Prothrombin Complex Concentrate Therapy Research Articles

Efficacy and Safety of Prothrombin Complex Concentrates in Liver Transplantation: Evidence from Observational Studies.

The risk/benefit ratio of using prothrombin complex concentrates (PCCs) to correct coagulation defects in patients with end-stage liver disease is still unclear. The primary aim of this review was to assess the clinical effectiveness of PCCs in reducing transfusion requirements in patients undergoing liver transplantation (LT). This systematic review of non-randomized clinical trials was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The protocol was previously registered (PROSPERO:CRD42022357627). The primary outcome was the mean number of transfused units for each blood product, including red blood cells (RBCs), fresh frozen plasma, platelets, and cryoprecipitate. Secondary outcomes included the incidence of arterial thrombosis, acute kidney injury, and haemodialysis, and hospital and intensive care unit length of stay. There were 638 patients from 4 studies considered for meta-analysis. PCC use did not affect blood product transfusions. Sensitivity analysis, including only four-factor PCC, showed a significant reduction of RBC effect size (MD: 2.06; 95%CI: 1.27-2.84) with no true heterogeneity. No significant differences in secondary outcomes were detected. Preliminary evidence indicated a lack of PCC efficacy in reducing blood product transfusions during LT, but further investigation is needed. In particular, future studies should be tailored to establish if LT patients will likely benefit from four-factor PCC therapy.

Prothrombin Complex Concentrate Utilization in Children's Hospitals.

Prothrombin complex concentrates (PCCs) are used to manage bleeding in critically ill children. We performed a repeat cross-sectional study using the Pediatric Health Information System registry to describe PCC utilization in the U.S. children's hospitals over time and determine the relationship between PCC use and specific risk factors for bleeding. We included children < 18 years who received three-factor or four-factor PCC during hospital admission between January 2015 and December 2020 to describe the association between PCC therapy, anticoagulation therapies, and inherited or acquired bleeding diatheses. PCC use steadily increased over the 6-year study period (from 1.3 to 4.6 per 10,000 encounters). Patients exhibited a high degree of critical illness, with 85.0% requiring intensive care unit admission and a mortality rate of 25.8%. PCCs were used in a primarily emergent or urgent fashion (32.6 and 39.3%, respectively) and more frequently in surgical cases (79.0% surgical vs. 21.0% medical). Coding analysis suggested a low rate of chronic anticoagulant use which was supported by review of concomitant anticoagulant medications. PCC use is increasing in critically ill children and does not correlate with specific anticoagulant therapy use or other bleeding risk factors. These findings suggest PCC use is not limited to vitamin K antagonist reversal. Indications, efficacy, and safety of PCC therapy in children require further study.

Blood Loss in Rivaroxaban Anticoagulated Pigs with Severe Polytrauma Is Significantly Reduced By Early Therapy with Prothrombin Complex Concentrate

Introduction: The reversal of the anticoagulant effects of rivaroxaban in severely bleeding patients remains uncertain with conflicting evidence. In this ongoing study we assessed the ability of a four-factor prothrombin complex concentrate (PCC) to reverse rivaroxaban anticoagulation in a porcine polytrauma model.Methods: After ethical approval, rivaroxaban was infused over 30 min (1 mg/kg/h) prior to injury in anaesthetized male pigs (n=24); the sham group (n=8) received placebo. A standardized blunt liver injury and bilateral femur fractures were induced. After trauma and hemorrhagic shock, animals were resuscitated 5 min post injury with Ringer's solution and blood loss (BL) was recorded 12 min post trauma. Randomized animals (n=8/group) received a single injection of PCC (25 or 50 IU/kg), or vehicle (control). Animals were observed up to 180 min after trauma, and total BL was assessed after the observation period or animal's death. Coagulation variables included rivaroxaban plasma concentration, global coagulation assays (PT, aPTT) and thromboelastometry. For a differentiated risk assessment, thrombin generation and thrombin-antithrombin (TAT) levels, indicating the extent of coagulation activation were obtained. BL and hemodynamic variables were monitored over 3 h or until time of death. For statistical analysis, ANOVA (mean ± SD) and the log-rank test for survival were used.Results: After infusion and prior to injury rivaroxaban levels were 666 ± 88 ng/mL. In contrast to sham animals (BL: 467 ± 56 mL), BL in in all anticoagulated animals was significantly elevated 12 min post injury (BL: 810 ± 83 mL). Anticoagulation with rivaroxaban without PCC therapy resulted in a total BL of 3111 ± 479 mL with 88 % mortality (survival time: 50-180 min; p<0.05 vs PCC treated animals and sham). The application of 25 IU/kg PCC (1497 ± 292 mL) or 50 IU/kg PCC (1468 ± 107 mL) showed a significant reduction in total BL with 100% survival and no significant difference between groups. The application of PCC was associated with a dose-depended increase in peak thrombin generation (Peak height; figure 1). D-Dimer increased after trauma in sham and PCC treated animals. However, no difference in D-Dimer concentration in the PCC 25 or 50 IU/kg group was measured post injury. Clinically and macroscopically no adverse events were observed.Conclusions: This porcine model demonstrates a four-factor PCC may be a reasonable and safe intervention for rivaroxaban-treated patients with life-threatening haemorrhage, though these data need clinical confirmation. [Display omitted] DisclosuresGrottke:Boehringer Ingelheim: Research Funding; Bayer: Research Funding; CSL Behring: Research Funding; Portola: Research Funding; Boehringer Ingelheim: Consultancy; Octapharma: Research Funding.

