Prothrombin Complex Concentrate Dose Research Articles

Prothrombin complex concentrate for emergency surgery in patients on oral Xa-inhibitors

BackgroundIt is uncertain whether prothrombin complex concentrate (PCC) improves hemostasis in patients on treatment with oral factor Xa-inhibitors (XaI) who require emergency surgery. ObjectivesTo evaluate whether, in patients with therapeutic levels of oral XaI, preoperative PCC prevents excessive bleeding during and after emergency surgery and is not associated with thrombotic complications. MethodsWe conducted a prospective cohort study wherein a fixed 2000 IU dose of 4-factor PCC was given to patients taking oral XaI with plasma XaI levels of at least 75 ng/mL before the emergency surgery with an expected blood loss of at least 50 mL. Patients were followed for 30 days. The primary efficacy outcome was the incidence of normal or mildly abnormal surgical hemostasis, as assessed by the surgeon; primary safety outcome was the incidence of thromboembolic events within 7 days. ResultsWe included 20 patients, of which 50% were female, on apixaban (75%) or rivaroxaban (25%) with median XaI level of 128 ng/mL (range, 77-497 ng/mL). The median duration of surgery was 2 hours 42 minutes (range, 15 minutes to 8 hours 17 minutes). Normal or mildly abnormal hemostasis was observed in 16 patients (80%); 2 patients had moderately abnormal and 2 had severely abnormal hemostasis, 1 each of those was considered due to local or technical factors. There were 4 deaths (20%) secondary to underlying disease and 1 incidental pulmonary embolism in a patient with cancer. ConclusionA fixed dose of PCC appears to control hemostasis in patients with therapeutic plasma levels of apixaban or rivaroxaban requiring emergency surgery.

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.

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 >48 hours prior to arrival, had known apixaban or rivaroxaban blood levels <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.

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.

Immediate Higher-Dose Prothrombin Complex Concentrate Without Fresh Frozen Plasma or Fibrinogen Concentrate for Significant Coagulopathic Cardiac Surgical Field Bleeding

Treatment of significant coagulopathic cardiac surgical field bleeding with immediate higher-dose prothrombin complex concentrate (PCC) without fresh frozen plasma (FFP) or fibrinogen concentrate is unexplored. To study characteristics, chest drainage, and clinical outcomes of patients with significant coagulopathic surgical field bleeding treated with immediate higher-dose (defined at >15 IU/kg based on factor IX) PCC without FFP or fibrinogen concentrate. We screened sequential cardiac surgery patients. We reviewed electronic blood bank data, Australian Society of Cardiothoracic Surgery database information and anaesthetic, intensive care unit (ICU), ward and radiological charts and electronic data. We identified patients deemed by the operating surgeon to require treatment for significant coagulopathic surgical field bleeding who underwent immediate higher-dose PCC without FFP or fibrinogen concentrate. Among 168 patients, we identified 30 who underwent immediate higher-dose PCC without FFP or fibrinogen concentrate. Median age was 68 years, 23 were male, 17 underwent coronary artery bypass surgery and three underwent complex surgery (David procedure, redo mitral valve surgery, and redo thoraco-abdominal aneurysm repair). Median dose of PCC was 2,500 IU. In addition, 27% underwent platelets and one underwent cryoprecipitate. Chest drainage at 24 hours was 505 ml. Survival to hospital discharge was 100%. There were no cases of pulmonary embolism, stroke, or other thrombotic events. Stage 1 AKI occurred in one patient. In a pilot cohort of patients with significant coagulopathic surgical field bleeding, immediate higher-dose PCC without FFP or fibrinogen concentrate was feasible and had an acceptable efficacy and safety profile, which justifies future controlled studies.

