Critical Care Update
David J. Dries, MSE, MD, and Colleen Morton, MBBCh, MS
Coagulation: Part 1 Siegal DM, Garcia DA, Crowther MA. How I treat target-specific oral anticoagulant-associated bleeding. Blood. 2014;123:1152-1158. Zuccotti G, Pflomm JM. New oral anticoagulants for acute venous thromboembolism. JAMA. 2014;311:731-732. Nutescu EA, Dager WE, Kalus JS, et al. Management of bleeding and reversal strategies for oral anticoagulants: clinical practice considerations. Am J Health Syst Pharm. 2013;70:1914-1929. Baumann Kreuziger LM, Morton CT, Dries DJ. New anticoagulants: a concise review. J Trauma Acute Care Surg. 2012;73:983-992. Oral anticoagulants are used to manage a variety of common age-related conditions, and the frequency of their use will likely rise significantly in the United States as the population ages. Warfarin has been the standard among oral anticoagulants since its introduction over 50 years ago. However, warfarin is a less than ideal anticoagulant because of its narrow therapeutic range, interaction with various drugs and foods, and the need for routine laboratory monitoring. Warfarin is a common cause of emergency hospitalization in elderly patients and serious, disabling or fatal injury from bleeding in patients of all ages. The recent introduction of oral direct thrombin inhibitor dabigatran and the direct factor Xa inhibitors rivaroxaban and apixaban (target-specific oral anticoagulants) has been anticipated because these agents do not require routine coagulation monitoring and are associated with a lower number of clinically significant drug interactions. Unlike warfarin, which inhibits the hepatic production of vitamin K–dependent clotting factors II, VII, IX, and X, these new oral anticoagulants act on specific components in the coagulation cascade. In clinical trials comparing dabigatran, rivaroxaban, or apixaban with warfarin for stroke prevention in patients with atrial fibrillation, the risk for major bleeding was significantly lower with apixaban compared with warfarin, and there was no significant difference in the risk of major bleeding between dabigatran and rivaroxaban when compared with warfarin. The rate of intracranial hemorrhage was significantly lower with all 3 target-specific oral anticoagulants when compared with warfarin. However, the rate of major gastrointestinal bleeding was significantly higher with dabigatran and rivaroxaban when compared with warfarin although there was no significant difference in gastrointestinal bleeding between apixaban and warfarin. A role for new oral anticoagulants is being investigated for deep vein thrombosis (DVT), pulmonary embolism (PE), and valvular heart disease. Of July-August 2014
the 3 new oral anticoagulants, rivaroxaban is now approved for the management of DVT/PE. In light of a growing body of evidence, it appears highly likely that emergency care providers will encounter these agents in the setting of emergent bleeding. It is important to recognize the pharmacokinetics of the new oral anticoagulants. For example, renal excretion is extremely important in the elimination of dabigatran compared with rivaroxaban and apixaban. The potential for drug accumulation and bleeding in patients with impaired renal function, a common condition in the elderly, is a great concern with direct thrombin inhibitor dabigatran in comparison with the other 2 new oral anticoagulants. On the other hand, protein binding of dabigatran is low, facilitating removal by hemodialysis. In contrast, rivaroxaban and apixaban are highly protein bound and, therefore, unlikely to be dialyzable. Laboratory assessment of patients on warfarin therapy is tightly standardized with the international normalized ratio and prothrombin time evaluation. The same cannot be said with the new oral anticoagulants. The availability of tests that may be useful in clinical practice is limited. The ecarin clotting time test is most useful for assessing dabigatran anticoagulation because it is sensitive to the drug at all concentrations, but this evaluation is not widely available. The commercially available nondiluted thrombin time test is very sensitive to the level of dabigatran, making this test useful at low concentrations but not higher concentrations of dabigatran. Prothrombin time and activated partial thromboplastin time are widely available but not ideal for quantifying the amount of dabigatran present. Even less data are available for the laboratory assessment of coagulation during treatment with factor Xa inhibitors rivaroxaban and apixaban. Antifactor Xa assays are useful for monitoring coagulation during therapy with these agents. However, these assays must be calibrated for the specific factor Xa inhibitor, and the contribution of variables that can influence results present challenges to those using the chromogenic antifactor Xa assay. Newer coagulation assays have been developed and may be helpful in the evaluation of the clinical effect of new oral anticoagulants. Newer tests include thromboelastography, thrombin generation curves, plasma diluted thrombin time, chromogenic ecarin clotting time, and diluted prothrombin time. Thromboelastography has been used to guide transfusion therapy in the presence of bleeding in surgery or in trauma centers and to provide insight into possible causes and ways to manage bleeding. The usefulness of this technology in the presence of new oral anticoagulants has not been established. With new anticoagulant agents, new strategies for coagulation restoration must be developed. Prothrombin complex concentrates (PCCs) are plasma-derived clotting factor products originally developed to help manage hemophilia. Prothrombin 129
