Management of Anticoagulation Agents in Tra u m a P a t i e n t s C. Cameron McCoy, Mark L. Shapiro, MDc

MD

a,

*, Jeffrey H. Lawson,

MD, PhD

b

,

KEYWORDS  Trauma  Anticoagulation  Thromboelastography  Hemorrhage  Hemostasis KEY POINTS  Early identification of anticoagulation status is key to injury management in the trauma patient.  Whereas some anticoagulant effects are detected on standard assays, such as prothrombin time and activated partial thromboplastin time, the effect of other, newer agents is only evident on specialized assays or thromboelastography.  Knowledge of specific reversal strategies for individual agents such as direct thrombin and factor Xa inhibitors is essential in managing acute, traumatic hemorrhage.  Direct antidotes are not available for many newer anticoagulants; the management of hemorrhage is complicated by these drugs, and is currently focused on resuscitation and factor replacement.

INTRODUCTION

Anticoagulation adds additional complexity to the assessment and management of the trauma patient.1,2 Trauma clinicians must act quickly to determine the patient’s medications, complexity of injury, coagulation status, and the most appropriate reversal strategy. The broad range of anticoagulants encountered includes antiplatelet agents, low molecular weight heparin (LMWH), vitamin K antagonists (VKAs), and newer, direct inhibitors of factors in the coagulation cascade. The use of particular agents may suggest concurrent medical comorbidities that should be taken into

The authors have no disclosures or conflicts of interest to declare. a Department of Surgery, Duke University Medical Center, Duke University, Box 3443, Room 3581, White Zone, Duke South, Durham, NC 27710, USA; b Division of Vascular Surgery, Department of Surgery, Duke University Medical Center, Duke University, Box 2622, Room 481 MSRB 1 Research Drive, Durham, NC 27710, USA; c Division of Trauma & Critical Care, Department of Surgery, Duke University Medical Center, Duke University, 1557 F Duke South, Blue Zone Box 2837, Durham, NC 27710, USA * Corresponding author. E-mail address: [email protected] Clin Lab Med - (2014) -–http://dx.doi.org/10.1016/j.cll.2014.06.013 labmed.theclinics.com 0272-2712/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.

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consideration during the initial phase of trauma assessment and care. Once anticoagulant medications are identified, the patient’s assessment should include laboratory assessment of their coagulation state. Traditional studies such as activated partial thromboplastin time (aPTT) and international normalized ratio (INR) may be augmented by functional assays of coagulation such as thromboelastography (TEG). Simultaneously, the patient’s complexity of injury should be assessed for any indications to administer reversal. In addition to an accurate physical examination, radiographic studies should be used to determine the presence of occult hemorrhage in the setting of anticoagulation. Once the clinician has determined the patient’s anticoagulation status and complexity of injury, reversal of anticoagulation can be targeted to specific agents and injuries. Failure to rapidly assess these factors can result in delays in restoring hemostasis, and increased morbidity and mortality from injury. INITIAL ASSESSMENT OF THE ANTICOAGULATED TRAUMA PATIENT

The identification of injuries and determination of the extent of anticoagulation are essential steps in the initial assessment of any trauma patient. The coagulation status should be identified early during ascertainment of the medical history. Injuries exacerbated by therapeutic coagulation will also be identified on examination and will guide further diagnostics. Laboratory studies should also be drawn to ensure their availability at the earliest opportunity to guide possible reversal. Based on the patient’s history and results from the primary survey and physical examination, radiographic studies should be performed to identify occult injuries that could also be complicated by the patient’s anticoagulation status. Patient’s History and Physical Examination

It is essential to identify patients on therapeutic anticoagulation during the secondary trauma survey. Special attention should be paid to current home medications to identify agents affecting coagulation. This information may be available from the patient, the patient’s family, or prehospital care providers. Other clues to medical conditions requiring anticoagulation treatment include previous surgical scars for procedures such as valve replacement and medical alert badges. Suspicion of anticoagulation based on clinical presentation and medical comorbidities may also be sufficient to warrant further investigation of a patient’s coagulation status. Failure to obtain a complete history, including medication, may result in serious complications from uncontrolled hemorrhage. Laboratory Analysis

