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.

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.

Effect of low- versus high-dose 4-factor prothrombin complex concentrate in factor Xa inhibitor-associated bleeding: A qualitative systematic review.

PURPOSE: The purpose of this review is to evaluate current literature on the treatment of factor Xa inhibitor-associated bleeds with 4-factor prothrombin complex concentrate (4F-PCC), with a focus on the effect of low versus high dosing of 4F-PCC on hemostatic efficacy and safety outcomes. SUMMARY: A search of PubMed and EBSCOhost was performed to identify studies evaluating patients with a factor Xa inhibitor-bleed treated with 4F-PCC at either low or high doses. Studies of patients receiving alternative reversal agents such as fresh frozen plasma and andexanet alfa or where no comparator group was evaluated were excluded from the analysis. To assess the effect of these 4F-PCC dosing strategies, the primary outcome of interest was hemostatic efficacy. Four studies meeting inclusion criteria were included in this review. In each of the included studies, similar rates of hemostatic efficacy, hospital mortality, and venous thromboembolism were observed in the low- and high-dose cohorts. CONCLUSION: These results suggest low- and high-dose 4F-PCC may confer similar clinical effectiveness and safety; however, these findings should be evaluated and confirmed with future prospective studies.

Fitusiran prophylaxis in people with hemophilia A or B who switched from prior BPA/CFC prophylaxis: the ATLAS-PPX trial.

ABSTRACT: Fitusiran, a subcutaneous investigational small interfering RNA therapeutic, targets antithrombin to rebalance hemostasis in people with hemophilia A or B (PwHA/B), irrespective of inhibitor status. This phase 3, open-label study evaluated the efficacy and safety of fitusiran prophylaxis in males aged ≥12 years with hemophilia A or B, with or without inhibitors, who received prior bypassing agent (BPA)/clotting factor concentrate (CFC) prophylaxis. Participants continued their prior BPA/CFC prophylaxis for 6 months before switching to once-monthly 80 mg fitusiran prophylaxis for 7 months (onset and efficacy periods). Primary end point was annualized bleeding rate (ABR) in the BPA/CFC prophylaxis and fitusiran efficacy period. Secondary end points included spontaneous ABR (AsBR) and joint ABR (AjBR). Safety and tolerability were assessed. Of 80 enrolled participants, 65 (inhibitor, n = 19; noninhibitor, n = 46) were eligible for ABR analyses. Observed median ABRs were 6.5 (interquartile range [IQR], 2.2-19.6)/4.4 (IQR, 2.2-8.7) with BPA/CFC prophylaxis vs 0.0 (IQR, 0.0-0.0)/0.0 (IQR, 0.0-2.7) in the corresponding fitusiran efficacy period. Estimated mean ABRs were substantially reduced with fitusiran by 79.7% (P = .0021) and 46.4% (P = .0598) vs BPA/CFC prophylaxis, respectively. Forty-one participants (63.1%) experienced 0 treated bleeds with fitusiran vs 11 (16.9%) with BPAs/CFCs. Median AsBR and AjBR were both 2.2 with BPA/CFC prophylaxis and 0.0 in the fitusiran efficacy period. Two participants (3.0%) experienced suspected or confirmed thromboembolic events with fitusiran. Once-monthly fitusiran prophylaxis significantly reduced bleeding events vs BPA/CFC prophylaxis in PwHA/B, with or without inhibitors, and reported adverse events were generally consistent with previously identified risks of fitusiran. This trial was registered at www.ClinicalTrials.gov as #NCT03549871.

Efficacy and Safety of Early Administration of 4-Factor Prothrombin Complex Concentrate in Patients With Trauma at Risk of Massive Transfusion: The PROCOAG Randomized Clinical Trial.