complex concentrates contain vitamin K–dependent coagulation factors II, IX, and X (3-factor PCCs) or II, VII, IX, and X (4-factor PCCs) and regulatory proteins C and S. At present, there is no high-quality evidence establishing the efficacy and safety of PCCs for the reversal of new anticoagulant effects in patients with bleeding complications. However, preclinical data and limited human data do suggest an opportunity for the development of management protocols in patients receiving new oral anticoagulant agents. One ongoing limitation is the lack of a consistent monitoring strategy for the new oral anticoagulants. Activated prothrombin complex concentrates contain factors II, VII, IX, and X, which are activated during the manufacturing process. These agents were originally developed as hemostatic therapy for bleeding in hemophiliacs with inhibitors to factors VIII or IX. Again, clinical data regarding the efficacy of activated prothrombin complex concentrates in the setting of new oral anticoagulant-associated bleeding are not available. Monitoring is an issue here as well. Although it has fallen out of favor as a first-line therapy in the management of trauma, recombinant factor VIIa (rFVIIa) was also developed for the management of bleeding episodes in hemophilia patients with inhibitors. As stated earlier, there are no consistent data showing a role for rFVIIa in the management of bleeding with new oral anticoagulants. However, like the agents described previously, rFVIIa offers the opportunity for coagulation system activation albeit with an increased risk of arterial thromboembolic events. Finally, the development of a humanized monoclonal antibody fragment against dabigatran is underway. This material has not yet reached general clinical trials. Recombinant and plasma-derived factor Xa derivatives are currently underway as specific factor Xa antidotes. Limited animal and human data suggest successful antagonism of anti-Xa activity (apixiban). In appropriate patients, rFVIIa may be used to initiate coagulation independent of tissue factor, factor VIII, and factor IX and, thus, is approved for patients with FVII deficiency and hemophilia with factor inhibitors. Prothrombin complex concentrates provide replacement of functional vitamin K–dependent proteins to directly reverse the anticoagulant effects of warfarin, which targets vitamin K–dependent factors II, VII, IX, and X. However, with the introduction of new anticoagulants, prothrombin concentrates and rFVIIa are used to activate the clotting system in patients with uncontrolled bleeding taking dabigatran, rivaroxaban, and apixaban.. The initial evaluation of bleeding patients receiving the new oral anticoagulants includes the evaluation of hemodynamic stability, severity of bleeding, and level of anticoagulation. Lifethreatening bleeding such as intracranial hemorrhage requires the most aggressive response. Baseline clotting times, fibrinogen activity, complete blood count, creatinine, and liver function testing should be performed. Alteration in renal function will affect the metabolism of dabigatran the most and apixaban the least. Apixaban and rivaroxaban metabolism is altered by changes in liver function. Assessment of anatomic etiology of hemorrhage should be emphasized with the use of local control measures if available. Activated charcoal will decrease the 130
absorption of new oral anticoagulants if administered within 23 hours of ingestion of the anticoagulant. Dialysis will remove dabigatran because of its low plasma protein binding, whereas rivaroxaban and apixaban, as noted earlier, are not dialyzable. Because of the large volume of distribution for dabigatran, multiple sessions of dialysis may be required. Our institution has created guidelines to facilitate the use of factor concentrates in the management of life-threatening bleeding in patients taking new oral anticoagulants. As noted previously, initial measures are the same as for any bleeding patient with local intervention and supportive care. The transfusion of packed red blood cells and a transfusion protocol using a balance of packed red blood cells, plasma, and platelets may be used depending on the severity of hemorrhage. Patients receiving specific antiplatelet agents should be considered for the administration of apheresis units of platelet concentrates. In the setting of life-threatening bleeding, patients receiving dabigatran, rivaroxaban, and apixaban are managed differently (Figure 1). Activated charcoal is given if the last dose of agent was ingested less than 2 hours (dabigatran or rivaroxaban) or 3 hours (apixaban). Dialysis was effective treatment in the vast majority of bleeding episodes associated with dabigatran. In cases of refractory bleeding, the recommended factor concentrate used in protocols differs between the new oral anticoagulants. In patients taking dabigatran, we administer 50 /kg intravenously of activated prothrombin complex concentrate anti-inhibitor coagulant complex (FEIBA) because of suggested benefit in human in vitro studies. Based on human clinical trial evidence, 50 /kg intravenously of factor PCC (Kcentra; CSL Behring, King of Prussia, PA) is suggested for patients with refractory hemorrhage associated with rivaroxaban or apixaban. If bleeding continues, rFVIIa can be considered. Thrombosis has been reported with administration of all of the factor concentrates listed earlier and, thus, relative risk of hemorrhage and thrombosis must be addressed.