Laboratory analysis to determine the extent of anticoagulation in the trauma patient is a crucial early assessment step. The initial laboratory analysis for most trauma patients, regardless of known coagulation status, often includes prothrombin time (PT), aPTT, and platelet count as the sole indicators of coagulation status.3 For some anticoagulants, such as VKAs, these data may be sufficient to determine the level of anticoagulation and guide reversal. With other agents, such as direct thrombin and factor Xa inhibitors, these assays provide unreliable means of identifying the level of anticoagulation and drug activity. Details regarding the laboratory assessment of specific anticoagulant medications during trauma are described in a subsequent section. Functional assays of coagulation such as TEG are also becoming more readily available and can guide care for patients on anticoagulants. TEG (TEG 5000; Haemonetics,

Anticoagulation Agents in Trauma Patients

Braintree, MA, USA) and rotational thromboelastometry (ROTEM; TEM Systems Inc, Durham, NC, USA) are increasingly used to provide a more complete assessment of coagulation status for trauma patients.4–6 These newer assays provide results more rapidly (15–20 minutes) than traditional assays such as aPTT or platelet count (45– 60 minutes).4,7 Originally described in 1948, TEG and ROTEM provide information on clot formation, propagation, stabilization, and dissolution.6 Various therapeutic anticoagulants produce distinct effects on these assays (Fig. 1). Thromboelastographic changes specific to individual agents are discussed in a subsequent section. Radiographic Studies

Following the initial assessment, and often run concurrently with laboratory assays, radiographic studies are used to detect occult injuries and internal hemorrhage in the anticoagulated trauma patient. Computed tomography (CT) is the most widely used diagnostic method for this purpose.8,9 In particular, anticoagulated patients suspected of traumatic brain injury should undergo a head CT scan to assess for occult intracranial hemorrhage (ICH). Although the UK National Institute for Health and Care Excellence guidelines suggest that routine head CT scanning is not necessary for all patients on therapeutic anticoagulation with head trauma,10 multiple studies have demonstrated missed ICH and current practice in many institutions is to obtain a head CT scan on presentation for these patients.11,12 Demonstration of ICH by the initial head CT scan of the anticoagulated trauma patient indicates the need for urgent anticoagulation reversal, unless the risk is prohibitive owing to the likelihood of thromboembolic complications for an individual patient. MANAGEMENT OF THE ANTICOAGULATED TRAUMA PATIENT Vitamin K Antagonists

Some of the most commonly used therapeutic anticoagulants are VKAs such as warfarin. Indications for warfarin use are some forms of atrial fibrillation, the presence of a metallic valve or ventricular assist device, deep vein thrombosis, and pulmonary embolism.13 Approximately 3% of patients presenting to Level 1 trauma centers in one study were anticoagulated with this agent. In these patients, warfarin treatment was associated with a 3-fold increase in mortality compared with those not taking warfarin or antiplatelet agents.14 Based on this evidence, trauma patients on warfarin should receive urgent reversal if an indication exists. Warfarin’s anticoagulation effect is monitored via the INR. Some guidelines recommend a target INR of 1.6 for anticoagulation reversal, with stepwise administration of

Fig. 1. Changes in thromboelastography secondary to anticoagulation. DFXaI, direct factor Xa inhibitor; DTI, direct thrombin inhibitor; LMWH, low molecular weight heparin.