Importance: Optimal transfusion strategies in traumatic hemorrhage are unknown. Reports suggest a beneficial effect of 4-factor prothrombin complex concentrate (4F-PCC) on blood product consumption. Objective: To investigate the efficacy and safety of 4F-PCC administration in patients at risk of massive transfusion. Design, Setting, and Participants: Double-blind, randomized, placebo-controlled superiority trial in 12 French designated level I trauma centers from December 29, 2017, to August 31, 2021, involving consecutive patients with trauma at risk of massive transfusion. Follow-up was completed on August 31, 2021. Interventions: Intravenous administration of 1 mL/kg of 4F-PCC (25 IU of factor IX/kg) vs 1 mL/kg of saline solution (placebo). Patients, investigators, and data analysts were blinded to treatment assignment. All patients received early ratio-based transfusion (packed red blood cells:fresh frozen plasma ratio of 1:1 to 2:1) and were treated according to European traumatic hemorrhage guidelines. Main Outcomes and Measures: The primary outcome was 24-hour all blood product consumption (efficacy); arterial or venous thromboembolic events were a secondary outcome (safety). Results: Of 4313 patients with the highest trauma level activation, 350 were eligible for emergency inclusion, 327 were randomized, and 324 were analyzed (164 in the 4F-PCC group and 160 in the placebo group). The median (IQR) age of participants was 39 (27-56) years, Injury Severity Score was 36 (26-50 [major trauma]), and admission blood lactate level was 4.6 (2.8-7.4) mmol/L; prehospital arterial systolic blood pressure was less than 90 mm Hg in 179 of 324 patients (59%), 233 patients (73%) were men, and 226 (69%) required expedient hemorrhage control. There was no statistically or clinically significant between-group difference in median (IQR) total 24-hour blood product consumption (12 [5-19] U in the 4F-PCC group vs 11 [6-19] U in the placebo group; absolute difference, 0.2 U [95% CI, -2.99 to 3.33]; P = .72). In the 4F-PCC group, 56 patients (35%) presented with at least 1 thromboembolic event vs 37 patients (24%) in the placebo group (absolute difference, 11% [95% CI, 1%-21%]; relative risk, 1.48 [95% CI, 1.04-2.10]; P = .03). Conclusions and Relevance: Among patients with trauma at risk of massive transfusion, there was no significant reduction of 24-hour blood product consumption after administration of 4F-PCC, but thromboembolic events were more common. These findings do not support systematic use of 4F-PCC in patients at risk of massive transfusion. Trial Registration: ClinicalTrials.gov Identifier: NCT03218722.

Avaliação do perfil clínico-terapêutico e da resposta à profilaxia dos portadores de hemofilia A e B em um centro de referência no Ceará / Evaluation of the clinical-therapeutic profile and the response to prophylaxis of patients with hemophilia A and B in a reference center in Ceará

Objetivo: Avaliar o perfil clínico-terapêutico e a resposta à profilaxia em pacientes hemofílicos A e B em um centro de referência no Ceará. Métodos: Estudo de coorte retrospectivo, com dados de 133 hemofílicos A e B, em profilaxia entre 2016 e 2021, por meio de prontuários médicos e sistema Web Coagulopatias. Resultados: Os pacientes todos do sexo masculino em sua maioria foram hemofílicos A (93,2%), na forma grave, residentes em Fortaleza, com maior prevalência do município de Guaiúba. A maioria fazia uso de Fator VIII recombinante e em profilaxia secundária, em relação ao comprometimento articular a maioria não apresentou relato de hemartroses (66,9%), articulação-alvo (87,9%) ou artropatia (54,9%), porém os hemofílicos em profilaxia terciária apresentaram um maior comprometimento articular em relação a profilaxia primária e secundária. Verificou-se uma correlação negativa entre o tempo de profilaxia e a dose de fator utilizada, demonstrando que quanto maior o tempo de profilaxia menor a dose do fator utilizada. Um total de 13 hemofílicos A grave desenvolveram inibidor de fator VIII realizando imunotolerância (ITI) com sucesso total em 84,6%. Por meio da curva ROC, foi verificado uma associação entre a necessidade de ITI e a dose de fator de coagulação, com acurácia de 67,7% de que o uso de doses maiores de fator predispõe ao desenvolvimento de inibidores. Conclusão: Os dados do estudo permitem inferir que quanto mais precoce o tratamento de profilaxia menor é comprometimento articular, dose do fator utilizada e menor predisposição de desenvolver inibidores dos fatores da coagulação.

Objective: to evaluate the clinical-therapeutic profile and response to prophylaxis in hemophiliac A and B patients at a referral center in Ceará. Methods: Retrospective cohort study, with data from 133 hemophiliacs A and B, undergoing prophylaxis between 2016 and 2021, using medical records and the Web Coagulopathies system. Results: Most of the patients were male patients with severe hemophilia A (93.2%), residing in Fortaleza, with a higher prevalence in the city of Guaiúba. Most made use of recombinant Factor VIII and in secondary prophylaxis, in relation to joint involvement, the majority did not report hemarthroses (66.9%), target joint (87.9%) or arthropathy (54.9%). however, hemophiliacs on tertiary prophylaxis showed greater joint impairment in relation to primary and secondary prophylaxis. There was a negative correlation between the prophylaxis time and the factor dose used, demonstrating that the longer the prophylaxis time, the lower the factor dose used. A total of 13 severe A hemophiliacs developed factor VIII inhibitor performing immunotolerance (ITI) with total success in 84.6%. Using the ROC curve, an association was verified between the need for ITI and the dose of coagulation factor, with an accuracy of 67.7% that the use of higher doses of factor predisposes to the development of inhibitors. Conclusion: The study data allow us to infer that the earlier the prophylaxis treatment, the less joint impairment, the dose of the factor used and the less predisposition to develop coagulation factor inhibitors.