Dries DJ. The contemporary role of blood products and components used in trauma resuscitation. Scand J Trauma Resusc Emerg Med. 2010;18:63. Tapia NM, Chang A, Norman M, et al. TEG-guided resuscitation is superior to standardized MTP resuscitation in massively transfused penetrating trauma patients. J Trauma Acute Care Surg. 2013;74:378-386. Cotton BA, Minei KM, Radwan ZA, et al. Admission rapid thrombelastography predicts development of pulmonary embolism in trauma patients. J Trauma Acute Care Surg. 2012;72:1470-1477. Branco BC, Inaba K, Ives C, et al. Thromboelastogram evaluation of the impact of hypercoagulability in trauma patients. Shock. 2014;41:200-207. Many reports identify coagulopathy occurring in the setting of severe injury. This coagulopathy is thought to be a cause of Air Medical Journal 33:4
Figure 1. Management Protocol for the High-risk Bleeding Patient Taking Dabigatran, Rivaroxaban, or Apixapan
potentially preventable death after significant trauma. Coagulopathy after injury is present in up to 25% of critically injured patients. However, this intriguing trial examines the hypercoagulable patient after injury. Historically, hypercoagulable changes have been seen more frequently in female patients and develop after splenectomy. These investigators show that in patients with a lesser degree of injury, a hypercoagulable presentation is also possible. The important piece of data not presented by these workers is hypercoagulable complications such as venous thromboembolic events, which have been reported by other investigators. In this trial, patients were not actively screened for DVT unless they developed symptoms. None of the hypercoagulable patients developed thromboembolic complications that were clinically significant, but none of these individuals had a venous duplex study performed during their hospital course. In addition, the impact of this hypercoagulable state on the microcirculation after trauma is unknown. This study emphasizes the use of thromboelastographic evaluation of coagulation state in the injured patient. Thromboelastography is receiving increasing attention as a means to monitor the effects of interventions on coagulation in real time as opposed to current standard evaluation of coagulation including tests such as prothombin time, international normalized ratio, activated partial thromboplastin time, thrombin time, and platelet counts. These static monitors are often flawed because of differences between laboratory condiJuly-August 2014
tions and the clinical environment together with intervals of time occurring between the collection of blood specimens and obtaining results. Thromboelastography offers the advantage of providing real-time graphic representation of clot formation in whole blood. Unlike standard laboratory tests, thromboelastography offers analysis of the whole coagulation cascade permitting identification of depleted components and directed therapy to correct coagulopathy. The procedure involves placing a small amount of blood in an oscillating cup at 37°C or at patient temperature. As blood in the cup clots, the motion of the cup as rotated is transmitted to a pin dipped in the blood. Thromboelastography has been used in a variety of studies to identify changes in coagulation in the setting of injury. This procedure can also be used to evaluate platelet function. An example of thromboelastography and a treatment protocol from a recent publication are given here (Figure 2). Other workers suggest that thromboelastography may facilitate the detection of hypercoagulable states. In a study of severely traumatized patients, individuals at risk for pulmonary embolism were identified using thromboelastography. Patients suffering pulmonary embolism in this study sustained blunt trauma, were older, and had higher milliampere values. A higher milliampere value was an independent predictor of PE in this study of over 2,000 patients conducted from 2009-2011. 131
Figure 2. Hemorrhagic Thromboelastographic Tracing Reprinted with permission from J Trauma Acute Care Surg. 2013;74:378-386.