3-Factor Versus 4-Factor PCC in Coagulopathy of Trauma: Four is Better Than Three.

Coagulopathy of trauma (COT) is common and highly lethal. Prothrombin complex concentrate (PCC) has been advocated for correction of COT. However, the difference in efficacy between three-factor PCC (3-PCC) versus four-factor PCC (4-PCC) remains unclear. The aim of our study was to compare efficacy of 3-PCC versus 4-PCC in COT. Five-year (2013-2017) review of coagulopathic trauma patients at our Level-I trauma center who received 3- or 4-PCC. Patients were divided into two groups (4-PCC and 3-PCC) and matched in 1:1 ratio using propensity-score-matching for demographics, injury parameters, admission vitals, and hematological parameters. Primary outcomes were time to correction of international normalized ratio (INR), blood products transfusion, thromboembolic complications, and mortality. Secondary outcomes were hospital-length of stay (LOS), intensive care unit (ICU)-LOS, cost of therapy, and total hospital cost. Six hundred fifty-seven patients met inclusion criteria of whom 250 patients (4-PCC:125; 3-PCC:125) were matched. The mean age was 50 ± 19.4 y, 64% were male, and median-injury severity score was 24[15-33]. 4-PCC was associated with accelerated correction of INR (365 vs. 428 min, P = 0.01), decrease in red blood cells (7 units vs. 10 units, P = 0.04) and FFP (6 units vs. 8 units, P = 0.03) transfused. There was no difference in platelet transfusion, thromboembolic complications, mortality, hospital, and ICU-LOS. 4-PCC was associated with higher cost of PCC therapy, and lower cost of transfusion. There was no difference regarding the total hospital cost between the two groups. Compared with 3-factor PCC, the use of 4-factor PCC is associated with a rapid reversal of INR and reduction in transfusion requirement without increasing the overall hospital cost or the risk of thromboembolic events. 4-PCC may be preferred as an adjunct for the resuscitation of coagulopathic trauma patients.

Abstract 283: Healthcare Resource Utilization and Costs Associated with Oral Anticoagulant Reversal Therapy

