Prothrombin Complex Concentrate Administration Research Articles

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.

Efficacy of human prothrombin complex concentrate in the treatment of warfarin overdose in patients receiving warfarin for mechanical heart valve replacement.

Warfarin, a widely utilized anticoagulant, is paramount for preventing thromboembolic events in patients with mechanical heart valve replacements. However, its narrow therapeutic index can lead to over-anticoagulation and overdose, resulting in serious health risks. This study examines the efficacy of human prothrombin complex concentrate (PCC) in managing warfarin overdose, in comparison with traditional treatments. A retrospective analysis was conducted on 162 adults who presented with warfarin overdose (INR > 5.0) at a tertiary care hospital between 2016 and 2020. Participants were divided into 2 groups-those treated with PCC (n = 57) and those treated with conventional methods (n = 105), including vitamin K and fresh frozen plasma. The primary outcome was the rate of reaching the target (International Normalized Ratio) INR within 24 hours. Secondary outcomes included transfusion requirements, thromboembolic events, adverse reactions, 30-day mortality, and length of hospital stay. PCC demonstrated significant efficacy, with 89.5% of patients achieving the target INR within 24 hours, compared to 64.8% in the control group (P < .05). The PCC group also had reduced transfusion requirements and a shorter average hospital stay. There was no significant difference in thromboembolic events or adverse reactions between the 2 groups, and the reduced 30-day mortality in the PCC group was not statistically significant. Human prothrombin complex concentrate is associated with rapid reaching the target INR, decreased transfusion needs, and shortened hospitalization, making it a promising option for warfarin overdose management. While the results are encouraging, larger, multicenter, randomized controlled trials are necessary to further validate these findings and optimize PCC administration protocols.

Abstract WP169: Thromboelastography as a Biomarker of Emergent Direct-Acting Oral Anticoagulant Reversal With Prothrombin Complex Concentrates for Intracranial Hemorrhage

Prothrombin complex concentrates (PCCs) are used to emergently reverse direct-acting oral anticoagulant (DOAC) activity. PCCs are recommended as an alternative to recombinant coagulation factor-Xa to reverse anticoagulation activity of apixaban or rivaroxaban. Measuring the degree of anticoagulation reversal in this population is limited. Thromboelastography (TEG) has been used to detect the presence of DOAC plasma levels in patients chronically taking a DOAC but has not been utilized to measure the effect on anticoagulant activity after PCC administration. We aimed to determine whether TEG R-time is useful in detecting the impact of PCC administration on anticoagulation activity in patients with anti-factor Xa-associated intracranial hemorrhage (ICH). We prospectively evaluated the utility of TEG to assess anticoagulation activity after factor Xa inhibitor reversal with 4-factor PCC. Adults with ICH taking apixaban or rivaroxaban were included. Patients were excluded if their last known dose of anticoagulation was &gt;48 hours prior to arrival, had known apixaban or rivaroxaban blood levels &lt;20 ng/mL, or had the following comorbidities: hepatic failure, hereditary disorders of hemostasis, polytrauma, or pregnancy. TEG samples were collected before PCC administration (if available), and 0.5, 12, and 24 hours after PCC administration. Thirty-one patients were enrolled between November 2022 and August 2023. The median PCC dose was 24.5 units/kg (IQR 20.3-26.9 units/kg; n=29). Nine patients received anticoagulation reversal after baseline TEG collection; the remainder received anticoagulation reversal at transferring facilities. Baseline R-time was negatively correlated with time since last dose of DOAC (n=9). A median decrease in R-time of 0.8 minutes after PCC (IQR -1.6 - 0.3; n=8) was found in patients with baseline TEG collection. R-time rebounded by a median of 0.75 minutes (IQR 0.2-2.0; n=8) from 0.5 hours to 12 hours after PCC administration (n=8). TEG R-time, a measure that inversely correlates with the degree of anticoagulant effect, rapidly decreases after PCC in patients taking DOACs that present with acute ICH. TEG R-time rebounds 12 hours after PCC administration. TEG-R time may be a useful biomarker in DOAC reversal with PCC.

Comparison of Fixed Versus Weight-Based Prothrombin Complex Concentrate Dosing Strategies for Factor Xa Inhibitor Reversal.

