OFFICIAL COMMUNICATIONS OF THE SSC
Comparison of disseminated intravascular coagulation in trauma with coagulopathy of trauma/acute coagulopathy of trauma-shock
Satoshi Gando, Division of Acute and Critical Care Medicine, Department of Anesthesiology and Critical Care Medicine, Hokkaido University Graduate School of Medicine, N15W7, Kita-ku, Sapporo 060-8638, Japan.
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Gando S, Wada H, Kim HK, Kurosawa S, Nielsen JD, Thachil J, Toh C-H, Scientific and Standardization Committee on DIC of the ISTH. Comparison of disseminated intravascular coagulation in trauma with coagulopathy of trauma/acute coagulopathy of trauma-shock. J Thromb Haemost 2012; 10: 2593–5.
Disseminated intravascular coagulation (DIC) has been considered to be one of the main pathogenetic features of traumatic coagulopathy for over three decades . It involves a dynamic imbalance of coagulation, anticoagulation and fibrinolytic pathways with distinct phenotypes induced by trauma. During the early phase of trauma, DIC has a fibrinolytic phenotype, and is associated with hyperfibrin(ogen)olysis and consumptive coagulopathy, contributing to massive hemorrhage. This type of DIC changes, at later stages of trauma, into DIC with a thrombotic phenotype, which gives rise to organ dysfunction, primarily because of fibrin clot deposition . Therefore, both types of DIC are determinants for the prognosis of severely injured trauma patients.
The Educational Initiative on Critical Bleeding in Trauma recently announced new disease entities at the early stage of trauma: coagulopathy of trauma and acute coagulopathy of trauma-shock (COT/ACOTS) . Their premise is that these conditions are distinct from DIC with respect to mechanisms and management, and there is nothing to suggest the process of DIC in the development of COT/ACOTS . Rebuttals to these concepts have been published , but the continued persistence and implications for clinical management result in the need to elucidate the mechanisms of pathologic hemostatic changes at the early stages of trauma.
This article focuses on DIC with a fibrinolytic phenotype, and proposes one concept and six considerations for discussion of the hemostatic changes at the early stage of trauma. The similarities and differences in the mechanisms, diagnosis and treatments between DIC and apparent COT/ACOTS are discussed.
One concept and six considerations
All insults (trauma, infection, and ischemia/reperfusion) bring about similar non-specific body responses, such as inflammation, neuroendocrine discharge, coagulation, and fibrinolysis, to maintain homeostasis, with responses being modified by the conditions derived from the disease itself, such as hypothermia/hyperthermia or shock. Thrombin generation is essential to control the four major hemostatic domains of coagulation, anticoagulation, fibrinolysis, and antifibrinolysis . This subcommittee emphasizes that trauma itself and trauma-induced inflammation lead to a deviation from the norm of this system by increased activation of tissue factor-dependent coagulation and microvascular endothelial injury, which is followed by continuous thrombin generation, and increased fibrinolysis. Collectively, this environment can be expressed as ‘DIC with a fibrinolytic phenotype’, and it occurs during the early stages of trauma.
Historically, DIC was defined simply as a consumption coagulopathy. A great amount of research has provided insights into the mechanisms leading to the coagulopathy, with the resultant awareness that DIC is not a single entity, but, as noted above, involves both fibrinolytic and thrombotic phenotypes. However, all share the same fundamental generation of thrombin driven by tissue factor exposure, whether on microparticles or on cells. We recognize that COT/ACOTS shares this fundamental pathophysiology with DIC, yet there are significant and important differences in terms of quantifiable clinical measurements.
Definition and diagnostic criteria
Any new clinical disease entity must be clearly distinguished from the established existing diseases and syndromes by the use of clear definitions and specific diagnostic criteria. COT/ACOTS patients should therefore be considered independently of patients with DIC diagnosed based on the internationally accepted ISTH DIC scoring systems with regard to their pathophysiology, clinical symptoms, laboratory data, time course, prognosis, and treatments . However, no clear and specific definition with validated diagnostic criteria has been established for COT/ACOTS.
Physiologic and pathologic hemostatic responses in trauma
Differences in the physiologic and pathologic conditions of trauma are important to understand the pathophysiology of DIC and COT/ACOTS. The pathologic reaction of DIC can be clearly distinguished from physiologic hemostasis and wound healing when the DIC diagnostic criteria are used. COT/ACOTS studies that fail to address these aspects have led to inconsistent results and various interpretations of COT/ACOTS [2,5]. One study pointed out that COT/ACOTS is probably one end of the continuum of the normal response to trauma, and is not a distinct pathophysiologic mechanism .
Time courses of hemostatic responses after trauma
Hemostatic change after trauma is a rapidly dynamic process, and the dynamics of the changes should always be evaluated on the basis of the balance between coagulation and fibrinolysis . Therefore, serial measurements of multiple markers of coagulation and fibrinolysis are essential. COT/ACOTS studies use only single-point sampling of the blood on arrival at the emergency department, and lack a control cohort. Caution is required when interpreting these results with respect to hemostasis or pathologic coagulopathy .