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a reversal agent followed by repeat INR measurement before additional administration.15 Indications for the reversal of warfarin in trauma patients include ICH and uncontrolled hemorrhage elsewhere in the body. The Eastern Association for the Surgery of Trauma guidelines state that patients with posttraumatic ICH should begin therapy to correct their INR to less than 1.6 within 2 hours of arrival, and reach an INR of less than 1.6 within 4 hours.15 Early reversal has been demonstrated to reduce hemorrhage progression and mortality.16 Anticoagulated patients with head trauma but without radiographic evidence of ICH should not receive preventive reversal. Patients presenting with a hemorrhage in other locations aside from the brain should have reversal considered on a patient-by-patient basis, taking into account the extent of injury and the potential risks associated with anticoagulation reversal. Fresh frozen plasma (FFP) has been the traditional reversal agent for warfarin in trauma patients.17 FFP, as a blood product, requires frozen storage and associated thawing time in addition to ABO compatibility testing, and carries a risk of transfusion-related complications.18,19 Thawing time and ABO compatibility testing may not pose a delay at centers capable of maintaining thawed FFP stores of type AB, but availability in large volumes or at smaller centers is not guaranteed.16 In addition, multiple doses of FFP are often required to reduce the INR to levels necessary for normal hemostasis. Administration of large volumes of FFP poses a risk for patients with medical comorbidities such as congestive heart failure who do not require volume resuscitation. Because of these issues, prothrombin complex concentrate (PCC) has gained favor as the agent of choice for emergent warfarin reversal. PCCs are available as 3-factor (factors II, IX, X) or 4-factor (factors II, VII, IX, X) concentrates. These agents have a low risk of infection because of viral inactivation, do not require cross-matching, and are administered in low volumes; moreover, therapeutic doses can be infused within 15 to 30 minutes.20,21 The current American College of Chest Physicians guidelines recommend the use of PCC over FFP for reversal of warfarin in patients with serious hemorrhage.22 Kcentra (CSL Behring, King of Prussia, PA, USA), a 4-factor PCC, has recently been licensed for urgent warfarin reversal in the United States.23 The lack of cross-matching and speed of correction make PCCs the ideal agents for correction of warfarin anticoagulation in trauma patients (Table 1). Limited evidence exists regarding the use of recombinant activated factor VII (rFVIIa) for reversal of VKA-related hemorrhage.17 Use of rFVIIa in VKAanticoagulated patients presenting with a traumatic hemorrhage should be reserved for cases when first-line agents are not available.24 rFVIIa carries a significant risk of thrombosis. By comparison, PCCs contain minimal levels of activated clotting factors in addition to some level of Protein C and S. As a result, PCCs carry a theoretically lower risk of thrombosis than rFVIIa. Direct Thrombin Inhibitors

Direct thrombin inhibitors (DTIs) are reversible, competitive inhibitors that block the active site of thrombin, and do not require a cofactor to exert their effect on the coagulation cascade. As DTIs are relatively new oral anticoagulants, fewer data exist regarding the management of posttraumatic hemorrhage in patients taking these agents. One such agent, dabigatran etexilate, is approved in several countries for the prevention of venous thromboembolism in patients undergoing total hip or knee replacement and the prevention of stroke or embolism in patients with nonvalvular atrial fibrillation.25–27 Dabigatran is mainly eliminated by renal clearance, and blood levels can be decreased through diuresis and dialysis.28

Anticoagulation Agents in Trauma Patients

Table 1 Anticoagulants and urgent reversal strategies Anticoagulant

Mechanism

Urgent Reversal Strategy

VKA (eg, warfarin)

Epoxide reductase inhibition

First line: PCC Second line: FFP

Oral DTI (eg, dabigatran)

Competitive, reversible direct inhibition of thrombin

First line: PCC including FEIBA, rFVIIa Second line: hemodialysis Pending: direct inhibitors (eg, anti-Dabi Fab)

Direct factor Xa inhibitor (eg, rivaroxaban)

Competitive, reversible direct inhibition of factor Xa

First line: PCC Poorly removed by hemodialysis

LMWH (eg, enoxaparin)

Potentiation of antithrombin III

First line: protamine (temporary, partial), rFVIIa

Aspirin

Cyclooxygenase-1 inhibition

First line: platelet transfusion Second line: desmopressin

Clopidogrel

Irreversible inhibition of platelet P2Y12 ADP receptor

First line: platelet transfusion Second line: desmopressin

Abbreviations: ADP, adenosine diphosphate; DTI, direct thrombin inhibitor; FEIBA, factor VIII inhibitor bypassing activity; FFP, fresh frozen plasma; LMWH, low molecular weight heparin; PCC, prothrombin complex concentrate; rFVIIa, recombinant activated factor VII; VKA, vitamin K antagonist.