Background: Our institution introduced fixed-dose prothrombin complex concentrate (PCC) to streamline order verification and medication administration. Previous studies using fixed-dose PCC for vitamin K antagonist reversal showed comparable efficacy to weight-based dosing. Objective: To compare fixed versus weight-based PCC dosing for reversal of Factor Xa Inhibitor (FXaI) effects. Methods: Retrospective cohort study conducted at a tertiary care academic medical center. Patients who received PCC to reverse the effects of apixaban or rivaroxaban were eligible. Subjects in the fixed-dose group (5000 units or 2000 units) were compared to weight-based PCC (50 units/kg). The primary outcome was time between order entry and medication administration. Secondary outcomes included: average PCC dose, postadministration procedures, achieved hemostasis, 30-day mortality, hospital length of stay, and adverse drug events. Results: 72 patients received fixed-dose PCC and 101 received weight-based PCC. Median time between order entry and administration was 4.5 min shorter in the fixed-dose group compared to weight-based (34.5 vs 39 min, P = .10). In patients who received fixed-dose, 79.2% achieved hemostasis versus 71.3% in the weight-based group (RR = 1.11, 95% CI = 0.94-1.32). There was no difference in the number of subsequent hemorrhage-related surgeries (29.2% vs 36.7%, RR = 0.80, 95% CI = 0.51-1.24) or mortality rate (26.4% vs 35.6%, RR = 0.73, 95% CI = 0.46-1.17). There were zero adverse drug events reported. Rates of thrombosis were 2.8% and < 1% (P = .57) in the fixed and weight-based groups, respectively. Conclusion and Relevance: The fixed-dosing strategy did not reduce time to PCC administration nor impact hemostasis or mortality. These data support that the fixed-dosing method is a viable option.

Reversal of pre-injury factor-Xa inhibitors with prothrombin complex concentrates in patients following traumatic brain injury

IntroductionThere is substantial debate on the best method to reverse factor Xa-inhibitors in patients following traumatic brain injury (TBI). Prothrombin complex concentrates (PCC) have been used for this indication but their role has been questioned. This study reported failure rates with PCC in patients following TBI and as a secondary objective, compared 4-factor (4 F-PCC) and activated PCC (APCC). Material and methodsConsecutive patients with TBI on factor Xa-inhibitors admitted to one of two trauma centers were retrospectively identified. Patients with penetrating TBI, delays in PCC administration (>6 h), receipt of tranexamic acid, factor VIIa or no follow up CT-scan were excluded. The primary outcome was treatment failure defined as hematoma expansion > 20% from baseline for SDH, EDH or IPH, a new hematoma not present on the initial CT scan or any expansion of a SAH or IVH. Hematoma expansion was further categorized as symptomatic or asymptomatic, designated by a change in the motor GCS score, neurologic exam or change ≥ 3 in NIH Stroke Scale. Multi-variate analysis was performed. ResultsThere were 43 patients with a mean age of 77 ± 13 years with primarily mild TBI (95%) after a ground level fall (79%). The mean dose was 41 ± 12 units/kg. Sixty percent received 4 F-PCC and 40% APCC. The incidence of treatment failure was 28% (12/43). Of the 12 patients with hematoma expansion, only 3 were symptomatic (9.3%). Hematoma expansion with 4 F-PCC and APCC were similar (27% vs. 29%,p = .859). Only sex was associated with hematoma expansion on multivariate analysis [OR (95% CI) = 6.7 (1.1 – 40.9)]. ConclusionPCC was an effective option for factor Xa inhibitor reversal following TBI. The relationship between radiographic expansion and clinical expansion was poor.

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.

Comparison of Prothrombin Complex Concentrate with Activated Factor VII Use for Bleeding Following Cardiopulmonary Bypass in Children.

