Prothrombin Complex Concentrate Infusion Research Articles

Thrombin generation after prothrombin complex concentrate or plasma transfusion during cardiac surgery.

Thrombin generation (TG) is reduced after cardiac surgery using cardiopulmonary bypass (CPB), contributing to coagulopathy and bleeding. Plasma transfusion or four-factor prothrombin complex concentrate (PCC) are commonly used to treat coagulopathic bleeding after CPB without knowledge of how each may restore TG. To determine the effect of PCC infusion on restoration of thrombin generation compared with plasma transfusion, we performed a laboratory-based secondary analysis of a randomized, controlled trial of adult patients undergoing cardiac surgery to assess efficacy and safety of 4F-PCC versus plasma for treatment of perioperative coagulopathic bleeding after CPB. Participants were randomized to receive either PCC (15 IU/kg) or plasma (10-15ml/kg) after separation from CPB. Participant blood samples were obtained at pre-specified serial timepoints, with laboratory assays for TG and factor levels subsequently performed. The primary outcome was change in thrombin generation (TG) parameters after each randomized treatment through postoperative day 5. Secondary outcomes included serially derived clotting factor levels. Of 100 randomized participants, 99 were included in this laboratory analysis (PCC group, N = 51; plasma group, N = 48). After treatment, participants in the PCC group compared with those in the plasma group showed higher endogenous thrombin potential (ETP, Median, Interquartile range, IQR: 688 [371-1069] vs. 1088 [550-1691] nM minutes, P = 0.01), a greater increase din ETP (P = 0.002) and peak TG (P = 0.01) in the timepoints between heparin reversal and after treatment administration. Both groups demonstrated similar values in all TG assays by postoperative day 1 (P > 0.05). The PCC group also demonstrated higher levels of proteins C, S, and Factors II, VII, IX and X, early after treatment (P < 0.001 for all comparisons). Antithrombin levels were initially higher in the plasma group after treatment (Median, IQR: 66% [61-71%] vs. 56% [51-65%], P = 0.002) but differences did not persist beyond postoperative day 3. In this laboratory analysis from a recent randomized trial in adult cardiac surgery, PCC administration restored thrombin generation more rapidly than plasma in the early postoperative period without laboratory evidence of hypercoagulability. ClinicalTrials.gov identifier: NCT02557672 [1].

Association of prothrombin complexe concentrate with venous thrombosis after cardiac surgery: a case-control study.

Prothrombin complex concentrate (PCC) enhances coagulation and controls bleeding. We aimed to assess whether perioperative infusion of PCC is associated with venous thrombosis after cardiac surgery. We conducted a case-control study of patients undergoing cardiac surgery at our hospital in 2021. Multivariate logistic regression was used to assess the correlation between perioperative PCC infusion and postoperative venous thrombosis in cardiac surgery. Stratified analysis was also performed by age, hospitalization days, and whether warfarin, warfarin combined with heparin, warfarin combined with antiplatelet drugs were used postoperatively. Data from 161 patients undergoing cardiac surgery were included in the analysis. Of these, 37 (23.0%) patients in the case group developed venous thrombosis, and 124 (77.0%) patients in the control group did not develop venous thrombosis. In the analysis without adjustment for confounders (model 1), perioperative PCC infusion significantly increased the risk of postoperative venous thrombosis (OR: 3.10, 95% CI: 1.26-7.59, P = 0.0135). In the model analysis adjusted for sex, age, and hospitalization days (model 2), perioperative PCC infusion was no longer significantly associated with the risk of postoperative venous thrombosis (OR: 1.76, 95% CI: 0.56-7.59, P = 0.3317). In the fully adjusted model (model 3), there was a marginally significant association between perioperative infusion of PCC and the risk of postoperative venous thrombosis (OR: 0.03, 95% CI: 0.00-1.23, P = 0.0637). Our findings show no significant association between perioperative PCC infusion in cardiac surgery and the development of postoperative venous thrombosis. Randomized controlled trials are needed to determine the causal relationship between perioperative PCC infusion and venous thrombosis in cardiac surgery.

