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Lani Lieberman - One of the best experts on this subject based on the ideXlab platform.
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Prothrombin Complex Concentrate for major bleeding on factor xa inhibitors a prospective cohort study
Thrombosis and Haemostasis, 2018Co-Authors: Sam Schulman, Peter L Gross, Bruce Ritchie, Susan Nahirniak, Yulia Lin, Lani LiebermanAbstract:Oral factor Xa inhibitors are increasingly used for anticoagulation, but there is no approved reversal agent. Prothrombin Complex Concentrate (PCC) for the management of Xa-inhibitor-associated bleeding has been described in small case series and one cohort study. Patients on apixaban or rivaroxaban, suffering a major bleed, were treated at nine Canadian hospitals as per existing hospital protocol with a fixed dose of PCC 2,000 units and subsequently recruited for a 30-day follow-up. The treating physician evaluated the haemostatic effectiveness as observed during the first day as good, moderate or poor/none, using an assessment guide. Safety outcomes were thromboembolism or death. We recruited 66 patients with major bleeding who were treated with PCC and who were receiving rivaroxaban (56%) or apixaban (44%). The effectiveness was assessed as good in 65% (95% confidence interval [CI], 53-77), moderate in 20% (95% CI, 10-30) and poor/none in 15% (95% CI, 6-24). For the 36 patients with intracranial haemorrhage, the corresponding ratings were 67, 17 and 17%, and for 16 patients with gastrointestinal bleeding they were 69, 12 and 19%, respectively. There were nine deaths (14%) by 30 days, and five (8%) major thromboembolic events. In a post hoc analysis, according to International Society on Thrombosis and Haemostasis criteria, reversal was effective in 68% and ineffective in 32%. For major bleeding associated with oral Xa inhibitors, PCC may have a beneficial effect. The risk of thromboembolism after reversal of anticoagulation in patients with a prothrombotic background has to be taken into account.
Gerhard Dickneite - One of the best experts on this subject based on the ideXlab platform.
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effective reversal of edoxaban associated bleeding with four factor Prothrombin Complex Concentrate in a rabbit model of acute hemorrhage
Anesthesiology, 2015Co-Authors: Eva Herzog, Franz Kaspereit, Wilfried Krege, Baerbel Doerr, Jochen Muellercohrs, Ingo Pragst, Yoshiyuki Morishima, Gerhard DickneiteAbstract:BACKGROUND Edoxaban is an oral, selective direct factor Xa inhibitor approved in Japan for venous thromboembolism prevention after orthopedic surgery. Data are lacking regarding reversal strategies for edoxaban; this study assessed whether four-factor Prothrombin Complex Concentrate (Beriplex/Kcentra; CSL Behring GmbH, Marburg, Germany) can effectively reverse its effects on hemostasis using a previously described rabbit model. METHODS The study comprised assessments of thrombin generation in vitro, pharmacokinetic parameters, and edoxaban reversal in vivo. In a blinded in vivo stage, a standardized kidney incision was performed in animals (n = 11 per group) randomized to receive vehicle + saline, edoxaban (1,200 μg/kg) + saline, or edoxaban (1,200 μg/kg) + four-factor Prothrombin Complex Concentrate (50 IU/kg). Animals were monitored for treatment impact on hemostasis and coagulation parameters. Data are median (range). Statistical tests were adjusted for multiple testing. RESULTS Edoxaban administration increased blood loss (30 [2 to 44] ml) and time to hemostasis (23 [8.5 to 30.0] min) compared with the control group (3 [1 to 8] ml and 3 [2.0 to 5.0] min, respectively). Biomarkers of coagulation (Prothrombin time, activated partial thromboplastin time, whole blood clotting time) and thrombin generation parameters (e.g., peak thrombin, endogenous thrombin potential, lag time) were also affected by edoxaban. Administration of four-factor Prothrombin Complex Concentrate significantly reduced time to hemostasis (to 8 [6.5 to 14.0] min, observed P < 0.0001) and total blood loss (to 9 [4 to 22] ml, observed P = 0.0050) compared with the edoxaban + saline group. Of the biomarkers tested, Prothrombin time, whole blood clotting time, and endogenous thrombin potential correlated best with clinical parameters. CONCLUSION In a rabbit model of hemostasis, four-factor Prothrombin Complex Concentrate administration significantly decreased edoxaban-associated hemorrhage.