The concept of blood coagulation ‘inside’ and ‘outside’ of the vessels
The terms hypercoagulable and hypocoagulable state should be used to clarify whether inside (in the circulation) or outside (in the viscoelastic devices) vessels in pathologic conditions such as DIC and COT/ACOTS. Circulating blood is hypercoagulable in DIC, whereas it is hypocoagulable and difficult to clot following injury, resulting in bleeding. The proposed mechanism of COT/ACOTS is that both blood in the circulation and blood outside the circulation following injury are hypocoagulable [2,6]. However, there is increased thrombin formation in COT/ACOTS, and thus, by definition, the blood must be hypercoagulable in the circulation, even though the viscoelastic assays have indicated otherwise . These results suggest that the hypocoagulable state observed in the viscoelastic assays does not reflect the nature of the blood in the circulation.
Trauma-induced and shock-induced hemostatic changes
Trauma and shock are discussed in combination as traumatic shock, because severely injured trauma patients rarely experience isolated hemorrhagic shock. Traumatic shock is one of the major pathogenetic contributors to DIC in trauma. However, trauma and shock can also independently cause DIC . A mixed study population of patients with penetrating trauma with profound hemorrhagic shock and patients with blunt trauma and only minor tissue injury may inadvertently lead to the conclusion that only trauma with shock is associated with DIC or COT/ACOTS .
Massive bleeding and oozing
Massive bleeding resulting from rupture of large vessels or surgical bleeding and DIC or COT/ACOTS are not synonymous concepts. Furthermore, massive bleeding is distinct from oozing-type non-surgical bleeding at mucosal lesions, serosal surfaces, and wounds such as injured and surgical sites, which are typical in DIC with a fibrinolytic phenotype.
DIC with a fibrinolytic phenotype shows a very limited function of soluble thrombomodulin, owing to the random proteolysis of endothelial thrombomodulin and endothelial injury with the resultant decreased expression and function of endothelial thrombomodulin. This is accompanied by and contributes to systemic continuous thrombin generation and consumption coagulopathy. The coexisting hyperfibrin(ogen)olysis induced by tissue-type plasminogen activator synergistically gives rise to bleeding [1,3,4].
According to the disease description, COT/ACOTS occurs only at injured sites. The anticoagulation pathway in this setting includes the conversion of protein C to activated protein C, both by soluble thrombomodulin with full domains and activity, and by newly expressed thrombomodulin on intact endothelium. This is followed by a shutdown of thrombin formation, leading to bleeding without consumption of coagulation factors [2,6,8].
Two studies have demonstrated excessive non-wound-related thrombin generation in both trauma patients with DIC and in those with COT/ACOTS immediately after injury [9,10]. Both DIC and COT/ACOTS patients showed lower platelet counts, lower levels of fibrinogen and antithrombin, a longer prothrombin time and higher D-dimer levels than control subjects. The first study showed marked thrombin generation resulting from circulating procoagulants, such as tissue factor or microparticles that initiate thrombin generation systemically, and a reduced ability to localize hemostasis at the wound site, owing to the loss of antithrombin. The second study found that the tissue factor activity constituted ∼ 80% of the total procoagulant activity. These studies clearly show that DIC and COT/ACOTS are synonymous concepts developed from the same mechanisms.
Diagnosis and treatments
The ISTH scoring system was prospectively validated in intensive care unit patients, including 16% of patients with trauma. The Japanese Association for Acute Medicine scoring system was retrospectively validated in 314 trauma patients. Therefore, two DIC scoring systems may be useful for the diagnosis of DIC with a fibrinolytic phenotype [4,11]. The key to the treatment of DIC with a fibrinolytic phenotype is the specific and vigorous treatment of the underlying disorder, trauma itself [1,12].
Trauma patients with DIC who present with bleeding and with low platelet counts, prolonged prothrombin times and low fibrinogen levels require substitution therapies with platelet concentrate, fresh frozen plasma, and fibrinogen concentrate or cryoprecipitate [1,12]. Anticoagulants such as heparin are contraindicated for DIC with a fibrinolytic phenotype. The antithrombin and protein C levels should be kept within the normal range . Tranexamic acid can reduce the risk of death in bleeding patients after trauma . Tranexamic acid should be given as early as possible, because its delayed administration after trauma is less effective and may be harmful . These studies add a theoretical background for antifibrinolytic therapy in DIC with a fibrinolytic phenotype at an early phase of trauma.
There are no prospectively validated diagnostic criteria for COT/ACOTS. The main concept of COT/ACOTS is the onset of bleeding resulting from the shutdown of thrombin formation, and fresh frozen plasma containing anticoagulants against thrombin such as protein C, thrombomodulin and antithrombin is therefore theoretically contraindicated for trauma patients with apparent COT/ACOTS [2,6,8].
Limitations and conclusions
Although they include some methodological flaws, recently published studies have raised important issues in the diagnosis and pathomechanisms of trauma-induced coagulopathy [15,16]. These results suggest that more information based on well-powered and appropriately controlled prospective clinical studies is needed to clearly define the major pathologic hemostatic mechanisms contributing to coagulopathy after trauma. However, the currently available evidence leads to the conclusion that COT/ACOTS is not a new concept, but is a disease entity similar or equal to DIC with a fibrinolytic phenotype. It is universally accepted that trauma and trauma-shock elicits pathogenic bleeding, but proclaiming a new coagulopathic entity without clear definitions and diagnostic tools could be misleading. What is needed now is the establishment of better diagnostic criteria for COT/ACOTS, or DIC with a fibrinolytic phenotype.
The authors thank D. J. Stearns-Kurosawa (Boston University School of Medicine) for editing the manuscript.
Disclosure of conflict of interests
The authors state that they have no conflict of interest.