Clinical outcome of patients with a vitamin K antagonist‐associated bleeding treated with prothrombin complex concentrate

Unlabelled Box BackgroundVitamin K antagonists (VKA) are used for the treatment of thromboembolism. Patients with severe VKA‐associated bleeding require immediate restoration of haemostasis. Clinical studies on the effect of prothrombin complex concentrate (PCC) are heterogeneous with respect to outcome of bleeding. ObjectiveTo evaluate the clinical outcome of patients treated with PCC for VKA‐associated bleeding. MethodsWe performed a cohort study of consecutive patients who received PCC for VKA‐related bleeding in five Dutch hospitals. Data were collected by chart review on the bleeding event, international normalized ratio (INR), haemostatic efficacy, thromboembolic (TE) complications, and mortality. The primary outcome was effective haemostasis, assessed by an adaptation of the Sarode criteria with a surrogate outcome for patients with ICH without repeat CT. ResultsOne hundred patients were included. Mean age was 74 years, 54% were male and 79% received VKA for atrial fibrillation. Most patients presented with ICH (41%) or GI bleeding (36%). Effective haemostasis was achieved in 67/98 (68%) patients using the adapted classification. Surrogate outcomes were applied for 32 patients and data for two patients was missing. Median pre‐treatment INR was 3.9 (IQR 2.9‐5.8). One hour after PCC infusion, the INR was available for 50 patients and of these, 35 (70%) had an INR ≤1.4. TE complications occurred in five patients and 22 died (60% bleeding‐related) within 30 days. ConclusionPCC achieved effective haemostasis in 68% of evaluable patients with VKA‐associated bleeding. TE complication rates were low, but mortality rates were high, due to the large number of patients with ICH.

Reversal of apixaban anticoagulation by four‐factor prothrombin complex concentrates in healthy subjects: a randomized three‐period crossover study

Background Currently, there is no approved reversal agent for direct activated factor Xa (FXa) inhibitors; however, several agents are under investigation, including prothrombin complex concentrates (PCCs). Objective This open-label, randomized, placebo-controlled, three-period crossover study assessed the effect of two four-factor PCCs on apixaban pharmacodynamics and pharmacokinetics in 15 healthy subjects. Methods Subjects received apixaban 10 mg twice daily for 3 days. On day 4, 3 h after apixaban, subjects received a 30-min infusion of 50 IU kg-1 Cofact, Beriplex P/N (Beriplex), or saline. Change in endogenous thrombin potential (ETP), measured with a thrombin generation assay (TGA), was the primary endpoint. Secondary endpoints included changes in other TGA parameters, prothrombin time (PT), International Normalized Ratio (INR), activated partial thromboplastin time, anti-FXa activity, apixaban pharmacokinetics, and safety. Results Apixaban-related changes in ETP and several other pharmacodynamic measures occurred following apixaban administration. Both PCCs reversed apixaban's effect on ETP; the differences in adjusted mean change from pre-PCC baseline to end of infusion were 425 nm min (95% confidence interval [CI] 219.8-630.7 nm min; P < 0.001) for Cofact, and 91 nm min (95% CI - 31.3 to 212.4 nm min; P > 0.05) for Beriplex. Both PCCs returned ETP to pre-apixaban baseline levels 4 h after PCC infusion, versus 45 h for placebo. For both PCCs, mean ETP peaked 21 h after PCC initiation, and then slowly decreased over the following 48 h. Both PCCs reversed apixaban's effect on TGA peak height, PT, and INR. Apixaban pharmacokinetic and anti-FXa profiles were consistent across treatments. Conclusions Cofact and Beriplex reversed apixaban's steady-state effects on several coagulation assessments.

Adverse Events Following International Normalized Ratio Reversal in Intracerebral Hemorrhage

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

Mechanistic Differences of Prothrombin Complex Concentrate and Idarucizumab in a Trauma Model Under Dabigatran Anticoagulation

