Thrombosis Research 133 (2014) S25–S27
Contents lists available at ScienceDirect
Thrombosis Research journal homepage: www.elsevier.com/locate/thromres
Regular Article
Acute traumatic coagulopathy: Clinical characterization and mechanistic investigation Mitchell Jay Cohen ⁎ Department of Surgery San Francisco General Hospital, The University of California San Francisco, San Francisco, CA, USA
a r t i c l e
i n f o
Keywords: Trauma Coagulation Coagulopathy Protein C Bleeding Resuscitation
a b s t r a c t Trauma remains the leading cause of death and morbidity worldwide and bleeding is the primary reason for this mortality. Over the past 11 years there has been a paradigm shift in our understanding of coagulopathy after trauma. Specifically its incidence, biological drivers, clinical sequalie have been elucidated. From this understanding a concurrent change in resuscitation practices has occurred. This manuscript will review the history of resuscitation after injury, the discovery and clinical and biological characterization of acute traumatic coagulopathy and the changes in resuscitation practices aimed at combating coagulopathy and inflammatory perturbation after trauma. Finally it will discuss the ongoing state of the science and suggest topics for continued biological and clinical study. © 2014 Published by Elsevier Ltd.
Trauma remains the leading cause of death worldwide with bleeding representing the primary cause of these preventable deaths [1]. The understanding of coagulation biology and its effect on the outcomes of severely injured patients has evolved considerably over the past few years and these new understandings have guided our resuscitation practices in turn improving outcome [2]. Hence here we aim to review the current understanding and recent advances in coagulation biology and suggest the knowledge gaps and needed future research to both improve our mechanistic understanding as well as guide our resuscitation practices for severely injured patients. Prior to 2003 there was a complicit understanding among those who cared for trauma patients that any coagulation perturbations resulted from the unfortunate iatrogenic sequelae of then believed beneficial resuscitation strategies centered solely around oxygen delivery [3,4]. Left with components in the blood bank due to advances in component separation and guided by luminary work in the understanding of shock resuscitation [5,6] the period from the late 1970s until the early 2000s was characterized by large volume packed red blood cell and crystalloid resuscitation with little attention paid to coagulation or inflammation biology [7]. Indeed the clinical mantra kept (and the data seemed to suggest) that what our severely injured patients needed after injury and shock was oxygen carrying capacity (given in packed red blood cells) and flow (provided by large volume crystalloid resuscitation)[7]. Any inflammatory or coagulation perturbations were of secondary
⁎ Department of Surgery, Ward 3A, San Francisco General Hospital, 1001 Potrero Avenue, Room 3C-38, San Francisco, CA 94110, United States. E-mail address: [email protected].
http://dx.doi.org/10.1016/j.thromres.2014.03.013 0049-3848/© 2014 Published by Elsevier Ltd.
importance to delivering oxygen to hypoperfused cells and tissues. As a result of these practices and thinking, coagulopathy was thought to result entirely from the iatrogenic effects of these ‘beneficial’ resuscitation practices. These iatrogenic effects include hypothermia (for which there is a vast literature detailing the effects of decreased temperature on thrombin production and platelet function), dilution (with a similar literature detailing the effects of factor dilution and depletion on clot) and acidosis (with similar data to dilution and hypothermia [8,9]. Taken together these effects now termed ‘iatrogenic coagulopathy’ were thought be unfortunate but necessary effects of our resuscitation. An extensive volume of literature detailing methods to mitigate significant hypothermia, dilution and acidosis emerged from this period [10]. While the iatrogenic effects were (and are) true and significant, many clinicians were anecdotally observing a separate coagulopathy which occurred independent of or prior to these iatrogenic insults. Working independently Brohi and Macleod published data in 2003 suggesting that there was an acute traumatic coagulopathy (ATC) which occurred after severe injury and was independent of iatrogenic causes [11,12]. This ATC was associated with increased mortality with the Brohi group reporting a greater than 4 fold increase in mortality. Armed with this new understanding that an ATC existed after injury, multiple groups began to characterize this newly described ATC. The San Francisco group did the initial characterization and showed that when severe tissue injury (high injury severity score) is associated with tissue hypoperfusion (shock) there is an acute traumatic coagulopathy characterized by elevated INR and PTT with incumbent increased blood transfusion requirements and poor outcomes with longer hospital stays, increased organ failure and mortality [13–15]. Other single center, multicenter, North American and European data followed all of which reported a remarkably similar incidence and result of ATC.