This study aims to compare the efficacy and safety of activated recombinant factor VII (rFVIIa) and prothrombin complex concentrate (PCC) in the treatment of bleeding complications following surgery requiring cardiopulmonary bypass (CPB) in children. This is a retrospective chart review of a single institution comprising patients aged 0 to 18 years old with congenital heart disease. Patients must have received either PCC or rFVIIa after coming off CPB. Our primary efficacy endpoint is time in the operating room from off-CPB to pediatric intensive care unit admission. Our primary safety endpoint is thrombosis through 30 days. Our primary efficacy outcome was significantly shorter in the PCC group compared with the rFVIIa group (P < .0001). Similarly, secondary efficacy outcomes of packed red blood cell administration, chest tube output, and transfusion exposures all significantly favored PCC administration. However, CPB time was significantly longer, and body temperatures were significantly lower, in the rFVIIa group. Safety outcomes, including our primary safety outcome of thrombosis through 30 days, were similar between the two groups. This study questions whether PCC could be favored over rFVIIa for hemostasis in children with congenital heart disease following CPB surgery. In addition, this study has found no difference when comparing PCC and rFVIIa in terms of safety outcomes, particularly thrombosis events. There are several limitations to this study due to the retrospective nature of the design and the differences between the two study groups. Despite the limitations, this study suggests that relatively early administration of PCC could be favored over delayed administration of rFVIIa to control recalcitrant post-CPB bleeding in the operating room.

Comparative study of predisposition to thrombosis with administration of known systemic hemostatic agents and fibrin monomer in the experiment

Aim. To compare predisposition to thrombosis caused by administration of known systemic hemostatic agents and fibrin monomer under the conditions of normal coagulation versus drug-induced hypocoagulation in the experiment.Materials and methods. The prothrombotic effect of intravenous (IV) administration of various systemic hemostatic agents was compared in a series of in vivo experiments. These agents included fibrin monomer (FM) (0.25 mg / kg), prothrombin complex concentrate (PCC) (40 IU / kg) or recombinant factor VIIa (rFVIIa) (270 mcg / kg). The studies were conducted under the conditions of hypocoagulation induced by the administration of warfarin (per os at a dose of 0.4–0.5 mg / kg / day for 14 days) or dabigatran etexilate (per os at a single dose of 15–20 mg / kg). Hemostatic system parameters were evaluated using thromboelastometry and calibrated automated thrombography.Results. It was found that PCC reversed anticoagulant effects and led to an overcompensated increase in the density characteristics of the blood clot along with an excessive increase in thrombin generation in the groups of animals with warfarin-induced coagulopathy. The use of PCC and rFVIIa in the groups of animals with dabigatran-induced hypocoagulation also resulted in an increase in blood thrombogenic properties. In the administration of PCC, it was manifested though an increased D-dimer level and in administration of rFVIIa – through an increase in the clot density characteristics. At the same time, replacement of these hemostatic agents with FM did not affect the hemostatic system parameters.Conclusion. FM at a dose of 0.25 mg / kg, as opposed to PCC and rFVIIa, is safer in terms of the risk of thrombosis.

UpToDate®

UpToDate| January 2023 UpToDate® ASA Monitor January 2023, Vol. 87, 19. https://doi.org/10.1097/01.ASM.0000911752.19079.af Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn MailTo Cite Icon Cite Get Permissions Search Site Citation UpToDate®. ASA Monitor 2023; 87:19 doi: https://doi.org/10.1097/01.ASM.0000911752.19079.af Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll PublicationsASA Monitor Search Advanced Search Topics: blood coagulation disorders, blood pressure, cardiopulmonary bypass, factor ix concentrates, hemorrhage, mortality, older adult, oxygen, plasma, sudden cardiac death UpToDate® and ASA Monitor are collaborating to present select content abstracts on “What's New in Anesthesiology.” UpToDate is an evidence-based, clinical support resource used worldwide by health care practitioners to make decisions at the point of care. For complete, current “What's New” content, or to become a subscriber for full content access, go to www.uptodate.com. “What's New” abstract information is free for all medical professionals. Unactivated prothrombin complex concentrate (PCC) is used to rapidly correct warfarin anticoagulation. Observational studies have described off-label use of PCC to treat surgical coagulopathic bleeding, but supporting data are limited. One randomized trial compared administration of PCC 15 IU/kg with fresh frozen plasma (FFP) 10 to 15 mL/kg in 100 patients who had excessive microvascular bleeding with prothrombin time (PT) >16.6 seconds and international normalized ratio (INR) >1.6 after cardiac surgery with cardiopulmonary bypass.1 Overall efficacy and safety were comparable between... You do not currently have access to this content.

