The American Journal of Surgery (2015) 209, 413-417
Review
Prothrombin complex concentrate in trauma patients Kazuhide Matsushima, M.D.*, Elizabeth Benjamin, M.D., Ph.D., Demetrios Demetriades, M.D., Ph.D. Division of Acute Care Surgery, University of Southern California, 1200 North State Street, Inpatient Tower (C), Room C5L100, Los Angeles, CA 90033, USA KEYWORDS: Prothrombin complex concentrate; Trauma; Coagulopathy
Abstract BACKGROUND: Despite recent advances, trauma care providers nowadays face a number of coagulopathic patients. Coagulopathy in trauma patients can be secondary to the traumatic insult or therapeutic effect of the anticoagulants including the Vitamin K antagonist. The efficacy of a concentrated product of Vitamin K–dependent coagulation factors, prothrombin complex concentrate (PCC), to reverse coagulopathy has been tested mainly in nontrauma setting. DATA SOURCES: Currently available literature on the use of PCC was identified by searches of electronic database. The indications (trauma vs nontrauma) and types of the PCC products (3 vs 4 factors) were also reviewed in each article. CONCLUSIONS: There are small studies that show promising results regarding PCC use to reverse the Vitamin K antagonist–related coagulopathy in trauma patients. It remains unanswered whether PCC can be effective as an adjunct in patients who require massive transfusion. Ó 2015 Elsevier Inc. All rights reserved.
Coagulopathy in Trauma Reversal of coagulopathy in the acutely injured and bleeding patient is one of the primary goals of the trauma surgeon. Coagulopathy is an acquired condition because of ongoing hemorrhage or a secondary effect of the traumatic insult. Adequate hemostasis needs to be achieved not only surgically but also by correcting acute traumatic coagulopathy (ATC).1 There are multiple factors that compromise a
All authors deny any potential conflicts of interest. No internal and external financial support was used for this study. * Corresponding author. Tel: 11-323-409-8597; fax: 11-323-4419907. E-mail address: [email protected] Manuscript received February 25, 2014; revised manuscript July 30, 2014 0002-9610/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjsurg.2014.08.019
normal coagulation process in major trauma patients.2,3 Coagulopathy in trauma patients is known as a component of catastrophic conditions called the ‘‘triad of death.’’4 It has been shown that coagulopathy in acutely injured patients is associated with a significantly higher mortality rate.5 In the last decade, the concept of ‘‘damage control resuscitation’’ has been adopted including early and aggressive administration of blood products with a higher ratio of packed red blood cells (PRBC) to fresh-frozen plasma (FFP) to platelets than the conventional resuscitation strategy.6–8 This has been thought to lower the incidence of coagulopathy.4,7–9 In contrast, it is also well described that FFP and platelets can potentiate the risk of volume overload, infection, or other side effect related to the transfusion of blood product.10,11 Further, recent data show that the risk of transfusion-related acute lung injury is the highest after the transfusion of FFP.10 These competing ideas regarding
414 the aggressive use of FFP in ATC have caused an interest in alternative measures to prevent or reverse the observed derangements in the coagulation cascade. An additional and increasingly common etiology of coagulopathy in the trauma patient is the intentional prehospital use of anticoagulation medication. A large number of anticoagulants are available in the United States for the treatment of thromboembolic conditions or prevention of stroke.12 Warfarin, a Vitamin K antagonist (VKA), is still the most commonly used agent for chronic anticoagulation. As the indication for anticoagulation therapy has expanded, so has the numbers of bleeding complications related to anticoagulation medications.13 Accordingly, trauma care providers now more frequently encounter patients with active bleeding secondary to traumatic injury that is complicated by the therapeutic effect of these medications. Anticoagulated patients are often older and, thus, more likely to have comorbidities that put them at higher risk of bleeding, particularly in the intracranial space. The mortality of anticoagulated patients with intracranial hemorrhage is reported as high as 60%.14,15 As intracranial bleeding can develop and progress rapidly, the reversal of VKA with correction of the international normalized ratio (INR) in a timely manner is fundamental to this treatment algorithm.