S26
M.J. Cohen / Thrombosis Research 133 (2014) S25–S27
Subsequent characterization suggests that ATC is mediated by activation of the protein C system. Protein C is s serine protease, which is active in a mechanism that involves thrombomodulin, thrombin and EPCR the endothelial protein C receptor [16]. Once active activated protein C proteolytically cleaves factors Va and VIIa and also derepresses fibrinolysis through its inhibitory actions on plasminogen activator inhibitor 1 (PAI-1) which prevents inhibition of tissue plasminogen activator. Interestingly these findings seem to be independent of thrombin production, which is necessary but insufficient to drive ATC. Indeed the presence of tissue injury results in thrombin production, which represents a basic and necessary coagulation response to injury. It is however only when thrombin production is combined with shock that protein C activation occurs, (despite the same level of thrombin production) resulting in ATC. While ATC is now understood as the primary coagulopathy after injury occurring in 25-40% of patients, iatrogenic coagulopathy remains an important adjunctive entity comprising (with ATC) trauma induced coagulopathy (TIC). Of important note is that this coagulopathic response to injury is distinct from the coagulopathy of disseminated intravascular coagulation (DIC)[17]. While ATC fits within the DIC criteria by either Japanese or International standards the mechanisms of ATC are unique with a combination of tissue injury and shock resulting in a specific protein C mediated mechanism. DIC in contrast results from overwhelming dysregulated action of clotting without specific mechanism. Indeed the protein C mediated ATC seems to result from an overzealous inflammomodulatory response of the protein C system which teleologically is aimed at maintaining endothelial and epithelial integrity and preventing cellular death. While the initial hypocoagulability after injury remains a hot topic with extreme interest in the trauma and basic science community, this hypocoagulable milieu transitions quickly to a hypercoaguable state with resultant thrombotic and hyperinflammatory sequelae. Indeed data suggests that after activation of protein C and resultant ATC patients quickly deplete their protein C stores and transition to a dysregulated inflammatory and procoagulant milieu with associated increased propensity to organ failure and infection [18]. Armed with these clinical findings several groups translated these findings into basic laboratory investigations aimed at elucidating the mechanisms behind ATC. Chesebro and colleagues reported in 2008 the first mouse model of ATC and recapitulated the finding in humans that shock and injury were necessary to drive ATC [19]. Antibody blockade of the protease domain of aPC rescued the coagulopathy back to normal. Interestingly when both the protease domain and cytoprotective domains (binding EPCR and PAR-1) were blocked none of the mice survived the initial injury and shock period, suggesting that the aPC response was necessary for survival and the sequelae of anticoagulation and ATC which has been observed in humans and animals is a ‘too much of a good thing’ maladaptive response to severe injury and shock. This cytoprotective effect of aPC has been elucidated in cell and murine models of sepsis, which further suggests that the aPC response is necessary for ‘inflammatory’ survival through the acute phase after both sterile injury and sepsis. In addition to the initial murine characterization coagulopathic work on ATC has been recapitulated in rat and larger animal models of by several groups [20]. In addition to elucidating the mechanisms involving thrombin and fibrin formation there is newer data detailing a platelet dysfunction after injury. Kutcher et al. recently published that along with the activated protein C mediated ATC there is a profound platelet dysfunction associated with injury and shock. Despite normal platelet counts there was platelet dysfunction (as measured by impedance aggregometry) in nearly 50% of patients on arrival to the emergency department. Building on this work others have corroborated and extended these findings. While it is a primary mechanism for ATC, we clearly acknowledge that protein C is likely only one mechanistic phenotype [21]. Others have published on the effects of fibrinogen, factor depletion, tissue factor activation and other anticoagulant mechanisms in the dysfunction of