146: FIXED-DOSE PROTHROMBIN COMPLEX CONCENTRATE FOR POST-CARDIAC SURGERY COAGULOPATHY AND BLEEDING

Introduction: Four-factor prothrombin complex concentrate (PCC) use has increased steadily for bleeding and coagulopathy correction post-cardiac surgery. Weight-based dosing has ranged from 15 to 25 units/kg most often for this indication. The aim of this study was to describe post-operative chest tube output and transfusion requirements following a fixed-dose of 1500 units of PCC. Methods: Adult patients receiving PCC post-cardiac surgery from August 2018 to June 2021 were retrospectively evaluated. The primary end point was average hourly chest tube output for 6 hours following PCC administration. Secondary end points included incidence of thromboembolic events, amount of blood products received, and need for additional PCC doses. Results: A total of 124 patients received fixed-dose PCC post-cardiac surgery during the study timeframe. The median equivalent weight-based dose was 16 units/kg. Median cardiopulmonary bypass time was 127 min (IQR 90-159). The most common procedures performed were coronary artery bypass grafting (CABG) and valve repair or replacement (19.4%), aortic replacement and CABG or valve repair or replacement (18.5%), and single valve repair or replacement (18.5%). Average hourly chest tube output for 6 hours post-PCC was 41 mL (IQR 22-75). Forty-seven patients also received fresh frozen plasma. Ten patients received a repeat dose, with the dose ranging from 500 to 1500 units. Five thromboembolic complications were reported within 30 days of PCC administration. Conclusions: Our results suggest that a fixed-dose PCC strategy is effective for bleeding post-cardiac surgery and could result in cost savings compared to traditional weight-based PCC dosing for this indication. Further investigation is warranted to identify optimal dosing strategies for PCC in cardiac surgery related bleeding.

Perioperative prothrombin complex concentrate and fibrinogen administration are associated with thrombotic complications after liver transplant.

Use of intraoperative prothrombin complex concentrates (PCC) and fibrinogen concentrate administration has been linked to thrombotic events. However, it is unknown if its use is associated with thrombotic events after liver transplant. We conducted a post hoc analysis of a prospectively conducted registry database study on patients who underwent liver transplant between 2004 and 2017 at Heidelberg University Hospital, Heidelberg, Germany. Univariate and multivariate analyses were used to determine the association between PCC and fibrinogen concentrate administration and thrombotic complications. Data from 939 transplantations were included in the analysis. Perioperative PCC or fibrinogen administration was independently associated with the primary composite endpoint Hepatic artery thrombosis (HAT), Portal vein thrombosis (PVT), and inferior vena cava thrombosis [adjusted HR: 2.018 (1.174; 3.468), p = 0.011]. PCC or fibrinogen administration was associated with the secondary endpoints 30-day mortality (OR 4.225, p < 0.001), graft failure (OR 3.093, p < 0.001), intraoperative blood loss, red blood cell concentrate, fresh frozen plasma and platelet transfusion, longer hospitalization, and longer length of stay in intensive care units (ICUs) (all p < 0.001). PCC or fibrinogen administration were not associated with pulmonary embolism, myocardial infarction, stroke, or deep vein thrombosis within 30 days after surgery. A critical review of established strategies in coagulation management during liver transplantation is warranted. Perioperative caregivers should exercise caution when administering coagulation factor concentrate during liver transplant surgery. Prospective randomized controlled trials are needed to establish causality for the relationship between coagulation factors and thrombotic events in liver transplantation. Further studies should be tailored to identify patient subgroups that will likely benefit from PCC or fibrinogen administration.

Characterization of 2 Different Prothrombin Complex Concentrates by Different Hemostatic Assays in an In Vitro Hemodilution Model.