Hypercoagulable patients identified by Branco et al required fewer blood products and tended to have lower mortality particularly as related to complications of hemorrhage. This study emphasizes the value of using coagulation testing in both severe and less severely injured patients because the less severely injured individuals may be at increased risk for complications associated with excess clotting.
Summary The following are important points: 1. Warfarin has been the standard among oral anticoagulants for an extended period of time. However, newer agents with targeted effectiveness against thrombin (dabigatran) and factor X (rivaroxaban and apixaban) offer advantages including reduced drug interaction and a lack of monitoring requirements compared with warfarin. 2. However, new oral anticoagulants cannot be reversed using standard plasma and vitamin K–based therapies. In addition to supportive care, prothrombin complex concentrates and possibly rFVIIa may be most reasonable choices. 3. It is important to note that prothrombin complex concentrates and rFVIIa are intended to upregulate the coagulation cascade rather than specifically antagonize the effects of new oral anticoagulants in the setting of bleeding. 132
4. Oral procoagulant agents such as prothrombin complex concentrates and rFVIIa are powerful tools favoring clot formation. The risk of clotting must be balanced against the need for rapid control of bleeding. 5. Up to 25% of patients after injury may be hyper- rather that hypocoagulable. These individuals can be identified using thromboelastography. 6. Hypercoagulable patients, after injury, are at increased risk for venous thromboembolic disorders. David J. Dries, MSE, MD, is assistant medical director for surgical services at HealthPartners Medical Group and professor of surgery and anesthesiology at the University of Minnesota in Minneapolis, MN, and can be reached at [email protected]. Colleen Morton, MBBCh, MS, is assistant professor in the department of hematology, oncology, and transplant at the University of Minnesota in Minneapolis, MN. 1067-9991X/$36.00 Copyright 2014 by Air Medical Journal Associates http://dx.doi.org/10.1016/j.amj.2014.04.003
Air Medical Journal 33:4
David J. Dries, MSE, MD, and Colleen Morton, MBBCh, MS
Coagulation: Part 1 Siegal DM, Garcia DA, Crowther MA. How I treat target-specific oral anticoagulant-associated bleeding. Blood. 2014;123:1152-1158. Zuccotti G, Pflomm JM. New oral anticoagulants for acute venous thromboembolism. JAMA. 2014;311:731-732. Nutescu EA, Dager WE, Kalus JS, et al. Management of bleeding and reversal strategies for oral anticoagulants: clinical practice considerations. Am J Health Syst Pharm. 2013;70:1914-1929. Baumann Kreuziger LM, Morton CT, Dries DJ. New anticoagulants: a concise review. J Trauma Acute Care Surg. 2012;73:983-992. Oral anticoagulants are used to manage a variety of common age-related conditions, and the frequency of their use will likely rise significantly in the United States as the population ages. Warfarin has been the standard among oral anticoagulants since its introduction over 50 years ago. However, warfarin is a less than ideal anticoagulant because of its narrow therapeutic range, interaction with various drugs and foods, and the need for routine laboratory monitoring. Warfarin is a common cause of emergency hospitalization in elderly patients and serious, disabling or fatal injury from bleeding in patients of all ages. The recent introduction of oral direct thrombin inhibitor dabigatran and the direct factor Xa inhibitors rivaroxaban and apixaban (target-specific oral anticoagulants) has been anticipated because these agents do not require routine coagulation monitoring and are associated with a lower number of clinically significant drug interactions. Unlike warfarin, which inhibits the hepatic production of vitamin K–dependent clotting factors II, VII, IX, and X, these new oral anticoagulants act on specific components in the coagulation cascade. In clinical trials comparing dabigatran, rivaroxaban, or apixaban with warfarin for stroke prevention in patients with atrial fibrillation, the risk for major bleeding was significantly lower with apixaban compared with warfarin, and there was no significant difference in the risk of major bleeding between dabigatran and rivaroxaban when compared with warfarin. The rate of intracranial hemorrhage was significantly lower with all 3 target-specific oral anticoagulants when compared with warfarin. However, the rate of major gastrointestinal bleeding was significantly higher with dabigatran and rivaroxaban when compared with warfarin although there was no significant difference in gastrointestinal bleeding between apixaban and warfarin. A role for new oral anticoagulants is being investigated for deep vein thrombosis (DVT), pulmonary embolism (PE), and valvular heart disease. Of July-August 2014