coagulation after injury [22,23]. Each of these topics remains the topic of considerable investigative effort. One group has published a hypothesis suggesting a mechanistic connection between noradrenergic activation, endothelial dysfunction and injury [24]. While intriguing this hypothesis is thus far limited to correlative data and awaits mechanistic exploration. Drawing from this initial characterization work many other groups have worked hard on early measurement and prediction of coagulation after injury and coordinating hemostatic resuscitation. In the prediction arena there has been significant renewed interest in using viscoelastic testing in the measurement of coagulation after injury. These viscoelastic tests have gained significant attention with at least one center having completely abandoned conventional coagulation tests in the emergency department and operating room. To date however the data remains mixed and significant work remains to correlate clinical coagulation tests to the underlying biology of clot formation, and relevance to outcome. As with any complex biological system, a large portion of the problem with rapid and accurate measurement tools is the degree of confounding clinical data made more complex by a still poorly characterized biological mechanism. Indeed because of the collinearity of the coagulation protease activation cascade and significant treatment confounding in the trauma arena, advanced statistical techniques and modeling will likely be necessary for both mechanistic clarity and useful inference to guide clinical treatment [25,26]. Despite these difficulties with accurate prediction and limited biological understanding of ATC, military and civilian data has shown that reproducing whole blood by transfusing injured patients with a balanced ratio of packed blood red cells, plasma and platelets was associated with reduced mortality [27–29]. As a result even as the knowledge of ATC is rapidly evolving the trauma community has largely adopted a resuscitation practice centered around hemostatic resuscitation which seeks to minimize crystalloid resuscitation and provide a balanced plasma based resuscitation [30]. This clinical topic, which is covered extensively elsewhere, has been the result of and driver of considerable work aimed at detailing the effects of these resuscitation practices on coagulation, inflammation and endothelial biology. Indeed whether hemostatic resuscitation actually ‘fixes’ acute traumatic coagulopathy remains unclear. Initial longitudinal evidence suggests repletion of some but not all clotting factors and only partial effects on platelet function. Taken together while ATC is conclusively an entity of biological importance and while the mortality benefits of hemostatic resuscitation are now widely accepted, there far too little understanding to date of the underlying mechanisms and biological drivers of coagulopathy, as well as the resultant effects on hemostatic resuscitation. Together these represent a clinically crucial and mechanistically interesting question, which should drive both basic and clinical research for many years. Conflict of Interest Statement The authors declare there is no conflict of interest. References [1] Kirkpatrick AW, Chun R, Brown R, Simons RK. Hypothermia and the trauma patient. Can J Surg 1999;42(5):333–43. [2] Cohen MJ, Kutcher M, Redick B, Nelson M, Call M, Knudson MM, et al. Clinical and mechanistic drivers of acute traumatic coagulopathy. J Trauma Acute Care Surg 2013;75(1 Suppl 1):S40–7. [3] Holcomb JB. Traditional transfusion practices are changing. Crit Care 2011;14(3):162. [4] Holcomb JB, Jenkins D, Rhee P, Johannigman J, Mahoney P, Mehta S, et al. Damage control resuscitation: directly addressing the early coagulopathy of trauma. J Trauma 2007;62(2):307–10. [5] Shires GT. Pathophysiology and fluid replacement in hypovolemic shock. Ann Clin Res 1977;9(3):144–50. [6] Shoemaker WC, Peitzman AB, Bellamy R, Bellomo R, Bruttig SP, Capone A, et al. Resuscitation from severe hemorrhage. Crit Care Med 1996;24(2 Suppl):S12–23.