Introduction: Oral anticoagulants (OAC) are essential for stroke prevention in atrial fibrillation (AF). Occasionally, reversal of anticoagulation is critical for treating life-threatening or uncontrolled bleeding episodes, as well as emergency surgery/urgent procedures. Prothrombin complex concentrates (PCC) or specific anticoagulant reversal agents such as idarucizumab (IDA) are initiated in patients who present with a significant bleed or who require urgent surgery. Currently, there is a scarcity of published data regarding healthcare resource utilization (HCRU) or costs incurred by these anticoagulant reversal agents in patients with AF or venous thromboembolism (VTE). Hence, we sought to describe the HCRU and total costs sustained among patients with AF or VTE receiving IDA or PCC in US-based healthcare systems. Methods: A retrospective observational study using the Premier Healthcare Database was undertaken. The study included adult patients aged ≥18 years treated with IDA or 3 or 4-factor PCC (Kcentra, Feiba, Profilnine, or unspecified) to reverse the effects of dabigatran or warfarin, respectively, between October 2015 and February 2018. Patients who received PCC were excluded if they had no evidence of warfarin use, or were administered a direct OAC within the 12-month period prior to first hospitalization admission with a record of IDA/PCC use (index hospitalization). Clinical characteristics, HCRU, and total costs during index hospitalization for patients treated with IDA or PCC were examined by use of unadjusted descriptive analysis. Results: The median ages for IDA (n=1,232) and PCC (n=4,939) patients were 78 [IQR: 70-85] and 74 [IQR: 65-83] years, respectively. Both treatment groups had a slightly higher representation of males (55.0% for IDA, 55.2% for PCC), and were predominantly of Caucasian race (86.6% in IDA, 79.7% in PCC). Among IDA patients, 59.3% had life-threatening bleeds and 30.4% underwent emergency/urgent surgery, with 56.7% and 30.8% for PCC patients, respectively. The median length of stay for the index hospitalization was 6 [IQR: 3-9] and 7 [IQR: 4-14] days for patients who received IDA or PCC, respectively. Intensive Care Unit admission rates were 61.3% for IDA patients and 68.7% for PCC patients. Median total costs per hospitalization were $19,357 for IDA patients and $26,920 for PCC patients, with the median cost of IDA and PCC therapy per hospitalization being $3,277 and $4,424, respectively. Conclusions: This observational, descriptive analysis revealed numerically lower HCRU and total hospital costs in patients administered IDA compared with PCC for reversal of OAC, though there were differences in population characteristics. Further studies are needed to determine the factors that potentially drive the disparate HCRU and associated costs between patients receiving IDA or PCC.

Prothrombin Complex Concentrates for Coagulopathy in Liver Disease: Single-Center, Clinical Experience in 105 Patients.

Patients with liver disease frequently develop coagulopathy, and fresh frozen plasma is traditionally used for correction of coagulopathy to manage and prevent bleeding. Prothrombin complex concentrates (PCCs) offer an attractive alternative because they are more readily available and avoid large‐volume transfusion. This retrospective, single‐center study reviewed clinical use of PCC in patients with acute/chronic liver disease. A total of 105 patients with 194 episodes of PCC administration were reviewed. Data pertaining to indication, dosing, effectiveness, and safety were collected. The effect of PCC on coagulation was analyzed in patients for whom coagulation results were available 7 hours before and after PCC. Data on thromboembolic events and mortality within 4 weeks of PCC administration were captured. Most patients (77%) had chronic liver disease; the remainder had acute liver failure. Indications for PCC were preprocedure prophylaxis and treatment for active/recent bleeding in 48% and 52% of 194 treatment episodes, respectively. The median dose of PCC administered was 22 IU/kg (interquartile range, 16‐29 IU/kg). Before PCC administration, 45% of patients had an international normalized ratio (INR) greater than 2.0, and 36% had fibrinogen levels of at least 1.5 g/L. PCC produced statistically significant reductions in prothrombin time and INR (coadministration with fibrinogen or cryoprecipitate: 3.1 versus 1.9; P < 0.001; no coadministration: 2.3 versus 1.8; P < 0.001). Three patients with multiple risk factors developed thrombotic events (hepatic artery thrombosis, incidental bilateral pulmonary embolism, nonocclusive portal vein thrombosis); there were no cardiovascular or cerebrovascular adverse events. Overall, 46 patients died of causes unrelated to PCC treatment. Conclusion: In patients with liver disease, PCC therapy was effective in improving coagulation test results without an excess of thrombotic events. Further assessment of PCC as hemostatic therapy in this setting is required.

Assessing the Efficacy of Prothrombin Complex Concentrate in Multiply Injured Patients With High-Energy Pelvic and Extremity Fractures.

Prothrombin complex concentrate (PCC) is being increasingly used for reversing induced coagulopathy of trauma. However, the use of PCC for reversing coagulopathy in multiply injured patients with pelvic and/or lower extremity fractures remains unclear. The aim of our study was to assess the efficacy of PCC for reversing coagulopathy in this group of patients. Two-year retrospective analysis. Our level I trauma center. All coagulopathic [International normalized ratio (INR) ≥1.5] trauma patients. Patients with femur, tibia, or pelvic fracture were included. Patients were divided into 2 groups: PCC (single dose) and fresh frozen plasma (FFP). Patients in the 2 groups were matched using propensity score matching. Time to correction of INR, time to intervention, development of thromboembolic complications, mortality, and cost of therapy. A total of 81 patients (PCC: 27, FFP: 54) were included. Patients who received PCC had faster correction of INR and shorter time to surgical intervention in comparison to patients who received FFP. PCC therapy was also associated with lower overall blood product requirement (P = 0.02) and lower transfusion costs (P = 0.0001). In a matched cohort of multiply injured patients with pelvic and/or lower extremity fractures, administration of a single dose of PCC significantly reduced the time to correction of INR and time to intervention compared with patients who received FFP therapy. This may allow orthopaedic surgeons to more safely proceed with early, definitive fixation strategies. Therapeutic level III. See Instructions for Authors for a complete description of levels of evidence.

