Four-factor Prothrombin Complex Concentrate Research Articles

111 Impact of Pharmacist Preparation of Four-Factor Prothrombin Complex Concentrate at the Bedside in Patients With Life-Threatening Hemorrhage in the Emergency Department

111 Impact of Pharmacist Preparation of Four-Factor Prothrombin Complex Concentrate at the Bedside in Patients With Life-Threatening Hemorrhage in the Emergency Department

Safety and Effectiveness of Four-Factor Prothrombin Complex Concentrate in Special Populations with INR Below 2: A Post-Marketing Surveillance Study.

We previously conducted a prospective, observational post-marketing surveillance study to assess the safety and effectiveness of four-factor prothrombin complex concentrate (4F-PCC) for rapid vitaminK antagonist (VKA) reversal in Japanese patients. This subgroup analysis compared the safety, especially thromboembolic events (TEEs), and effectiveness of 4F-PCC by stratifying patients into two subgroups according to baseline international normalized ratio (INR) levels with < 2.0 and ≥ 2.0. Of 1271 eligible patients, 215 (17.9%) had INR < 2.0 and 987 (82.1%) had INR ≥ 2.0. Overall baseline characteristics were similar between groups; age (74.0years vs 74.0years), body mass index (22.1kg/m2 vs 21.9kg/m2), ratio of inpatients (90.2% vs 88.7%), manifested atrial fibrillation (46.0% vs 48.8%). Median INRs at baseline were 1.72 (minimum 0.92, maximum 1.99) in the INR < 2.0 group and 2.95 (2.00, 27.11) in the INR ≥ 2.0 group. The most common reason for 4F-PCC administration was intracranial hemorrhage (67.0% vs 59.5%), and lesser gastrointestinal bleeding (0.9% vs 7.5%). After 4F-PCC administration (average doses 24.5IU/kg [INR < 2.0 group] and 29.2IU/kg [INR ≥ 2.0 group]), INRs were significantly reduced to 1.21 (- 28%) and 1.31 (- 68%), respectively, and resulted in hemostasis in a similarly rapid manner. The incidences of adverse drug reactions were 3.7% in each group. TEEs occurred in 4 (1.9%) patients in the INR < 2.0 group and 11 (1.1%) patients in the INR ≥ 2.0 group and were predominantly composed of stroke, while similar rates (67.0% vs 62.9%) of bleeding events post-anticoagulant resumption were observed between groups. This study supports the favorable tolerability and efficacy of 4F-PCC regardless of baseline INR (< 2.0 or ≥ 2.0), with a prompt reduction of INR and substantial hemostatic effectiveness in the real-world setting for patients requiring urgent VKA reversal, although no indicated 4F-PCC dose for VKA reversal exists for INR < 2.0 to date.

Evaluation of the use and efficacy of prothrombin complex concentrates in patients presenting to the emergency department with warfarin

Aims: Warfarin administration has been a standard treatment for preventing thromboembolism in patients with atrial fibrillation prosthetic heart valves for many years. It is one of the leading drugs implicated in emergency room visits for adverse drug reactions. Because of a narrow therapeutic window, as many as 3% to 7% of patients taking warfarin are at risk of significant, life-threatening bleeding, and it is generally considered that this requires rapid and complete warfarin reversal. Although there are treatments such as vitamin K and fresh frozen plasma to reverse the effects of warfarin, the most effective method involves using prothrombin complex concentrates (PCC). This study aims to evaluate the use and efficacy of PCC in patients with warfarin-induced bleeding in the emergency department. Methods: The patients receiving PCC for warfarin reversal in the emergency department between January 1, 2019 – April 1, 2021, were identified from the hospital's electronic database. Demographic data, reasons for warfarin use, PCC indications, INR values before and after PCC, and mortality of the patients were evaluated. The four-factor PCC dose was determined according to the patient's body weight, admission INR level, and target INR level. The study was conducted with 73 patients. Results: The mean age of the patients was 69.3 ± 15.5 years. The female/male ratio was 1/1.5. The most common PCC indications were gastrointestinal bleeding (32.9%), urogenital bleeding (23.3%), epistaxis (12.3%), and urgent surgical need (12.3%), respectively. The median international normalized ratio (INR) before and after treatment with PCC was 9.2 (min-max 2.1-11.8) and 1.8 (min-max 1.0-4.6). The mean dose of PCC was 1500 IU (min-max 750-3250 IU). In addition to PCC, all patients received vitamin K; 17.8% received erythrocyte suspension, and 10.9% received fresh frozen plasma. There were no PCC-related complications in the emergency department. While 38.4% of the patients consulted the inpatient services after the emergency department, 5.5% were referred to an external center, and 56.2% were discharged from the emergency department after successful treatment. 26% of the patients were followed in the intensive care unit. No patient died in the emergency department. However, in-hospital mortality was 5.5%. Conclusion: Four-factor PCC is an effective and safe treatment for reversing warfarin-associated bleeding.