Background: A proportion of trauma patients presenting with coagulopathy also receive anticoagulant therapy, which can exacerbate coagulopathy and increase bleeding. Emergency reversal of anticoagulation therapy may require therapy with specific reversal agents, as with idarucizumab for dabigatran or non-specific reversal agents, such as prothrombin complex concentrates (PCC).Methods: Using a lethal polytrauma model under dabigatran anticoagulation, we investigated the mechanism and procoagulant properties of a four-factor PCC or idarucizumab in dabigatran-anticoagulated pigs following multiple injuries. Blood markers of coagulation associated with procoagulant effects, platelet activation and hyperfibrinolysis were determined over time and related to blood loss.After ethical approval, dabigatran etexilate was given orally for 3 days and iv on day 4 to 18 pigs after anesthesia. Animals were randomized to receive idarucizumab (60 mg/kg), PCC (50 IU/kg) or saline (control), administered 15 minutes after bilateral femur fracture and blunt liver injury. Plasma dabigatran was determined using diluted thrombin time. Thrombin-antithrombin (TAT) complexes and fibrinopeptide A (FPA) were quantified using ELISA and D-Dimer with a clotting assay. Thrombin generation (ETP) in plasma was measured using Calibrated Automated Thrombogram. Platelet function was evaluated as aggregation using platelet-rich plasma in response to tissue factor, collagen, or adenosine diphosphate (ADP) agonism using light transmission aggregometry.Results: Mean dabigatran levels were 543±186 ng/ml prior to injury. Blood loss was 4056±537 mL after saline treatment (control), 1822±222 mL after PCC (P<0.0001 vs. control) and 1086±134 mL after idarucizumab (P<0.0001 vs. all). All controls developed severe coagulopathy and exsanguinated with a mean survival time of 93 min (range: 62-146 min). Post-injury and after PCC infusion, TAT, D-dimers and FPA were significantly increased vs idarucizumab and control and remained elevated over 300 minutes. Similarly thrombin generation (baseline ETP 267±84 nM*min) increased immediately after PCC administration and persisted elevated 848±114 nM*min at 120 min. In contrast, following therapy with idarucizumab ETP was restored to baseline values. Thrombin-dependent tissue factor-induced platelet aggregation was inhibited with dabigatran, partially restored with PCC and fully restored with idarucizumab. There was no effect with thrombin-independent collagen- and ADP-induced aggregation.Conclusion: Although four-factor PCC (50 IU/kg) is effective in reducing blood loss, its efficacy is less than therapy with idarucizumab (60 mg/kg). Most importantly the activation of coagulation is explained by different mechanisms. Supernormal activation of coagulation (e.g. TAT, FPA, ETP) was evident after PCC administration, whereas idarucizumab normalized ETP to baseline values. Since thrombin is a potent activator of platelets via PAR, restoration of active thrombin after PCC also partially restored aggregation. In contrast, idarucizumab binds dabigatran and forms an irreversible complex, inactivating dabigatran in plasma, thereby restoring hemostatic function. This difference may influence the choice of therapy when idarucizumab is clinically available. Disclosuresvan Ryn:Boehringer Ingelheim: Employment. Grottke:NovoNordisk: Research Funding; Portola Pharmaceuticals: Consultancy; CSL Behring: Honoraria, Research Funding; Boehringer Ingelheim: Consultancy, Honoraria, Research Funding; Biotest: Research Funding.

Restoration of Procoagulant Factor Levels after Cardiac Surgery Causes Thrombin Generation to Rise to Thrombotic Levels

IntroductionCardiac surgery with cardiopulmonary bypass (CPB) causes hemodilution and coagulation factor consumption. The administration of unfractionated heparin accelerates thrombin inactivation and leads to elevated consumption of antithrombin (AT). The heparin-mediated release of tissue factor pathway inhibitor (TFPI) from the vessel wall reduces prothrombin activation. CPB surgery thus affects both pro- and anticoagulant processes, which are reflected in changes in a patient's thrombin generation potential.In this study we investigated how cardiac surgery changes thrombin generation (TG), prothrombin conversion and thrombin inactivation. In addition, we studied the consequences of these changes in pro- and anticoagulant processes for transfusion management using in silico experimentation.MethodsThirty patients undergoing cardiac surgery with CPB were included and samples were collected before and after surgery and protamine administration. AT and prothrombin levels were determined and TG was measured at 5 pM tissue factor by calibrated automated thrombinography. Prothrombin conversion and thrombin inactivation were quantified from each TG curve.The effect of transfusion of prothrombin complex concentrate (PCC) was simulated by an in silico increase of prothrombin conversion. The effect of PCC administration in combination with AT was modeled as an increase of prothrombin conversion and antithrombin levels. The effect of in silico transfusion of PCC on coagulation was quantified by TG parameters.ResultsCPB surgery causes a reduction of plasma coagulation factor levels: AT (47%, p<0.001), prothrombin (63%, p<0.001), and decreases TG peak height by 71% (p<0.001). After surgery prothrombin conversion is significantly impaired (402 ± 218 vs 701 ± 181 nM; p<0.001), which is partly compensated for by lower thrombin inactivation (63%, p<0.001), resulting in a reduction of TG.We modeled the effect of the transfusion of prothrombin complex concentrate with or without added antithrombin on TG. If the prothrombin conversion capacity was increased to pre-surgery levels in the absence of antithrombin, TG peak height increases to 454 ± 72 nM (figure A). A slight increase of prothrombin conversion (up to 83% of the pre-surgery level) brings TG peak height into the normal range (386±61 nM), but the ETP remains elevated (3278 ± 1141 nM). The optimal way to restore thrombin generation is the simultaneous infusion of PCC and antithrombin. Our in silico experiments indicate that this restores both the peak height (362 ± 69 nM) and the ETP (1601 ± 369 nM∙min) to the pre-surgery level (figure B).ConclusionsCardiac surgery with CPB causes the hemostatic balance to shift toward bleeding due to a reduction of prothrombin conversion. This is only partially compensated by a reduction of thrombin inactivation, resulting in reduced TG after surgery.Post-surgery bleeding can be (and often is) remedied by the transfusion of PCC. However, full restoration of the prothrombin conversion capacity results in a TG profile that predicts a prothrombotic state, as an ETP value in the highest quartile is associated with a 5 times elevated thrombosis risk according to Winckers et al. Equilibrated restoration of the hemostatic capacity asks for the simultaneous supplementation of both pro- and anticoagulant factors, i.e. PCC containing AT or fresh frozen plasma. [Display omitted] DisclosuresKremers:Synapse bv: Employment. Bloemen:Synapse bv: Employment. De Laat:Synapse bv: Employment. Wagenvoord:Synapse bv: Employment. Al Dieri:Synapse bv: Employment. Hemker:Synapse bv: Employment.