Adverse Events Following International Normalized Ratio Reversal in Intracerebral Hemorrhage

Background: Prothrombin complex concentrates (PCCs) are frequently used to reverse the effect of vitamin K antagonists (VKAs) in patients with non-traumatic intracerebral hemorrhage (ICH). However, information on the rate of thromboembolic events (TEs) and allergic events after PCC therapy in VKA-ICH patients is limited. Methods: Consecutive VKA-ICH patients treated with PCC at our institution between December 2004 and June 2014 were included into this retrospective observational study. We recorded international normalized ratio (INR) values before and after PCC treatment, baseline clinical characteristics including the premorbid modified Rankin Scale (pmRS) score, TE and allergic event that occurred during the hospital stay. All events were classified by 3 reviewers as being ‘related', ‘probably related', ‘possibly related', ‘unlikely related' or ‘not related' to treatment with PCC. To identify factors associated with TEs, log-rank analyses were applied. Results: Two hundred and five patients were included. Median INR was 2.8 (interquartile range (IQR) 2.2-3.8) before and 1.3 (IQR 1.2-1.4) after PCC treatment and a median of 1,500 IU PCC (IQR 1,000-2,500) was administered. Nineteen TEs were observed (9.3%); none were classified ‘related' but 9 were classified as ‘possibly' or ‘probably related' to PCC infusion (4.4%). One allergic reaction (0.5%), ‘unlikely related' to PCC, was observed. In the whole cohort, PCC doses >2,000-3,000 IU, ICH volumes >40 ml, National Institute of Health Stroke Scale values >10 and a pmRS >2 were associated with the development of TEs (p = 0.031, p = 0.034, p = 0.050 and p = 0.036, respectively). Conclusions: Overall, INR reversal with PCC appears safe. Though no clear relationship between higher PCC dosing and TEs was observed, PCC doses between >2,000 and 3,000 IU and higher morbidity at ICH onset were associated with TEs. Hence, individual titration of PCC to avoid exposure to unnecessarily high doses using point-of-care devices should be prospectively explored.

Periprocedural warfarin reversal with prothrombin complex concentrate

IntroductionApproximately 10% of chronically anticoagulated patients require an invasive procedure annually. One in 10 procedures is emergent and requires prompt anticoagulation reversal. The study objective is to determine the safety and efficacy of a 3 factor prothrombin complex concentrate (PCC) for periprocedural anticoagulation reversal. Materials and MethodsConsecutive patients receiving 3 factor PCC for warfarin reversal for either urgent/emergent invasive procedures or major bleeding were analyzed. Primary endpoints included percent achieving INR <1.5, peri-operative major hemorrhage, thromboembolism and death during the 40day post-infusion period. ResultsBetween January 1, 2010–December 31, 2012, 52 patients were treated with PCC for pre-procedural warfarin reversal and 113 patients for major bleeding. Within the peri-procedure group, there were 24 intra-abdominal surgeries, 12 percutaneous interventions, 6 cardiothoracic surgeries, 5 orthopedic and 3 endoscopic procedures. INR values <1.5 were achieved in 51% at 2.5h post-infusion. Major bleeding (13%), thromboembolism (13%) and mortality rates (15%) were high. Within the major bleeding group, PCC therapy reversed INR values (<1.5) in 75% of patients within 4h. For this group, thromboembolism (21%) and mortality rates (16%) were likewise high. Post-PCC anticoagulation, reinitiated in 37%, had no impact on bleeding or thrombotic complications. Mortality rates were threefold higher for those patients not restarting warfarin therapy. ConclusionsAlthough PCC therapy promptly and effectively reverses INR values for patients requiring urgent/emergent invasive procedure both thromboembolic and fatal complications are soberingly high and call for judicious use of these agents in these high risk populations.

Effect of coagulation factor concentrate administration on ROTEM® parameters in major trauma.