M.J. Cohen / Thrombosis Research 133 (2014) S25–S27 [7] Cohen MJ. Towards hemostatic resuscitation: the changing understanding of acute traumatic biology, massive bleeding, and damage-control resuscitation. Surg Clin North Am 2012;92(4):877–91 [viii]. [8] Cosgriff N, Moore EE, Sauaia A, Kenny-Moynihan M, Burch JM, Galloway B. Predicting life-threatening coagulopathy in the massively transfused trauma patient: hypothermia and acidoses revisited. J Trauma 1997;42(5):857–61 [discussion 61–2]. [9] Duchesne JC, Barbeau JM, Islam TM, Wahl G, Greiffenstein P, McSwain Jr NE. Damage control resuscitation: from emergency department to the operating room. Am Surg 2011;77(2):201–6. [10] Rotondo MF, Zonies DH. The damage control sequence and underlying logic. Surg Clin North Am 1997;77(4):761–77. [11] Brohi K, Singh J, Heron M, Coats T. Acute traumatic coagulopathy. J Trauma 2003;54(6):1127–30. [12] MacLeod JB, Lynn M, McKenney MG, Cohn SM, Murtha M. Early coagulopathy predicts mortality in trauma. J Trauma 2003;55(1):39–44. [13] Brohi K, Cohen MJ, Ganter MT, Matthay MA, Mackersie RC, Pittet JF. Acute traumatic coagulopathy: initiated by hypoperfusion: modulated through the protein C pathway? Ann Surg 2007;245(5):812–8. [14] Cohen MJ, Brohi K, Ganter MT, Manley GT, Mackersie RC, Pittet JF. Early coagulopathy after traumatic brain injury: the role of hypoperfusion and the protein C pathway. J Trauma 2007;63(6):1254–61 [discussion 61–2]. [15] Cohen MJ, Call M, Nelson M, Calfee CS, Esmon CT, Brohi K, et al. Critical Role of Activated Protein C in Early Coagulopathy and Later Organ Failure, Infection and Death in Trauma Patients. Ann Surg 2011. [16] Esmon CT. The protein C pathway. Chest 2003;124(3 Suppl):26S–32S. [17] Hess JR, Lawson JH. The coagulopathy of trauma versus disseminated intravascular coagulation. J Trauma 2006;60(6 Suppl):S12–9. [18] Cohen MJ, Call M, Nelson M, Calfee CS, Esmon CT, Brohi K, et al. Critical role of activated protein C in early coagulopathy and later organ failure, infection and death in trauma patients. Ann Surg 2012;255(2):379–85. [19] Chesebro BB, Rahn P, Carles M, Esmon CT, Xu J, Brohi K, et al. Increase in activated protein C mediates acute traumatic coagulopathy in mice. Shock 2009;32(6):659–65.
S27
[20] Brohi K, Cohen MJ, Ganter MT, Schultz MJ, Levi M, Mackersie RC, et al. Acute coagulopathy of trauma: hypoperfusion induces systemic anticoagulation and hyperfibrinolysis. J Trauma 2008;64(5):1211–7 [discussion 7]. [21] Maegele M, Schochl H, Cohen MJ. An Up-date on the Coagulopathy of Trauma. Shock 2013. [22] Hess JR, Holcomb JB, Hoyt DB. Damage control resuscitation: the need for specific blood products to treat the coagulopathy of trauma. Transfusion 2006;46(5):685–6. [23] Martini WZ, Holcomb JB. Acidosis and coagulopathy: the differential effects on fibrinogen synthesis and breakdown in pigs. Ann Surg 2007;246(5):831–5. [24] Ostrowski SR, Berg RM, Windelov NA, Meyer MA, Plovsing RR, Moller K, et al. Coagulopathy, catecholamines, and biomarkers of endothelial damage in experimental human endotoxemia and in patients with severe sepsis: a prospective study. J Crit Care 2013;28(5):586–96. [25] Kutcher ME, Ferguson AR, Cohen MJ. A principal component analysis of coagulation after trauma. J Trauma Acute Care Surg 2013;74(5):1223–9 [discussion 9–30]. [26] Van der Laan M, Mark J. Statistical Inference for Variable Importance. Int J Biostat 2006;2(1):2. [27] Borgman MA, Spinella PC, Perkins JG, Grathwohl KW, Repine T, Beekley AC, et al. The ratio of blood products transfused affects mortality in patients receiving massive transfusions at a combat support hospital. J Trauma 2007;63(4):805–13. [28] Holcomb JB, Del Junco DJ, Fox EE, Wade CE, Cohen MJ, Schreiber MA, et al. The Prospective, Observational, Multicenter, Major Trauma Transfusion (PROMMTT) Study: Comparative Effectiveness of a Time-Varying Treatment With Competing Risks. Arch Surg 2012:1–10. [29] Holcomb JB, Wade CE, Michalek JE, Chisholm GB, Zarzabal LA, Schreiber MA, et al. Increased plasma and platelet to red blood cell ratios improves outcome in 466 massively transfused civilian trauma patients. Ann Surg 2008;248(3):447–58. [30] Kutcher ME, Kornblith LZ, Narayan R, Curd V, Daley AT, Redick BJ, et al. A paradigm shift in trauma resuscitation: evaluation of evolving massive transfusion practices. JAMA Surg 2013;148(9):834–40.