Four-factor Prothrombin Complex Concentrate During Liver Transplantation: A Retrospective Cohort Study.

Four-factor prothrombin complex concentrate (PCC) is a plasma product that contains factors II, VII, IX, X, protein C, and protein S. PCC can be used off-label to treat coagulopathy during orthotopic liver transplantation (OLT). However, its use comes with safety concerns regarding thrombosis. The purpose of our study is to determine the safety of PCC in OLT. We conducted a retrospective cohort study of patients who received 4-factor PCC during OLT at our institution from January 1, 2018, to May 1, 2022, with a 1:1 match of 83 patients who received PCC and 83 patients who did not. We evaluated 30-d mortality, 1-y mortality, prevalence of thrombotic complications (portal vein thrombosis, deep venous thrombosis, myocardial infarction, and pulmonary embolus), and postoperative intensive care (ICU) length of stay (LOS). There was no significant difference in 30-d mortality (odds ratio [OR] 5; 95% confidence interval [CI], 0.58-42.8; P = 0.14), 1-y mortality (OR 3; 95% CI, 0.61-14.86; P = 0.18), or ICU LOS (OR -13.8; 95% CI, -39.2 to 11.6; P = 0.29). There was no increased incidence of thrombotic complications among patients receiving PCC 90 d after surgery, including portal vein thrombosis (OR 1.5; 95% CI, 0.42-5.32; P = 0.53), pulmonary embolus (OR 1; 95% CI, 0.14-7.1; P = 0.99), deep venous thrombosis (OR 0.67; 95% CI, 0.11-3.99; P = 0.66), and myocardial infarction (OR 1.67; 95% CI, 0.4-6.97; P = 0.48). Although there was a statistically insignificant increase in mortality after PCC administration during OLT, we did not see a significant increase in perioperative complications, including thrombotic events and increased ICU LOS.

Balfaxar: Another four-factor PCC for warfarin reversal.

Balfaxar (Octapharma), a human plasma-derived four-factor prothrombin complex concentrate (PCC), has been approved by the FDA for rapid reversal of warfarin anticoagulation in adults who require an urgent surgical/invasive procedure. It is the second four-factor PCC to become available in the US; Kcentra, which has been available since 2013, is approved for the same indication and for urgent reversal of warfarin anticoagulation in adults with acute major bleeding. Balfaxar is marketed in Canada and Europe as Octaplex.

Dosing, Monitoring, Blood Product Utilization, and Thromboembolic Complications of Four-Factor Prothrombin Complex Concentrate as Part of an Institutional Protocol in Pediatric Cardiac Surgery: A Retrospective Cohort Study.