BackgroundPurified coagulation factor concentrates, such as fibrinogen concentrate (FC) and prothrombin complex concentrate (PCC) are increasingly used as haemostatic therapy for trauma-induced coagulopathy (TIC). The impact of FC and PCC administration on ROTEM parameters among patients with TIC has not been adequately investigated.MethodsIn this retrospective observational study, changes to ROTEM parameters, induced by three different therapeutic interventions, were investigated: patients receiving FC only (FC-group); patients treated with FC and PCC (FC + PCC-group) and patients treated with PCC only (PCC-group).ResultsThe study population comprised 96 patients who were predominately male (69 [71.9 %]), median age was 45.0 (26.3–60.0) years, and the median injury severity score was 34.0 (25.0–44.5). Administration of FC resulted in a significant reduction of the clotting time (CT) in both the EXTEM and FIBTEM assays but had no effect on INTEM CT. Clot amplitude (CA) increased significantly in the FIBTEM assay but remained unchanged in the EXTEM and INTEM assays. The combined administration of FC and PCC increased FIBTEM maximum clot firmness (MCF) and normalized EXTEM CT but did not change either INTEM or FIBTEM CT. Following PCC therapy, EXTEM and FIBTEM CT normalized; CA at 10 min after CT measurements decreased significantly in EXTEM, INTEM and FIBTEM.ConclusionsAdministration of FC alone or in combination with PCC resulted in a significant improvement of fibrin polymerisation as measured by an increase in FIBTEM MCF. CT is dependent not only on thrombin generation but also on the availability of substrate (fibrinogen). Accelerated fibrin polymerisation rate results in earlier clot formation and consequently shorter CT. PCC administration normalised EXTEM CT below the upper threshold of 80 s.This study was performed at the AUVA Trauma Centre Salzburg, Salzburg, Austria.Electronic supplementary materialThe online version of this article (doi:10.1186/s13049-015-0165-4) contains supplementary material, which is available to authorized users.

Limb-threatening Deep Venous Thrombosis Complicating Warfarin Reversal with Three-factor Prothrombin Complex Concentrate: A Case Report

BackgroundThree- and four-factor prothrombin complex concentrates (PCC) are gaining popularity for acute reversal of vitamin K antagonist-associated bleeding. Although acute thrombosis after PCC administration has been described, it seems to be rare. Case ReportAn 83-year-old woman on warfarin for history of deep venous thrombosis (DVT) presented to the Emergency Department with life-threatening gastrointestinal bleeding, requiring urgent PCC administration. After stabilization, she subsequently developed a new limb-threatening upper-extremity DVT. Why Should an Emergency Physician Be Aware of This?As PCC therapy gains popularity for reversal of anticoagulant-induced bleeding in urgent bleeding scenarios, the emergency physician must be aware of the complications of PCC administration, including new limb-threatening DVT.

Prothrombin complex concentrates and a specific antidote to dabigatran are effective ex-vivo in reversing the effects of dabigatran in an anticoagulation/liver trauma experimental model

IntroductionNew oral anticoagulants are effective alternatives to warfarin. However, no specific reversal agents are available for life-threatening bleeding or emergency surgery. Using a porcine model of trauma, this study assessed the ability of prothrombin complex concentrate (PCC), activated PCC (aPCC), recombinant FVIIa (rFVIIa) and a specific antidote to dabigatran (aDabi-Fab) to reverse the anticoagulant effects of dabigatran.MethodsDabigatran etexilate (DE) was given orally for 3 days (30 mg/kg bid) and intravenously on day 4 to achieve consistent, supratherapeutic concentrations of dabigatran. Blood samples were collected at baseline, after oral DE, after intravenous dabigatran, and 60 minutes post-injury. PCC (30 and 60 U/kg), aPCC (30 and 60 U/kg), rFVIIa (90 and 180 μg/kg) and antidote (60 and 120 mg/kg) were added to blood samples ex-vivo. Coagulation was assessed by thromboelastometry, global coagulation assays and diluted thrombin time.ResultsPlasma concentrations of dabigatran were 380 ± 106 ng/ml and 1423 ± 432 ng/ml after oral and intravenous administration, respectively, and all coagulation parameters were affected by dabigatran. Both PCCs and aDabi-Fab, but not rFVIIa, reversed the effects of dabigatran on thromboelastometry parameters and prothrombin time. In contrast, aPTT was only normalised by aDabi-Fab. Plasma concentration (activity) of dabigatran remained elevated after PCC and rFVIIa therapy, but was not measureable after aDabi-Fab.ConclusionIn conclusion, PCC and aPCC were effective in reducing the anticoagulant effects of dabigatran under different conditions, while aDabi-Fab fully corrected all coagulation measures and decreased the plasma concentration of dabigatran below the limit of detection. No significant effects were observed with rFVIIa.