Fixed Versus Variable Dosing of Prothrombin Complex Concentrate for Bleeding Complications of Vitamin K Antagonists-The PROPER3 Randomized Clinical Trial.

STUDY OBJECTIVE: To determine if a fixed dose of 1000 IU of 4-factor prothrombin complex concentrate (4F-PCC) is as effective as traditional variable dosing based on body weight and international normalized ratio (INR) for reversal of vitamin K antagonist (VKA) anticoagulation. METHODS: In this open-label, multicenter, randomized clinical trial, patients with nonintracranial bleeds requiring VKA reversal with 4F-PCC were allocated to either a 1,000-IU fixed dose of 4F-PCC or the variable dose. The primary outcome was the proportion of patients with effective hemostasis according to the International Society of Thrombosis and Haemostasis definition. The design was noninferiority with a lower 95% confidence interval of no more than -6%. When estimating sample size, we assumed that fixed dosing would be 4% superior. RESULTS: From October 2015 until January 2020, 199 of 310 intended patients were included before study termination due to decreasing enrollment rates. Of the 199 patients, 159 were allowed in the per-protocol analysis. Effective hemostasis was achieved in 87.3% (n=69 of 79) in fixed compared to 89.9% (n=71 of 79) in the variable dosing cohort (risk difference 2.5%, 95% confidence interval -13.3 to 7.9%, P=.27). Median door-to-needle times were 109 minutes (range 16 to 796) in fixed and 142 (17 to 1076) for the variable dose (P=.027). INR less than 2.0 at 60 minutes after 4F-PCC infusion was reached in 91.2% versus 91.7% (P=1.0). CONCLUSION: The large majority of patients had good clinical outcome after 4F-PCC use; however, noninferiority of the fixed dose could not be demonstrated because the design assumed the fixed dose would be 4% superior. Door-to-needle time was shortened with the fixed dose, and INR reduction was similar in both dosing regimens.

Indirect antiplatelet effects of rivaroxaban in a patient with intracranial hemorrhage: An underappreciated coagulopathy of factor Xa inhibitors?

Rivaroxaban is a direct oral anticoagulant (DOAC) used for prophylaxis and treatment of many prothrombotic states. The anticoagulation effects of rivaroxaban are produced by selectively binding and inhibiting factor Xa, causing delayed thrombin generation. Additionally, the delay in thrombin generation produces an indirect, dose dependent antiplatelet effect via reduction in tissue factor platelet aggregation. As with any anticoagulant, rivaroxaban use increases a patient's risk for major and minor hemorrhagic events. With mortality rates reported as high as 25% for those who experience an intracranial hemorrhage (ICH), immediate mitigation of hematoma and hemorrhage volume expansion is imperative. Management strategies include utilizing prothrombin complex concentrates (PCC) and factor Xa inhibitor specific antidotes, such as coagulation factor Xa recombinant, inactivated-zhzo. Routine monitoring or management of DOAC induced antiplatelet effects is ill-defined and not a part of routine standard of care. We report the first case, to our knowledge, of rivaroxaban's indirect antiplatelet effects identified by platelet function assays and managed with four-factor PCC and desmopressin in a patient experiencing an ICH. Further exploration is needed to determine the true clinical impact attributed to rivaroxaban's antiplatelet effects.

In silico evaluation of limited sampling strategies for individualized dosing of extended half-life factor IX concentrates in hemophilia B patients.