Contents lists available at ScienceDirect
Thrombosis Research journal homepage: www.elsevier.com/locate/thromres
Regular Article
Acute traumatic coagulopathy: Clinical characterization and mechanistic investigation Mitchell Jay Cohen ⁎ Department of Surgery San Francisco General Hospital, The University of California San Francisco, San Francisco, CA, USA
a r t i c l e
i n f o
Keywords: Trauma Coagulation Coagulopathy Protein C Bleeding Resuscitation
a b s t r a c t Trauma remains the leading cause of death and morbidity worldwide and bleeding is the primary reason for this mortality. Over the past 11 years there has been a paradigm shift in our understanding of coagulopathy after trauma. Specifically its incidence, biological drivers, clinical sequalie have been elucidated. From this understanding a concurrent change in resuscitation practices has occurred. This manuscript will review the history of resuscitation after injury, the discovery and clinical and biological characterization of acute traumatic coagulopathy and the changes in resuscitation practices aimed at combating coagulopathy and inflammatory perturbation after trauma. Finally it will discuss the ongoing state of the science and suggest topics for continued biological and clinical study. © 2014 Published by Elsevier Ltd.
Trauma remains the leading cause of death worldwide with bleeding representing the primary cause of these preventable deaths [1]. The understanding of coagulation biology and its effect on the outcomes of severely injured patients has evolved considerably over the past few years and these new understandings have guided our resuscitation practices in turn improving outcome [2]. Hence here we aim to review the current understanding and recent advances in coagulation biology and suggest the knowledge gaps and needed future research to both improve our mechanistic understanding as well as guide our resuscitation practices for severely injured patients. Prior to 2003 there was a complicit understanding among those who cared for trauma patients that any coagulation perturbations resulted from the unfortunate iatrogenic sequelae of then believed beneficial resuscitation strategies centered solely around oxygen delivery [3,4]. Left with components in the blood bank due to advances in component separation and guided by luminary work in the understanding of shock resuscitation [5,6] the period from the late 1970s until the early 2000s was characterized by large volume packed red blood cell and crystalloid resuscitation with little attention paid to coagulation or inflammation biology [7]. Indeed the clinical mantra kept (and the data seemed to suggest) that what our severely injured patients needed after injury and shock was oxygen carrying capacity (given in packed red blood cells) and flow (provided by large volume crystalloid resuscitation)[7]. Any inflammatory or coagulation perturbations were of secondary
⁎ Department of Surgery, Ward 3A, San Francisco General Hospital, 1001 Potrero Avenue, Room 3C-38, San Francisco, CA 94110, United States. E-mail address: [email protected].
http://dx.doi.org/10.1016/j.thromres.2014.03.013 0049-3848/© 2014 Published by Elsevier Ltd.
importance to delivering oxygen to hypoperfused cells and tissues. As a result of these practices and thinking, coagulopathy was thought to result entirely from the iatrogenic effects of these ‘beneficial’ resuscitation practices. These iatrogenic effects include hypothermia (for which there is a vast literature detailing the effects of decreased temperature on thrombin production and platelet function), dilution (with a similar literature detailing the effects of factor dilution and depletion on clot) and acidosis (with similar data to dilution and hypothermia [8,9]. Taken together these effects now termed ‘iatrogenic coagulopathy’ were thought be unfortunate but necessary effects of our resuscitation. An extensive volume of literature detailing methods to mitigate significant hypothermia, dilution and acidosis emerged from this period [10]. While the iatrogenic effects were (and are) true and significant, many clinicians were anecdotally observing a separate coagulopathy which occurred independent of or prior to these iatrogenic insults. Working independently Brohi and Macleod published data in 2003 suggesting that there was an acute traumatic coagulopathy (ATC) which occurred after severe injury and was independent of iatrogenic causes [11,12]. This ATC was associated with increased mortality with the Brohi group reporting a greater than 4 fold increase in mortality. Armed with this new understanding that an ATC existed after injury, multiple groups began to characterize this newly described ATC. The San Francisco group did the initial characterization and showed that when severe tissue injury (high injury severity score) is associated with tissue hypoperfusion (shock) there is an acute traumatic coagulopathy characterized by elevated INR and PTT with incumbent increased blood transfusion requirements and poor outcomes with longer hospital stays, increased organ failure and mortality [13–15]. Other single center, multicenter, North American and European data followed all of which reported a remarkably similar incidence and result of ATC.
