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Hemostatic abnormalities in the acute phase of trauma
Thrombosis Research 126 (2010) 1–2
Contents lists available at ScienceDirect
Thrombosis Research j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / t h r o m r e s
Editorial
Hemostatic abnormalities in the acute phase of trauma
Hemostatic abnormalities after trauma Severe trauma must be considered a systemic disease that can lead to severe systemic complications. Many studies [1–6] of hemostatic abnormalities after trauma have so far been performed, thus describing the prolongation of the prothrombin time (PT), thrombin clotting time and activated partial thromboplastin time (APTT), low platelet counts, prothrombin, fibrinogen and antithrombin activity, a shortened euglobulin lysis time (ELT), increased fibrin and fibrinogen degradation products (FDP), plasmin plasmin inhibitor complex (PPIC), thrombin antithrombin complex (TAT) and D-dimer. Sawamura A et al. [7; page - ] examined 314 patients with severe trauma. Forty-eight of 55 nonsurvivors were complicated with DIC, thus showing a prolonged PT and higher FDP and D-dimer levels in comparison to those of the 289 survivors. Coagulopathy has been reported to be present at admission in 25% of the patients with trauma, and it is also associated with shock and a 5-fold increase in mortality [6]. A hypercoagulable state after such injuries has been examined by many methods and it is sensitively detected by the thrombin generation test (TGT) and rotation thromboelastography (ROTEM) but not by either PT or APTT [8]. Patients demonstrating a hypercoagulable state show dysregulated hemostasis characterized by excessive non-wound-related thrombin generation due to a combination of circulating procoagulants capable of systemically activating coagulation and reduced inhibitor levels, thus allowing systemic thrombin generation to continue once initiated [4]. Complication of DIC after trauma These hemostatic abnormalities after trauma are similar to those in disseminated intravascular coagulation (DIC) [5,9] and are frequently associated with organ failure, severe bleeding and a poor outcome due to massive bleeding [1]. The relationship between hemostatic abnormalities in trauma and DIC has been discussed [10,11], and an increased DIC score reflects an increased mortality associated with trauma [3].Trauma and sepsis after severe trauma is one of the important underlying diseases of DIC. DIC is classified into three types; namely, the asymptomatic type, hyperfibrinolytic type and hypofibrinolytic type in “expert consensus for the treatment of DIC in Japan” [12]. The hypofibrinolytic type which shows high plasma levels of fibrinogen and plasminogen activator inhibitor–I (PAI-I) and a low PPIC/ TAT ratio, usually has a poor outcome [13]. Sepsis exacerbates organ failure due to hypofibrinolyis in several days after the onset of DIC. The mortality of DIC due to trauma is significantly lower than that due to sepsis [14]. The severity of organ failure and hemostatic abnormalities are significantly worse in DIC due to sepsis than DIC due to trauma [14]. The severity of trauma in the study might not be 0049-3848/$ – see front matter © 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.thromres.2009.10.013
markedly severe since the mortality of DIC depends on the severity of the underlying diseases. Sawamura [7] reported that the FDP/D-dimer ratio and lactate levels are significantly higher in the nonsurvivors than those of the survivors. Low fibrinogen levels and a higher FDP/Ddimer ratio suggest fibrinogenolysis due to DIC in nonsurvivors, thus suggesting that severe hyperfibrinolysis may pose a high risk for fatal bleeding in trauma patients. Hemostatic abnormalities are independent predictors of early mortality in moderate-to-severe head injury patients [3]. Hyperfibrinolysis after trauma Hyperfibrinolysis has been observed in the acute phase of trauma [6,15,16] and the relationship between this hyperfibrinolysis and DIC has been discussed. Although hyperfibrinolysis after trauma may be caused by primary fibrinolysis, acute coagulopathy following trauma is associated with systemic