Prothrombin Complex Concentrate vs Plasma for Post–Cardiopulmonary Bypass Coagulopathy and Bleeding

Post-cardiopulmonary bypass (CPB) coagulopathy and bleeding are among the most common reasons for blood product transfusion in surgical practices. Current retrospective data suggest lower transfusion rates and blood loss in patients receiving prothrombin complex concentrate (PCC) compared with plasma after cardiac surgery. To analyze perioperative bleeding and transfusion outcomes in patients undergoing cardiac surgery who develop microvascular bleeding and receive treatment with either PCC or plasma. A single-institution, prospective, randomized clinical trial performed at a high-volume cardiac surgical center. Patients were aged 18 years or older and undergoing cardiac surgery with CPB. Patients undergoing complex cardiac surgical procedures (eg, aortic replacement surgery, multiple procedures, or repeated sternotomy) were preferentially targeted for enrollment. During the study period, 756 patients were approached for enrollment, and 553 patients were randomized. Of the 553 randomized patients, 100 patients met criteria for study intervention. Patients with excessive microvascular bleeding, a prothombin time (PT) greater than 16.6 seconds, and an international normalized ratio (INR) greater than 1.6 were randomized to receive treatment with either PCC or plasma. The PCC dose was 15 IU/kg or closest standardized dose; the plasma dose was a suggested volume of 10 to 15 mL/kg rounded to the nearest unit. The primary outcome was postoperative bleeding (chest tube output) from the initial postsurgical intensive care unit admission through midnight on postoperative day 1. Secondary outcomes were PT/INR, rates of intraoperative red blood cell (RBC) transfusion after treatment, avoidance of allogeneic transfusion from the intraoperative period to the end of postoperative day 1, postoperative bleeding, and adverse events. One hundred patients (mean [SD] age, 66.8 [13.7] years; 61 [61.0%] male; and 1 [1.0%] Black, 1 [1.0%] Hispanic, and 98 [98.0%] White) received the study intervention (49 plasma and 51 PCC). There was no significant difference in chest tube output between the plasma and PCC groups (median [IQR], 1022 [799-1575] mL vs 937 [708-1443] mL). After treatment, patients in the PCC arm had a greater improvement in PT (effect estimate, -1.37 seconds [95% CI, -1.91 to -0.84]; P < .001) and INR (effect estimate, -0.12 [95% CI, -0.16 to -0.07]; P < .001). Fewer patients in the PCC group required intraoperative RBC transfusion after treatment (7 of 51 patients [13.7%] vs 15 of 49 patients [30.6%]; P = .04); total intraoperative transfusion rates were not significantly different between groups. Seven (13.7%) of 51 patients receiving PCCs avoided allogeneic transfusion from the intraoperative period to the end of postoperative day 1 vs none of those receiving plasma. There were no significant differences in postoperative bleeding, transfusions, or adverse events. The results of this study suggest a similar overall safety and efficacy profile for PCCs compared with plasma in this clinical context, with fewer posttreatment intraoperative RBC transfusions, improved PT/INR correction, and higher likelihood of allogeneic transfusion avoidance in patients receiving PCCs. ClinicalTrials.gov Identifier: NCT02557672.

Therapeutic Plasma Exchange for Apixaban Removal in the Setting of Delayed Clearance and Life-Threatening Bleeding