Hemostatic Resuscitation in Acute Trauma Setting A protocol-based resuscitation strategy to prevent ATC is known to improve the outcome of severely injured patients requiring massive blood transfusion.16,17 Trauma resuscitation with massive transfusion protocol is mainly characterized as a higher ratio of FFP and platelets to PRBC called ‘‘hemostatic resuscitation.’’18 In military environments, the use of fresh whole blood is often considered advantageous for patients who required massive transfusion compared with the components therapy, although its experience in the civilian setting is limited.19,20 It was reported that the amount of warm fresh whole blood was independently associated with improved survival of military patients who received massive transfusion protocol.20 It is these data that have helped drive the contemporary movement toward equal component resuscitation in the civilian setting, with equivalent infusion of PRBC, FFP, and platelets to mimic this ‘‘whole-blood’’ resuscitation. In addition to these blood products, several adjunct products are currently available for resuscitation in trauma patients. The effect of recombinant activated factor VII (rFVIIa) has been evaluated for patients with traumatic brain injury (TBI) and active hemorrhage.21–25 Although these studies do not show improvement of patient outcomes, they do report a significantly increased number of arterial thromboses.25 In a large randomized prospective study, it has been shown that early administration of tranexamic acid to severely injured trauma patients significantly reduced their mortality because of bleeding without increasing risk of
The American Journal of Surgery, Vol 209, No 2, February 2015 vascular occlusive complications.26 However, the subsequent analyses stratified by the time from injury to treatment showed that late treatment (.3 hours) of tranexamic acid was significantly associated with higher mortality rate because of bleeding compared with the placebo group.27
Prothrombin Complex Concentrate Prothrombin complex concentrate (PCC) is a concentrated vitamin K–dependent coagulation factor product (factors II, VII, IX, and X) derived from large donor– pooled plasma that is stored as a lyophilized powder. PCC is designed to provide rapid factor replacement with smallvolume administration. PCC was originally approved for use in the treatment of hemophilia B; however, the indication has extended to use in patients with VKAacquired coagulopathy, primarily in those requiring urgent reversal.28–31 Although large-volume FFP was previously the standard of care for VKA reversal in this population, PCC has become the first-line reversal recommendation both abroad and in the United States.13,30,31 The use of PCC is currently recommended in the most recent edition of clinical practice guideline by the American College of Chest Physicians for urgent VKA reversal in patients with active bleeding or urgent procedures.13 Although VKA reversal with administration of vitamin K and FFP is commonly used, it can take several hours for the INR to be corrected.32 One of the major advantages of PCC over FFP is the rapidity with which VKA reversal is achieved. This is especially important in the actively bleeding or head-injured patient. Although FFP requires time for acquisition and large-volume infusion, PCC can be rapidly reconstituted and infused with immediate effect.33 With PCC, the data have shown a reversal of INR to less than 1.5 within 10 to 30 minutes with a smallvolume (20 to 100 mL) administration.34 A multicenter European prospective trial with 4-factor PCC showed an INR decline to 1.4 or less in 100% of patients at 30 minutes post-transfusion.35 A prospective cohort study in Italy mirrored these results with the median INR decrease to 1.4 (range .9 to 3.1) from 3.3 (range 2 to 9) on admission, 30 minutes after administration of 3-factor PCC.36 A small study of neurosurgical patients from the United Kingdom used PCC in 6 consecutive admissions and age and sex matched them to patients receiving FFP.37 Mean INR reduced from 4.86 to 1.32 within 15 minutes of PCC administration with a mean correction time of 41 minutes. The mean INR of the FFP group declined from 5.32 to 2.30 when measured 15 minutes after infusion completion with a mean correction time of 115 minutes. In 1999, a randomized control trial compared correction with FFP alone or PCC with FFP. The authors showed improved correction, more rapid correction, and fewer complications in the group receiving PCC.38 The time to correction was 2.95 vs 8.9 hours (P , .01) for the group receiving PCC, and the volume of FFP infused was 399 6 271 vs 2,712 6
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PCC in trauma patients
346 mL (P , .0007) with complications of fluid overload noted in the FFP-only group. In addition, the volume of FFP required for reversal can be large, often leading to significant infusion-related complications. The reported risks of FFP transfusion, such as transfusion-related acute lung injury or transfusion-related acute circulatory overload, can theoretically be lowered by using PCC for a reversal. A randomized trial conducted by Sarode et al39 showed a higher incidence of fluid overload or similar cardiac events in the plasma group compared with the 4-factor PCC group (12.8% vs 4.9%). Cost-effectiveness is another positive impact related to the use of PCC. Although the cost of therapy adding PCC to FFP versus FFP alone was found to be significantly higher, the total cost of transfusion was significantly lower in the coagulopathic trauma patient receiving PCC.40 In cost-effective analyses using the cost per life-year gained, Guest et al41 concluded that the use of PCC appeared to be more cost effective than FFP in VKA reversal after several types of hemorrhage. Two types of PCCs are currently available in the market, 3- and 4-factor PCC. Three-factor PCC contains Vitamin K– dependent coagulation factors II, IX, and X, whereas 4-factor PCC, recently approved for use in the United States, contains factors II, IX, X, with the addition of factor VII.34,35,42–44 Because of this difference in factor VII concentration, the efficacy and utility of 3-factor PCC have been questioned. A systematic literature review by Voils and Baird45 included 654 patients from 18 prospective and retrospective studies investigating the use of PCC for warfarin reversal (8 studies with 3-factor PCC and 10 studies with 4-factor PCC). The authors concluded that 4-factor PCC is more effective than 3factor PCC to lower INR of 1.5 of less within 1 hour after administration. These conclusions, however, are limited by significant product and delivery variability. Despite the lack of data with direct comparison between the 3- and 4factor products, the existing data would suggest that the 4factor product will be used preferentially in the acute setting. As most studies were too small to evaluate the risk of thromboembolic complications related to the treatment with PCC, the actual incidence after the administration of PCC remains unknown.42,43 Majeed et al46 identified 6 patients (3.8%) with thromboembolic events after treatment with 4-factor PCCs. Of note, 74% and 34% of the patients also received Vitamin K and FFP in addition to PCC in their study. Similarly, 3.9% of PCC-related thromboembolic events were reported in a recent phase III study to compare 4-factor PCC with FFP.43 In a total of 460 patients from 14 studies reviewed by Leissinger et al,47 thrombotic complications occurred in 7 cases (1.8%) after the treatment with either a 3- or 4-factor PCC.