hypoperfusion and is characterized by anticoagulation and hyperfibrinolysis [6]. Traumatic brain injury alone does not causes early coagulopathy, but it must be coupled with hypoperfusion in order to lead to coagulation defects associated with the activation of the protein C (PC) pathway [15]. Coagulation is activated and thrombin generation is related to the severity of injury [6]. Thrombin binding to thrombomodulin contributes to hypofibrinolysis via activated PC consumption of PAI-I [6]. Blood loss and uncontrollable bleeding due to hyperfibrinolysis in the early phase of trauma are major factors affecting the survival in patients with trauma, thus suggesting the importance of an early diagnosis of hyperfibrinolysis in patients with severe trauma. ROTEM makes the rapid and accurate detection of hyperfibrinolysis possible in patients with severe trauma [16,17]. ROTEM-based diagnosis of hyperfibrinolysis predicts poor outcome due to hemorrhagic shock [17]. The activation of both the coagulation and fibrinolysis systems explains the low incidence of deep vein thrombosis and pulmonary embolism in patients with severe trauma. Causes of hemostatic abnormalities after trauma Hemostatic abnormalities after trauma may relate to tissue injuries, shock, acidosis, inflammation, hypoperfusion, vascular endothelial cell injuries, platelet activation and hemodilution [1–6]. Thromboplastin (tissue factor; TF), which is abundant in the brain, plays an important role in initiating coagulopathy following head trauma. Early coagulopathy after traumatic brain injury has been thought to be the result of the injury-mediated local release of TF. TF initially activates the extrinsic pathway of blood coagulation and increased expression of TF is observed in thrombotic disorders such as DIC and sepsis [18]. This connection between brain injuries and DIC provides a possible explanation for much
2
Editorial
of the cerebral ischemia associated with hypoperfusion, which accompanies traumatic brain injuries, thus resulting in intravascular microthrombosis [2]. Therefore, TF in trauma is thought to play an important role not only in organ dysfunction but also DIC [10]. Therefore, the early use of high dose antithrombin concentrates could be of importance to prevent DIC and multiple organ failure [5], but this needs verification in controlled clinical studies. Conclusion In conclusion, a report from Sawamura A [7] suggests that the acute phase trauma is frequently accompanied with hyperfibrinolysis, thus contributing to a poor outcome due to massive bleeding. Furthermore, such hyperfibrinolysis may be caused by hypoperfusion and DIC.
[9] [10] [11] [12]
[13]
[14]
[15]
[16]
Conflict of interest statement [17]
Authors have no conflict of interest. References [1] Lozance K, Dejanov I, Mircevski M. Role of coagulopathy in patients with head trauma. J Clin Neurosci 1998;5:394–8. [2] Stein SC, Smith DH. Coagulopathy in traumatic brain injury. Neurocrit Care 2004;1:479–88. [3] Saggar V, Mittal RS, Vyas MC. Hemostatic Abnormalities in Patients with Closed Head Injuries and Their Role in Predicting Early Mortality. J Neurotrauma 2009;26: 1665–8. [4] Dunbar NM, Chandler WL. Thrombin generation in trauma patients. Transfusion Aug 4 2009 [Electronic publication ahead of print]. [5] Miniello S, Testini M, Balzanelli MG, Cristallo G. Coagulation disorders following severe trauma: surgeon's role in prevention. Ann Ital Chir 2004;75:293–7. [6] 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;64:1211–7. [7] Sawamura A, Hayakawa M, Gando S, Kubota N, Sugano M, Wada T, et al. Disseminated intravascular coagulation with a fibrinolytic phenotype at an early phase of trauma ppredicts mortality. Thromb Res 2009;124:608–13. [8] Park MS, Martini WZ, Dubick MA, Salinas J, Butenas S, Kheirabadi BS, et al. Thromboelastography as a better indicator of hypercoagulable state after injury
[18]