Introduction:The management of bleeding associated with direct oral anticoagulants (DOACs) is challenging and associated with high risk of morbidity/mortality despite the use of various reversal agents (Gomez-Outes et al. 2021). Routine tests cannot determine the level of DOAC anticoagulation and reversal agents carry potential prothrombotic complications (Garcia & Crowther 2021). We present an unusual case of a patient requiring emergent surgery with significant post-op bleeding due to profoundly delayed apixaban elimination.Case Description:A 63-year-old female presented to the emergency department (ED) with a 10-day history of worsening abdominal pain, distension, nausea and constipation. Her past medical history was notable for right sided heart failure, COVID-19 pneumonia requiring intubation, tissue mitral valve replacement, and post-op atrial fibrillation for which she was prescribed apixaban 5 mg BID. Her last dose of apixaban had been the night prior to ED presentation.In the ED, a CT of the abdomen revealed a 6 cm partially obstructing lesion involving the mid-sigmoid colon. Findings were consistent with evolving peritonitis and the patient underwent an emergent exploratory laparotomy, sigmoid resection, and end colostomy. Pre-op labs revealed WBC 12.4 x10 9/L, hemoglobin (hgb) 9.2 g/dL, and platelets 318 x10 9/L. Coagulation studies revealed a PT of 28 sec and INR of 2.5. The patient was given prothrombin complex concentrate (PCC) 25 units/kg and 1 mg of vitamin K prior to surgery. Postoperatively, the INR remained elevated, 2.0, and her hgb downtrended from 8.8 g/dL to 7.8 g/dL. On post-op day 1 the patient became hypotensive, with increased abdominal pain/distension, she also started bleeding from her ostomy. The INR was 2.4 and her hgb dropped to 6.0 g/dL. Red blood cells were given along with FFP, vitamin K and a 2 nd dose of PCC. The patient continued to decline, was transferred to the ICU where she was intubated and placed on CRRT. Hematology was consulted for the persistently prolonged PT/INR in the setting of bleeding despite multiple interventions to correct the INR.The patient's last dose of apixaban was ~48 h prior to ICU admission. A rapid heparin anti-Xa assay was performed and upon comparison with an in-house nomogram the result, 1.78 IU/mL, correlated to an apixaban dose between 180-200 ng/ml (average peak levels 2-4 h after administration are 171 ng/mL). This result was confirmed the following day by an apixaban anti-Xa assay, 190 ng/mL. A repeat test performed 11 h later showed a minimal decrease in apixaban indicating impaired clearance.Therapeutic plasma exchange (TPE) was considered for rapid removal of apixaban. We performed a 1.0 plasma volume exchange, using plasma as the replacement fluid, to remove apixaban. Pre and post TPE drug levels were 172 and 108 ng/mL, respectively. Due to an elevated apixaban level the next day, a second TPE was performed which dropped the level to 87 ng/mL. The patient began to improve clinically, with hgb stabilization ~10 g/dL. She was extubated and transferred to a medical floor for further management. Apixaban levels were still measurable, 16 ng/mL, on post op day 8, 11 days after her last dose.Discussion:Apixaban is a highly protein-bound drug (~90%) that is rapidly absorbed in the small intestine with a large Vd (21 L) and a t1/2 of ~12 h. Elimination primarily occurs through the fecal route (Byon et al. 2019). The factors impairing the elimination of the drug in this patient were the following: 1. Pre-op constipation resulting in 10 days without a bowel movement; 2. Minimal bowel function post-op; and 3. Renal failure requiring CRRT after admission to the ICU.This case illustrates the profound effect intestinal obstruction/dysfunction can have on apixaban clearance. It also highlights the importance of laboratory test interpretation when managing coagulopathic patients. TPE is an effective way to remove drugs with high protein binding affinity (Mahmoud et al. 2021). TPE significantly reduced apixaban levels in our patient allowing for hemostasis and clinical improvement. To our knowledge, there are only two case reports regarding the effect of TPE on DOACs, one for apixaban, the other rivaroxaban (Hodulik et al. 2019).Conclusion:TPE can be considered as an option for rapid clearance of apixaban, or other highly protein bound anti-Xa inhibitors, in the setting of delayed elimination or when specific reversal agents are not safe/available. DisclosuresNo relevant conflicts of interest to declare.

The association of prothrombin complex concentrates with postoperative outcomes in cardiac surgery: an observational substudy of the FIBRES randomized controlled trial

