors. While no patient had thrombocytopenia upon arrival, 46% of patients had impaired
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platelet function to at least one agonist at admission and 91.1% had impaired function during the first 120 hours of hospitalization [35]. Impaired admission platelet function to AA, collagen, and TRAP were predictive of death. An Austrian group separately reported platelet hypo-responsiveness in patients after injury, with decreased platelet function to ADP and TRAP more frequent in non-survivors than in patients who survived their injuries [36]. Additional thrombelastograph platelet mapping data from the Denver group demonstrated that severely injured trauma patients had impaired median ADP and AA stimulation after trauma as
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compared to healthy human volunteers [37]. As in other cohorts, impaired platelet function correlated with severity of injury.
1.6 CHANGES IN RESUSCITATION
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Beginning in the early 2000s, retrospective data from the US military campaigns in Afghanistan and Iraq suggested that injured warfighters who received a balanced ratio of packed red blood cells to plasma were more likely to survive [38].
Subsequent retrospective studies in civilian populations showed similar benefits
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using a 1:1:1 ratio of PRBCs, FFP and platelets [39, 40]. Rapidly, the resuscitation paradigm shifted away from utilizing large volume crystalloid towards balanced
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blood product resuscitation.
However, despite this general change in practice, no prospective or randomized trial had established the benefit of balanced hemostatic resuscitation raising the concern that the retrospective results were possibly attributable to survival bias [41]. Two trials were conducted to address this concern. The Prospective, Observational, Multicenter, Major Trauma Transfusion study (PROMMTT) was a prospective
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observational trial of 1245 patients which ultimately confirmed reduced 6-hour mortality in injured patients who received increased plasma to PRBC ratios [42]. The Pragmatic, Randomized Optimal Platelet and Plasma Ratios trial (PROPPR) was a prospective trial which randomized severely-injured patients to resuscitation
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using a 1:1:1 vs 1:1:2 PRBC to FFP to platelet ratio. This trial ultimately failed to demonstrate a difference between resuscitation groups for 24 hour and 28 day
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mortality [43]. The lack of difference may have been attributable to poor separation between treatment groups; pre-randomization transfusion was not accounted for and patients who died or came off protocol early did not have time to receive the intervention. Ultimately, the ideal transfusion ratio of PRBC to FFP to platelets remains unknown. However, there is clear consensus that balanced resuscitation with the goal of recreating whole blood from components while limiting crystalloid has become the standard of care.
1.7 CONCLUSION 8
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In summary, over the past 15 years there has been significant change in the understanding and treatment of coagulopathy in critically injured patients. Acute traumatic coagulopathy has been identified as independent from iatrogenic and resuscitation-associated etiologies of coagulopathy. It has been characterized as
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hypocoagulable state arising in the setting of tissue injury and hypoperfusion and is mediated by activation of the Protein C pathway, resulting in retarded clot
formation and hyperfibrinolysis. However, activated Protein C is likely only one of multiple implicated pathways, which underscores the importance of ongoing
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investigation of other mediators of coagulopathy. Platelet count and function are now understood to be critical players in post-injury physiology and are closely
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linked with outcomes. Resuscitation practice has also undergone evolution to a current model of balanced product transfusion. Mechanistic understanding underlying the efficacy of hemostatic resuscitation remains uncertain and may be attributable either to reversal of coagulopathy or to correction of endotheliopathy. The relative contribution of coagulation versus inflammation on ATC has yet to be determined. Current and ongoing research efforts include further characterization
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of the effects of aPC pathway, the role of other components and mechanisms in traumatic coagulopathy, and determination of optimal transfusion ratios and platelet targets for optimal resuscitation of the severely injured patient.
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Development and current understanding of the mechanisms, implicated mediators, and physiology of Acute Traumatic Coagulopathy Role of the activated Protein C pathway. Resuscitation practice, including the evidence for balanced product administration, importance of platelet count and function. ongoing knowledge deficits in traumatic coagulopathy and resuscitation as directions for future investigation.
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