than prothrombin time or activated partial thromboplastin time. J Trauma 2009;67:266–75. Wada H. Disseminated intravascular coagulation. Clin Chim Acta 2004;344:13–21. Gando S. Tissue factor in trauma and organ dysfunction. Semin Thromb Hemost 2006;32:48–53. Hess JR, Lawson JH. The coagulopathy of trauma versus disseminated intravascular coagulation. J Trauma Jun 2006;60(6 Suppl):S12–9. Wada H, Asakura H, Okamoto K, Iba T, Uchiyama T, Kawasugi K, et al. Expert consensus for the treatment of disseminated intravascular coagulation in Japan. Thromb Res 2010;125:6–11. Wada H, Mori Y, Sakakura M, Gabazza EC, Kushiya F, Watanabe M, et al. High plasma levels of fibrinogen are associated with poor outcome. Am J Hematol 2003;72:1–7. Kushimoto S, Gando S, Saitoh D, Ogura H, Mayumi T, Koseki K, et al. Clinical course and outcome of disseminated intravascular coagulation diagnosed by Japanese Association for Acute Medicine acriteria. Comparison between sepsis and trauma. Thromb Haemost 2008;100:1099–105. 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;63:1254–61. Levrat A, Gros A, Rugeri L, Inaba K, Floccard B, Negrier C, et al. Evaluation of rotation thrombelastography for the diagnosis of hyperfibrinolysis in trauma patients. Br J Anaesth 2008;100:792–7. Schöchl H, Frietsch T, Pavelka M, Jámbor C. Hyperfibrinolysis after major trauma: differential diagnosis of lysis patterns and prognostic value of thrombelastometry. J Trauma 2009;67:125–31. Sase T, Wada H, Kamikura Y, Kaneko T, Abe Y, Nishioka J, et al. Tissue factor messenger RNA levels in leukocytes compared with tissue factor antigens in plasma from patients in hypercoagulable state caused by various diseases. Thromb Haemost 2004;92:132–9.
Hideo Wada Department of Molecular and Laboratory Medicine, Mie University Graduate School of Medicine, Tsu, Japan Corresponding author. E-mail address: [email protected]. Takeshi Hatada Department Emergency Medicine, Mie University Graduate School of Medicine, Tsu, Japan 6 October 2009
Contents lists available at ScienceDirect
Thrombosis Research j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / t h r o m r e s
Editorial
Hemostatic abnormalities in the acute phase of trauma
Hemostatic abnormalities after trauma Severe trauma must be considered a systemic disease that can lead to severe systemic complications. Many studies [1–6] of hemostatic abnormalities after trauma have so far been performed, thus describing the prolongation of the prothrombin time (PT), thrombin clotting time and activated partial thromboplastin time (APTT), low platelet counts, prothrombin, fibrinogen and antithrombin activity, a shortened euglobulin lysis time (ELT), increased fibrin and fibrinogen degradation products (FDP), plasmin plasmin inhibitor complex (PPIC), thrombin antithrombin complex (TAT) and D-dimer. Sawamura A et al. [7; page - ] examined 314 patients with severe trauma. Forty-eight of 55 nonsurvivors were complicated with DIC, thus showing a prolonged PT and higher FDP and D-dimer levels in comparison to those of the 289 survivors. Coagulopathy has been reported to be present at admission in 25% of the patients with trauma, and it is also associated with shock and a 5-fold increase in mortality [6]. A hypercoagulable state after such injuries has been examined by many methods and it is sensitively detected by the thrombin generation test (TGT) and rotation thromboelastography (ROTEM) but not by either PT or APTT [8]. Patients demonstrating a hypercoagulable state show dysregulated hemostasis characterized by excessive non-wound-related thrombin generation due to a combination of circulating procoagulants capable of systemically activating coagulation and reduced inhibitor levels, thus allowing systemic thrombin generation to continue once initiated [4]. Complication of DIC after trauma These hemostatic abnormalities after trauma are similar to those in disseminated intravascular coagulation (DIC) [5,9] and are frequently associated with organ failure, severe bleeding and a poor outcome due to massive bleeding [1]. The relationship between hemostatic abnormalities in trauma and DIC has been discussed [10,11], and an increased DIC score reflects an increased mortality associated with trauma [3].Trauma and sepsis after severe trauma is one of the important underlying diseases of DIC. DIC is classified into three types; namely, the asymptomatic type, hyperfibrinolytic type and hypofibrinolytic type in “expert consensus for the treatment of DIC in