In vivo reversal of the anticoagulant effect of rivaroxaban with four-factor prothrombin complex concentrate.

Four-factor prothrombin complex concentrate (PCC) 50 iu/kg is able to swiftly restore haemostatic parameters in healthy subjects on rivaroxaban. We hypothesized that lower dosages of PCC may be sufficient to restore normal haemostasis. In this double-blind, crossover, placebo-controlled study, we compared the effects of PCC 37.5 iu/kg, PCC 25 iu/kg, and placebo on thrombin generation (endogenous thrombin potential, ETP) and prothrombin time in six healthy subjects receiving twice-daily rivaroxaban 15 mg for 2.5 days. Fifteen min after infusion of PCC 37.5 iu/kg, ETP increased from 47 ± 16% to 64 ± 22% (P = 0.03; pre-rivaroxaban ETP: 92 ± 14%) and remained higher than after placebo over 24 h (P = 0.001). PCC 25 iu/kg did not modify ETP within 15 min (53 ± 11% to 59 ± 12%; P = 0.14) and was not different from placebo over 24 h (P = 0.31). ETP reached pre-rivaroxaban levels within 6 h after PCC 37.5 iu/kg infusion and within 12-24 h after PCC 25 iu/kg infusion. Both dosages restored rivaroxaban-induced prothrombin time prolongation after 15 min (P < 0.001). Placebo did not have an effect on coagulation parameters. 37.5 iu/kg of PCC leads to partial restoration of thrombin generation, whereas 25 iu/kg does not. PCC 37.5 iu/kg may be insufficient for immediate full reversal of peak therapeutic rivaroxaban levels.

Comparison between Prothrombin Complex Concentrate (PCC) and Fresh Frozen Plasma (FFP) for the Urgent Reversal of Warfarin in Patients with Mechanical Heart Valves in a Tertiary Care Cardiac Center.

Fresh frozen plasma (FFP) and prothrombin complex concentrate (PCC) reverse oral anticoagulants such as Warfarin. We compared the standard dosage of FFP and PCC in terms of efficacy and safety for patients with mechanical heart valves undergoing interventional procedures while receiving Warfarin. Fifty patients were randomized (25 for each group) with mechanical heart valves [international normalized ratio (INR) >2.5]. FFP dosage was administered based on body weight (10-15 mL/Kg), while PCC dosage was administered based on both body weight and target INR. INR measurements were obtained at different time after PCC and FFP infusion. The mean ± SD of INR pre treatment was not significantly different between the PCC and FFP groups. However, over a 48-hour period following the administration of PCC and FFP, 76% of the patients in the PCC group and only 20% of the patients in the FFP group reached the INR target. Five (20%) patients in the PCC group received an additional dose of PCC, whereas 17 (68%) patients in the FFP group received a further dose of FFP (P=0.001). There was no significant difference between the two groups in Hb and Hct before and during a 48-hour period after PCC and FFP infusion. As regards safety monitoring and adverse drug reaction screening in the FFP group, the INR was high (INR > 2.5) in 86% of the patients. There was no report of hemorrhage in both groups. PCC reverses anticoagulation both effectively and safely while having the advantage of obviating the need to extra doses.

EP News: Allied Professionals

In this phase 1 study by Zahir et al (Circulation 2014; Epub ahead of print, PMID 25403645), the investigators tested the reversal of bleeding after punch biopsy in healthy volunteers who took 60 mg of edoxaban, a factor Xa inhibitor, and 1 of 3 doses of a commercially available 4-factor prothrombin complex concentrate (PCC) or edoxaban plus placebo. The subjects were crossed over after 2 weeks and the punch biopsy repeated with edoxaban and the alternate treatment. The primary end point was bleeding duration with secondary end points of bleeding volume and various biomarkers to assess bleeding and clotting potential. Each subject was given 60 mg of edoxaban followed by an infusion of PCC (50, 25, or 10 IU/kg) over 2.25 hours and followed 60 minutes later by the 5-mm-wide/5-mm-deep punch biopsy on the back of the thigh. Bleeding duration and bleeding volume were assessed in a standardized fashion and biomarker levels drawn at specified intervals. Of note, the same investigators, in part 1 of the study presented in online supplements, determined the baseline bleeding duration and bleeding volume with punch biopsy after 60 and 180 mg edoxaban treatment in 17 healthy volunteers.