Viscoelastically guided coagulation factor concentrate-based algorithms for the treatment of trauma-induced coagulopathy include the administration of prothrombin complex concentrates (PCCs). However, the exact role of PCC preparations in this context is a matter of debate. Particularly, the ideal diagnostic trigger for their administration and potential differences between heparin-containing and heparin-free preparations remain unclear. We investigated the hypothesis that 2 different PCCs might have distinct influences on in vitro blood coagulation. We conducted a direct comparison of 2 commercially available PCC preparations (the heparin-containing Beriplex P/N and the heparin-free Cofact) in an in vitro hemodilution model. Sole fibrinogen substitution served as the control group. To characterize the hemostatic changes, we utilized conventional coagulation tests, a thrombin generation assay (TGA), and 2 different viscoelastic hemostatic assays (VHAs; ROTEM delta and ClotPro). Irrespective of the diagnostic assay used, no significant differences between the 2 PCC groups were observed. Fibrinogen levels remained stable from the baseline throughout every dilution level. The control group already showed an increased endogenous thrombin potential (ETP; nM·L -1 ·min -1 ) at all dilution levels compared to baseline (baseline, 2829.4 (432.8); 40% dilution, 4211.7 (391.6); 60% dilution, 4290.9 (300.8); 80% dilution, 3861.4 (303.5); all P < .001). Spiking with both PCC preparations led to a further-pronounced thrombin elevation in comparison to the control group (ETP at 40% dilution, PCC1: 4913.3 [370.2], PCC2: 4988.1 [265.7]; 60% dilution, PCC1: 5174.5 [234.7], PCC2: 5390.4 [334.9]; 80% dilution, PCC1: 5253.8 [357.9], PCC2: 5392.6 [313.4]; all P < .001). Conventional coagulation tests did not mirror the TGA results. Despite increased thrombin generation, prothrombin time was significantly prolonged at all dilution levels for the control group, and both PCC groups exhibited significant prolongations at the 60% and 80% dilution levels (all P < .001) compared to baseline. Similarly, VHA did not depict the thrombin elevation. Furthermore, descriptive analyses revealed relevant differences between the 2 VHA devices, particularly at baseline. Both PCC preparations (ie, irrespective of heparin content) induced significant elevation of thrombin generation, which was not depicted by conventional coagulation tests or VHA. Our in vitro results suggest that diagnostic assays routinely used to guide PCC administration might not adequately reflect thrombin generation in bleeding patients.

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.

Prophylactic fresh frozen plasma versus prothrombin complex concentrate for preprocedural management of the coagulopathy of liver disease: A systematic review

BackgroundThe optimal prophylactic preprocedural management of patients with coagulopathy due to liver disease is not known. ObjectivesOur objective was to compare the efficacy and safety of fresh frozen plasma (FFP) with prothrombin complex concentrate (PCC) in the preprocedural management of patients with coagulopathy of liver disease. MethodsWe conducted a systematic review to examine published evidence regarding treatment with FFP or PCC in adults with coagulopathy of liver disease undergoing an invasive procedure. Direct comparisons and single‐arm studies were eligible. Efficacy outcomes included major bleeding, mortality, and correction of prothrombin time (PT) and/or international normalized ratio (INR). Safety outcomes included thrombosis and transfusion‐related complications. ResultsA total of 95 articles were identified for full‐text review. Nine studies were eligible and included in the review. No randomized trials comparing FFP versus PCC were identified. Only two studies directly compared FFP versus PCC. In these studies, PCC appeared to result in higher rates of correction of PT/INR, but bleeding outcomes were not different. In the single‐arm studies, bleeding events appeared low overall. Volume overload was the most common recorded adverse event in patients receiving FFP. Thromboembolic events occurred rarely, but exclusively in the PCC group. Due to heterogeneity in study definitions and bias, meta‐analysis was not possible. Our study found no evidence to favor a specific product over another. ConclusionsInsufficient data exist on the effects of FFP versus PCC administration before invasive procedures in patients with coagulopathy of liver disease to make conclusions with respect to relative efficacy or safety.

American College of Gastroenterology-Canadian Association of Gastroenterology Clinical Practice Guideline: Management of Anticoagulants and Antiplatelets During Acute Gastrointestinal Bleeding and the Periendoscopic Period.