DTIs affect multiple coagulation studies, including thrombin clotting time (TCT), PT, aPTT and ecarin clotting time (ECT).29,30 The aPTT does not provide a linear representation of plasma DTI levels. The aPTT underestimates DTI activity at high plasma concentrations, whereas TCT may overestimate DTI levels; its use should be reserved to ruling out the presence of any residual DTI activity, as a normal TCT ensures that no DTI anticoagulation effect is present. The preferred assay for quantitative assessment of DTI activity is ECT, which was originally developed to monitor hirudin-type DTI activity. ECT is the only dose-responsive assay for DTIs. Unfortunately, it is uncommon and its availability in smaller institutions may be limited. DTIs such as dabigatran and argatroban produce dose-dependent increases in clotting time on InTEM (ellagic acid–activated intrinsic pathway thromboelastometry) (see Fig. 1).31 These changes in clotting time are based on direct inhibition of thrombin by the drug. Initial management of uncontrolled bleeding complicated by DTIs should focus on volume and blood product resuscitation. Although the manufacturer recommends FFP to assist with restoring circulating coagulation factors, it is unlikely to reverse the drug effect based on its mechanism.32,33 Animal models and case study reports suggest that rFVIIa significantly reduces bleeding time and may be useful in treating hemorrhage in subjects receiving a DTI, but this effect is agent-dependent and dose-dependent.34–38 Both activated and nonactivated PCCs have also been evaluated as agents for emergency reversal of dabigatran (see Table 1). Animal models suggest that these agents significantly reduce dabigatran-induced prolongation of bleeding time. However, clinical data regarding their use in hemorrhaging patients are limited to case reports.39,40 Further details on results from these case reports are available in the article by Levy and Levi elsewhere in this issue. Looking forward, a true antidote

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(anti-Dabi Fab), which complexes with dabigatran in a similar manner to that of thrombin and functions as a high-affinity competitive inhibitor, is under development for emergency reversal of dabigatran anticoagulation.41 At present, PCCs are the agent of choice to treat posttraumatic hemorrhage in patients on DTIs. Direct Factor Xa Inhibitors

Another class of new oral anticoagulants, direct factor Xa inhibitors, are associated with many of the same difficulties in controlling posttraumatic hemorrhage as DTIs. Direct factor Xa inhibitors, like DTIs with thrombin, are capable of accessing not only free factor Xa but also factor Xa associated with the prothrombinase complex and established clot.42,43 One direct factor Xa inhibitor, rivaroxaban, is currently approved in the United States for the prevention of venous thromboembolism in patients undergoing total hip or knee replacement surgery.44,45 In clinical practice, rivaroxaban is replacing LMWH as the agent of choice in this role. Treatment with direct factor Xa inhibitors results in prolongation of the PT and aPTT. Platelet aggregation does not seem to be affected.46 Direct factor Xa inhibitor treatment also produces dose-dependent increases in clotting time on InTEM (see Fig. 1). These changes in clotting time also mirror dose-dependent changes in PT and are similar to changes seen with DTIs.47,48 FFP is unlikely to provide direct factor Xa reversal, but will help to maintain coagulation factor levels during an ongoing hemorrhage. High-dose PCC (50 IU/kg) and activated PCC (50 IU/kg) administration have demonstrated efficacy in normalizing bleeding time in an animal model (see Table 1).49 This dose is approximately twice the amount of PCC administered to reverse hemorrhage secondary to VKAs in patients with a pretreatment INR of 2 to 4 (25 IU/kg).23 High-affinity competitive inhibitors, such as those for DTIs, are also under development and are being tested in animal models, with promising results showing complete PT normalization. Similarly to DTI reversal, PCCs are currently the best available agents for reversal of direct factor Xa inhibitors. Low Molecular Weight Heparin