Pediatric cardiac surgery patients are predisposed to blood loss. Blood product administration can lead to complications. Prothrombin complex concentrates (PCCs) offer potential advantages of factor composition, small volume, decreased immunogenicity/infectious risks, and accessibility. The objective of this study was to describe dosing, monitoring, blood product utilization, and thromboembolic complications of administering four-factor PCC (4F-PCC) in pediatric cardiac surgery. We performed a retrospective review of patients aged <18 years undergoing cardiac surgery from June 2020 to May 2022 (inclusive) who received 4F-PCC. Outcomes of interest included 4F-PCC dosing (units/kg) and number of doses administered, chest tube output, blood product administration, donor exposure, length of stay, and thromboembolic events. Eighty-six patients met eligibility criteria. The median (range) age and weight were 0.37 (0.01-16.3) years and 5.3 (1.6-98) kg, respectively. Median (range) total 4F-PCC dose per patient was 25 (9.2-50) units/kg, with 6 patients (7%) receiving a total of two doses. Median (range) 24-hour postoperative packed red blood cells, platelet, plasma, and cryoprecipitate administration volumes were 0 (0-2.57) mL/kg/24 h, 0 (0-1.09), 0 (0-2.64), and 0 (0-0.28 mL/kg/24 h), respectively. Median (range) length of stay and 24-hour postoperative chest tube output were 10 (6-26) days and 1.1 (0.1-4.2) mL/kg/h, respectively. Two (2%) patients experienced a thromboembolic event within 30 days of 4F-PCC administration. These retrospective findings suggest no worsening of hemostatic parameters, a mild median improvement in fibrinogen, low blood product utilization, and low thromboembolism rates following 4F-PCC use in pediatric cardiac surgery.

Updated Protocol for the Phase 3, Randomized, Double-Blinded Lex-210 Study of Four-Factor Prothrombin Complex Concentrate in Patients with Acute Major Bleeding on Factor Xa Inhibitor Therapy

Background and Significance: Despite significantly reduced risk of intracranial hemorrhage compared with vitamin K antagonists, direct oral anticoagulant therapy with factor Xa inhibitors (FXaI) is associated with similar incidences of other major bleeds. Although hemostatic agents such as prothrombin complex concentrates (PCCs) are often used (off-label), the efficacy and safety of PCCs for managing FXaI-related bleeding requires further investigation. This study aims to evaluate superior hemostatic efficacy of high-dose vs low-dose four-factor (4F) PCC (Octaplex®; Octapharma) in adults with FXaI-related major bleeding. Study Design and Methods: LEX-210 (NCT04867837) is a Phase 3, multicenter, prospective, randomized, double-blinded, group-sequential, parallel-group, adaptive design study. Significant modifications have recently been made to the study design. Patients aged ≥18 years with acute major bleeding (e.g., gastrointestinal, intracranial) and baseline anti-factor Xa activity of ≥100 ng/mL are eligible. To increase rate of recruiting suitable patients into the study, the eligibility criteria have been optimized. For inclusion (full criteria in Table 1), baseline anti-factor Xa activity of ≥100 ng/mL may be either confirmed by locally available tests (including retrospectively by the central laboratory) or suspected by the investigator and later confirmed by the central lab. Prospective written informed consent will be obtained from all patients or patients' legally authorized representative prior to enrolment. If this is not possible, in countries outside the US where it is permitted under local regulations or approved by local ethics committees, deferred consent procedures may be applied. Key exclusion criteria (Table 2) include acute trauma for which FXaI reversal alone would not be expected to control bleeding, and thromboembolic events in the last 3 months. In addition, hypersensitivity to heparin and platelet inhibitors are specified. Patients will be excluded if they score &amp;lt;7 on the Glasgow Coma Scale (with allowances for intubation), or have expected survival of &amp;lt;24 hours. While patients scheduled for surgery in &amp;lt;12 hours are excluded, minor surgeries and invasive procedures for diagnostic or therapeutic reasons are allowed, or if intended to address a second (non-index) bleeding event. Patients will be randomized 1:1 to 50 or 15 IU/kg 4F-PCC. The primary objective is to demonstrate superior hemostatic efficacy of the higher dose in patients with major bleeding associated with FXaI. Hemostatic efficacy through 24 hours after receipt of 4F-PCC will be evaluated by an independent data monitoring and endpoint adjudication committee using objective criteria, with a binary outcome of effective or ineffective. Secondary endpoints include change in endogenous thrombin potential (baseline to 1 hour after 4F-PCC), 30-day rates of thromboembolic events, and all-cause mortality. The study is conducted in accordance with the ethical principles laid down in the Declaration of Helsinki The proportion of patients with an effective outcome will be compared between groups using a one-sided z-test. The primary statistical model will be adjusted for the baseline anti-factor Xa activity as determined retrospectively by the central laboratory. A logistic regression model for the success rate using treatment group (dose level) and the anti-factor Xa activity as fixed effects will be used to determine the one-sided z-statistic. LEX-210 launched in Q4 2021 and will be performed across ~60 sites in North America and the European Continent. Target enrollment is ~260 patients, assuming a 30% dropout rate. So far, 26 sites in the US, Italy, Germany, and Spain have been initiated, with 5 patients enrolled. Study completion is anticipated in Q3 2024.