415 evaluate PCC use in trauma patients, several small studies have shown that coagulopathy in trauma patients can be effectively reversed with PCC.48–50 Safaoui et al48 published a preliminary report using 3-factor PCC for 28 patients on warfarin that presented with TBI. During the study period, suspected TBI patients with pre-injury warfarin use received 2,000 units of PCC pre-emptively following the protocol. Mean INR was significantly reduced after PCC was given (5.1 to 1.9, P 5 .008). For patients who had a repeat INR within 30 minutes, a mean time to correction of INR was 13.5 minutes. Joseph et al49 reviewed 45 coagulopathic trauma patients who received 3-factor PCC (Profilnine SD) at their level I trauma center. This group included patients both with and without pre-injury warfarin use. In 20 patients without pre-injury warfarin use (44%), INR was reduced significantly from 2.0 6 .6 to 1.4 6 .4 (P 5.001). Significant reduction of PRBC administration was also observed after the administration of PCC (9.8 6 6.8 vs. 3.8 6 4.8, P 5 .002). INR was significantly reduced with PCC (2.6 6 1.0 vs. 1.5 6 .2, P 5 .001) in the 25 patients with pre-injury warfarin use, but no significant differences in the dosage of PRBC were identified.
PCC in the Geriatric Trauma Population The number of geriatric trauma patients in the United States continues to increase.51 The elderly trauma patients are more likely to have significant comorbidities and more likely to be on prehospital anticoagulation medication, thus complicating their trauma injury management. It has been proposed that the management of elderly trauma victims needs to be tailored because of significant difference in pre-existing medical conditions.52,53 Underlying cardiac, respiratory, or renal dysfunction can significantly alter the fluid management and product resuscitation goals in a bleeding elderly trauma patient. Furthermore, in rural communities, the access to blood products can be limited. The use of PCC could potentially aid in these dilemmas. Quick et al50 reported their preliminary experience with PCC for warfarin reversal of geriatric patients in rural trauma setting. Fifteen patients who were taking warfarin before injury received PCC (15 to 30 IU/kg) alone or in conjunction with FFP. Compared with 10 patients who received FFP alone, they showed benefit in patients receiving PCC including lower volume infusion (,50 mL vs 1 L), a trend toward fewer units of FFP administration, and a greater decrease in INR. Although significance was not reached, fewer units of PRBC transfusion were required in the PCC group. There has also been proposed the potential positive impact of PCC use in rural hospitals with limited financial resources and limited ready access to blood bank facilities.
PCC in the Trauma Population PCC vs Recombinant activated Factor VII As the use of PCC becomes more widely adopted, there is increasing interest in the use of this product in the trauma population. Although there is no high-quality study to
In the past decade, rFVIIa has fallen in and out of favor among the trauma community for use in treating
416 trauma-associated coagulopathy.21,23,24 Furthermore, rFVIIa has previously been recommended for VKA reversal in the acutely bleeding patient.54,55 PCC, also a factor concentrate product has, therefore, been compared not only with FFP but also with rFVIIa for safety and efficacy. Using a porcine coagulopathy model, Dickneite et al56 compared the use of PCC with rFVIIa for the treatment of acquired coagulopathy because of traumatic hemorrhage. Coagulopathy was induced by experimental splenic injury and hemodilution with crystalloid and colloid resuscitation. Both PCC and rFVIIa reversed prolonged prothrombin time to normal range. Time to hemostasis at the splenic injury site was significantly shorter with PCC than with rFVIIa (35 vs 94 minutes, P 5.016). In a retrospective study by Joseph et al,57 85 TBI patients with coagulopathy either with or without preinjury warfarin use were reviewed to compare the efficacy of 3-factor PCC with rFVIIa (NovoSeven). In both PCC and rFVIIa groups, INR was similarly decreased (mean INR after therapy: 1.58 vs 1.4, P 5 .77). Clinical outcomes including craniotomy rate and Glasgow Coma Scale on discharge were not significantly different between each group. No thromboembolic complications were seen in the PCC group in this study. In the rFVIIa group, 1 patient developed deep vein thrombosis. Furthermore, the mean cost of therapy using PCC was significantly lower in the PCC group ($1,007 vs $5,757, P,.01).