the 3 new oral anticoagulants, rivaroxaban is now approved for the management of DVT/PE. In light of a growing body of evidence, it appears highly likely that emergency care providers will encounter these agents in the setting of emergent bleeding. It is important to recognize the pharmacokinetics of the new oral anticoagulants. For example, renal excretion is extremely important in the elimination of dabigatran compared with rivaroxaban and apixaban. The potential for drug accumulation and bleeding in patients with impaired renal function, a common condition in the elderly, is a great concern with direct thrombin inhibitor dabigatran in comparison with the other 2 new oral anticoagulants. On the other hand, protein binding of dabigatran is low, facilitating removal by hemodialysis. In contrast, rivaroxaban and apixaban are highly protein bound and, therefore, unlikely to be dialyzable. Laboratory assessment of patients on warfarin therapy is tightly standardized with the international normalized ratio and prothrombin time evaluation. The same cannot be said with the new oral anticoagulants. The availability of tests that may be useful in clinical practice is limited. The ecarin clotting time test is most useful for assessing dabigatran anticoagulation because it is sensitive to the drug at all concentrations, but this evaluation is not widely available. The commercially available nondiluted thrombin time test is very sensitive to the level of dabigatran, making this test useful at low concentrations but not higher concentrations of dabigatran. Prothrombin time and activated partial thromboplastin time are widely available but not ideal for quantifying the amount of dabigatran present. Even less data are available for the laboratory assessment of coagulation during treatment with factor Xa inhibitors rivaroxaban and apixaban. Antifactor Xa assays are useful for monitoring coagulation during therapy with these agents. However, these assays must be calibrated for the specific factor Xa inhibitor, and the contribution of variables that can influence results present challenges to those using the chromogenic antifactor Xa assay. Newer coagulation assays have been developed and may be helpful in the evaluation of the clinical effect of new oral anticoagulants. Newer tests include thromboelastography, thrombin generation curves, plasma diluted thrombin time, chromogenic ecarin clotting time, and diluted prothrombin time. Thromboelastography has been used to guide transfusion therapy in the presence of bleeding in surgery or in trauma centers and to provide insight into possible causes and ways to manage bleeding. The usefulness of this technology in the presence of new oral anticoagulants has not been established. With new anticoagulant agents, new strategies for coagulation restoration must be developed. Prothrombin complex concentrates (PCCs) are plasma-derived clotting factor products originally developed to help manage hemophilia. Prothrombin 129
complex concentrates contain vitamin K–dependent coagulation factors II, IX, and X (3-factor PCCs) or II, VII, IX, and X (4-factor PCCs) and regulatory proteins C and S. At present, there is no high-quality evidence establishing the efficacy and safety of PCCs for the reversal of new anticoagulant effects in patients with bleeding complications. However, preclinical data and limited human data do suggest an opportunity for the development of management protocols in patients receiving new oral anticoagulant agents. One ongoing limitation is the lack of a consistent monitoring strategy for the new oral anticoagulants. Activated prothrombin complex concentrates contain factors II, VII, IX, and X, which are activated during the manufacturing process. These agents were originally developed as hemostatic therapy for bleeding in hemophiliacs with inhibitors to factors VIII or IX. Again, clinical data regarding the efficacy of activated prothrombin complex concentrates in the setting of new oral anticoagulant-associated bleeding are