S26
M.J. Cohen / Thrombosis Research 133 (2014) S25–S27
Subsequent characterization suggests that ATC is mediated by activation of the protein C system. Protein C is s serine protease, which is active in a mechanism that involves thrombomodulin, thrombin and EPCR the endothelial protein C receptor [16]. Once active activated protein C proteolytically cleaves factors Va and VIIa and also derepresses fibrinolysis through its inhibitory actions on plasminogen activator inhibitor 1 (PAI-1) which prevents inhibition of tissue plasminogen activator. Interestingly these findings seem to be independent of thrombin production, which is necessary but insufficient to drive ATC. Indeed the presence of tissue injury results in thrombin production, which represents a basic and necessary coagulation response to injury. It is however only when thrombin production is combined with shock that protein C activation occurs, (despite the same level of thrombin production) resulting in ATC. While ATC is now understood as the primary coagulopathy after injury occurring in 25-40% of patients, iatrogenic coagulopathy remains an important adjunctive entity comprising (with ATC) trauma induced coagulopathy (TIC). Of important note is that this coagulopathic response to injury is distinct from the coagulopathy of disseminated intravascular coagulation (DIC)[17]. While ATC fits within the DIC criteria by either Japanese or International standards the mechanisms of ATC are unique with a combination of tissue injury and shock resulting in a specific protein C mediated mechanism. DIC in contrast results from overwhelming dysregulated action of clotting without specific mechanism. Indeed the protein C mediated ATC seems to result from an overzealous inflammomodulatory response of the protein C system which teleologically is aimed at maintaining endothelial and epithelial integrity and preventing cellular death. While the initial hypocoagulability after injury remains a hot topic with extreme interest in the trauma and basic science community, this hypocoagulable milieu transitions quickly to a hypercoaguable state with resultant thrombotic and hyperinflammatory sequelae. Indeed data suggests that after activation of protein C and resultant ATC patients quickly deplete their protein C stores and transition to a dysregulated inflammatory and procoagulant milieu with associated increased propensity to organ failure and infection [18]. Armed with these clinical findings several groups translated these findings into basic laboratory investigations aimed at elucidating the mechanisms behind ATC. Chesebro and colleagues reported in 2008 the first mouse model of ATC and recapitulated the finding in humans that shock and injury were necessary to drive ATC [19]. Antibody blockade of the protease domain of aPC rescued the coagulopathy back to normal. Interestingly when both the protease domain and cytoprotective domains (binding EPCR and PAR-1) were blocked none of the mice survived the initial injury and shock period, suggesting that the aPC response was necessary for survival and the sequelae of anticoagulation and ATC which has been observed in humans and animals is a ‘too much of a good thing’ maladaptive response to severe injury and shock. This cytoprotective effect of aPC has been elucidated in cell and murine models of sepsis, which further suggests that the aPC response is necessary for ‘inflammatory’ survival through the acute phase after both sterile injury and sepsis. In addition to the initial murine characterization coagulopathic work on ATC has been recapitulated in rat and larger animal models of by several groups [20]. In addition to elucidating the mechanisms involving thrombin and fibrin formation there is newer data detailing a platelet dysfunction after injury. Kutcher et al. recently published that along with the activated protein C mediated ATC there is a profound platelet dysfunction associated with injury and shock. Despite normal platelet counts there was platelet dysfunction (as measured by impedance aggregometry) in nearly 50% of patients on arrival to the emergency department. Building on this work others have corroborated and extended these findings. While it is a primary mechanism for ATC, we clearly acknowledge that protein C is likely only one mechanistic phenotype [21]. Others have published on the effects of fibrinogen, factor depletion, tissue factor activation and other anticoagulant mechanisms in the dysfunction of