Future Direction PCC has been extensively evaluated for use in reversal of acquired coagulopathy because of warfarin. In contrast, it remains unknown whether there is any role of PCC as an adjunct in the resuscitation of coagulopathic trauma patients who require massive transfusion.58 The use of rFVIIa for this purpose has been investigated in prospective studies with controversial results.59,60 Morse et al60 compared the clinical outcomes and transfusion requirement between patients who received massive transfusion with and without rFVIIa. They found minimal effect both on patient clinical outcome and transfusion requirement. Preliminary data shown by Bruce and Nokes43 suggests that PCC can be effective for non– VKA-related coagulopathy after surgical bleeding. Significant decrease in the requirement of blood products after PCC administration was observed in all the patients (cardiac and other surgery groups). There is a single-center prospective study that shows comparable outcomes of patients after major blunt trauma (injury severity score . 15) between conventional FFP-based and coagulation factor concentrate (fibrinogen or PCC)–alone transfusion protocol.61 In fact, higher transfusion rates for PRBC and platelets were observed in FFP group. In 2013, the first 4-factor PCC was approved by the Food and Drug Administration for the urgent reversal of VKA therapy in patients with severe bleeding or need for urgent surgery. This specific formula of 4-factor PCC has been studied in Europe for a decade with promising results.36,59 With the approval of 4-factor PCC by the Food and Drug
The American Journal of Surgery, Vol 209, No 2, February 2015 Administration, prospective data investigating the role of this product in our trauma population are imperative.
Conclusions Although the use of PCC has been shown to improve the outcome of patients with VKA-induced coagulopathy in the nontrauma setting, its use for VKA-associated coagulopathic patients with TBI still needs to be evaluated with further prospective investigation. Also, PCC may be considered for adjunct use in the resuscitation of trauma patients who require massive transfusion.
Acknowledgment Author contribution: Study concept and designdK.M., E.B., and D.D.; literature searchdK.M. and E.B.; writingdK.M. and E.B.; critical revisiondE.B. and D.D.
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417 40. Joseph B, Aziz H, Pandit V, et al. Prothrombin complex concentrate versus fresh-frozen plasma for reversal of coagulopathy of trauma: is there a difference? World J Surg 2014;38:1875–81. 41. Guest JF, Watson HG, Limaye S. Modeling the cost-effectiveness of prothrombin complex concentrate compared with fresh frozen plasma in emergency warfarin reversal in the United kingdom. Clin Ther 2010;32:2478–93. 42. Kerebel D, Joly LM, Honnart D, et al. A French multicenter randomised trial comparing two dose-regimens of prothrombin complex concentrates in urgent anticoagulation reversal. Crit Care 2013;17:R4. 43. Bruce D, Nokes TJ. Prothrombin complex concentrate (Beriplex P/N) in severe bleeding: experience in a large tertiary hospital. Crit Care 2008;12:R105. 44. Yasaka M, Sakata T, Minematsu K, et al. Correction of INR by prothrombin complex concentrate and vitamin K in patients with warfarin related hemorrhagic complication. Thromb Res 2002;108:25–30. 45. Voils SA, Baird B. Systematic review: 3-factor versus 4-factor prothrombin complex concentrate for warfarin reversal: does it matter? Thromb Res 2012;130:833–40. 46. Majeed A, Eelde A, Agren A, et al. Thromboembolic safety and efficacy of prothrombin complex concentrates in the emergency reversal of warfarin coagulopathy. Thromb Res 2012;129:146–51. 47. Leissinger CA, Blatt PM, Hoots WK, et al. Role of prothrombin complex concentrates in reversing warfarin anticoagulation: a review of the literature. Am J Hematol 2008;83:137–43. 