Enoxaparin is the most widely used LMWH for outpatient anticoagulation, and the heparinoid most likely to be encountered in the setting of acute trauma.50 Owing to their lighter weight compared with unfractionated heparin, LMWHs exhibit antithrombin III–dependent coagulation factor inactivation but also significant anti–factor Xa activity. LMWH activity may be assessed using an anti–factor Xa assay, available in many hospital clinical laboratories.51 Unfortunately, this assay takes a minimum of 1 to 2 hours to complete and does not provide timely data in acute trauma care. Patients taking heparinoid anticoagulation demonstrate prolonged clotting time on the InTEM assay of ROTEM and prolonged reaction time on TEG (see Fig. 1). These changes represent inhibition of thrombin burst formation by the circulating anticoagulant.52 This finding can be confirmed in ROTEM by performing the HEPTEM (heparinasemodified thromboelastometry) test. There is no US Food and Drug Administration (FDA)-approved antidote for LMWHs, but protamine sulfate exhibits partial, temporary reversal of anti–factor IIa activity (see Table 1).20,53 Anticoagulant activity may return as soon as 3 hours following reversal, so ongoing administration is vital. Case reports, small series, and in vitro studies have documented successful outcomes and laboratory assay normalization using rFVIIa.54 However, the risk of thrombosis must be balanced with the possibility of ongoing hemorrhage when using this agent for the reversal of LMWHs.

Anticoagulation Agents in Trauma Patients

Antiplatelet Agents

Antiplatelet agents such as aspirin and clopidogrel are used individually and in combination for the treatment of cardiovascular disease.55,56 Patients who have undergone percutaneous coronary intervention are often temporarily or permanently dependent on these medications to maintain stent patency. As a result, caution must be used during attempted reversal of traumatic hemorrhage, owing to the risk of stent thrombosis and subsequent myocardial infarction. Numerous studies have demonstrated a greater degree of progression of ICH and worse outcomes in trauma patients taking antiplatelet agents.57,58 Aspirin irreversibly acetylates a specific serine moiety of platelet cyclooxygenase (COX)-1, thereby reducing the synthesis of thromboxane A2.59 Thromboxane A2 acts as a potent platelet aggregator and vasoconstrictor. Aspirin’s effect is clinically evident in arachidonic acid (AA)-based or collagen-based aggregation assays, but bleeding time is rarely prolonged.60 The platelet function assay using collagenbased and adenosine diphosphate (ADP)-based activation also demonstrates aspirin inactivation, but results are not available in the acute setting owing to the test duration. Newer assays, such as VerifyNow (Accumetrics, San Diego, CA, USA), aim to provide faster results that reflect the true bleeding potential of patients taking antiplatelet agents.61 Clopidogrel irreversibly blocks the binding of ADP to platelet P2Y12 receptors and thereby inhibits further release of ADP from platelets.59 ADP is a potent platelet activator, and clopidogrel interrupts the self-feedback activation loop normally established by ADP release from platelet dense bodies.62 Unlike aspirin, clopidogrel demonstrates both inhibition of platelet aggregation assays and a prolongation in bleeding time.59 Early TEG poorly detected changes in platelet activation secondary to antiplatelet agents such as aspirin and clopidogrel. Modern TEG for platelet function uses platelet-specific activators. TEG Platelet Mapping (Haemonetics) using AA-based or ADP-based assays of blood from patients taking as little as 75 mg of aspirin daily for 1 week demonstrates significant time-dependent reductions in maximum amplitude and curve area (see Fig. 1).63,64 Similar reductions are seen in patients on clopidogrel using the ADP-based assay, but not the AA-based assay. Owing to their irreversible mechanisms of action, aspirin and clopidogrel do not have direct antidotes. When traumatic hemorrhage is present, the traditional belief is that platelet function may be reestablished by the transfusion of nonacetylated platelets. Some studies have demonstrated restoration of platelet activity with transfusion for patients on a low-dose (75–81 mg/d) aspirin regimen, whereas others have demonstrated failure of transfusion to halt ICH progression in patients on a high-dose (325 mg/d) aspirin regimen.61,65 In the event of clinically significant bleeding, such as traumatic ICH, older literature recommends the urgent transfusion of multiple units of platelets for patients on clopidogrel.20 Numerous subsequent studies and reviews have now demonstrated that platelet transfusion is not effective in reducing mortality or altering outcomes from traumatic ICH complicated by some antiplatelet agents.65,66 Because many of these studies were based at institutions without specific protocols for platelet transfusion, recent studies have hypothesized that the extent and duration of platelet transfusion were insufficient to affect outcomes.57 As a result a new protocol was developed, recommending 5 platelet concentrate units for patients with small ICH on aspirin and 10 platelet concentrate units for patients with small ICH on clopidogrel. In more severe cases of ICH, this protocol recommends the addition of desmopressin and serial platelet transfusions every 12 hours for 48 hours (see Table 1). Additional platelet