PURPOSE: Hemophilia B is a bleeding disorder, caused by a factor IX (FIX) deficiency. Recently, FIX concentrates with extended half-life (EHL) have become available. Prophylactic dosing of EHL-FIX concentrates can be optimized by assessment of individual pharmacokinetic (PK) parameters. To determine these parameters, limited sampling strategies (LSSs) may be applied. The study aims to establish adequate LSSs for estimating individual PK parameters of EHL-FIX concentrates using in silico evaluation. METHODS: Monte Carlo simulations were performed to obtain FIX activity versus time profiles using published population PK models for N9-GP (Refixia), rFIXFc (Alprolix), and rIX-FP (Idelvion). Fourteen LSSs, containing three or four samples taken within 8 days after administration, were formulated. Bayesian analysis was applied to obtain estimates for clearance (CL), half-life (t1/2), time to 1% (Time1%), and calculated weekly dose (Dose1%). Bias and precision of these estimates were assessed to determine which LSS was adequate. RESULTS: For all PK parameters of N9-GP, rFIXFc and rIX-FP bias was generally acceptable (range: -5% to 5%). For N9-GP, precision of all parameters for all LSSs was acceptable (< 25%). For rFIXFc, precision was acceptable for CL and Time1%, except for t1/2 (range: 27.1% to 44.7%) and Dose1% (range: 12% to 29.4%). For rIX-FP, all LSSs showed acceptable bias and precision, except for Dose1% using LSS with the last sample taken on day 3 (LSS 6 and 10). CONCLUSION: Best performing LSSs were LSS with samples taken at days 1, 5, 7, and 8 (N9-GP and rFIXFc) and at days 1, 4, 6, and 8 (rIX-FP), respectively.

Fixed-dose prothrombin complex concentrate for emergent warfarin reversal among patients with intracranial hemorrhage.

INTRODUCTION: Four-factor prothrombin complex concentrate (4PCC) is the preferred reversal agent for warfarin reversal, although the ideal dose is unknown. Fixed-dose 4PCC offers simplified dosing compared to standard-dosing algorithms with potentially lower risks of thromboembolic complications given lower doses are typically utilized. METHODS: Retrospective, observational, multicentered, pre- post- study of patients who received 4PCC for warfarin reversal among four hospitals within the same regional health system. Standard-dose patients received variable doses ranging from 25 to 50 units/kg based on total body weight and initial INR and fixed-dose patients received 2000 units. The primary outcome was achievement of a target INR ≤ 1.4 on the first post-4PCC INR result. RESULTS: After exclusions, 48 and 42 patients were analyzed in the standard-dose and fixed-dose groups, respectively. There was no difference in the ability to achieve a target INR of ≤1.4 (82.6% vs 81.5%, p = 0.14). Both groups received the same median dose of 2000 units, although fixed-dose patients actually received a higher weight-based dose than standard-dose patients (27 units/kg vs 24.5 units/kg). CONCLUSION: A fixed-dose 4PCC regimen of 2000 units among patients with ICH was as effective as standard-dose 4PCC for INR reversal among patients with ICH. However, fixed-doses of 2000 units at times exceeded standard 4PCC doses which may be contradictory to the goals of fixed-dose 4PCC for warfarin reversal.

Safety and efficacy of a strategy of vitamin K antagonist reversal with prothrombin complex concentrates compared to vitamin K in patients with hip fracture.

Background: Increased preoperative delay in patients with hip fractures may be responsible for increased morbidity and mortality. We hypothesized that a strategy of reversal of vitamin K antagonist (VKA) by prothrombin complexes concentrates (PCCs), as compared to vitamin K, is safe and reduces preoperative delay and hospital length of stay (LOS). Methods: In this pilot study, we reviewed the records of patients admitted to a university-affiliated hospital for hip fracture between Jan. 1, 2012, and Dec. 31, 2016, who were taking VKA. Patients were stratified according to reversal strategy (vitamin K v. PCC). Adverse effects, time to surgery, LOS and mortality were collected from the electronic medical record and were compared between the 2 study groups and a control group not treated with VKA. Results: A total of 141 patients were included in the study: 65 in the vitamin K group, 26 in the PCC group and 50 in the control group. The median preoperative delay in the PCC group (20 h [interquartile range (IQR)] 13-25 h]) and the control group (20 h [IQR 15-33 h]) was lower than that in the vitamin K group (45 h [IQR 31-52 h]) (p < 0.001). Patients in the PCC group had a shorter median hospital LOS than those in the vitamin K group (6 d [IQR 4-9 d] v. 8 d [IQR 6-11 d], p < 0.05). No difference was observed in the proportion of patients who received a red blood cell transfusion, or had thrombotic or hemorrhagic complications. No difference in mortality at 12 months was observed between the groups. Conclusion: In patients with hip fracture, the use of PCCs as compared to vitamin K to reverse the effect of VKA significantly reduced preoperative delay and hospital LOS, and was not associated with an increase in the rates of thrombotic or hemorrhagic complications. Prospective studies involving a greater number of patients are required to confirm these promising results.