We conducted systematic reviews of predefined clinical questions and used the Grading of Recommendations, Assessment, Development and Evaluations approach to develop recommendations for the periendoscopic management of anticoagulant and antiplatelet drugs during acute gastrointestinal (GI) bleeding and the elective endoscopic setting. The following recommendations target patients presenting with acute GI bleeding: For patients on warfarin, we suggest against giving fresh frozen plasma or vitamin K; if needed, we suggest prothrombin complex concentrate (PCC) compared with fresh frozen plasma administration; for patients on direct oral anticoagulants (DOACs), we suggest against PCC administration; if on dabigatran, we suggest against the administration of idarucizumab, and if on rivaroxaban or apixaban, we suggest against andexanet alfa administration; for patients on antiplatelet agents, we suggest against platelet transfusions; and for patients on cardiac acetylsalicylic acid (ASA) for secondary prevention, we suggest against holding it, but if the ASA has been interrupted, we suggest resumption on the day hemostasis is endoscopically confirmed. The following recommendations target patients in the elective (planned) endoscopy setting: For patients on warfarin, we suggest continuation as opposed to temporary interruption (1-7 days), but if it is held for procedures with high risk of GI bleeding, we suggest against bridging anticoagulation unless the patient has a mechanical heart valve; for patients on DOACs, we suggest temporarily interrupting rather than continuing these; for patients on dual antiplatelet therapy for secondary prevention, we suggest temporary interruption of the P2Y12 receptor inhibitor while continuing ASA; and if on cardiac ASA monotherapy for secondary prevention, we suggest against its interruption. Evidence was insufficient in the following settings to permit recommendations. With acute GI bleeding in patients on warfarin, we could not recommend for or against PCC administration when compared with placebo. In the elective periprocedural endoscopy setting, we could not recommend for or against temporary interruption of the P2Y12 receptor inhibitor for patients on a single P2Y12 inhibiting agent. We were also unable to make a recommendation regarding same-day resumption of the drug vs 1-7 days after the procedure among patients prescribed anticoagulants (warfarin or DOACs) or P2Y12 receptor inhibitor drugs because of insufficient evidence.

American College of Gastroenterology-Canadian Association of Gastroenterology Clinical Practice Guideline: Management of Anticoagulants and Antiplatelets During Acute Gastrointestinal Bleeding and the Periendoscopic Period.

We conducted systematic reviews of predefined clinical questions and used the Grading of Recommendations, Assessment, Development and Evaluations approach to develop recommendations for the periendoscopic management of anticoagulant and antiplatelet drugs during acute gastrointestinal (GI) bleeding and the elective endoscopic setting. The following recommendations target patients presenting with acute GI bleeding: For patients on warfarin, we suggest against giving fresh frozen plasma or vitamin K; if needed, we suggest prothrombin complex concentrate (PCC) compared with fresh frozen plasma administration; for patients on direct oral anticoagulants (DOACs), we suggest against PCC administration; if on dabigatran, we suggest against the administration of idarucizumab, and if on rivaroxaban or apixaban, we suggest against andexanet alfa administration; for patients on antiplatelet agents, we suggest against platelet transfusions; and for patients on cardiac acetylsalicylic acid (ASA) for secondary prevention, we suggest against holding it, but if the ASA has been interrupted, we suggest resumption on the day hemostasis is endoscopically confirmed. The following recommendations target patients in the elective (planned) endoscopy setting: For patients on warfarin, we suggest continuation as opposed to temporary interruption (1–7 days), but if it is held for procedures with high risk of GI bleeding, we suggest against bridging anticoagulation unless the patient has a mechanical heart valve; for patients on DOACs, we suggest temporarily interrupting rather than continuing these; for patients on dual antiplatelet therapy for secondary prevention, we suggest temporary interruption of the P2Y12 receptor inhibitor while continuing ASA; and if on cardiac ASA monotherapy for secondary prevention, we suggest against its interruption. Evidence was insufficient in the following settings to permit recommendations. With acute GI bleeding in patients on warfarin, we could not recommend for or against PCC administration when compared with placebo. In the elective periprocedural endoscopy setting, we could not recommend for or against temporary interruption of the P2Y12 receptor inhibitor for patients on a single P2Y12 inhibiting agent. We were also unable to make a recommendation regarding same-day resumption of the drug vs 1–7 days after the procedure among patients prescribed anticoagulants (warfarin or DOACs) or P2Y12 receptor inhibitor drugs because of insufficient evidence.