not available. Monitoring is an issue here as well. Although it has fallen out of favor as a first-line therapy in the management of trauma, recombinant factor VIIa (rFVIIa) was also developed for the management of bleeding episodes in hemophilia patients with inhibitors. As stated earlier, there are no consistent data showing a role for rFVIIa in the management of bleeding with new oral anticoagulants. However, like the agents described previously, rFVIIa offers the opportunity for coagulation system activation albeit with an increased risk of arterial thromboembolic events. Finally, the development of a humanized monoclonal antibody fragment against dabigatran is underway. This material has not yet reached general clinical trials. Recombinant and plasma-derived factor Xa derivatives are currently underway as specific factor Xa antidotes. Limited animal and human data suggest successful antagonism of anti-Xa activity (apixiban). In appropriate patients, rFVIIa may be used to initiate coagulation independent of tissue factor, factor VIII, and factor IX and, thus, is approved for patients with FVII deficiency and hemophilia with factor inhibitors. Prothrombin complex concentrates provide replacement of functional vitamin K–dependent proteins to directly reverse the anticoagulant effects of warfarin, which targets vitamin K–dependent factors II, VII, IX, and X. However, with the introduction of new anticoagulants, prothrombin concentrates and rFVIIa are used to activate the clotting system in patients with uncontrolled bleeding taking dabigatran, rivaroxaban, and apixaban.. The initial evaluation of bleeding patients receiving the new oral anticoagulants includes the evaluation of hemodynamic stability, severity of bleeding, and level of anticoagulation. Lifethreatening bleeding such as intracranial hemorrhage requires the most aggressive response. Baseline clotting times, fibrinogen activity, complete blood count, creatinine, and liver function testing should be performed. Alteration in renal function will affect the metabolism of dabigatran the most and apixaban the least. Apixaban and rivaroxaban metabolism is altered by changes in liver function. Assessment of anatomic etiology of hemorrhage should be emphasized with the use of local control measures if available. Activated charcoal will decrease the 130
absorption of new oral anticoagulants if administered within 23 hours of ingestion of the anticoagulant. Dialysis will remove dabigatran because of its low plasma protein binding, whereas rivaroxaban and apixaban, as noted earlier, are not dialyzable. Because of the large volume of distribution for dabigatran, multiple sessions of dialysis may be required. Our institution has created guidelines to facilitate the use of factor concentrates in the management of life-threatening bleeding in patients taking new oral anticoagulants. As noted previously, initial measures are the same as for any bleeding patient with local intervention and supportive care. The transfusion of packed red blood cells and a transfusion protocol using a balance of packed red blood cells, plasma, and platelets may be used depending on the severity of hemorrhage. Patients receiving specific antiplatelet agents should be considered for the administration of apheresis units of platelet concentrates. In the setting of life-threatening bleeding, patients receiving dabigatran, rivaroxaban, and apixaban are managed differently (Figure 1). Activated charcoal is given if the last dose of agent was ingested less than 2 hours (dabigatran or rivaroxaban) or 3 hours (apixaban). Dialysis was effective treatment in the vast majority of bleeding episodes associated with dabigatran. In cases of refractory bleeding, the recommended factor concentrate used in protocols differs between the new oral anticoagulants. In patients taking dabigatran, we administer 50 /kg intravenously of activated prothrombin complex concentrate anti-inhibitor coagulant complex (FEIBA) because of suggested benefit in human in vitro studies. Based on human clinical trial evidence, 50 /kg intravenously of factor PCC (Kcentra; CSL Behring, King of Prussia, PA) is suggested for patients with refractory hemorrhage associated with rivaroxaban or apixaban. If bleeding continues, rFVIIa can be considered. Thrombosis has been reported with administration of all of the factor concentrates listed earlier and, thus, relative risk of hemorrhage and thrombosis must be addressed.