PurposeThe mainstay of therapy for coagulation factor deficiency in cardiac surgical patients is frozen plasma (FP); however, prothrombin complex concentrates (PCCs) may offer logistical and safety advantages. As there is limited comparative evidence, we conducted this study to explore the association of comparable PCC or FP doses with transfusion and outcomes.MethodsThis was a post hoc analysis of a multicentre randomized trial comparing fibrinogen concentrate with cryoprecipitate (FIBRES trial) in bleeding cardiac surgical patients. This analysis included 415 patients who received only PCC (n = 72; 17%) or only FP (n = 343; 83%) for factor replacement. The main outcomes of interest were red blood cell (RBC) and platelet transfusion within 24 hr of cardiopulmonary bypass. Secondary outcomes included postoperative adverse events. Associations were examined by hierarchical generalized estimating equation models adjusted for demographic and surgical characteristics.ResultsThe median [interquartile range (IQR)] PCC dose was 1,000 [1,000–2,000] units, while the median [IQR] FP dose was 4 [2–6] units. Each unit of FP was independently associated with increased adjusted odds of RBC (1.60; 95% confidence interval [CI], 1.36 to 1.87; P < 0.01) and platelet transfusion (1.40; 95% CI, 1.15 to 1.69; P < 0.01) while each 500 units of PCC was independently associated with reduced adjusted odds of RBC (0.67; 95% CI, 0.50 to 0.90; P < 0.01) and platelet transfusion (0.80; 95% CI, 0.70 to 0.92; P < 0.01). Adverse event rates were comparable.ConclusionsIn cardiac surgical patients with post-cardiopulmonary bypass bleeding, PCC use was associated with lower RBC and platelet transfusion than FP use was. Prospective, randomized clinical trials comparing FP with PCC in this setting are warranted.

This Month in Anesthesiology

This Month in Anesthesiology

Comparison of 3 Different Prothrombin Complex Concentrate Regimens for Emergent Warfarin Reversal: PCCWaR Study.

The ideal dose and specific prothrombin complex concentrate (PCC) for warfarin reversal is unknown. To evaluate the reduction in international normalized ratio (INR) of 3 different PCC dosing regimens: fixed-dose activated 4-factor PCC (aPCC), fixed-dose 4-factor PCC (4PCC), and standard-dose 4PCC. This was a multicenter retrospective cohort review. Patients >18 years of age who received PCC for warfarin reversal between January 1, 2017, and December 31, 2017, were screened for inclusion. Patients were excluded if they did not receive the correct PCC dosing regimen, received PCC for nonwarfarin bleeding, had a baseline INR less than 2, or received a massive transfusion protocol. Two institutions utilized aPCC dosed at 500 IU for INR <5 and 1000 IU for INR ≥5. Two institutions utilized fixed-dose 4PCC at 1500 to 2000 units depending on patient factors. Two institutions utilized 4PCC package insert dosing. The primary outcome was achievement of post-PCC target INR ≤1.4. Secondary outcomes included percentage change in INR, lowest 24-hour INR, and mortality. A total of 154 patients were included (fixed-dose aPCC: n = 29; fixed-dose 4PCC: n = 53; standard-dose 4PCC: n = 72). There was no statistical difference between groups in achieving the primary outcome (58.6% vs 69.8% vs 79.2%, respectively; P = 0.103) or any secondary outcomes. There was no difference in the ability to achieve a post-PCC INR of ≤1.4 between 3 different PCC regimens for warfarin reversal. Additional research is warranted to determine the ideal dose and PCC agent for warfarin reversal.

Thromboembolic Complications After Receipt of Prothrombin Complex Concentrate.

Purpose: Patients presenting with life-threatening bleeding associated with oral anticoagulants (OACs) are challenging with few available treatments. Prothrombin complex concentrate (PCC) is an option for OAC reversal in the setting of life-threatening bleeding with a relatively benign safety profile. Little is known about the risk of developing thromboembolic complications (TEC) in patients receiving PCC who were previously anticoagulated. The aim of this study is to characterize the rate of TEC after receipt of PCC. Methods: All adult patients who received 4-Factor PCC for life-threatening bleeding were retrospectively evaluated over a 2-year time period. Data collected included anticoagulant and indication, bleeding source, PCC dose, INR, and TEC within 14 days of PCC dose, including venous thromboembolism (VTE), acute myocardial infarction, and ischemic stroke. Results: Three hundred thirty-three patients received 383 PCC doses. Of these, 55 (16.5%) patients developed TEC, including VTE, ischemic stroke, and acute myocardial infarction. There was increased rivaroxaban use in patients who developed TEC (25.4% vs 12.2%; P = .011). Additionally, there were more patients who had anticoagulation for a previous TEC in those who developed a new TEC (38.2% vs 23.4%; P = .022). Lastly, there was a higher rate of TEC in those who received >1 dose of PCC (21.8% vs 7.9%; P = .002). Conclusion: PCC administration in the setting of life-threatening bleeding is not benign. Risk of TEC increases in patients who have rivaroxaban reversal, receive a repeat dose of PCC, and have a TEC indication for their anticoagulation and these factors should be further investigated.