Prothrombin Complex Concentrates Compared with Frozen Plasma for Urgent Reversal of Vitamin K Antagonists: A Single Centre Retrospective Review

▪Background: Vitamin K antagonists (VKAs) are associated with a risk of major bleeding requiring urgent reversal with frozen plasma (FP) or prothrombin complex concentrates (PCC) and concurrent vitamin K administration. Several treatment guidelines currently recommend PCC over FP for urgent reversal in VKA-associated bleeding. Four-factor PCC (Octaplex®, Beriplex®) has been available in Canada since 2008 with a change in national dosing recommendations in 2012. We conducted a retrospective study to determine the efficacy and safety of PCC in comparison with FP in patients presenting with bleeding and requiring VKA reversal.Methods: We retrospectively reviewed all consecutive bleeding episodes requiring VKA reversal at Vancouver General Hospital (VGH) for 2 cohorts of patients: i) those who received FP (July 28, 2008 to July 27, 2010); and ii) those who received PCC, during two time periods (July 28, 2008 to July 27, 2010; and September 1, 2011 to December 31, 2012) during which Canadian national dosing recommendations had changed. The PCC data however were pooled as no significant differences between the early and later PCC cohorts were found. Details of VKA reversal were reviewed, including patient demographics, bleeding type, indication for VKA therapy, dose of PCC or FP, admission hematologic parameters, INR value subsequent to completion of PCC or FP infusion, time to complete infusion, transfusion requirements, vitamin K dose and route of administration, transfusion reactions, thrombotic events (within 30 days) and mortality during hospitalization. The primary outcome was the proportion of patients achieving a target INR defined as ≤1.5 following the initial order of PCC or FP. Subject characteristics were compared using two-sided t-tests for continuous and Chi-square analysis for categorical variables. Predictors of mortality were analyzed with binary logistic regression.Results: A total of 201 bleeding episodes occurred in 191 patients. PCC was used in 89 episodes (44%). The most common indication for VKA was atrial fibrillation (81%). Mean PCC dose was 1489 U (range 500-3000 U). Mean FP dose was 3.1 U (range 1-10 U). Target INR was achieved in 86% of episodes in the PCC group versus 60% with FP (p<0.001). Mean time to complete the reversal agent was 4.4 hours with PCC versus 8.7 hours with FP (p<0.001). There was no significant difference in thromboembolic events between FP and PCC with 4 thromboembolic events occurring in each treatment group: 2 strokes, 1 myocardial infarction, and 1 recurrent deep vein thrombosis occurred in the PCC cohort. No transfusion-related reactions occurred in the PCC group compared with 12.6% with FP (p<0.001). Mortality was significantly higher in the PCC group (25% vs. 11%, p=0.010); however, intracranial bleeding (ICH) was more common in the PCC group (62% vs. 31%, p<0.001) and was the only independent predictor of mortality. Vitamin K was not administered in 20% of episodes, including 17% of episodes of ICH.Conclusion: PCC is effective in the urgent reversal of VKA with faster and more complete INR reversal, significantly fewer transfusion reactions and no increase in thromboembolic events in comparison to FP. Along with vitamin K, PCC should be the agent of choice for VKA reversal in bleeding patients. DisclosuresChipperfield:Boehringer Ingelheim: Honoraria. Yenson:Octapharma Canada: Unrestricted Education Grant Other; Alexion Pharmaceuticals: Honoraria.