Effect of PCC on Thrombin Generation among Patients on Factor Xa Inhibitors with Major Bleeding or Needing Urgent Surgery (GAUGE): Design and Rationale.

Background Direct factor Xa inhibitors (FXaIs) account for most oral anticoagulant use and FXaI-associated bleeding events are common. Clinicians have variable national and regional access to specific FXaI reversal agents such as andexanet alfa. Many centers have adopted the use of prothrombin complex concentrates (PCCs) as hemostatic therapy for FXaI-associated major bleeding events. PCC does not impact circulating FXaI levels and its mechanism of action to achieve hemostasis in FXaI-associated bleeding is uncertain. While PCC increases quantitative thrombin generation assay (TGA) parameters, it does not correct FXaI-altered thrombin generation kinetics, nor does it normalize thrombin generation. Clinical data supporting the use of PCC are based on cohort studies reporting clinical hemostatic efficacy, which is difficult to measure. The benefits of PCC for FXaI-associated bleeding beyond supportive care are uncertain. Objective GAUGE is a prospective observational study designed to measure the effects of four-factor PCC administration (Octaplex) on TGA parameters among patients with FXaI-associated bleeding or needing urgent surgery. Methods Laboratory outcomes will include the mean paired change in TGA parameters from pre- to post-PCC administration and the proportion of participants whose post-PCC TGA values fall within a defined reference range. Clinical outcomes will include hemostatic efficacy, thromboembolic complications, and all-cause death at 30 days post-PCC. Conclusion Development of a viable and universally accessible FXaI bleed management strategy is crucial. GAUGE will provide in vivo data on the effects of PCC among patients with FXaI-associated bleeding.

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.

1139: FOUR-FACTOR PROTHROMBIN COMPLEX CONCENTRATE FOR REFRACTORY BLEEDING IN TRAUMA AND CARDIAC SURGERY

Introduction: Four-Factor Prothrombin Complex Concentrate (4F-PCC) is a concentrated product containing factors II, VII, IX, X, proteins C and S, that is FDA approved for reversal of vitamin K antagonists in adults with acute major bleeding or need for urgent surgery. The utilization of factor products for off-label indications has been increasing secondary to continued national blood shortages and ease of administration, with the hope of reducing blood product utilization. Methods: This single-center retrospective study at an academic level I trauma center analyzed the use of 4F-PCC for refractory bleeding between June 2018 and March 2022 in adult trauma and cardiovascular surgery patients. The primary objective was to determine blood product utilization in patients during a time period of six hours pre and post 4F-PCC administration. Secondary outcomes included thrombotic events, mortality, and use of supportive hemostatic medications. Results: Thirty-five patients received 4F-PCC for significant exsanguination refractory to massive transfusion: cardiac (n=32, 91%) and trauma surgery (n=3, 9%). The median age was 62 years (IQR 50-69) and the majority were male (n=21, 60%). The median dose administered was 2128 units (IQR 1668-2750) or 25 units/kg of factor IX (IQR 20.7-29). Units of blood products given pre and post 4F-PCC administration were: packed red blood cells (PRBC) [5.4 (IQR 3.2-8.9), 2.1 (IQR 1.8-4.1) p< 0.01], fresh frozen plasma (FFP) [4.4 (IQR 2.5-8.0), 3.4 (IQR 1.3-4.7) p=0.03], platelets [1.9 (IQR 1.1-2.2), 1.2 (IQR 1.0-2.2) p=0.20] and cryoprecipitate [1.3 (IQR 0.8-2.4), 0.9 (IQR 0.8-1.8) p=0.83]. Five patients experienced thrombotic events and the mortality was 29%. Three patients received concomitant phytonadione and seven received desmopressin. Conclusions: There was a significant reduction in PRBC and FFP units transfused after 4F-PCC administration in patients for refractory bleeding for trauma and cardiac surgery patients. Further investigation is warranted to determine if the reduction in product administration results in differences in clinical outcomes and if this finding is replicated in other surgical populations.