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Prothrombin Complex Concentrate vs fresh frozen plasma for reversal of dilutional coagulopathy in a porcine trauma model
BJA: British Journal of Anaesthesia, 2009Co-Authors: Gerhard Dickneite, Ingo PragstAbstract:Background Fluid resuscitation following traumatic injury causes haemodilution and can contribute to coagulopathy. Coagulation factor replacement may be necessary to prevent bleeding complications of dilutional coagulopathy. Compared with fresh frozen plasma (FFP), Prothrombin Complex Concentrate (PCC) may potentially offer a more rapid and effective means of normalizing coagulation factor levels.
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effects of Prothrombin Complex Concentrate and recombinant activated factor vii on vitamin k antagonist induced anticoagulation
Thrombosis Research, 2008Co-Authors: Kenichi A Tanaka, Gerhard Dickneite, Fania Szlam, Jerrold H LevyAbstract:Abstract Introduction Warfarin and its derivatives are widely used for prevention of thrombotic incidents. Prothrombin Complex Concentrate (PCC) and recombinant activated factor VII (rFVIIa) have been used clinically for the acute reversal of this agent but there is a paucity of data on comparative efficacies of these hemostatic interventions. Materials and methods Using in vivo rat and in vitro human models of anticoagulation, we compared PCC and rFVIIa on the recovery of endogenous thrombin generation. For in vivo reversal of anticoagulation, saline (control), PCC 50 U ml − 1 , or rFVIIa100 μg ml − 1 was given to rats which received phenprocoumon (2.5 mg kg − 1 ) orally. For in vitro model, plasma samples from warfarin-treated individuals with INR values of 2.1–6.7 were spiked with PCC (0.2, 0.4, or 0.72 U ml − 1 ) or rFVIIa (3.0 μg/ml). The treatments were evaluated using Prothrombin time (PT) and thrombin generation (Thrombinoscope™). Results Administration of phenprocoumon to rats prolonged PT (14.7 ± 0.5 to 50.43 ±0.7 s) and decreased peak thrombin generation by 89 ± 2.3%. Administration of PCC dose dependently reversed the anticoagulation effects both in warfarin-treated human plasma and in phenprocoumon-treated rats by shortening PT and increasing peak thrombin levels. However, rFVIIa only reversed PT, but had minimal effects on peak thrombin levels. Conclusion Both PCC and rFVIIa reverse warfarin anticoagulation based on PT, but only PCC restores overall thrombin generation.
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Prothrombin Complex Concentrate versus recombinant factor viia for reversal of coumarin anticoagulation
Thrombosis Research, 2007Co-Authors: Gerhard DickneiteAbstract:Abstract Introduction Prothrombin Complex Concentrate (PCC) is recommended for emergency reversal of oral coumarin anticoagulation. Recently, recombinant factor VIIa (rFVIIa) has also been investigated for this purpose, although no direct comparison of PCC and rFVIIa has been reported. This study was designed to compare the effectiveness of PCC and rFVIIa for reversal of both acute and sustained coumarin anticoagulation. Materials and methods In the acute model, rats received 2.5 mg·kg− 1 phenprocoumon, and reversal of anticoagulation by 4.88 mL·kg− 1 saline, 100 μg·kg− 1 rFVIIa (NovoSeven) or 50 U·kg− 1 PCC (Beriplex P/N) was assessed at 16 h. For the sustained model, a second phenprocoumon dose was administered at 24 h and anticoagulation reversal evaluated at 48 h. Study endpoints were activated partial thromboplastin time (aPTT), Prothrombin time (PT) and tail tip bleeding. Results Acute anticoagulation raised median PT to 4.3 fold the normal level. This elevation was nearly completely reversed both by rFVIIa and PCC. aPTT increase was minor. Effects of sustained anticoagulation were more severe and pervasive, with aPTT, PT and blood loss increasing to 7.7, 51 and 30 fold the control levels, respectively. In the sustained model, rFVIIa substantially reduced and PCC fully normalized PT. In this model, PCC also diminished aPTT (p Conclusions In a sustained anticoagulation animal model designed to simulate standard long-term oral coumarin therapy in patients, PCC was more effective than rFVIIa in restoring hemostatic function.
Belinda Lovelace - One of the best experts on this subject based on the ideXlab platform.