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Introduction: Anticoagulation with warfarin is associated with numerous adverse events and complications, the most significant being intracranial hemorrhage (ICH). Prothrombin complex concentrate (PCC) is recommended for international normalization ratio (INR) reversal, however data regarding its use following ICH is variable with regards to dosing, infusion rate, and product choice. Available evidence supports efficacy of 4-factor PCC when compared to fresh frozen plasma (FFP), yet there are no direct comparisons with 3-factor products. Methods: We conducted a retrospective chart review of all patients receiving 3-factor PCC for reversal of INR following ICH between the dates of January 1, 2012 and August 1, 2013. Patients were excluded if they received PCC for an alternate indication or did not have an available baseline and/or repeat INR following PCC administration. Results: A total of 36 patients were included, one half of which were female. On presentation, the median age was 69 years and the mean INR was 4.1 ± 1.0. Thirty-three of 36 patients (91.7%) achieved an initial goal INR (≤ 1.4) following a single PCC dose, with the mean INR after PCC infusion being 1.2 ± 0.2. The average dose of PCC given after rounding to the nearest vial size was 31 IU/kg. Median time from PCC infusion to INR was 49 minutes. Vitamin K was utilized in 34 (94.4%) patients while FFP was given to only 5 (13.9%). In those with a baseline INR greater than 4.5, there was no difference in the probability of INR reversal, with 8 of 9 patients reaching goal INR after a single dose per our protocol (p<0.99). No patient experienced a documented thrombotic event within 7 days of PCC administration. PCC was infused over a median duration of 14 minutes (198 IU/minute) without any documented infusion reactions. Conclusions: Implementation of a fixed weight-based dosing protocol for 3-factor PCC was effective at providing rapid and complete INR reversal without any adverse events. With the new FDA approval of 4-factor PCC, 3-factor PCC may offer significant cost savings with similar efficacy however direct comparisons are needed.

Prothrombin complex concentrate: Urgent anticoagulation reversal

Prothrombin complex concentrate: Urgent anticoagulation reversal

A French multicenter randomised trial comparing two dose-regimens of prothrombin complex concentrates in urgent anticoagulation reversal

IntroductionProthrombin complex concentrates (PCC) are haemostatic blood preparations indicated for urgent anticoagulation reversal, though the optimal dose for effective reversal is still under debate. The latest generation of PCCs include four coagulation factors, the so-called 4-factor PCC. The aim of this study was to compare the efficacy and safety of two doses, 25 and 40 IU/kg, of 4-factor PCC in vitamin K antagonist (VKA) associated intracranial haemorrhage.MethodsWe performed a phase III, prospective, randomised, open-label study including patients with objectively diagnosed VKA-associated intracranial haemorrhage between November 2008 and April 2011 in 22 centres in France. Patients were randomised to receive 25 or 40 IU/kg of 4-factor PCC. The primary endpoint was the international normalised ratio (INR) 10 minutes after the end of 4-factor PCC infusion. Secondary endpoints were changes in coagulation factors, global clinical outcomes and incidence of adverse events (AEs).ResultsA total of 59 patients were randomised: 29 in the 25 IU/kg and 30 in the 40 IU/kg group. Baseline demographics and clinical characteristics were comparable between the groups. The mean INR was significantly reduced to 1.2 - and ≤1.5 in all patients of both groups - 10 minutes after 4-factor PCC infusion. The INR in the 40 IU/kg group was significantly lower than in the 25 IU/kg group 10 minutes (P = 0.001), 1 hour (P = 0.001) and 3 hours (P = 0.02) after infusion. The 40 IU/kg dose was also effective in replacing coagulation factors such as PT (P = 0.038), FII (P = 0.001), FX (P <0.001), protein C (P = 0.002) and protein S (0.043), 10 minutes after infusion. However, no differences were found in haematoma volume or global clinical outcomes between the groups. Incidence of death and thrombotic events was similar between the groups.ConclusionsRapid infusion of both doses of 4-factor PCC achieved an INR of 1.5 or less in all patients with a lower INR observed in the 40 IU/kg group. No safety concerns were raised by the 40 IU/kg dose. Further trials are needed to evaluate the impact of the high dose of 4-factor PCC on functional outcomes and mortality.Trial registrationEudra CT number 2007-000602-73.

Experience on Using Prothrombin Complex Concentrate in Urgent Warfarin Reversal

We evaluated the effectiveness and safety of prothrombin complex concentrate (PCC) in urgent warfarin reversal in Iran. This is a nonrandomized, pre-post intervention study. Thirty-seven high-risk patients with prolonged international normalized ratio ([INR] >8) or with bleeding symptoms were enrolled in this study. Prothrombin complex concentrate was infused with a dose of 22.4 ± 11.2 IU/kg. The INR was measured 30 minutes postinfusion. Mean age of the participants was 63.9 ± 14.5 (22-89 years). After 30 minutes of PCC injection, INR reversed to <3.5 in 31 patients (84%) in whom 12 patients achieved INR 1.5 to 2.5, and 19 patients achieved INR 2.5 to 3.5. Bleeding symptoms were subsided during 0.5 hour after PCC infusion in patients with hemorrhagic symptoms. Not any adverse reaction was observed in patients during 3-month follow-up. Our experience in use of single injection of PCC in high-risk patients with prolonged INR or with bleeding symptoms was successful without any complication.