Meta-Analysis and Meta-Regression to Assess Four-Factor Prothrombin Complex Concentrate's Ability to Achieve Hemostatic Effectiveness in Patients with Oral Factor Xa Inhibitor-Associated Intracranial Hemorrhage

Background: Four-factor prothrombin complex concentrates (4FPCCs), both non-activated and activated products, are commonly used off-label to manage oral factor Xa (FXa) inhibitor-associated severe or life-threatening bleeds including intracranial hemorrhage (ICH). Available evidence supporting 4FPCC use in the management of oral FXa inhibitor-associated ICH patients come from small-to-modest sized studies or case series. These studies or case series often differed in key inclusion and exclusion criteria employed and definition of hemostatic effectiveness utilized. We performed a systematic review and meta-analysis including multivariable meta-regression to assess the proportion of oral FXa inhibitor-associated ICH patients achieving hemostatic effectiveness with 4FPCC and the effect of key methodological decisions on this estimate. Methods: We searched PubMed and Embase from the earliest date possible through May 31, 2022. Studies or case series were included if: 4FPCC was administered for the management of oral FXa inhibitor-associated bleeding; reported solely on ICH patients (or a subgroup of); evaluated ≥10 patients; was performed within the United States; and provided data on the proportion of patients achieving hemostatic effectiveness. Meeting abstracts were not included. We performed a random-effects meta-analysis to calculate the pooled arcsine square root transformation weighted proportion of patients achieving hemostatic effectiveness with 95% confidence intervals (CIs). Multivariable meta-regression was used to determine the impact of studies’ inclusion or exclusion of severe ICH; requirement that the oral FXa inhibitor was taken within 24-hours and/or drug concentration or FXa levels were drawn; handling of patients with missing repeat imaging; and use (or non-use) of an accepted definition of hemostatic effectiveness on our pooled estimate. Results: We identified 36 studies or case series reporting on 38 unique study arms and including 1,732 oral FXa inhibitor-associated ICH patients managed with 4FPCC. Nearly 16% of study arms excluded patients with severe ICH (i.e., those with a hematoma volume >60 mL and/or Glasgow Coma Scale score <7) and fewer than 8% required the last oral intake of FXa inhibitor be within 24 hours or drug or FXa levels be drawn prior to 4FPCC administration. More than half (55.3%) of study arms excluded patients due to missing repeat imaging and 21.1% of arms failed to use an accepted definition to assess hemostatic effectiveness. The weighted pooled proportion of ICH patients achieving hemostatic effectiveness was 79.7% (95% CI 76.5, 82.8) (Figure). Upon multivariable meta-regression, study arms that excluded severe ICH patients reported a significant 8.5% increase in in the proportion achieving hemostatic effectiveness compared to those who retained these patients (p<0.001). Moreover, study arms that did not require oral FXa inhibitor intake within 24 hour or drug concentration/FXa levels reported a 12.5% (95% CI 4.0, 21.0, p=0.004) higher incidence of achieving hemostatic effectiveness. Exclusion of patients with missing repeat imaging and the use of an accepted definition of hemostatic effectiveness were not shown in this meta-regression analysis to significantly impact hemostatic effectiveness estimates. Conclusions: Studies’ and case series’ exclusion of patients with severe ICH and lack of implementation of inclusion criteria to increase the likelihood of therapeutic anticoagulation being present at time of treatment may result in the overestimation of 4FPCC's hemostatic effectiveness in oral FXa inhibitor-associated ICH. Readers of these (and future) studies should consider these methodological decisions when using them in clinical decision-making. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Impact of Factor Xa Inhibitor Reversal with Prothrombin Complex Concentrate in Patients with Traumatic Brain Injuries.