304 Comparative Thromboembolic Risk of 3-Factor Versus 4-Factor Prothrombin Complex Concentrate for Emergent Warfarin Reversal

Prothrombin complex concentrates (PCCs) rapidly reverse anticoagulant-associated coagulopathy; however, thromboembolic complications (TECs) are a known risk. Studies designed to evaluate thromboembolic risk between 3-factor and 4-factor PCC have not been performed. The purpose of this study was to evaluate the risk of TEC between 3-factor and 4-factor PCC for warfarin reversal. This single center, multi-campus, retrospective cohort study included adult patients on warfarin who received at least one dose of 3-factor or 4-factor PCC for emergent warfarin reversal from December 1, 2011 to September 30, 2018. Hemophiliacs, pregnancy, incarcerated, and concomitant administration of recombinant FVIIa were excluded. The primary outcome was comparison of early TECs between 3-factor and 4-factor PCC for emergent warfarin reversal. Early TEC was defined as an acute deep venous thrombosis, pulmonary embolism, myocardial infarction, transient ischemic attack, or stroke within 14 days of PCC. Statistical analysis was performed with Fisher’s exact test and Student’s t-test as appropriate. Two-hundred and fifty patients were included with 125 patients in each group. Median age was 68 (IQR 59,80) years. Patients were most often anticoagulated for atrial fibrillation in both 4-factor and 3-factor PCC groups (70% vs 59%, p=0.11). The most common indication for reversal in both groups was intracerebral hemorrhage (50% vs 62%, p=0.098). TECs occurred in 26 patients (10.4%), with a median time to TEC of 6.5 (IQR 2,9.75) vs 4 (IQR 1.5,7.25) days (p=0.3). There was no difference in the rate of early TEC with 4-factor compared to 3-factor PCC (11.2% vs 9.6%, p=0.84). Arterial TECs trended towards being more common with 4-factor PCC (57.1% vs 16.7%, p=0.051). Risk factors for TECs present in >50% of the total TEC population included cardiovascular disease (88%) and concomitant administration of blood and/or reversal agents (81%). Of the 100 patients started on venous thromboembolism (VTE) prophylaxis, there was a trend towards delay of VTE prophylaxis initiation in patients who developed TECs (3.65 vs 2.70 days; 95% CI -0.39 to 2.29, p=0.16). In the 82 patients who had anticoagulation re-initiated, there was significant delay in time to re-initiation in patients experiencing TECs (9.07 vs 3.98 days; 95% CI 2.89 to 7.69, p<0.01). Patients had a lower median INR after receiving 4-factor PCC (1.4 vs 1.5 p<0.001) and greater frequency of achieving an INR <1.4 (45.2% vs 27.3%, p<0.01). Mean hospital length of stay trended towards being longer with 4-factor PCC (10.28 vs 8.96 days, p=0.23), while overall mortality was lower compared to 3-factor PCC (15.2% vs 26.4%, p=0.043). There was no difference in the early TEC rate between 3-factor and 4-factor PCC when administered for emergent warfarin reversal; however, this may be the first study to identify a trend towards greater risk of arterial thrombus with 4-factor PCC. It is prudent to assess patient-specific risk factors for development of TECs prior to warfarin reversal. Additionally, early re-initiation of anticoagulation may decrease the risk of TECs. The risk-benefit of anticoagulation re-initiation must be considered in all patients, especially those at risk for development of an arterial TEC.

Prothrombin Complex Concentrate-induced Disseminated Intravascular Coagulation Can Be Prevented by Coadministering Antithrombin in a Porcine Trauma Model.