coagulation after injury [22,23]. Each of these topics remains the topic of considerable investigative effort. One group has published a hypothesis suggesting a mechanistic connection between noradrenergic activation, endothelial dysfunction and injury [24]. While intriguing this hypothesis is thus far limited to correlative data and awaits mechanistic exploration. Drawing from this initial characterization work many other groups have worked hard on early measurement and prediction of coagulation after injury and coordinating hemostatic resuscitation. In the prediction arena there has been significant renewed interest in using viscoelastic testing in the measurement of coagulation after injury. These viscoelastic tests have gained significant attention with at least one center having completely abandoned conventional coagulation tests in the emergency department and operating room. To date however the data remains mixed and significant work remains to correlate clinical coagulation tests to the underlying biology of clot formation, and relevance to outcome. As with any complex biological system, a large portion of the problem with rapid and accurate measurement tools is the degree of confounding clinical data made more complex by a still poorly characterized biological mechanism. Indeed because of the collinearity of the coagulation protease activation cascade and significant treatment confounding in the trauma arena, advanced statistical techniques and modeling will likely be necessary for both mechanistic clarity and useful inference to guide clinical treatment [25,26]. Despite these difficulties with accurate prediction and limited biological understanding of ATC, military and civilian data has shown that reproducing whole blood by transfusing injured patients with a balanced ratio of packed blood red cells, plasma and platelets was associated with reduced mortality [27–29]. As a result even as the knowledge of ATC is rapidly evolving the trauma community has largely adopted a resuscitation practice centered around hemostatic resuscitation which seeks to minimize crystalloid resuscitation and provide a balanced plasma based resuscitation [30]. This clinical topic, which is covered extensively elsewhere, has been the result of and driver of considerable work aimed at detailing the effects of these resuscitation practices on coagulation, inflammation and endothelial biology. Indeed whether hemostatic resuscitation actually ‘fixes’ acute traumatic coagulopathy remains unclear. Initial longitudinal evidence suggests repletion of some but not all clotting factors and only partial effects on platelet function. Taken together while ATC is conclusively an entity of biological importance and while the mortality benefits of hemostatic resuscitation are now widely accepted, there far too little understanding to date of the underlying mechanisms and biological drivers of coagulopathy, as well as the resultant effects on hemostatic resuscitation. Together these represent a clinically crucial and mechanistically interesting question, which should drive both basic and clinical research for many years. Conflict of Interest Statement The authors declare there is no conflict of interest. References [1] Kirkpatrick AW, Chun R, Brown R, Simons RK. Hypothermia and the trauma patient. Can J Surg 1999;42(5):333–43. [2] Cohen MJ, Kutcher M, Redick B, Nelson M, Call M, Knudson MM, et al. Clinical and mechanistic drivers of acute traumatic coagulopathy. J Trauma Acute Care Surg 2013;75(1 Suppl 1):S40–7. [3] Holcomb JB. Traditional transfusion practices are changing. Crit Care 2011;14(3):162. [4] Holcomb JB, Jenkins D, Rhee P, Johannigman J, Mahoney P, Mehta S, et al. Damage control resuscitation: directly addressing the early coagulopathy of trauma. J Trauma 2007;62(2):307–10. [5] Shires GT. Pathophysiology and fluid replacement in hypovolemic shock. Ann Clin Res 1977;9(3):144–50. [6] Shoemaker WC, Peitzman AB, Bellamy R, Bellomo R, Bruttig SP, Capone A, et al. Resuscitation from severe hemorrhage. Crit Care Med 1996;24(2 Suppl):S12–23.