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.

Prothrombin complex concentrates in cardiac surgery: where are we?

Major bleeding in cardiac surgery is commonly encountered, and, until recently, most frequently managed with fresh frozen plasma (FFP). However, a Cochrane review found this practice to be associated with a significant increase in red blood cell (RBC) transfusions and costs. These findings have led to off-label uses of prothrombin complex concentrates (PCCs) in cardiac surgery. The purpose of this review is to compare and contrast the use of FFP and PCC, review the components, limitations and risks of different types of PCCs, and discuss the latest evidence for the use of PCC versus FFP in cardiac surgery. A recent review and meta-analysis suggests that PCC administration in cardiac surgery is more effective than FFP in reducing RBC transfusions and costs. The current data supports the use of 4F-PCC instead of FFP as the primary hemostatic agent in cases of major bleeding in cardiac surgery. The use of PCCs is associated with reduced rates of RBC transfusions while maintaining a favorable safety profile. Clear advantages of PCC over FFP include its smaller volume, higher concentration of coagulation factors and shorter acquisition and administration times.

Efficacy of prothrombin complex concentrate in the management of oral factor Xa inhibitors associated major bleed assessed by ISTH and ANNEXA-4 criteria.

Direct oral anticoagulants (DOACs) are increasingly used for stroke prevention in atrial fibrillation and treatment and prevention of venous thromboembolism. They are also associated with bleeding risk. Existing literature suggests that prothrombin complex concentrate (PCC) administration may help control bleeding due to factor Xa inhibitors (FXaI). To determine the hemostatic efficacy of PCC in patients with major bleeding due to FXaI,we performed a retrospective chart review of 50 patients who presented with FXaI associated major bleeding that required urgent hemostatic management. Hemostatic assessment was performed using ISTH and ANNEXA-4 criteria. Twenty patients presented with intracranial hemorrhage (ICH), 20 had gastrointestinal bleeding, 3 had visceral bleeding, 3 had genitourinary bleeding, and 4 had miscellaneous types of bleeding. Fifty-six percent (28/50) had effective hemostasis using ISTH criteria and 84% (42/50) achieved effective hemostasis by ANNEXA-4 criteria. Hemostatic efficacy was similar by both tools for ICH (75% each). However, there was a major difference between ISTH and ANNEXA-4 hemostatic efficacy assessments for GI bleeding(45% and 95%, respectively). When comparing rivaroxaban and apixaban, there was no significant difference in effective hemostasis using either criteria, time to hemostasis, thromboembolic events, or patient mortality. Five (10%) patients had thromboembolic events within seven days of PCC administration, and the 30-day mortality rate was 14% (7/50). Our study shows similar efficacy, thromboembolic events, and mortality associated with PCC compared to andexanet alfa using ANNEXA-4 criteria, suggesting that PCC may be a viable alternative.

Is antivitamin K reversal required in patients with cirrhosis undergoing liver transplantation?

Antivitamin K agent (AVK) reversal in patients with cirrhosis awaiting liver transplantation (LT) is not defined in guidelines. We investigated the effect of reversion with prothrombin complex concentrate (PCC) on intraoperative transfusion, bleeding, and safety in LT patients on AVK. In 511 patients undergoing LT, we identified 25 patients treated with AVK (AVK group) and 13 patients with incidental portal vein thrombosis (PVT) without AVK (incidental PVT group). Fifty patients who underwent LT without PVT or AVK matched by age, model for end stage of liver disease (MELD), body mass index (BMI), and cirrhosis etiology were selected as the control group. There were no significant differences between the three groups in intraoperative blood loss, transfusion, and postoperative bleeding. In the AVK group, there were no differences between patients who received PCC and those who did not in intraoperative blood loss, red blood cells, fibrinogen, and platelet transfusion, or postoperative bleeding. PCC use had no effect on RBC transfusion in patients who had international normalized ratio or clotting time above versus below median values of the two parameters at baseline (2.3 and 103 s, respectively). No thrombotic events were detected in patients who received PCC. These data suggest that systematic administration of PCC to revert AVK prior to LT should be reconsidered.