Contexte: L'allongement du délai préopératoire chez les patients atteints d'une fracture de la hanche pourrait expliquer l'augmentation de la morbidité et de la mortalité. Selon notre hypothèse, une stratégie d'inversion des antagonistes de la vitamine K (AVK) au moyen de concentrés de complexes prothrombiques (CCP), plutôt que de vitamine K, est sécuritaire et réduit le délai préopératoire et la durée du séjour hospitalier. Méthodes: Pendant cette étude pilote, nous avons passé en revue les dossiers de patients sous AVK admis dans un centre universitaire pour fracture de la hanche entre le 1er janvier 2012 et le 31 décembre 2016. Les patients ont été stratifiés selon la stratégie d'inversion choisie (vitamine K c. CCP). Les effets indésirables, le délai préopératoire, la durée du séjour hospitalier et la mortalité ont été recueillis à partir des dossiers médicaux électroniques et ont été comparés entre les 2 groupes de l'étude et un groupe témoin non sous AVK. Résultats: En tout, 141 patients ont été inclus dans l'étude, 65 dans le groupe sous vitamine K, 26 dans le groupe sous CCP et 50 dans le groupe témoin. Le délai préopératoire médian pour le groupe sous CCP (20 h [éventail interquartile (ÉIQ)] 13­25 h]) et le groupe témoin (20 h [ÉIQ 15­33 h]) a été plus bref que pour le groupe sous vitamine K (45 h [ÉIQ 31­52 h]) (p < 0,001). Les patients du groupe sous CCP ont eu un séjour hospitalier médian plus bref que les patients du groupe sous vitamine K (6 j [ÉIQ 4­9 j] c. 8 j [ÉIQ 6­11 j]) (p < 0,05). Aucune différence n'a été observée quant à la proportion de patients ayant reçu une transfusion de culot globulaire ou ayant manifesté des complications thrombotiques ou hémorragiques. Aucune différence quant à la mortalité à 12 mois n'a été observée entre les groupes. Conclusion: Chez les patients atteints d'une fracture de la hanche, l'utilisation des CCP plutôt que de la vitamine K pour inverser l'effet des AVK a significativement abrégé le délai préopératoire et la durée du séjour hospitalier, et n'a pas été associée à une augmentation des taux de complications thrombotiques ou hémorragiques. Des études prospectives sur un plus grand nombre de patients sont nécessaires pour confirmer ces résultats prometteurs.

Fixed- versus variable-dose prothrombin complex concentrate protocol for vitamin K antagonist reversal.

Fixed-dose prothrombin complex concentrates (PCCs) for the reversal of vitamin K antagonists may decrease the incidence of thromboembolic events, treatment costs, and treatment delays. However, the ideal fixed dose is unknown, with some studies showing inadequate reversal with suboptimal dosing or in patients with a higher international normalized ratio (INR) or weight. This indicates a need for a modified fixed-dose strategy that considers weight and INR. This study was a retrospective chart review comparing efficacy and safety outcomes of the standard variable-dose protocol versus a fixed-dose protocol. The primary outcome was the proportion of patients who achieved INR reversal. Of the total of 113 patients reviewed, INR reversal to < 1.5 was achieved in 23 patients (46%) in the variable-dose group versus 27 patients (43%) in the fixed-dose group (P = 0.83). Of the 27 patients with ICH, INR reversal to ≤ 1.3 was achieved in five patients (71%) in the variable dose group versus ten patients (50%) in the fixed-dose group (P = 0.41). The rate of INR reversal did not differ significantly between groups, but the fixed-dose group used less PCCs and had lower treatment costs.

Evaluation of fixed versus variable dosing of 4-factor prothrombin complex concentrate for emergent warfarin reversal.

STUDY OBJECTIVE: This study compares the safety and efficacy of a fixed dose of 4-factor prothrombin complex concentrate (4FPCC) to the FDA-approved variable dosing for reversal of warfarin-induced anticoagulation. METHODS: This was a single-center, prospective, open-label, randomized controlled trial with subjects randomized to 4FPCC at a fixed dose of 1500 IU or the FDA-approved variable dosing regimen. The primary efficacy outcome (reversal success) was defined as a post-intervention international normalized ratio (INR) of less than or equal to 1.5. Given that 4FPCC is the standard of care for reversal of warfarin-induced anticoagulation an active-controlled approach was employed with the two dosing regimens compared based on efficacy, cost, and safety outcomes. RESULTS: 71 subjects (34 in the fixed dose group and 37 in the variable dose group) completed the study. There were no significant differences in age, gender, weight, initial INR, or indication for 4FPCC administration between the two treatment groups. Reversal success in the fixed-dose group was 61.8%, while in the variable dose group reversal success was 89.2%. Reversal success in the fixed-dose group was significantly lower than the rate of reversal success in the variable dose group (27.4% lower, p = 0.011). CONCLUSION: The results of this study provide evidence that fixed dosing results in lower reversal success rates as compared to variable dosing of 4FPCC for warfarin-induced anticoagulation.