Japan” [12]. The hypofibrinolytic type which shows high plasma levels of fibrinogen and plasminogen activator inhibitor–I (PAI-I) and a low PPIC/ TAT ratio, usually has a poor outcome [13]. Sepsis exacerbates organ failure due to hypofibrinolyis in several days after the onset of DIC. The mortality of DIC due to trauma is significantly lower than that due to sepsis [14]. The severity of organ failure and hemostatic abnormalities are significantly worse in DIC due to sepsis than DIC due to trauma [14]. The severity of trauma in the study might not be 0049-3848/$ – see front matter © 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.thromres.2009.10.013
markedly severe since the mortality of DIC depends on the severity of the underlying diseases. Sawamura [7] reported that the FDP/D-dimer ratio and lactate levels are significantly higher in the nonsurvivors than those of the survivors. Low fibrinogen levels and a higher FDP/Ddimer ratio suggest fibrinogenolysis due to DIC in nonsurvivors, thus suggesting that severe hyperfibrinolysis may pose a high risk for fatal bleeding in trauma patients. Hemostatic abnormalities are independent predictors of early mortality in moderate-to-severe head injury patients [3]. Hyperfibrinolysis after trauma Hyperfibrinolysis has been observed in the acute phase of trauma [6,15,16] and the relationship between this hyperfibrinolysis and DIC has been discussed. Although hyperfibrinolysis after trauma may be caused by primary fibrinolysis, acute coagulopathy following trauma is associated with systemic hypoperfusion and is characterized by anticoagulation and hyperfibrinolysis [6]. Traumatic brain injury alone does not causes early coagulopathy, but it must be coupled with hypoperfusion in order to lead to coagulation defects associated with the activation of the protein C (PC) pathway [15]. Coagulation is activated and thrombin generation is related to the severity of injury [6]. Thrombin binding to thrombomodulin contributes to hypofibrinolysis via activated PC consumption of PAI-I [6]. Blood loss and uncontrollable bleeding due to hyperfibrinolysis in the early phase of trauma are major factors affecting the survival in patients with trauma, thus suggesting the importance of an early diagnosis of hyperfibrinolysis in patients with severe trauma. ROTEM makes the rapid and accurate detection of hyperfibrinolysis possible in patients with severe trauma [16,17]. ROTEM-based diagnosis of hyperfibrinolysis predicts poor outcome due to hemorrhagic shock [17]. The activation of both the coagulation and fibrinolysis systems explains the low incidence of deep vein thrombosis and pulmonary embolism in patients with severe trauma. Causes of hemostatic abnormalities after trauma Hemostatic abnormalities after trauma may relate to tissue injuries, shock, acidosis, inflammation, hypoperfusion, vascular endothelial cell injuries, platelet activation and hemodilution [1–6]. Thromboplastin (tissue factor; TF), which is abundant in the brain, plays an important role in initiating coagulopathy following head trauma. Early coagulopathy after traumatic brain injury has been thought to be the result of the injury-mediated local release of TF. TF initially activates the extrinsic pathway of blood coagulation and increased expression of TF is observed in thrombotic disorders such as DIC and sepsis [18]. This connection between brain injuries and DIC provides a possible explanation for much
2
Editorial
of the cerebral ischemia associated with hypoperfusion, which accompanies traumatic brain injuries, thus resulting in intravascular microthrombosis [2]. Therefore, TF in trauma is thought to play an important role not only in organ dysfunction but also DIC [10]. Therefore, the early use of high dose antithrombin concentrates could be of importance to prevent DIC and multiple organ failure [5], but this needs verification in controlled clinical studies. Conclusion In conclusion, a report from Sawamura A [7] suggests that the acute phase trauma is frequently accompanied with hyperfibrinolysis, thus contributing to a poor outcome due to massive bleeding. Furthermore, such hyperfibrinolysis may be caused by hypoperfusion and DIC.