The risk of thromboembolic complications with prothrombin complex concentrates (PCCs) appears low when used for reversal of vitamin K antagonists but might be different in other indications (e.g., trauma). A difference in risk could arise from the plasma ratio of pro- versus anticoagulant proteins. This study used a porcine trauma model to investigate combined treatment with PCC and antithrombin. The hypothesis was that antithrombin can modulate prothrombotic effects and prevent adverse events of PCC. Nine treatment groups (n = 7 per group) were included: control (placebo), PCC (50 IU/kg), PCC plus antithrombin (three groups, with antithrombin doses of 12.5, 25, or 50 IU/kg), fibrinogen concentrate (100 mg/kg) plus PCC, fibrinogen concentrate plus PCC plus antithrombin dose of 50 IU/kg, tranexamic acid (15 mg/kg) plus fibrinogen concentrate plus PCC, and tranexamic acid plus fibrinogen concentrate plus PCC plus antithrombin dose of 50 IU/kg. In each group, bilateral femur fractures and thorax contusion were followed 60 min later by blunt liver injury. Study treatment was then administered, and animals were subsequently observed for 210 min. Total blood loss (mean ± SD) was statistically significantly lower in all three PCC plus antithrombin groups (PCC plus antithrombin dose of 50 IU/kg, 672 ± 63 ml; PCC plus antithrombin dose of 25 IU/kg, 535 ± 72 ml; and PCC plus antithrombin dose of 12.5 IU/kg, 538 ± 50 ml) than in the PCC group (907 ± 132 ml), which in turn had statistically significantly reduced bleeding versus the control group (1,671 ± 409 ml). Signs of disseminated intravascular coagulation were apparent with PCC monotherapy, and early deaths occurred with fibrinogen concentrate plus PCC, attributable to pulmonary emboli. Antithrombin was protective against both of these effects: signs of disseminated intravascular coagulation were absent from the PCC plus antithrombin groups, and there were no early deaths in the group with fibrinogen concentrate plus PCC plus antithrombin dose of 50 IU/kg. According to this trauma model, 50 IU/kg PCC increases the risk of disseminated intravascular coagulation and other thromboembolic complications, most notably when coadministered with fibrinogen concentrate. The addition of antithrombin appears to reduce this risk.

Three-factor prothrombin complex concentrates for refractory bleeding after cardiovascular surgery within an algorithmic approach to haemostasis.

Prothrombin complex concentrates (PCC) are increasingly administered off-label in the United States to treat bleeding in cardiovascular surgical patients and carry the potential risk for acquired thromboembolic side-effects after surgery. Therefore, we hypothesized that the use of low-dose 3-factor (3F) PCC (20-30IU/kg), as part of a transfusion algorithm, reduces bleeding without increasing postoperative thrombotic/thromboembolic complications. After IRB approval, we retrospectively analysed 114 consecutive, complex cardiovascular surgical patients (age>18years), between February 2014 and June 2015, that received low-dose 3F-PCC (Profilnine® ), of which seven patients met established exclusion criteria. PCC was dosed according to an institutional perioperative algorithm. Allogeneic transfusions were recorded before and after PCC administration (n=107). The incidence of postoperative thromboembolic events was determined within 30days of surgery, and Factor II levels were measured in a subset of patients (n=20) as a quality control measure to avoid excessive PCC dosing. Total allogeneic blood product transfusion reached a mean of 12·4±9·9 units before PCC and 5·0±6·3 units after PCC administration (P<0·001). The mean PCC dose was 15·8±7·1IU/kg. Four patients (3·8%) each experienced an ischaemic stroke on postoperative day 1, 2, 4 and 27. Seven patients (6·5%) had acquired venous thromboembolic disease within 10 days of surgery. Median factor II level after transfusion algorithm adherence and PCC administration was 87%. 3F-PCC use for refractory bleeding after cardiovascular surgery resulted in reduced transfusion of allogeneic blood and blood products. Adherence to this algorithmic approach was associated with an acceptable incidence of postoperative thrombotic/thromboembolic complications.