M.J. Cohen / Thrombosis Research 133 (2014) S25–S27 [7] Cohen MJ. Towards hemostatic resuscitation: the changing understanding of acute traumatic biology, massive bleeding, and damage-control resuscitation. Surg Clin North Am 2012;92(4):877–91 [viii]. [8] Cosgriff N, Moore EE, Sauaia A, Kenny-Moynihan M, Burch JM, Galloway B. Predicting life-threatening coagulopathy in the massively transfused trauma patient: hypothermia and acidoses revisited. J Trauma 1997;42(5):857–61 [discussion 61–2]. [9] Duchesne JC, Barbeau JM, Islam TM, Wahl G, Greiffenstein P, McSwain Jr NE. Damage control resuscitation: from emergency department to the operating room. Am Surg 2011;77(2):201–6. [10] Rotondo MF, Zonies DH. The damage control sequence and underlying logic. Surg Clin North Am 1997;77(4):761–77. [11] Brohi K, Singh J, Heron M, Coats T. Acute traumatic coagulopathy. J Trauma 2003;54(6):1127–30. [12] MacLeod JB, Lynn M, McKenney MG, Cohn SM, Murtha M. Early coagulopathy predicts mortality in trauma. J Trauma 2003;55(1):39–44. [13] Brohi K, Cohen MJ, Ganter MT, Matthay MA, Mackersie RC, Pittet JF. Acute traumatic coagulopathy: initiated by hypoperfusion: modulated through the protein C pathway? Ann Surg 2007;245(5):812–8. [14] Cohen MJ, Brohi K, Ganter MT, Manley GT, Mackersie RC, Pittet JF. Early coagulopathy after traumatic brain injury: the role of hypoperfusion and the protein C pathway. J Trauma 2007;63(6):1254–61 [discussion 61–2]. [15] Cohen MJ, Call M, Nelson M, Calfee CS, Esmon CT, Brohi K, et al. Critical Role of Activated Protein C in Early Coagulopathy and Later Organ Failure, Infection and Death in Trauma Patients. Ann Surg 2011. [16] Esmon CT. The protein C pathway. Chest 2003;124(3 Suppl):26S–32S. [17] Hess JR, Lawson JH. The coagulopathy of trauma versus disseminated intravascular coagulation. J Trauma 2006;60(6 Suppl):S12–9. [18] Cohen MJ, Call M, Nelson M, Calfee CS, Esmon CT, Brohi K, et al. Critical role of activated protein C in early coagulopathy and later organ failure, infection and death in trauma patients. Ann Surg 2012;255(2):379–85. [19] Chesebro BB, Rahn P, Carles M, Esmon CT, Xu J, Brohi K, et al. Increase in activated protein C mediates acute traumatic coagulopathy in mice. Shock 2009;32(6):659–65.
S27
[20] Brohi K, Cohen MJ, Ganter MT, Schultz MJ, Levi M, Mackersie RC, et al. Acute coagulopathy of trauma: hypoperfusion induces systemic anticoagulation and hyperfibrinolysis. J Trauma 2008;64(5):1211–7 [discussion 7]. [21] Maegele M, Schochl H, Cohen MJ. An Up-date on the Coagulopathy of Trauma. Shock 2013. [22] Hess JR, Holcomb JB, Hoyt DB. Damage control resuscitation: the need for specific blood products to treat the coagulopathy of trauma. Transfusion 2006;46(5):685–6. [23] Martini WZ, Holcomb JB. Acidosis and coagulopathy: the differential effects on fibrinogen synthesis and breakdown in pigs. Ann Surg 2007;246(5):831–5. [24] Ostrowski SR, Berg RM, Windelov NA, Meyer MA, Plovsing RR, Moller K, et al. Coagulopathy, catecholamines, and biomarkers of endothelial damage in experimental human endotoxemia and in patients with severe sepsis: a prospective study. J Crit Care 2013;28(5):586–96. [25] Kutcher ME, Ferguson AR, Cohen MJ. A principal component analysis of coagulation after trauma. J Trauma Acute Care Surg 2013;74(5):1223–9 [discussion 9–30]. [26] Van der Laan M, Mark J. Statistical Inference for Variable Importance. Int J Biostat 2006;2(1):2. [27] Borgman MA, Spinella PC, Perkins JG, Grathwohl KW, Repine T, Beekley AC, et al. The ratio of blood products transfused affects mortality in patients receiving massive transfusions at a combat support hospital. J Trauma 2007;63(4):805–13. [28] Holcomb JB, Del Junco DJ, Fox EE, Wade CE, Cohen MJ, Schreiber MA, et al. The Prospective, Observational, Multicenter, Major Trauma Transfusion (PROMMTT) Study: Comparative Effectiveness of a Time-Varying Treatment With Competing Risks. Arch Surg 2012:1–10. [29] Holcomb JB, Wade CE, Michalek JE, Chisholm GB, Zarzabal LA, Schreiber MA, et al. Increased plasma and platelet to red blood cell ratios improves outcome in 466 massively transfused civilian trauma patients. Ann Surg 2008;248(3):447–58. [30] Kutcher ME, Kornblith LZ, Narayan R, Curd V, Daley AT, Redick BJ, et al. A paradigm shift in trauma resuscitation: evaluation of evolving massive transfusion practices. JAMA Surg 2013;148(9):834–40.