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transfusion for up to 5 days may be necessary in patients on clopidogrel, owing to the persistence of the drug’s active metabolite. SUMMARY

Therapeutic anticoagulation presents unique challenges during the care of trauma patients. Failure of normal hemostatic measures secondary to pharmacologic blockade may turn clinically insignificant hemorrhage into an organ-threatening or life-threatening situation. The spectrum of agents encountered by trauma clinicians requires familiarity with coagulation physiology, drug mechanisms, and appropriate reversal strategies. The advent of new anticoagulation agents poses additional challenges because of the lack of adequate reversal agents. To provide optimal trauma care for the anticoagulated patient, research and clinician education must continue to match pace with drug development and transition to these newer agents. REFERENCES

1. Coimbra R, Hoyt DB, Anjaria DJ, et al. Reversal of anticoagulation in trauma: a North-American survey on clinical practices among trauma surgeons. J Trauma 2005;59(2):375–82. 2. Fortuna GR, Mueller EW, James LE, et al. The impact of preinjury antiplatelet and anticoagulant pharmacotherapy on outcomes in elderly patients with hemorrhagic brain injury. Surgery 2008;144(4):598–603 [discussion: 603–5]. 3. 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: 1229–30]. 4. Romlin BS, Wahlander H, Synnergren M, et al. Earlier detection of coagulopathy with thromboelastometry during pediatric cardiac surgery: a prospective observational study. Paediatr Anaesth 2013;23(3):222–7. 5. McCully SP, Fabricant LJ, Kunio NR, et al. The International Normalized Ratio overestimates coagulopathy in stable trauma and surgical patients. J Trauma Acute Care Surg 2013;75(6):947–53. 6. Whiting D, Dinardo JA. TEG and ROTEM: technology and clinical applications. Am J Hematol 2014;89(2):228–32. 7. Solomon C, Sorensen B, Hochleitner G, et al. Comparison of whole blood fibrinbased clot tests in thrombelastography and thromboelastometry. Anesth Analg 2012;114(4):721–30. 8. Ahmed N, Kassavin D, Kuo YH, et al. Sensitivity and specificity of CT scan and angiogram for ongoing internal bleeding following torso trauma. Emerg Med J 2013;30(3):e14. 9. Roudsari B, Psoter KJ, Fine GC, et al. Falls, older adults, and the trend in utilization of CT in a level I trauma center. AJR Am J Roentgenol 2012;198(5): 985–91. 10. Prowse SJ, Sloan J. NICE guidelines for the investigation of head injuries–an anticoagulant loop hole? Emerg Med J 2010;27(4):277–8. 11. National Institute for Health and Care Excellence. Head injury clinical guidelines (CG56): triage, assessment, investigation and early management of head injury in infants, children and adults. 2007. Available at: http://www.nice.org.uk/ guidance/index.jsp?action5byID&o511836. Accessed February 10, 2014. 12. Cohen DB, Rinker C, Wilberger JE. Traumatic brain injury in anticoagulated patients. J Trauma 2006;60(3):553–7.