Endogenous thrombin potential following hemostatic therapy with 4-factor prothrombin complex concentrate: a 7-day observational study of trauma patients.

IntroductionPurified prothrombin complex concentrate (PCC) is increasingly used as hemostatic therapy for trauma-induced coagulopathy (TIC). However, the impact of PCC administration on coagulation status among patients with TIC has not been adequately investigated.MethodsIn this observational, descriptive study, data relating to thrombin generation were obtained from plasma samples gathered prospectively from trauma patients upon emergency room (ER) admission and over the following 7 days. Standard coagulation tests, including measurement of antithrombin (AT) and fibrinogen, were performed. Three groups were investigated: patients receiving no coagulation therapy (NCT group), patients receiving fibrinogen concentrate only (FC group), and patients treated with PCC and fibrinogen concentrate (FC-PCC group).ResultsThe study population (77 patients) was predominantly male (84.4%); mean age was 40 ± 15 years and mean injury severity score was 25.6 ± 12.7. There were no significant differences between the three study groups in thrombin-related parameters upon ER admission. Endogenous thrombin potential (ETP) was significantly higher in the FC-PCC group compared with the NCT group on days 1 to 4 and the FC group on days 1 to 3. AT levels were significantly lower in the FC-PCC group from admission until day 3 (versus FC group) or day 4 (versus NCT group). Fibrinogen increased over time, with no significant between-group differences after ER admission. Despite ETP being higher, prothrombin time and activated partial thromboplastin time were significantly prolonged in the FC-PCC group from admission until day 3 to 4.ConclusionsTreatment with PCC increased ETP for several days, and patients receiving PCC therapy had low AT concentrations. These findings imply a potential pro-thrombotic state not reflected by standard coagulation tests. This is probably important given the postoperative acute phase increase in fibrinogen levels, although studies with clinical endpoints are needed to ascertain the implications for patient outcomes. We recommend careful use of PCC among trauma patients, with monitoring and potentially supplementation of AT.

Management of Bleeding in Post-liver Disease, Surgery and Biopsy in Patients With High Uncorrected International Normalized Ratio With Prothrombin Complex Concentrate: An Iranian Experience

Background:To evaluate the efficacy of prothrombin complex concentrate (PCC) in the management of bleeding in patients with liver disease and patients undergoing surgery or biopsy who had a high uncorrected international normalized ratio (INR).Objectives:In this study, we examined an Iranian sample and investigated the efficacy of PCC to manage bleeding in patients with liver disease and also patients with high uncorrected INR who were scheduled for surgery or biopsy.Materials and Methods:A total of 25 patients including 16 patients with post-liver disease bleeding (group 1) and 9 patients with high uncorrected INR who were scheduled for surgery or biopsy (group 2) were enrolled. All patients were treated with 25 IU/kg PCC, and efficacy was defined as any reduction in or cessation of bleeding episodes and correction of INR before surgery or biopsy. The patients were also evaluated for any adverse effects.Results:INR decreased significantly in both groups of patients, with no bleeding episodes during or after the study in group 1 and during or after surgery/biopsy in group 2. All patients tolerated the therapy well without any significant adverse effects.Conclusions:The efficacy of PCC therapy was satisfactory in this study. PCC therapy in patients with liver disease and patients undergoing surgery or biopsy seems to be effective and safe, and may be a good treatment strategy for these patients, if fresh frozen plasma or vitamin K are not effective.

Case Scenario: Management of Trauma-induced Coagulopathy in a Severe Blunt Trauma Patient

Case Scenario: Management of Trauma-induced Coagulopathy in a Severe Blunt Trauma Patient

Poor Prognosis in Warfarin-Associated Intracranial Hemorrhage Despite Anticoagulation Reversal