Anticoagulant use prior to trauma has been associated with increased incidence of traumatic brain injury (TBI), intracranial hemorrhage (ICH) progression, and mortality. Prothrombin complex concentrates (PCCs) are commonly used as off-label treatments for factor Xa inhibitor-associated life-threatening hemorrhage. At this time, there is no consensus regarding appropriate indication, target dose, or outcomes of PCC administration in patients presenting with traumatic ICH. This study seeks to evaluate the impact of reversal with PCC on hemorrhage progression and outcomes in patients with TBI on preinjury factor Xa inhibitors. This single-center retrospective cohort study included patients ≥ 18years presenting with an acute TBI of any severity on apixaban or rivaroxaban from September 1, 2016, to September 1, 2019. Patients were grouped on the basis of receipt of PCCs for reversal (i.e., reversal or no reversal). Exclusion criteria included spontaneous ICH or known coagulopathy. Propensity score matching was conducted with the following variables: age, Abbreviated Injury Scale (head) score, and Charlson Comorbidity Index score. The primary outcome was hemorrhage stability within 48h. Secondary outcomes included degree of hemorrhage progression, in-hospital mortality, discharge disposition, and incidence of thromboembolic events. Of the 115 patients meeting inclusion criteria, 84 were included in the propensity score matched data set. Baseline characteristics, comorbidities, and TBI severity were similar. The majority of patients in the reversal group (35 [83.3%]) and the no reversal (NR) group (40 [95.2%]) experienced a mild TBI (admission Glasgow Coma Scale score of 14 to 15). In the reversal group, patients received 34.3 units/kg activated PCC, 30.5 units/kg four-factor PCC, or 54.9 units/kg four-factor PCC and activated PCC on average. There was no difference observed in the incidence of hemorrhage progression (10.8% NR vs. 15.0% reversal; p = 0.739) or in median change in ICH volume (0mL NR vs. 1mL reversal; p = 0.2199) between groups. Additionally, reversal did not affect in-hospital mortality (3 [7.1%] NR vs. 4 [9.5%] reversal; p > 0.999). One patient in the reversal group developed a deep vein thrombosis (DVT) during the hospitalization; however, this did not result in a statistically significant difference in the occurrence of DVT (p > 0.999). This study demonstrated that PCC used for the treatment of factor Xa inhibitor-associated ICH related to mild TBI did not significantly impact the incidence or degree of hemorrhage progression, and PCC treatment did not result in increased thromboembolic events.

Comparison of 4F-PCC and aPCC time to administration and outcomes for oral anticoagulant-related ICH

IntroductionIntracranial hemorrhages (ICHs) are associated with increased morbidity and mortality. Use of oral anticoagulants are a potential risk factor for ICH, and reversal of the anticoagulant with agents such as Four-Factor Prothrombin Complex Concentrate (4F-PCC) or Activated Prothrombin Complex Concentrate (aPCC) is vital to prevent hematoma expansion. The objective of the study was to the compare the time to administration and outcomes of 4F-PCC or aPCC in patients with ICH taking an oral anticoagulant. MethodsThis was a multicenter, retrospective cohort chart review of patients with ICH taking an oral anticoagulants who received 4F-PCC or aPCC over a two year period. The primary outcome of the study was to the compare the time to administration of 4F-PCC or aPCC in patients with ICH on an oral anticoagulant. Secondary outcomes included evaluating mortality rate, modified Rankin scale (mRs) score, presence of worsening bleed volume on first computed tomography (CT) six hours after the initial reading, and hospital and intensive care unit (ICU) length of stay. The tertiary outcome was to evaluate the effect of risk factors for delay on time to administration, with delay being greater than 60 min. ResultsA total of 350 patient charts were reviewed and 193 patients (4F-PCC [n = 99] and aPCC [n = 94]) were included in the study. There was no significant difference in the primary outcome of median time to administration for the 4F-PCC group (141 min, IQR [93–185]) compared to aPCC (121 min, IQR [107–194]; p = 0.08). No difference was identified between the two groups for all secondary outcomes. Only time to CT results was found to be a risk factor for administration delay (OR, 1.160; 95% CI, 1.073–1.255; p < 0.001). DiscussionIn patients with ICH taking oral anticoagulants, there was no significant difference in the time to administration between 4F-PCC and aPCC. More prospective randomized controlled trials are warranted to determine an ideal reversal time to improve patient outcomes.

Prothrombin Complex Concentrates to Treat Coagulation Disturbances: An Overview With a Focus on Use in Infants and Children.