48. Safaoui MN, Aazami R, Hotz H, et al. A promising new alternative for the rapid reversal of warfarin coagulopathy in traumatic intracranial hemorrhage. Am J Surg 2009;197:785–90. 49. Joseph B, Amini A, Friese RS, et al. Factor IX complex for the correction of traumatic coagulopathy. J Trauma Acute Care Surg 2012;72:828–34. 50. Quick JA, Bartels AN, Coughenour JP, et al. Experience with prothrombin complex for the emergent reversal of anticoagulation in rural geriatric trauma patients. Surgery 2012;152:722–6. 51. US Census Bureau. Age and sex composition: 2010. Available at: http://www.census.gov/prod/cen2010/briefs/c2010br-03.pdf. Accessed November 5, 2013. 52. Bradburn E, Rogers FB, Krasne M, et al. High-risk geriatric protocol: improving mortality in the elderly. J Trauma Acute Care Surg 2012;73: 435–40. 53. Jacobs DG, Plaisier BR, Barie PS, et al, EAST Practice Management Guidelines Work Group. Practice management guidelines for geriatric trauma: the EAST Practice Management Guidelines Work Group. J Trauma 2003;54:391–416. 54. Ansell J, Hirsh J, Hylek E, et al. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians EvidenceBased Clinical Practice Guidelines (8th edition). Chest 2008;133:160S–98S. 55. American Society of Hematology. Clinical Practice Guide on Anticoagulant Dosing and Management of Anticoagulant-Associated Bleeding Complications in Adults Available at, http://www.hematology.org/ Practice/Guidelines/2934.aspx; 2011. Accessed October 15, 2013. 56. Dickneite G, Do¨rr B, Kaspereit F, et al. Prothrombin complex concentrate versus recombinant factor VIIa for reversal of hemodilutional coagulopathy in a porcine trauma model. J Trauma 2010;68:1151–7. 57. Joseph B, Hadjizacharia P, Aziz H, et al. Prothrombin complex concentrate: an effective therapy in reversing the coagulopathy of traumatic brain injury. J Trauma Acute Care Surg 2013;74:248–53. 58. Sorensen B, Fries D. Emerging treatment strategies for traumainduced coagulopathy. Br J Surg 2012;99:40–50. 59. Spinella PC, Perkins JG, McLaughlin DF, et al. The effect of recombinant activated factor VII on mortality in combat-related casualties with severe trauma and massive transfusion. J Trauma 2008;64:286–93. 60. Morse BC, Dente CJ, Hodgman EI, et al. The effects of protocolized use of recombinant factor VIIa within a massive transfusion protocol in a civilian level I trauma center. Am Surg 2011;77:1043–9. 61. Innerhofer P, Westermann I, Tauber H, et al. The exclusive use of coagulation factor concentrates enables reversal of coagulopathy and decreases transfusion rates in patients with major blunt trauma. Injury 2013;44:209–16.
Review
Prothrombin complex concentrate in trauma patients Kazuhide Matsushima, M.D.*, Elizabeth Benjamin, M.D., Ph.D., Demetrios Demetriades, M.D., Ph.D. Division of Acute Care Surgery, University of Southern California, 1200 North State Street, Inpatient Tower (C), Room C5L100, Los Angeles, CA 90033, USA KEYWORDS: Prothrombin complex concentrate; Trauma; Coagulopathy
Abstract BACKGROUND: Despite recent advances, trauma care providers nowadays face a number of coagulopathic patients. Coagulopathy in trauma patients can be secondary to the traumatic insult or therapeutic effect of the anticoagulants including the Vitamin K antagonist. The efficacy of a concentrated product of Vitamin K–dependent coagulation factors, prothrombin complex concentrate (PCC), to reverse coagulopathy has been tested mainly in nontrauma setting. DATA SOURCES: Currently available literature on the use of PCC was identified by searches of electronic database. The indications (trauma vs nontrauma) and types of the PCC products (3 vs 4 factors) were also reviewed in each article. CONCLUSIONS: There are small studies that show promising results regarding PCC use to reverse the Vitamin K antagonist–related coagulopathy in trauma patients. It remains unanswered whether PCC can be effective as an adjunct in patients who require massive transfusion. Ó 2015 Elsevier Inc. All rights reserved.