Four-factor prothrombin complex concentrate in adjunct to whole blood in trauma-related hemorrhage: Does whole blood replace the need for factors?

BACKGROUND: The use of whole blood (WB) for the treatment of hemorrhagic shock and coagulopathy is increasing in civilian trauma patients. Four-factor prothrombin complex concentrate (4-PCC) in adjunct to component therapy showed improved outcomes in trauma patients. Our study aims to evaluate the outcomes of trauma patients who received 4-PCC and WB (4-PCC-WB) compared with WB alone. METHODS: We performed a 3-year (2015-2017) analysis of the American College of Surgeons-Trauma Quality Improvement Program database. All adult (age, ≥18 years) trauma patients who received WB were included. We excluded patients who were on preinjury anticoagulants. Patients were stratified into two groups, 4-PCC-WB versus WB alone, and matched in a 1:2 ratio using propensity score matching. Outcome measures were packed red blood cells, plasma, platelets, and cryoprecipitate transfused, in-hospital complications, hospital and intensive care unit (ICU) length of stay (LOS) among survivors, and mortality. RESULTS: A total of 252 patients (4-PCC-WB, 84; WB alone, 168) were matched. The mean ± SD age was 47 ± 21 years, 63% were males, median Injury Severity Score was 30 (21-40), and 87% had blunt injuries. Patients who received 4-PCC-WB had decreased requirement for packed red blood cell (8 U vs. 10 U, p = 0.04) and fresh frozen plasma (6 U vs. 8 U, p = 0.01) transfusion, lower rates of acute kidney injury (p = 0.03), and ICU LOS (5 days vs. 8 days, p = 0.01) compared with WB alone. There was no difference in the platelet transfusion (p = 0.19), cryoprecipitate transfusion (p = 0.37), hospital LOS (p = 0.72), and in-hospital mortality (p = 0.72) between the two groups. CONCLUSION: Our study demonstrates that the use of 4-PCC as an adjunct to WB is associated with a reduction in transfusion requirements and ICU LOS compared with WB alone in the resuscitation of trauma patients. Further studies are required to evaluate the role of PCC with WB in the resuscitation of trauma patients. LEVEL OF EVIDENCE: Therapeutic, level III.

Low-dose versus standard-dose four-factor prothrombin complex concentrate for factor-Xa inhibitor reversal in spontaneous and traumatic intracranial hemorrhage.

STUDY OBJECTIVES: Current neurocritical care guidelines recommend 50 IU/kg four-factor prothrombin complex concentrate (4PCC) for factor Xa inhibitor (FXaI) reversal in intracranial hemorrhage (ICH) based on few clinical studies conducted among non-ICH subjects. Two recent studies suggest that low-dose (25 IU/kg) 4PCC may be similar to 50 IU/kg in reversal of FXaI in ICH, and both 25 and 50 IU/kg doses are used in clinical practice for this indication. To our knowledge, no studies have directly compared 25 IU/kg versus 50 IU/kg 4PCC for FXaI reversal in ICH. The purpose of this study is to determine whether there is a difference in hemostatic efficacy between 25 IU/kg versus 50 IU/kg 4PCC for FXaI reversal in ICH. DESIGN: This multicenter, retrospective cohort study was performed in five hospitals in central Texas from November 2013 to December 2019. DATA SOURCE: Patients were identified with a medication use report of 4PCC and were classified in the low- or standard-dose group based on whether the 25 IU/kg or 50 IU/kg dose was received, respectively. PATIENTS: A total of 93 patients were included (25 IU/kg, n = 62; 50 IU/kg, n = 31). MEASUREMENTS AND MAIN RESULTS: There was no difference in hemostatic efficacy between groups (82.3% low dose vs. 83.9% standard dose, p = 0.846). No differences were identified in-hospital mortality, length of stay, thrombotic events, or the need for surgery or additional blood products between groups. CONCLUSION: For the reversal of FXaI in ICH, a 25 IU/kg dose may be an effective alternative to 50 IU/kg 4PCC dosing.