[9] [10] [11] [12]
[13]
[14]
[15]
[16]
Conflict of interest statement [17]
Authors have no conflict of interest. References [1] Lozance K, Dejanov I, Mircevski M. Role of coagulopathy in patients with head trauma. J Clin Neurosci 1998;5:394–8. [2] Stein SC, Smith DH. Coagulopathy in traumatic brain injury. Neurocrit Care 2004;1:479–88. [3] Saggar V, Mittal RS, Vyas MC. Hemostatic Abnormalities in Patients with Closed Head Injuries and Their Role in Predicting Early Mortality. J Neurotrauma 2009;26: 1665–8. [4] Dunbar NM, Chandler WL. Thrombin generation in trauma patients. Transfusion Aug 4 2009 [Electronic publication ahead of print]. [5] Miniello S, Testini M, Balzanelli MG, Cristallo G. Coagulation disorders following severe trauma: surgeon's role in prevention. Ann Ital Chir 2004;75:293–7. [6] 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;64:1211–7. [7] Sawamura A, Hayakawa M, Gando S, Kubota N, Sugano M, Wada T, et al. Disseminated intravascular coagulation with a fibrinolytic phenotype at an early phase of trauma ppredicts mortality. Thromb Res 2009;124:608–13. [8] Park MS, Martini WZ, Dubick MA, Salinas J, Butenas S, Kheirabadi BS, et al. Thromboelastography as a better indicator of hypercoagulable state after injury
[18]
than prothrombin time or activated partial thromboplastin time. J Trauma 2009;67:266–75. Wada H. Disseminated intravascular coagulation. Clin Chim Acta 2004;344:13–21. Gando S. Tissue factor in trauma and organ dysfunction. Semin Thromb Hemost 2006;32:48–53. Hess JR, Lawson JH. The coagulopathy of trauma versus disseminated intravascular coagulation. J Trauma Jun 2006;60(6 Suppl):S12–9. Wada H, Asakura H, Okamoto K, Iba T, Uchiyama T, Kawasugi K, et al. Expert consensus for the treatment of disseminated intravascular coagulation in Japan. Thromb Res 2010;125:6–11. Wada H, Mori Y, Sakakura M, Gabazza EC, Kushiya F, Watanabe M, et al. High plasma levels of fibrinogen are associated with poor outcome. Am J Hematol 2003;72:1–7. Kushimoto S, Gando S, Saitoh D, Ogura H, Mayumi T, Koseki K, et al. Clinical course and outcome of disseminated intravascular coagulation diagnosed by Japanese Association for Acute Medicine acriteria. Comparison between sepsis and trauma. Thromb Haemost 2008;100:1099–105. 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;63:1254–61. Levrat A, Gros A, Rugeri L, Inaba K, Floccard B, Negrier C, et al. Evaluation of rotation thrombelastography for the diagnosis of hyperfibrinolysis in trauma patients. Br J Anaesth 2008;100:792–7. Schöchl H, Frietsch T, Pavelka M, Jámbor C. Hyperfibrinolysis after major trauma: differential diagnosis of lysis patterns and prognostic value of thrombelastometry. J Trauma 2009;67:125–31. Sase T, Wada H, Kamikura Y, Kaneko T, Abe Y, Nishioka J, et al. Tissue factor messenger RNA levels in leukocytes compared with tissue factor antigens in plasma from patients in hypercoagulable state caused by various diseases. Thromb Haemost 2004;92:132–9.
Hideo Wada Department of Molecular and Laboratory Medicine, Mie University Graduate School of Medicine, Tsu, Japan Corresponding author. E-mail address: [email protected]. Takeshi Hatada Department Emergency Medicine, Mie University Graduate School of Medicine, Tsu, Japan 6 October 2009