The use of new procoagulants in blunt and penetrating trauma

Uncontrolled bleeding in trauma secondary to a combination of surgical bleeding and trauma-induced complex coagulopathy is a leading cause of death. Prothrombin complex concentrates (PCCs), recombinant activated factor seven (rFVIIa) and recombinant human prothrombin act as procoagulants by increasing thrombin generation and fibrinogen concentrate aids stable clot formation. This review summarizes current evidence for procoagulant use in the management of bleeding in trauma, and data and evidence gaps for routine clinical use. Retrospective and prospective studies of PCCs (±fibrinogen concentrate) have demonstrated a decreased time to correction of trauma coagulopathy and decreased red cell transfusion with no obvious effect on mortality or thromboembolic outcomes. PCCs in a porcine model of dilutional coagulopathy demonstrated a sustained increase in thrombin generation, unlike recombinant human prothrombin which showed a transient increase and has been studied only in animals. In other retrospective studies, there is a suggestion that lower doses of PCCs may be effective in the setting of acquired coagulopathy. There is increasing evidence that early correction of coagulopathy has survival benefits, and the use of procoagulants as first-line therapy has the potential benefit of rapid access and timely treatment. This requires confirmation in prospective studies.

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.

Contemporary Reversal of Oral Anticoagulation in Intracerebral Hemorrhage.

Author(s): Bower, Matthew M; Sweidan, Alexander J; Shafie, Mohammad; Atallah, Steven; Groysman, Leonid I; Yu, Wengui

Efficacy and Safety of Prothrombin Complex Concentrate in Patients Treated with Rivaroxaban or Apixaban Compared to Warfarin Presenting with Major Bleeding

IntroductionBleeding is the major complication of anticoagulant therapy. Reversal of vitamin K antagonists (VKAs) in patients with major bleeding events (MBE) including intracranial haemorrhage (ICH) is achieved with prothrombin complex concentrate (PCC) and intravenous vitamin K. Administration of PCC or activated PCC is approved UK strategy for treating MBE associated with rivaroxaban or apixaban, pending approval of a specific reversal agent. In all cases there is concern regarding the incidence of thrombotic events.MethodsIn this respective review, the efficacy and safety of 4-factor PCCs for the management of MBE in 344 patients receiving rivaroxaban, apixaban or warfarin were compared from January 2016 to April 2018.All patients had full blood count, coagulation screen (INR for VKA) and biochemistry profile at presentation and prior to receiving PCC. Patients on rivaroxaban or apixaban had samples taken for drug level but did not wait for the results to administer PCC. Concomitant antiplatelet or nonsteroidal anti-inflammatory drugs, length of stay, thromboembolic events, re-bleeding at the same site and 30-day mortality were documented from medical records.ResultsTable 1: Baseline characteristics of the 344 patientsOverall median (range) dose of PCC was 2000 units of Factor IX (500-5000). As expected, AF was more frequently the indication for apixaban and rivaroxaban (36/40, 90% and 29/40, 72.5%) than it was for warfarin (165/264, 62.5%). Patients with metallic heart valves or left ventricular thrombus received only warfarin. ICH was the most common indication for PCC in all three anticoagulant groups (137/344, 39.8%) followed by gastrointestinal bleeding (93/344, 27%). ICH was more frequently the indication for PCC in patients receiving rivaroxaban (25/40, 62.5%) and apixaban (21/40, 52.5%) compared to warfarin (91/264, 34.5%), p=0.003. Patients on warfarin more frequently received PCC for musculoskeletal bleeding (12.9%) compared to those on rivaroxaban (5%) and apixaban (5%), p=0.003. There were no differences in the other bleeding sites based on type of anticoagulant.No differences were observed in hemoglobin, platelet count and fibrinogen in patients based on type of anticoagulant or site of bleeding. Median (range) rivaroxaban and apixaban levels at time of receiving PCC were 230ng/ml (47-759) and 159ng/ml (45-255) respectively. Median INR pre- and post-PCC in patients on warfarin were 3.4 (1.9-15.4) and 1.2 (1.0-1.9) respectively. A significantly higher proportion of patients on apixaban (17/40, 42.5%) or rivaroxaban (14/40, 35%) received tranexamic acid compared to warfarin (51/264, 19.2%), p=0.001. Vitamin K was given to 227/264, 86% of patients on warfarin with median dose 5mg (range 1mg-10mg). There was no difference in number of red cell units, platelet or FFP used in the three anticoagulant groups. Overall 30-day mortality rate was 24.7% (85/344) and did not differ according to type of anticoagulant (p=0.17). Recurrent bleeding occurred in 18% overall, warfarin 15.8%, rivaroxaban 20% and apixaban 30.8%, p=0. 07. Recurrent thrombosis occurred in 4.1% (14/344) patients within 30 days of receiving PCC with no difference in three anticoagulant groups, p=0.83 (warfarin 4.2%, rivaroxaban 5.1% and apixaban 2.5%). Nearly half of the patients (48.1%), restarted anticoagulation in a median 13.5 days (6-44). Anticoagulation was restarted in a significantly higher proportion of patients on warfarin (138/264, 52.3%) compared to (10/40, 25%) on rivaroxaban and (13/40, 32.5%) on apixaban, p=0.001.In patients with ICH there were no differences in age or sex between groups. There were no differences in concomitant use of antiplatelet treatment, recurrent bleeding (overall 17.8%, warfarin 17.8%, rivaroxaban 20% and apixaban 15%, p=0.90) or 30-day mortality (overall 30-day mortality was 35%; warfarin 31.9%, rivaroxaban 44% and apixaban 38.1%, p=0.50). None of the patients with ICH on rivaroxaban or apixaban had thrombotic events and only 2/91 (2.2%) patients on warfarin had ischemic strokes within 30 days post PCC. Overall 30.6% of patients with ICH restarted anticoagulation with a median 15 days (10-42).In conclusion, there was no difference in the safety (thrombosis) and efficacy (30-day mortality and re-bleeding) in use of PCC to treat MBE in patients on warfarin, rivaroxaban and apixaban. Some differences may reflect indications for anticoagulation. [Display omitted] DisclosuresJayakody Arachchillage:Octapharma: Other: Sponsored to attend an educational meeting; Mitsubishi Phama: Other: Sponsored to attend an educational meeting; Bayer: Other: Sponsored to attend educational meetings. Laffan:Roche: Consultancy, Speakers Bureau; Pfizer: Honoraria.