Four-factor Prothrombin Complex Concentrate for Reversal of Factor Xa Inhibitors versus Warfarin in Life-threatening Bleeding.

INTRODUCTION: Factor Xa (fXa) inhibitor reversal for life-threatening bleeding is controversial due to a lack of high-quality evidence. The purpose of this study was to determine the hemostatic efficacy of four-factor prothrombin complex concentrate (4F-PCC) for the reversal of fXa inhibitors compared to warfarin for life-threatening bleeding. METHODS: This was a multicenter, retrospective cohort study at two academic medical centers between January 1, 2014-December 31, 2019, which included patients who presented to the emergency department with a life-threatening bleed necessitating anticoagulation reversal with 4F-PCC. The primary endpoint was achievement of hemostatic efficacy after 4F-PCC administration. RESULTS: Of the 525 patients who had an order for 4F-PCC during the study period, 148 patients met the criteria for inclusion (n = 48 fXa inhibitor group; n = 100 warfarin group). Apixaban (52.1%) and rivaroxaban (45.8%) were the most commonly used fXa inhibitors. Effective hemostasis was similar between groups (79.2% fXa inhibitor group vs 85% warfarin group, p = 0.38). This was consistent across all types of bleeding. Thrombotic events were rare in both groups (2% vs 3%). CONCLUSION: This multicenter, retrospective cohort study demonstrated that using 4F-PCC for treatment of life-threatening bleeding produced effective hemostasis in patients on fXa inhibitors and warfarin.

Compliance with Early Long-Term Prophylaxis Guidelines for Severe Hemophilia A.

OBJECTIVES: To evaluate the applicability and compliance with guidelines for early initiation of long-term prophylaxis in infants with severe hemophilia A and to identify factors associated with guideline compliance. STUDY DESIGN: This real-world, prospective, multicenter, population-based FranceCoag study included almost all French boys with severe hemophilia A, born between 2000 and 2009 (ie, after guideline implementation). RESULTS: We included 333 boys in the study cohort. The cumulative incidence of long-term prophylaxis use was 61.2% at 3 years of age vs 9.5% in a historical cohort of 39 boys born in 1996 (ie, before guideline implementation). The guidelines were not applicable in 23.1% of patients due to an early intracranial bleeding or inhibitor development. Long-term prophylaxis was delayed in 10.8% of patients. In the multivariate analysis, 2 variables were significantly associated with "timely long-term prophylaxis" as compared with "delayed long-term prophylaxis": hemophilia treating center location in the southern regions of France (OR 23.6, 95% CI 1.9-286.7, P = .013 vs Paris area) and older age at long-term prophylaxis indication (OR 7.2 for each additional year, 95% CI 1.2-43.2, P = .031). Long-term prophylaxis anticipation was observed in 39.0% of patients. Earlier birth year (OR 0.5, 95% CI 0.3-0.8, P = .010 for birth years 2005-2009 vs 2000-2004) and age at first factor replacement (OR 1.9 for each additional year, 95% CI 1.2-3.0, P = .005) were significantly associated with "long-term prophylaxis guideline compliance" vs "long-term prophylaxis anticipation." CONCLUSIONS: This study suggests that long-term prophylaxis guidelines are associated with increased long-term prophylaxis use. However, early initiation of long-term prophylaxis remains a challenge.

Anticoagulant-related intracranial haemorrhage: time to anticoagulant reversal improving but still slower than thrombolysis for ischaemic stroke.

AIMS: This study aims to determine whether door-to-needle times (DNT) for reversal of anticoagulant-associated intracerebral haemorrhage (ICH) (1) have improved over time, (2) differ between warfarin and dabigatran and (3) are comparable to ischaemic stroke (IS) thrombolysis DNT, and (4) whether reversal is monitored. METHODS: Retrospective review of all warfarin- and dabigatran-associated ICH presenting to Christchurch Hospital over a 15-year period. DNT data from 2013-2018 were compared between warfarin-related ICH (WRICH), dabigatran-related ICH (DRICH) and IS thrombolysis. RESULTS: 172 WRICH were identified. Over time there were significant reductions in door-to-first-reversal-agent (r=-0.21, p=0.01), scan-to-first-reversal-agent (r=-0.27, p=0.001) and scan-to-prothrombin-complex-concentrate (PCC) (r=-0.33, p=0.001) times. In the 2013-2018 cohort, WRICH had significantly slower DNT, door-to-scan time and scan-to-needle time compared to DRICH and IS thrombolysis (all p<0.001). There was no statistical difference between DRICH and IS. Median DNT was 183 minutes for WRICH, 72 minutes for DRICH and 52 minutes for IS. Median time to repeat international normalised ratio was 231 minutes, and the median time to repeat thrombin clotting time was 825 minutes. CONCLUSION: Door-to-any-reversal-agent and scan-to-PCC times have improved over time, but they remain significantly longer than IS thrombolysis times. Monitoring of reversal is inadequate, particularly for WRICH receiving PCC.