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13. Hirsh J, Dalen J, Anderson DR, et al. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest 2001;119(1 Suppl): 8S–21S. 14. Bonville DJ, Ata A, Jahraus CB, et al. Impact of preinjury warfarin and antiplatelet agents on outcomes of trauma patients. Surgery 2011;150(4):861–8. 15. Calland JF, Ingraham AM, Martin N, et al. Evaluation and management of geriatric trauma: an Eastern Association for the Surgery of Trauma practice management guideline. J Trauma Acute Care Surg 2012;73(5 Suppl 4):S345–50. 16. Ivascu FA, Howells GA, Junn FS, et al. Rapid warfarin reversal in anticoagulated patients with traumatic intracranial hemorrhage reduces hemorrhage progression and mortality. J Trauma 2005;59(5):1131–7 [discussion: 1137–9]. 17. Ageno W, Garcia D, Aguilar MI, et al. Prevention and treatment of bleeding complications in patients receiving vitamin K antagonists, part 2: treatment. Am J Hematol 2009;84(9):584–8. 18. Contreras M, Ala FA, Greaves M, et al. Guidelines for the use of fresh frozen plasma. British Committee for Standards in Haematology, Working Party of the Blood Transfusion Task Force. Transfus Med 1992;2(1):57–63. 19. Popovsky MA. Transfusion-related acute lung injury: incidence, pathogenesis and the role of multicomponent apheresis in its prevention. Transfus Med Hemother 2008;35(2):76–9. 20. Beshay JE, Morgan H, Madden C, et al. Emergency reversal of anticoagulation and antiplatelet therapies in neurosurgical patients. J Neurosurg 2010;112(2): 307–18. 21. Sarode R, Matevosyan K, Bhagat R, et al. Rapid warfarin reversal: a 3-factor prothrombin complex concentrate and recombinant factor VIIa cocktail for intracerebral hemorrhage. J Neurosurg 2012;116(3):491–7. 22. Ageno W, Gallus AS, Wittkowsky A, et al. Oral anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012;141(2 Suppl):e44S–88S. 23. CSL Behring GmbH. Kcentra prescribing information. 2013. Available at: http:// www.kcentra.com/prescribing-information.aspx. Accessed February 27, 2014. 24. Rosovsky RP, Crowther MA. What is the evidence for the off-label use of recombinant factor VIIa (rFVIIa) in the acute reversal of warfarin? ASH evidence-based review 2008. Hematology Am Soc Hematol Educ Program 2008;36–8. http://dx. doi.org/10.1182/asheducation-2008.1.36. 25. Lazo-Langner A, Rodger MA, Wells PS. Lessons from ximelagatran: issues for future studies evaluating new oral direct thrombin inhibitors for venous thromboembolism prophylaxis in orthopedic surgery. Clin Appl Thromb Hemost 2009; 15(3):316–26. 26. Boudes PF. The challenges of new drugs benefits and risks analysis: lessons from the ximelagatran FDA Cardiovascular Advisory Committee. Contemp Clin Trials 2006;27(5):432–40. 27. Nutescu EA, Shapiro NL, Chevalier A. New anticoagulant agents: direct thrombin inhibitors. Cardiol Clin 2008;26(2):169–87, v–vi. 28. Blech S, Ebner T, Ludwig-Schwellinger E, et al. The metabolism and disposition of the oral direct thrombin inhibitor, dabigatran, in humans. Drug Metab Dispos 2008;36(2):386–99. 29. Wienen W, Stassen JM, Priepke H, et al. In-vitro profile and ex-vivo anticoagulant activity of the direct thrombin inhibitor dabigatran and its orally active prodrug, dabigatran etexilate. Thromb Haemost 2007;98(1):155–62.