Various factors may lead to coagulation disturbances following cardiopulmonary bypass and surgery for congenital heart disease. In addition to the risks associated with the administration of allogeneic blood products, persistent disturbances in coagulation function and ongoing bleeding may lead to prolonged surgical times, hemodynamic alterations, intracranial hemorrhage, and even mortality. In most clinical scenarios, coagulation disturbances are treated by targeted blood product therapy including fresh frozen plasma, platelet transfusions, or the administration of cryoprecipitate. When routine blood product therapy fails, coagulation adjuncts such as activated recombinant factor VII or prothrombin complex concentrates (PCCs) may be an option to rapidly replenish depleted coagulation factors and correct coagulation disturbances. The PCC formulations including three-factor PCC, four-factor PCC, and factor eight-inhibitor bypass activator (FEIBA) have been used mainly in the adult population with sporadic case series and anecdotal reports in the pediatric population. The following manuscript discusses the various PCC products available for clinical use, reviews previous reports of their use in infants and children with an emphasis on their role following surgery for congenital heart disease, and outlines their potential role in these clinical scenarios.

A Phase 3, Randomized, Double-Blinded Study of Four-Factor Prothrombin Complex Concentrate in Patients with Acute Major Bleeding on Direct Oral Anticoagulant Therapy with Factor Xa Inhibitor: The Lex-210 Study

Introduction: The benefit of direct oral anticoagulants (DOAC; Factor Xa Inhibitors [FXaI]) has been demonstrated in both clinical trials and real-world studies. However, 2% to 3.5% of DOAC-treated patients experience major bleeding annually, and this is associated with substantial morbidity, mortality, and the need for hospitalization. Therefore, reversal/hemostatic agents are used to control FXaI-related bleeding. The efficacy and safety profile of prothrombin complex concentrates (PCCs) as hemostatic agents in patients with FXaI-related bleeding requires further investigation.Methods: The pivotal LEX-210 study (NCT04867837) is a Phase 3, multicenter, prospective, randomized, double-blinded, group-sequential, parallel-group, adaptive design study to demonstrate the hemostatic efficacy and safety of four-factor PCC (Octaplex®, Octapharma) in patients with acute major bleeding on DOAC therapy with FXaI. LEX-210 will include patients aged ≥18 years who have received or are believed to have received a dose of oral FXaI. Patients must have a baseline anti-factor Xa activity equivalent to at least 100 ng/mL according to the available test (e.g., chromogenic assay) and have acute major bleeding. Key exclusion criteria are bleeding that is immediately life-threatening and acute trauma for which reversal of DOAC therapy with FXaI alone would not be expected to control the bleeding event.The study will enroll approximately 200 patients, with the aim to include at least 91 evaluable patients in each group. Patients will be randomized 1:1 to either of two study groups: low-dose 15 IU/kg body weight vs. high-dose 50 IU/kg body weight PCC. The primary objective of this study is to demonstrate superior hemostatic effectiveness of PCC dosed at 50 IU/kg vs. 15 IU/kg for emergency reversal of the anticoagulant effect of DOACs in patients with major bleeding associated with FXaI.The primary endpoint of LEX-210 is the proportion of patients in whom PCC demonstrates hemostatic effectiveness, i.e., binary outcome of effective (rating of excellent or good) or non-effective (rating of poor or none) in management of major bleeding events within 24 hours after the start of initial management, as assessed by an Independent Data Monitoring and Endpoint Adjudication Committee according to predefined criteria modified from those used by Sarode et al., (see Table 1). Secondary endpoints are the change in endogenous thrombin potential as measured by thrombin generation assay from baseline to 1 hour after PCC administration, the 30-day event rate of thromboembolic events and all-cause mortality, the occurrence of adverse events, and vital signs and laboratory parameters.Results: LEX-210 is planned to start in Q3 2021 and will be performed at approximately 60 sites in North America and Europe. Completion is expected by Q1 2024.Conclusions: The LEX-210 study is designed to confirm the safety and hemostatic efficacy of PCC in the management of FXaI-related major bleeding, offering an effective alternative for the management of major bleeding events in these patients. [Display omitted] DisclosuresSarode: Portola: Consultancy; CSL Behring: Consultancy; Octapharma: Consultancy; Cerus: Research Funding; Siemens: Research Funding. Maack: Octapharma: Current Employment. Solomon: Octapharma: Current Employment. Knaub: Octapharma: Current Employment. Schulman: Octapharma: Research Funding; Boehringer-Ingelheim: Research Funding.