Intraoperative prothrombin complex concentrate administration and outcomes in patients undergoing left ventricular assist device implantation.

Prothrombin complex concentrate (PCC) administration has increased among cardiac surgery patients in recent years; however, use in LVAD implantation/exchange is not widespread due to the fear of thrombotic complications. The purpose of this study was to compare the clinical outcomes of patients undergoing LVAD implantation/exchange with intraoperative PCC administration versus traditional transfusion practices alone. Adult LVAD implants/exchanges at our institution between 2015 and 2018 were included. Patients were categorized as receiving intraoperative PCC or no-PCC (traditional). The primary outcome was the need for allogenic transfusion and transfusion volume at 48 hours after initial intensive care unit (ICU) admission. Secondary outcomes included metrics of morbidity and mortality. A total of 160 patients (39 PCC, 121 traditional) were analyzed. In unadjusted analysis, patients in the PCC group received lower intraoperative transfusion volumes compared to the traditional group although not statistically significant (1464 mL [IQR 796, 4876] vs. 2568 mL [IQR 1292, 3606]; P value .37). In the fully adjusted analysis, patients in the PCC group had increased odds of transfusion within 48 hours of ICU admission (OR 4.06, 95% CI: 1.35-12.20; P < .01); however, there was no significant difference in transfusion volumes (P = .09). Patients receiving PCCs had higher incidence of deep vein thrombosis (10.3% vs. 0%; P  < .01) and 30-day mortality (17.9% vs. 4.1%; P < .01). LVAD pump thrombosis occurred in 2.6% versus 0.8% in the PCC and traditional groups, respectively; P = .98. Patients undergoing LVAD implantation and exchange represent a complex surgical cohort. The results of this study suggest that the intraoperative PCC use during LVAD implant/exchange was associated with reduced intraoperative transfusions. Intraoperative PCC use was, however, associated with higher odds of postoperative transfusion, although transfusion volumes were not significantly different. While the deep vein thrombosis and 30-day mortality rates were higher in the PCC group, these results are likely related to the degree of surgical and patient complexity rather than PCC use itself. Further studies are needed to assess PCC use in this surgical cohort.

Weight-Based Dosing Versus a Fixed-Dose Regimen of 4-Factor Prothrombin Complex Concentrate in Obese Patients Requiring Vitamin K Antagonist Reversal.

INTRODUCTION: Despite an increase in the use of fixed-dose protocols of 4-factor prothrombin complex concentrate (4F-PCC) for the reversal of vitamin K antagonists (VKAs), there remains a paucity of data in obese patients. In this study, we aimed to compare the proportion of patients attaining international normalized ratio (INR) goals using a weight-based dosing strategy versus a fixed-dose regimen of 4F-PCC. METHODS: This was a retrospective study conducted in patients 18 years of age or older, weighing ≥ 100 kg, who received either a weight-based dose or fixed dose of 4F-PCC (2000 units) for the reversal of VKA, and had a documented baseline and post-treatment INR. The primary outcome was the proportion of patients achieving an INR of < 2 for all indications of warfarin reversal, except in patients with intracranial hemorrhage, where the goal was an INR of < 1.5. RESULTS: A total of 44 patients met the inclusion criteria; 25 patients in the weight-based dosing group and 19 patients in the fixed-dose group. The median baseline INR was similar in both groups (weight-based dosing group 3.2 [interquartile range {IQR} 2.8-3.7] vs fixed-dose group 3.0 [IQR 2.7-4.9], p = 1). The median post-treatment INR was significantly lower in the weight-based dosing group compared to the fixed-dose group (1.3 [IQR 1.2-1.5] vs 1.6 [IQR 1.5-1.9], p < 0.01). However, there was no significant difference in the primary outcome between both groups (weight-based dosing strategy 84% vs fixed dose strategy 90%, p = 0.68). CONCLUSION: Our findings suggest that a fixed-dose regimen of 2000 units in obese patients weighing ≥ 100 kg is adequate to achieve these INR goals.