Coagulopathy in Trauma Reversal of coagulopathy in the acutely injured and bleeding patient is one of the primary goals of the trauma surgeon. Coagulopathy is an acquired condition because of ongoing hemorrhage or a secondary effect of the traumatic insult. Adequate hemostasis needs to be achieved not only surgically but also by correcting acute traumatic coagulopathy (ATC).1 There are multiple factors that compromise a
All authors deny any potential conflicts of interest. No internal and external financial support was used for this study. * Corresponding author. Tel: 11-323-409-8597; fax: 11-323-4419907. E-mail address: [email protected] Manuscript received February 25, 2014; revised manuscript July 30, 2014 0002-9610/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjsurg.2014.08.019
normal coagulation process in major trauma patients.2,3 Coagulopathy in trauma patients is known as a component of catastrophic conditions called the ‘‘triad of death.’’4 It has been shown that coagulopathy in acutely injured patients is associated with a significantly higher mortality rate.5 In the last decade, the concept of ‘‘damage control resuscitation’’ has been adopted including early and aggressive administration of blood products with a higher ratio of packed red blood cells (PRBC) to fresh-frozen plasma (FFP) to platelets than the conventional resuscitation strategy.6–8 This has been thought to lower the incidence of coagulopathy.4,7–9 In contrast, it is also well described that FFP and platelets can potentiate the risk of volume overload, infection, or other side effect related to the transfusion of blood product.10,11 Further, recent data show that the risk of transfusion-related acute lung injury is the highest after the transfusion of FFP.10 These competing ideas regarding
414 the aggressive use of FFP in ATC have caused an interest in alternative measures to prevent or reverse the observed derangements in the coagulation cascade. An additional and increasingly common etiology of coagulopathy in the trauma patient is the intentional prehospital use of anticoagulation medication. A large number of anticoagulants are available in the United States for the treatment of thromboembolic conditions or prevention of stroke.12 Warfarin, a Vitamin K antagonist (VKA), is still the most commonly used agent for chronic anticoagulation. As the indication for anticoagulation therapy has expanded, so has the numbers of bleeding complications related to anticoagulation medications.13 Accordingly, trauma care providers now more frequently encounter patients with active bleeding secondary to traumatic injury that is complicated by the therapeutic effect of these medications. Anticoagulated patients are often older and, thus, more likely to have comorbidities that put them at higher risk of bleeding, particularly in the intracranial space. The mortality of anticoagulated patients with intracranial hemorrhage is reported as high as 60%.14,15 As intracranial bleeding can develop and progress rapidly, the reversal of VKA with correction of the international normalized ratio (INR) in a timely manner is fundamental to this treatment algorithm.
Hemostatic Resuscitation in Acute Trauma Setting A protocol-based resuscitation strategy to prevent ATC is known to improve the outcome of severely injured patients requiring massive blood transfusion.16,17 Trauma resuscitation with massive transfusion protocol is mainly characterized as a higher ratio of FFP and platelets to PRBC called ‘‘hemostatic resuscitation.’’18 In military environments, the use of fresh whole blood is often considered advantageous for patients who required massive transfusion compared with the components therapy, although its experience in the civilian setting is limited.19,20 It was reported that the amount of warm fresh whole blood was independently associated with improved survival of military patients who received massive transfusion protocol.20 It is these data that have helped drive the contemporary movement toward equal component resuscitation in the civilian setting, with equivalent infusion of PRBC, FFP, and platelets to mimic this ‘‘whole-blood’’ resuscitation. In addition to these blood products, several adjunct products are currently available for resuscitation in trauma patients. The effect of recombinant activated factor VII (rFVIIa) has been evaluated for patients with traumatic brain injury (TBI) and active hemorrhage.21–25 Although these studies do not show improvement of patient outcomes, they do report a significantly increased number of arterial thromboses.25 In a large randomized prospective study, it has been shown that early administration of tranexamic acid to severely injured trauma patients significantly reduced their mortality because of bleeding without increasing risk of
The American Journal of Surgery, Vol 209, No 2, February 2015 vascular occlusive complications.26 However, the subsequent analyses stratified by the time from injury to treatment showed that late treatment (.3 hours) of tranexamic acid was significantly associated with higher mortality rate because of bleeding compared with the placebo group.27