Anticoagulant-associated intracranial hemorrhage (aaICH) presents with larger hematoma volumes, higher risk of hematoma expansion, and worse outcome than spontaneous intracranial hemorrhage. Prothrombin complex concentrates (PCCs) are indicated for urgent reversal of anticoagulation after aaICH. Given the lack of randomized controlled trial evidence of efficacy, and the potential for thrombotic complications, we aimed to determine outcomes in patients with aaICH treated with PCC. We conducted a prospective multicenter registry of patients treated with PCC for aaICH in Canada. Patients were identified by local blood banks after the release of PCC. A chart review abstracted clinical, imaging, and laboratory data, including thrombotic events after therapy. Hematoma volumes were measured on brain CT scans and primary outcomes were modified Rankin Scale at discharge and in-hospital mortality. Between 2008 and 2010, 141 patients received PCC for aaICH (71 intraparenchymal hemorrhages). The median age was 78 years (interquartile range, 14), 59.6% were male, and median Glasgow Coma Scale was 14. Median international normalized ratio was 2.6 (interquartile range, 2.0) and median parenchymal hematoma volume was 15.8 mL (interquartile range, 31.8). Median post-PCC therapy international normalized ratio was 1.4: 79.5% of patients had international normalized ratio correction (<1.5) within 1 hour of PCC therapy. Patients with intraparenchymal hemorrhage had an in-hospital mortality rate of 42.3% with median modified Rankin Scale of 5. Significant hematoma expansion occurred in 45.5%. There were 3 confirmed thrombotic complications within 7 days of PCC therapy. PCC therapy rapidly corrected international normalized ratio in the majority of patients, yet mortality and morbidity rates remained high. Rapid international normalized ratio correction alone may not be sufficient to alter prognosis after aaICH.

Factor IX complex for the correction of traumatic coagulopathy

Damage control resuscitation advocates correction of coagulopathy; however, options are limited and expensive. The use of prothrombin complex concentrate (PCC), also known as factor IX complex, can quickly accelerate reversal of coagulopathy at relatively low cost. The purpose of this study is to describe our experience in the use of factor IX complex in coagulopathic trauma patients. All patients receiving PCC at our Level I trauma center over a two-year period (2008-2010) were reviewed. PCC was used at the discretion of the trauma attending for treatment of coagulopathy, reversal of coumadin, and when recombinant factor VIIa was indicated. Forty-five trauma patients received 51 doses of PCC. Sixty-two per cent were male and mean Injury Severity Score was 23 (± 14.87). Standard dose was 25 units per kg and mean cost per patient was $1,022 ($504-3,484). Fifty-eight per cent of patients were on warfarin before admission. Mean international normalized ratio (INR) was decreased after PCC administration (p = 0.001). Packed red blood cell transfusion was also reduced after factor IX complex (p = 0.018). Mean INR was reduced in both the nonwarfarin (p = 0.001) and warfarin (p = 0.001) groups. Packed red blood cell transfusion was less in the nonwarfarin group (p = 0.002) however was not significant in the warfarin group. Subsequent thromboembolic events were observed in 3 of the 45 patients (7%). Mortality was 16 of 45 (36%). PCC rapidly and effectively treats coagulopathy after traumatic injury. PCC therapy leads to a significant correction in INR in all trauma patients, regardless of coumadin use, and concomitant reduction in blood product transfusion. PCC should be considered as an effective tool to treat acute coagulopathy of trauma. Further prospective studies examining the safety, efficacy, cost, and outcomes comparing PCC and recombinant factor VIIa are needed.

Increasing concentrations of prothrombin complex concentrate induce disseminated intravascular coagulation in a pig model of coagulopathy with blunt liver injury

AbstractDespite increasing use of prothrombin complex concentrate (PCC) to treat hemorrhage-associated coagulopathy, few studies have investigated PCC in trauma, and there is a particular lack of safety data. This study was performed to evaluate PCC therapy in a porcine model of coagulopathy with blunt liver injury. Coagulopathy was induced in 27 anesthetized pigs by replacing approximately 70% blood volume with hydroxyethyl starch 130/0.4 and Ringer's lactate solution; erythrocytes were collected and retransfused. Ten minutes after trauma, animals randomly received PCC (35 or 50 IU/kg) or saline. Coagulation parameters including thromboelastometry, thrombin generation, and blood loss were monitored for 2 hours. Internal organs were examined macroscopically and histologically to determine the presence of emboli and assess liver injury. Total blood loss was significantly lower and survival was higher in both PCC groups versus the control group (P < .05). These outcomes appeared to be dose-independent. Thromboembolism was found in all animals treated with 50 IU/kg PCC; 44% also showed signs of disseminated intravascular coagulation. Liver injury was similar in all animals. In conclusion, 35 IU/kg PCC safely improved coagulation and attenuated blood loss. However, the higher dose of PCC (50 IU/kg) appeared to increase the risk of thromboembolism and disseminated intravascular coagulation.

SAFETY of PROTHROMBIN COMPLEX CONCENTRATES IN PATIENTS REQUIRING RAPID REVERSAL of ANTICOAGULANT TREATMENT with the VITAMIN K ANTAGONISTS: a Systematic Review and a Meta-Analysis of the Literature.