Roles of Four-Factor Prothrombin Complex Concentrate in the Management of Critical Bleeding.

Four-factor prothrombin complex concentrate (4F-PCC) is the term used to describe a pathogen-reduced, lyophilized concentrate that contains therapeutic amounts of at least 4 coagulation factors: Factor II (FII), Factor VII (FVII), Factor IX (FIX), and Factor X (FX). 4F-PCC has proven to be an effective hemostatic agent compared to plasma transfusion in several prospective randomized trials in acute warfarin reversal. In recent years, 4F-PCC has been used in various acquired coagulopathies including post-cardiopulmonary bypass bleeding, trauma-induced coagulopathy, coagulopathy in liver failure, and major bleeding due to anti-FXa (anti-Xa) inhibitors (eg, rivaroxaban and apixaban). As transfusion of frozen plasma (FP) has not been found efficacious in the above critical bleeding scenarios, there is increasing interest in expanding the use of 4F-PCC. However, efficacy, safety, and clinical implications of expanded use of 4F-PCC have not been fully elucidated. Prothrombin time and international normalized ratio are commonly used to assess dose effects of 4F-PCC. Prothrombin time/international normalized ratio are standardly use for warfarin titration, but they are not suited for real-time monitoring of complex coagulopathies. Optimal dosing of 4F-PCC outside of the current approved use for vitamin K antagonist reversal is yet to be determined. In this review, we will discuss the use of 4F-PCC in four critical bleeding settings: cardiac surgery, major trauma, end-stage liver disease, and oral anti-Xa reversal. We will discuss recent studies in each area to explore the dosing, efficacy, and safety of 4F-PCC.

Four-factor prothrombin complex concentrate to reduce allogenic blood product transfusion in patients with major trauma, the PROCOAG trial: study protocol for a randomized multicenter double-blind superiority study

BackgroundOptimal management of severe trauma patients with active hemorrhage relies on adequate initial resuscitation. Early administration of coagulation factors improves post-traumatic coagulation disorders, and four-factor prothrombin complex concentrate (PCC) might be useful in this context. Our main hypothesis is that four-factor PCC in addition to a massive transfusion protocol decreases blood product consumption at day 1 in severe trauma patients with major bleeding.MethodsThis is a prospective, randomized, multicenter, double-blind, parallel, controlled superiority trial. Eligible patients are trauma patients with major bleeding admitted to a French level-I trauma center. Patients randomized in the treatment arm receive 1 mL/kg (25 IU/ml of Factor IX/Kg) four-factor PCC within 1-h post-admission while patients randomized in the controlled group receive 1 mL/kg of saline solution 0.9% as a placebo. Treatments are given as soon as possible using syringe pumps (120 mL/h). The primary endpoint is the amount of blood products transfused in the first 24 h post-admission (including red blood cells, frozen fresh plasma, and platelets). The secondary endpoints are the amount of each blood product transfused in the first 24 h, time to achieve prothrombin time ratio < 1.5, time to hemostasis, number of thrombo-embolic events at 28 days, mortality at 24 h and 28 days, number of intensive care unit-free days, number of ventilator-free days, number of hospital-free days within the first 28 days, hospitalization status at day 28, Glasgow outcome scale extended for patients with brain lesions on initial cerebral imaging, and cost of each strategy at days 8 and 28. Inclusions have started in December 2017 and are expected to be complete by June 2021.DiscussionIf PCC reduces total blood consumption at day 1 after severe trauma, this therapy, in adjunction to a classic massive transfusion protocol, may be used empirically on admission in patients at risk of massive transfusion to enhance coagulation. Moreover, this treatment may decrease blood product-related complications and may improve clinical outcomes after post-traumatic hemorrhage.Trial registrationClinicalTrials.gov NCT03218722. Registered on July 14, 2017

This Month in Anesthesiology

This Month in Anesthesiology

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.