Prothrombin Complex Concentrate Prothrombin complex concentrate (PCC) is a concentrated vitamin K–dependent coagulation factor product (factors II, VII, IX, and X) derived from large donor– pooled plasma that is stored as a lyophilized powder. PCC is designed to provide rapid factor replacement with smallvolume administration. PCC was originally approved for use in the treatment of hemophilia B; however, the indication has extended to use in patients with VKAacquired coagulopathy, primarily in those requiring urgent reversal.28–31 Although large-volume FFP was previously the standard of care for VKA reversal in this population, PCC has become the first-line reversal recommendation both abroad and in the United States.13,30,31 The use of PCC is currently recommended in the most recent edition of clinical practice guideline by the American College of Chest Physicians for urgent VKA reversal in patients with active bleeding or urgent procedures.13 Although VKA reversal with administration of vitamin K and FFP is commonly used, it can take several hours for the INR to be corrected.32 One of the major advantages of PCC over FFP is the rapidity with which VKA reversal is achieved. This is especially important in the actively bleeding or head-injured patient. Although FFP requires time for acquisition and large-volume infusion, PCC can be rapidly reconstituted and infused with immediate effect.33 With PCC, the data have shown a reversal of INR to less than 1.5 within 10 to 30 minutes with a smallvolume (20 to 100 mL) administration.34 A multicenter European prospective trial with 4-factor PCC showed an INR decline to 1.4 or less in 100% of patients at 30 minutes post-transfusion.35 A prospective cohort study in Italy mirrored these results with the median INR decrease to 1.4 (range .9 to 3.1) from 3.3 (range 2 to 9) on admission, 30 minutes after administration of 3-factor PCC.36 A small study of neurosurgical patients from the United Kingdom used PCC in 6 consecutive admissions and age and sex matched them to patients receiving FFP.37 Mean INR reduced from 4.86 to 1.32 within 15 minutes of PCC administration with a mean correction time of 41 minutes. The mean INR of the FFP group declined from 5.32 to 2.30 when measured 15 minutes after infusion completion with a mean correction time of 115 minutes. In 1999, a randomized control trial compared correction with FFP alone or PCC with FFP. The authors showed improved correction, more rapid correction, and fewer complications in the group receiving PCC.38 The time to correction was 2.95 vs 8.9 hours (P , .01) for the group receiving PCC, and the volume of FFP infused was 399 6 271 vs 2,712 6
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346 mL (P , .0007) with complications of fluid overload noted in the FFP-only group. In addition, the volume of FFP required for reversal can be large, often leading to significant infusion-related complications. The reported risks of FFP transfusion, such as transfusion-related acute lung injury or transfusion-related acute circulatory overload, can theoretically be lowered by using PCC for a reversal. A randomized trial conducted by Sarode et al39 showed a higher incidence of fluid overload or similar cardiac events in the plasma group compared with the 4-factor PCC group (12.8% vs 4.9%). Cost-effectiveness is another positive impact related to the use of PCC. Although the cost of therapy adding PCC to FFP versus FFP alone was found to be significantly higher, the total cost of transfusion was significantly lower in the coagulopathic trauma patient receiving PCC.40 In cost-effective analyses using the cost per life-year gained, Guest et al41 concluded that the use of PCC appeared to be more cost effective than FFP in VKA reversal after several types of hemorrhage. Two types of PCCs are currently available in the market, 3- and 4-factor PCC. Three-factor PCC contains Vitamin K– dependent coagulation factors II, IX, and X, whereas 4-factor PCC, recently approved for use in the United States, contains factors II, IX, X, with the addition of factor VII.34,35,42–44 Because of this difference in factor VII concentration, the efficacy and utility of 3-factor PCC have been questioned. A systematic literature review by Voils and Baird45 included 654 patients from 18 prospective and retrospective studies investigating the use of PCC for warfarin reversal (8 studies with 3-factor PCC and 10 studies with 4-factor PCC). The authors concluded that 4-factor PCC is more effective than 3factor PCC to lower INR of 1.5 of less within 1 hour after administration. These conclusions, however, are limited by significant product and delivery variability. Despite the lack of data with direct comparison between the 3- and 4factor products, the existing data would suggest that the 4factor product will be used preferentially in the acute setting. As most studies were too small to evaluate the risk of thromboembolic complications related to the treatment with PCC, the actual incidence after the administration of PCC remains unknown.42,43 Majeed et al46 identified 6 patients (3.8%) with thromboembolic events after treatment with 4-factor PCCs. Of note, 74% and 34% of the patients also received Vitamin K and FFP in addition to PCC in their study. Similarly, 3.9% of PCC-related thromboembolic events were reported in a recent phase III study to compare 4-factor PCC with FFP.43 In a total of 460 patients from 14 studies reviewed by Leissinger et al,47 thrombotic complications occurred in 7 cases (1.8%) after the treatment with either a 3- or 4-factor PCC.
415 evaluate PCC use in trauma patients, several small studies have shown that coagulopathy in trauma patients can be effectively reversed with PCC.48–50 Safaoui et al48 published a preliminary report using 3-factor PCC for 28 patients on warfarin that presented with TBI. During the study period, suspected TBI patients with pre-injury warfarin use received 2,000 units of PCC pre-emptively following the protocol. Mean INR was significantly reduced after PCC was given (5.1 to 1.9, P 5 .008). For patients who had a repeat INR within 30 minutes, a mean time to correction of INR was 13.5 minutes. Joseph et al49 reviewed 45 coagulopathic trauma patients who received 3-factor PCC (Profilnine SD) at their level I trauma center. This group included patients both with and without pre-injury warfarin use. In 20 patients without pre-injury warfarin use (44%), INR was reduced significantly from 2.0 6 .6 to 1.4 6 .4 (P 5.001). Significant reduction of PRBC administration was also observed after the administration of PCC (9.8 6 6.8 vs. 3.8 6 4.8, P 5 .002). INR was significantly reduced with PCC (2.6 6 1.0 vs. 1.5 6 .2, P 5 .001) in the 25 patients with pre-injury warfarin use, but no significant differences in the dosage of PRBC were identified.