AbstractAbstract 1113▪ Background:Prothrombin complex concentrates (PCCs) are currently recommended by several international guidelines as the treatment of choice in warfarin-related coagulopathy. However, while the efficacy of PCCs is well established, their safety in terms of risk of thromboembolic complications, some of which may be severe or even life-threatening, is still not clear.Thus, we performed a systematic review of the literature with the aim of evaluating the rate of thromboembolic complications in patients on Vitamin K antagonists (VKAs) treated with PCCs for a bleeding event or before an urgent invasive procedure. Methods:MEDLINE and EMBASE databases were searched up to June 2010. Two reviewers performed study selection independently. Studies providing data on incidence thromboembolic complications in patients on VKAs were potentially eligible for the study. Two reviewers independently extracted data on study and population characteristics, type, dose of PCC treatment. Weighted mean proportion of the rate of thromboembolic complications and the mortality rate were calculated. Results:28 studies for a total of 1104 patients were included in our systematic review. Seven studies used 3-factor PCCs, 21 studies used 4-factor PCCs. Concomitant vitamin K was administered in 21 studies, while fresh frozen plasma in 6.Seventeen patients had a thromboembolic complication after PCCs administration (weighted mean 1.9%; 95% CI 1.1–2.9 %). Of the thromboembolic events, 4 were fatal (23%). The incidence of thromboembolic events was 1.9%; (95% CI 1.0–3.1 %) in patients treated for bleeding and 0.8% (95% CI 0.1–2.0 %) in patients treated before urgent surgery or invasive procedures. For 5 of the reported events we were unable to define the subgroup.The incidence of thromboembolic events was 2.3% (95% CI 1.2–3.8) in patients treated with 4-factor PCCs, and 0.7% (95% CI 0.0–2.4) in patients treated with 3-factor PCCs.One hundred and seven patients died for a mean mortality rate of 11.1% (95% CI 6.4–17.0 %).Only 7 studies for a total 257 patients provided data on the incidence of viral transmission after PCCs administration. In this subgroup of patients there were 4 episode of positivity for parvovirus B19 for a mean incidence of 1.9% (95% CI 0.3–4.9%). Conclusions:The results of our systematic review of the literature show that the treatment with PCCs in patients on VKAs therapy is associated with a low risk of thromboembolic complications providing important information on the safety of this approach. Moreover, also the risk of viral transmission, although evaluated in few studies only, appears to be negligible. The findings of a low thromboembolic risk have been further confirmed by the results of the subgroup analyses separately evaluating treatment with 3 or 4-factors PCCs and different indications for PCCs therapy. Disclosures:Crowther:Pfizer: Consultancy; Leo Pharma: Research Funding; Boehringer Ingelheim: Research Funding.

Suboptimal effect of a three‐factor prothrombin complex concentrate (Profilnine‐SD) in correcting supratherapeutic international normalized ratio due to warfarin overdose

Plasma transfusion is standard therapy for urgent warfarin reversal in the United States. "Four-factor" prothrombin complex concentrate (PCC), available in Europe, has advantages over plasma therapy for warfarin reversal; however, only "three-factor" PCCs (containing relatively low Factor [F]VII) are available in the United States. The efficacy of a three-factor PCC for urgent warfarin reversal was evaluated in 40 patients presenting with supratherapeutic international normalized ratio (ST-INR > 5.0) with bleeding (n = 29) or at high risk for bleeding (n = 11). In 13 patients, pre- and posttherapy vitamin K-dependent factors were assayed. Historical controls (n = 42) treated with plasma alone were used for rate of ST-INR correction comparison. Treatment with plasma alone (mean, 3.6 units) lowered the INR to less than 3.0 in 63 percent of historical controls. Low-dose (25 U/kg) and high-dose (50 U/kg) PCC alone lowered INR to less than 3.0 in 50 and 43 percent of patients, respectively. Additional transfusion of a small amount of plasma (mean, 2.1 units) increased the rate of achieving an INR of less than 3.0 to 89 and 88 percent for low- and high-dose PCC therapy, respectively. FII, F IX, and FX increments were similar for PCC-treated patients with or without supplemental plasma; FVII was significantly higher in the PCC plus plasma group compared to the PCC-only group (p = 0.001). Three-factor PCC does not satisfactorily lower ST-INR due to low FVII content. Infusion of a small amount of plasma increases the likelihood of satisfactory INR lowering.