Prothrombin Complex Concentrate Is Safe and Effective for Achieving Hemostasis in the Setting of Urgent Surgery for Patients Treated with Direct Xa Inhibitors

Introduction: Patients treated with direct Xa inhibitors may require an urgent surgery. A reversal agent for Xa inhibitors was recently approved for major bleeding but not prior to urgent surgery. Administration of prothrombin complex concentrate (PCC) in this setting is a common practice; however, it is based on limited experience in healthy volunteers.Objective: To characterize the population receiving PCC for apixaban/rivaroxaban reversal prior to an urgent surgery/procecdure and evaluate its efficacy and safety.Methods: A retrospective study in two tertiary hospitals. Bleeding was evaluated by surgical reports, hemoglobin drop and use of packed red blood cells or additional PCC during 48h. Safety measures were thrombotic complications and 30-day mortality.Results: Sixty-two patients, aged 80.7±9, received PCC prior to urgent invasive procedures ;39 (63%) received apixaban and 23( 37%) rivaroxaban. Ninety percent of them received anticoagulation due to atrial fibrillation. Most urgent procedures were abdominal surgery (61%), orthopedic surgery (13%) or transhepatic cholecystostomy insertion (10%). Mean dose of PCC was 26.6±8 U/kg. Fourteen patients (23%) received 1 gram of tranexamic acid. Bleeding was reported by surgeons in 3(5%) patients and no patient required additional PCC. Sixteen (26%) patients received packed cells (median 1 unit, range 1-5). Thirty day mortality and thrombosis were 13(21%) and 2(3%) respectively. Cause of death was related to the primary disease or sepsis. No patient died due to bleeding/thrombosis.Conclusions: PCC is safe and effective for the reversal of Xa inhibitors prior to an urgent surgery/procedure. DisclosuresNo relevant conflicts of interest to declare.