PCC in the Geriatric Trauma Population The number of geriatric trauma patients in the United States continues to increase.51 The elderly trauma patients are more likely to have significant comorbidities and more likely to be on prehospital anticoagulation medication, thus complicating their trauma injury management. It has been proposed that the management of elderly trauma victims needs to be tailored because of significant difference in pre-existing medical conditions.52,53 Underlying cardiac, respiratory, or renal dysfunction can significantly alter the fluid management and product resuscitation goals in a bleeding elderly trauma patient. Furthermore, in rural communities, the access to blood products can be limited. The use of PCC could potentially aid in these dilemmas. Quick et al50 reported their preliminary experience with PCC for warfarin reversal of geriatric patients in rural trauma setting. Fifteen patients who were taking warfarin before injury received PCC (15 to 30 IU/kg) alone or in conjunction with FFP. Compared with 10 patients who received FFP alone, they showed benefit in patients receiving PCC including lower volume infusion (,50 mL vs 1 L), a trend toward fewer units of FFP administration, and a greater decrease in INR. Although significance was not reached, fewer units of PRBC transfusion were required in the PCC group. There has also been proposed the potential positive impact of PCC use in rural hospitals with limited financial resources and limited ready access to blood bank facilities.
PCC in the Trauma Population PCC vs Recombinant activated Factor VII As the use of PCC becomes more widely adopted, there is increasing interest in the use of this product in the trauma population. Although there is no high-quality study to
In the past decade, rFVIIa has fallen in and out of favor among the trauma community for use in treating
416 trauma-associated coagulopathy.21,23,24 Furthermore, rFVIIa has previously been recommended for VKA reversal in the acutely bleeding patient.54,55 PCC, also a factor concentrate product has, therefore, been compared not only with FFP but also with rFVIIa for safety and efficacy. Using a porcine coagulopathy model, Dickneite et al56 compared the use of PCC with rFVIIa for the treatment of acquired coagulopathy because of traumatic hemorrhage. Coagulopathy was induced by experimental splenic injury and hemodilution with crystalloid and colloid resuscitation. Both PCC and rFVIIa reversed prolonged prothrombin time to normal range. Time to hemostasis at the splenic injury site was significantly shorter with PCC than with rFVIIa (35 vs 94 minutes, P 5.016). In a retrospective study by Joseph et al,57 85 TBI patients with coagulopathy either with or without preinjury warfarin use were reviewed to compare the efficacy of 3-factor PCC with rFVIIa (NovoSeven). In both PCC and rFVIIa groups, INR was similarly decreased (mean INR after therapy: 1.58 vs 1.4, P 5 .77). Clinical outcomes including craniotomy rate and Glasgow Coma Scale on discharge were not significantly different between each group. No thromboembolic complications were seen in the PCC group in this study. In the rFVIIa group, 1 patient developed deep vein thrombosis. Furthermore, the mean cost of therapy using PCC was significantly lower in the PCC group ($1,007 vs $5,757, P,.01).
Future Direction PCC has been extensively evaluated for use in reversal of acquired coagulopathy because of warfarin. In contrast, it remains unknown whether there is any role of PCC as an adjunct in the resuscitation of coagulopathic trauma patients who require massive transfusion.58 The use of rFVIIa for this purpose has been investigated in prospective studies with controversial results.59,60 Morse et al60 compared the clinical outcomes and transfusion requirement between patients who received massive transfusion with and without rFVIIa. They found minimal effect both on patient clinical outcome and transfusion requirement. Preliminary data shown by Bruce and Nokes43 suggests that PCC can be effective for non– VKA-related coagulopathy after surgical bleeding. Significant decrease in the requirement of blood products after PCC administration was observed in all the patients (cardiac and other surgery groups). There is a single-center prospective study that shows comparable outcomes of patients after major blunt trauma (injury severity score . 15) between conventional FFP-based and coagulation factor concentrate (fibrinogen or PCC)–alone transfusion protocol.61 In fact, higher transfusion rates for PRBC and platelets were observed in FFP group. In 2013, the first 4-factor PCC was approved by the Food and Drug Administration for the urgent reversal of VKA therapy in patients with severe bleeding or need for urgent surgery. This specific formula of 4-factor PCC has been studied in Europe for a decade with promising results.36,59 With the approval of 4-factor PCC by the Food and Drug
The American Journal of Surgery, Vol 209, No 2, February 2015 Administration, prospective data investigating the role of this product in our trauma population are imperative.
Conclusions Although the use of PCC has been shown to improve the outcome of patients with VKA-induced coagulopathy in the nontrauma setting, its use for VKA-associated coagulopathic patients with TBI still needs to be evaluated with further prospective investigation. Also, PCC may be considered for adjunct use in the resuscitation of trauma patients who require massive transfusion.
Acknowledgment Author contribution: Study concept and designdK.M., E.B., and D.D.; literature searchdK.M. and E.B.; writingdK.M. and E.B.; critical revisiondE.B. and D.D.
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