Reversal of Vitamin K Antagonist (VKA) effect in patients with severe bleeding: a French multicenter observational study (Optiplex) assessing the use of Prothrombin Complex Concentrate (PCC) in current clinical practice

IntroductionProthrombin Complex Concentrate (PCC) is a key treatment in the management of bleeding related to Vitamin K antagonists (VKA). This study aimed to evaluate prospectively PCC use in patients with VKA-related bleeding in view of the French guidelines published in 2008.MethodsAll consecutive patients with VKA-related bleeding treated with a 4-factor PCC (Octaplex®) were selected in 33 French hospitals. Collected data included demographics, site and severity of bleeding, modalities of PCC administration, International Normalized Ratio (INR) values before and after PCC administration, outcomes and survival rate 15 days after infusion.ResultsOf 825 patients who received PCC between August 2008 and December 2010, 646 had severe bleeding. The main haemorrhage sites were intracranial (43.7%) and abdominal (24.3%). Mean INR before PCC was 4.4 ± 1.9; INR was unavailable in 12.5% of patients. The proportions of patients who received a PCC dose according to guidelines were 15.8% in patients with initial INR 2-2.5, 41.5% in patients with INR 2.5-3, 40.8% in patients with INR 3-3.5, 26.9% in patients with INR > 3.5, and 63.5% of patients with unknown INR. Vitamin K was administered in 84.7% of patients. The infused dose of PCC did not vary with initial INR; the mean dose was 25.3 ± 9.8 IU/Kg. Rates of controlled bleeding and target INR achievement were similar, regardless of whether or not patients were receiving PCC doses as per the guidelines. No differences in INR after PCC treatment were observed, regardless of whether or not vitamin K was administered. INR was first monitored after a mean time frame of 4.5 ± 5.6 hours post PCC. The overall survival rate at 15 days after PCC infusion was 75.4% (65.1% in patients with intracranial haemorrhage). A better prognosis was observed in patients reaching the target INR.ConclusionsSevere bleeding related to VKA needs to be better managed, particularly regarding the PCC infused dose, INR monitoring and administration of vitamin K. A dose of 25 IU/kg PCC appears to be efficacious in achieving a target INR of 1.5. Further studies are required to assess whether adjusting PCC dose and/or better management of INR would improve outcomes.

Dosing of 3-Factor Prothrombin Complex Concentrate for International Normalized Ratio Reversal

Three-factor prothrombin complex concentrate (PCC) is commonly used for reversal of international normalized ratio (INR) in patients who are bleeding or require emergency surgery. However, there is little information regarding the optimal dosing strategy for achieving adequate INR reversal. To determine whether patients with higher initial INR levels are less likely to achieve adequate INR reversal after receiving 3-factor PCC. A retrospective cohort study was conducted in a tertiary care medical center in the US. Patients who received 3-factor PCC were grouped into 2 categories based on degree of INR reversal after PCC infusion: (1) adequate reversal (final INR ≤1.5) or (2) inadequate reversal (final INR >1.5). Initial INR was compared between the 2 groups using the Wilcoxon rank-sum test. A multivariate logistic regression analysis was used to adjust for confounders and determine predictors of adequate INR reversal. Fifty patients met criteria for inclusion in the final analyses. Of these, 58% achieved adequate reversal after PCC. There were no significant differences in patient demographics or in vitamin K or fresh frozen plasma (FFP) use between the 2 groups. Median PCC dose was also similar between the adequate and inadequate reversal groups (25.2 vs 24.5 units/kg, respectively; p = 0.2). The group that did not achieve adequate reversal had a significantly higher initial INR (3.5 vs 2.5, p = 0.012) prior to PCC administration. In the multivariate logistic regression analysis, initial INR was a significant predictor of adequate INR reversal (ie, reversal less likely as INR increases) after adjusting for PCC dose and concurrent use of vitamin K or FFP (OR = 0.38; 95% CI 0.17 to 0.87; p = 0.02). Patients with a higher initial INR are less likely to achieve adequate INR reversal after receiving 3-factor PCC and may require higher doses than were used in the study.

Prothrombin complex concentrate reduces blood loss and enhances thrombin generation in a pig model with blunt liver injury under severe hypothermia