Dries DJ. The contemporary role of blood products and components used in trauma resuscitation. Scand J Trauma Resusc Emerg Med. 2010;18:63. Tapia NM, Chang A, Norman M, et al. TEG-guided resuscitation is superior to standardized MTP resuscitation in massively transfused penetrating trauma patients. J Trauma Acute Care Surg. 2013;74:378-386. Cotton BA, Minei KM, Radwan ZA, et al. Admission rapid thrombelastography predicts development of pulmonary embolism in trauma patients. J Trauma Acute Care Surg. 2012;72:1470-1477. Branco BC, Inaba K, Ives C, et al. Thromboelastogram evaluation of the impact of hypercoagulability in trauma patients. Shock. 2014;41:200-207. Many reports identify coagulopathy occurring in the setting of severe injury. This coagulopathy is thought to be a cause of Air Medical Journal 33:4
Figure 1. Management Protocol for the High-risk Bleeding Patient Taking Dabigatran, Rivaroxaban, or Apixapan
potentially preventable death after significant trauma. Coagulopathy after injury is present in up to 25% of critically injured patients. However, this intriguing trial examines the hypercoagulable patient after injury. Historically, hypercoagulable changes have been seen more frequently in female patients and develop after splenectomy. These investigators show that in patients with a lesser degree of injury, a hypercoagulable presentation is also possible. The important piece of data not presented by these workers is hypercoagulable complications such as venous thromboembolic events, which have been reported by other investigators. In this trial, patients were not actively screened for DVT unless they developed symptoms. None of the hypercoagulable patients developed thromboembolic complications that were clinically significant, but none of these individuals had a venous duplex study performed during their hospital course. In addition, the impact of this hypercoagulable state on the microcirculation after trauma is unknown. This study emphasizes the use of thromboelastographic evaluation of coagulation state in the injured patient. Thromboelastography is receiving increasing attention as a means to monitor the effects of interventions on coagulation in real time as opposed to current standard evaluation of coagulation including tests such as prothombin time, international normalized ratio, activated partial thromboplastin time, thrombin time, and platelet counts. These static monitors are often flawed because of differences between laboratory condiJuly-August 2014
tions and the clinical environment together with intervals of time occurring between the collection of blood specimens and obtaining results. Thromboelastography offers the advantage of providing real-time graphic representation of clot formation in whole blood. Unlike standard laboratory tests, thromboelastography offers analysis of the whole coagulation cascade permitting identification of depleted components and directed therapy to correct coagulopathy. The procedure involves placing a small amount of blood in an oscillating cup at 37°C or at patient temperature. As blood in the cup clots, the motion of the cup as rotated is transmitted to a pin dipped in the blood. Thromboelastography has been used in a variety of studies to identify changes in coagulation in the setting of injury. This procedure can also be used to evaluate platelet function. An example of thromboelastography and a treatment protocol from a recent publication are given here (Figure 2). Other workers suggest that thromboelastography may facilitate the detection of hypercoagulable states. In a study of severely traumatized patients, individuals at risk for pulmonary embolism were identified using thromboelastography. Patients suffering pulmonary embolism in this study sustained blunt trauma, were older, and had higher milliampere values. A higher milliampere value was an independent predictor of PE in this study of over 2,000 patients conducted from 2009-2011. 131
Figure 2. Hemorrhagic Thromboelastographic Tracing Reprinted with permission from J Trauma Acute Care Surg. 2013;74:378-386.
Hypercoagulable patients identified by Branco et al required fewer blood products and tended to have lower mortality particularly as related to complications of hemorrhage. This study emphasizes the value of using coagulation testing in both severe and less severely injured patients because the less severely injured individuals may be at increased risk for complications associated with excess clotting.
Summary The following are important points: 1. Warfarin has been the standard among oral anticoagulants for an extended period of time. However, newer agents with targeted effectiveness against thrombin (dabigatran) and factor X (rivaroxaban and apixaban) offer advantages including reduced drug interaction and a lack of monitoring requirements compared with warfarin. 2. However, new oral anticoagulants cannot be reversed using standard plasma and vitamin K–based therapies. In addition to supportive care, prothrombin complex concentrates and possibly rFVIIa may be most reasonable choices. 3. It is important to note that prothrombin complex concentrates and rFVIIa are intended to upregulate the coagulation cascade rather than specifically antagonize the effects of new oral anticoagulants in the setting of bleeding. 132
4. Oral procoagulant agents such as prothrombin complex concentrates and rFVIIa are powerful tools favoring clot formation. The risk of clotting must be balanced against the need for rapid control of bleeding. 5. Up to 25% of patients after injury may be hyper- rather that hypocoagulable. These individuals can be identified using thromboelastography. 6. Hypercoagulable patients, after injury, are at increased risk for venous thromboembolic disorders. David J. Dries, MSE, MD, is assistant medical director for surgical services at HealthPartners Medical Group and professor of surgery and anesthesiology at the University of Minnesota in Minneapolis, MN, and can be reached at [email protected]. Colleen Morton, MBBCh, MS, is assistant professor in the department of hematology, oncology, and transplant at the University of Minnesota in Minneapolis, MN. 1067-9991X/$36.00 Copyright 2014 by Air Medical Journal Associates http://dx.doi.org/10.1016/j.amj.2014.04.003
Air Medical Journal 33:4