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30. Lange U, Nowak G, Bucha E. Ecarin chromogenic assay–a new method for quantitative determination of direct thrombin inhibitors like hirudin. Pathophysiol Haemost Thromb 2003;33(4):184–91. 31. Engstrom M, Rundgren M, Schott U. An evaluation of monitoring possibilities of argatroban using rotational thromboelastometry and activated partial thromboplastin time. Acta Anaesthesiol Scand 2010;54(1):86–91. 32. van Ryn J, Stangier J, Haertter S, et al. Dabigatran etexilate–a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost 2010;103(6):1116–27. 33. Boehringer Ingelheim Pharmaceuticals. Pradaxa prescribing information. 2013. Available at: http://bidocs.boehringer-ingelheim.com/BIWebAccess/ViewServlet. ser?docBase5renetnt&folderPath5/Prescribing%20Information/PIs/Pradaxa/ Pradaxa.pdf. Accessed February 27, 2014. 34. Crowther MA, Warkentin TE. Managing bleeding in anticoagulated patients with a focus on novel therapeutic agents. J Thromb Haemost 2009;7(Suppl 1):107–10. 35. Garber ST, Sivakumar W, Schmidt RH. Neurosurgical complications of direct thrombin inhibitors–catastrophic hemorrhage after mild traumatic brain injury in a patient receiving dabigatran. J Neurosurg 2012;116(5):1093–6. 36. Gruber A, Carlsson S, Kotze HF, et al. Hemostatic effect of activated factor VII without promotion of thrombus growth in melagatran-anticoagulated primates. Thromb Res 2007;119(1):121–7. 37. Oh JJ, Akers WS, Lewis D, et al. Recombinant factor VIIa for refractory bleeding after cardiac surgery secondary to anticoagulation with the direct thrombin inhibitor lepirudin. Pharmacotherapy 2006;26(4):569–77. 38. Wolzt M, Levi M, Sarich TC, et al. Effect of recombinant factor VIIa on melagatran-induced inhibition of thrombin generation and platelet activation in healthy volunteers. Thromb Haemost 2004;91(6):1090–6. 39. Faust AC, Peterson EJ. Management of dabigatran-associated intracerebral and intraventricular hemorrhage: a case report. J Emerg Med 2014;46(4): 525–9. http://dx.doi.org/10.1016/j.jemermed.2013.11.097. 40. Dumkow LE, Voss JR, Peters M, et al. Reversal of dabigatran-induced bleeding with a prothrombin complex concentrate and fresh frozen plasma. Am J Health Syst Pharm 2012;69(19):1646–50. 41. Schiele F, van Ryn J, Canada K, et al. A specific antidote for dabigatran: functional and structural characterization. Blood 2013;121(18):3554–62. 42. Perzborn E, Roehrig S, Straub A, et al. Rivaroxaban: a new oral factor Xa inhibitor. Arterioscler Thromb Vasc Biol 2010;30(3):376–81. 43. Gerotziafas GT, Elalamy I, Depasse F, et al. In vitro inhibition of thrombin generation, after tissue factor pathway activation, by the oral, direct factor Xa inhibitor rivaroxaban. J Thromb Haemost 2007;5(4):886–8. 44. Kakkar AK, Brenner B, Dahl OE, et al. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet 2008; 372(9632):31–9. 45. Eriksson BI, Borris LC, Friedman RJ, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med 2008;358(26):2765–75. 46. Samama MM, Martinoli JL, LeFlem L, et al. Assessment of laboratory assays to measure rivaroxaban–an oral, direct factor Xa inhibitor. Thromb Haemost 2010; 103(4):815–25. 47. Martin AC, Le Bonniec B, Fischer AM, et al. Evaluation of recombinant activated factor VII, prothrombin complex concentrate, and fibrinogen concentrate to

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48.

49. 50.

51. 52.

53. 54.

55.

56.

57.

58.

59.

60.

61.

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Management of anticoagulation agents in trauma patients.

A lack of consensus on anticoagulant reversal during acute trauma is compounded by an aging population and the expanding spectrum of new anticoagulati...
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