Although prothrombin complex concentrate (PCC) is increasingly used for the treatment of trauma-induced coagulopathy, few studies have investigated the impact and safety of PCC for this indication. The present study was performed to assess PCC for treatment of coagulopathy after blunt liver injury under severe hypothermia. Coagulopathy in 14 anaesthetised pigs was induced by haemodilution. Subsequently, standardised blunt liver injury was induced under severe hypothermia (32.8-33.2°C). Animals were randomised to receive either PCC (35 IU kg⁻¹) or saline (control). Coagulation was assessed over the following 2 hours by thromboelastometry and thrombin generation. Internal organs were examined to determine presence of emboli. The administration of PCC showed a significant reduction in blood loss (p=0.002 vs. controls) and a significant increase in the rate of survival (p=0.022 vs. controls). Plasma thrombin generation in the PCC group increased considerably above baseline levels, with significant increases in peak thrombin levels and endogenous thrombin potential versus controls throughout the follow-up period. In addition, PT decreased significantly in the PCC group versus the control group. However, only slight improvements in thromboelastometry variables were observed. Histology showed an equal degree of liver injury in both groups, and no thromboembolism. In severely hypothermic pigs, the application of PCC corrected trauma-induced coagulopathy and reduced blood loss. Thus, the infusion of PCC might be a reasonable approach to reduce the need for blood cell transfusion in trauma. Furthermore, the impact and safety of PCC application can be monitored through thrombin generation and thromboelastometry under hypothermia.

Prothrombin Complex Concentrate Reverses the Anticoagulant Effect of Rivaroxaban In Healthy Volunteers.

AbstractAbstract 1094 Background:Rivaroxaban is a novel oral antithrombotic agent in the class of specific factor Xa inhibitors, and is licensed in Europe and Canada for the prevention of venous thromboembolism after elective orthopedic surgery. Despite its stable pharmacokinetic and pharmacodynamic profile, immediate reversal may be required in case of a major bleeding or emergency surgery. No specific antidote is currently available, although Prothrombin Complex Concentrate (PCC) seems effective in animal studies. This study is the first to investigate the ability of PCC to reverse the antithrombotic effect of Rivaroxaban in humans. Methods:In a randomized, double-blind, placebo-controlled trial, twelve healthy male subjects received Rivaroxaban 20mg twice daily for two and a half days. One group (n=6) was then randomized to receive a single bolus of 50 IU/kg PCC (Co-fact®, Sanquin, the Netherlands) while the other group (n=6) was given a similar volume of saline. Results:The prothrombin time (PT) was significantly prolonged by Rivaroxaban (15.8 sec ± 1.3 versus 12.3 ± 0.7 at baseline; p< 0.001). Immediately after the infusion of PCC, the PT normalised almost completely (12.8 ± 1.0; p< 0.001), which was sustained for 24 hours. Saline did not reverse the PT prolongation (16.2 ± 0.8; p= 0.4). Furthermore, Rivaroxaban inhibited the endogenous thrombin potential (ETP) (51% ± 22, baseline 92 ± 22; p= 0.002), with normalisation after administration of PCC (114 ± 26; p< 0.001), but not after saline (41 ± 6; p= 0.2). Conclusions:This study provides the first data that Prothrombin Complex Concentrate reverses the anticoagulant effect of Rivaroxaban in humans and may serve as an antidote for the new oral factor Xa inhibitors. [Display omitted] Disclosures:Eerenberg:Sanquin Netherlands: Research Funding, make available of Prothrombin Complex Concentrate for this study. Kamphuisen:Sanquin Netherlands: Research Funding, make available of Prothrombin Complex Concentrate for this study. Levi:Sanquin Netherlands: Research Funding, make available of Prothrombin Complex Concentrate for this study.

Impact of infusion speed on the safety and effectiveness of prothrombin complex concentrate

Prothrombin complex concentrate (PCC) infusion is preferred for emergency reversal of coumarin therapy. Rapid infusion can potentially save crucial time; however, the possible impact of high infusion speed on PCC safety and effectiveness has not been delineated. In a prospective multinational clinical trial with 43 patients receiving PCC (Beriplex P/N) for emergency reversal of coumarin therapy, infusion speeds were selected by the investigators. In a two-phase statistical analysis, the influence of baseline patient variables and dose on selected infusion speed was assessed. Then, the effect of infusion speed on reduction in international normalized ratio (INR) and on thrombogenicity marker pharmacokinetics was evaluated. Infusion speed ranged widely from 2.0 to 40.0 mL min(-1) with a median of 7.5 mL min(-1). Selection of infusion speed was not significantly influenced by gender, age, body mass index, presence of acute bleeding, indication for coumarin therapy, baseline INR, or PCC dose. Infusion speed was higher by a median of 2.2 mL min(-1) (95% confidence interval, 1.0-4.3 mL min(-1)) among patients receiving Beriplex P/N volumes > or =80 mL compared with smaller infusion volumes. Infusion speed did not affect INR attained 30 min following PCC infusion. None of the evaluated thrombogenicity marker pharmacokinetic parameters was affected by infusion speed. Infusions in one patient with questionable hemostatic efficacy and another with a possibly PCC-related thromboembolic event were at moderate and slow speeds, respectively. This study provides the first direct evidence that Beriplex P/N can be rapidly infused for emergency coumarin therapy reversal without altering safety or effectiveness.