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real world management of oral factor xa inhibitor related bleeds with reversal or replacement agents including andexanet alfa and four factor Prothrombin Complex Concentrate a multicenter study
Future Cardiology, 2021Co-Authors: Craig I Coleman, Paul P Dobesh, Sherry Danese, Julie Ulloa, Belinda LovelaceAbstract:Aim: We describe the real-world utilization and outcomes associated with managing oral factor Xa inhibitor (FXai)-related major bleeds. Materials & methods: Electronic records from 45 US hospitals were queried (ICD-10-CM billing codes D68.32, T45.515x or T45.525x) to identify major bleed hospitalizations related to FXai use. Patient demographics, bleed type (intracranial hemorrhage, gastrointestinal, critical compartment, traumatic, other), FXai taken, reversal or replacement agents administered (including andexanet alfa, four-factor Prothrombin Complex Concentrate, fresh frozen plasma, others), in-hospital mortality and length of stay were recorded. Results: Of 3030 FXai-related hospitalizations for major bleeds, patients averaged 68 years old and 47% were women. In-hospital mortality was highest for intracranial hemorrhage (23%, n = 507) and lowest for gastrointestinal bleeds (4%, n = 1453). In-hospital mortality was lowest (4%) for bleeds managed with andexanet alfa (n = 342), compared with 10% for four-factor Prothrombin Complex Concentrate (n = 733), 11% for fresh frozen plasma (n = 925) and 8% for both other agents (n = 794) and no agents (n = 438). Median length of stay was 5 days across all agents, while ICU length of stay was shorter andexanet alfa (2 days) compared with other agents (3 days). Conclusion: In-hospital mortality differed by bleed type and agents administered. Andexanet alfa was associated with the lowest rate of in-hospital mortality across all bleed types.
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real world management of oral factor xa inhibitor bleeding related hospitalizations with andexanet alfa or 4 factor Prothrombin Complex Concentrate
Journal of the American College of Cardiology, 2020Co-Authors: Craig I Coleman, Sherry Danese, Julie Ulloa, Grace Xiao, Belinda LovelaceAbstract:Prior to US approval of andexanet, clinicians often relied on off label use of 4 factor Prothrombin Complex Concentrate (4FPCC) to manage oral factor Xa inhibitor (oFXaI) associated bleeding related hospitalizations. We describe utilization and outcomes associated with andexanet and 4FPCC for
Sam Schulman - One of the best experts on this subject based on the ideXlab platform.
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management of direct factor xa inhibitor related major bleeding with Prothrombin Complex Concentrate a meta analysis
Blood Advances, 2019Co-Authors: Siavash Piran, Sam Schulman, Rasha Khatib, Ammar Majeed, Anne Holbrook, Daniel M Witt, Wojtek Wiercioch, Holger J Schunemann, Robby NieuwlaatAbstract:A targeted antidote for reversal of direct factor Xa (FXa) inhibitors is now available for clinical use in the United States, but it is costly and has limited availability. In a systematic review, we evaluated the safety and effectiveness of 4-factor Prothrombin Complex Concentrate (4F-PCC) as an alternative for managing direct FXa inhibitor-related major bleeding. A systematic literature search was conducted using Medline, Embase, and the Cochrane Register of Controlled Trials up to September 2018. No comparative studies were found. Ten case series with 340 patients who received PCC for direct FXa inhibitor-related major bleeding were included. The pooled proportion of patients with effective management of major bleeding was 0.69 (95% confidence interval [CI], 0.61-0.76) in 2 studies using the International Society on Thrombosis and Haemostasis (ISTH) criteria and 0.77 (95% CI, 0.63-0.92) in 8 studies that did not use the ISTH criteria; all-cause mortality was 0.16 (95% CI, 0.07-0.26), and thromboembolism rate was 0.04 (95% CI, 0.01-0.08). On the basis of evidence with very low certainty from single-arm case series, it is difficult to determine whether 4F-PCC in addition to cessation of direct oral FXa inhibitor is more effective than cessation of direct oral FXa inhibitor alone in patients with direct FXa inhibitor-related major bleeding.
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Prothrombin Complex Concentrate for major bleeding on factor xa inhibitors a prospective cohort study
Thrombosis and Haemostasis, 2018Co-Authors: Sam Schulman, Peter L Gross, Bruce Ritchie, Susan Nahirniak, Yulia Lin, Lani LiebermanAbstract:Oral factor Xa inhibitors are increasingly used for anticoagulation, but there is no approved reversal agent. Prothrombin Complex Concentrate (PCC) for the management of Xa-inhibitor-associated bleeding has been described in small case series and one cohort study. Patients on apixaban or rivaroxaban, suffering a major bleed, were treated at nine Canadian hospitals as per existing hospital protocol with a fixed dose of PCC 2,000 units and subsequently recruited for a 30-day follow-up. The treating physician evaluated the haemostatic effectiveness as observed during the first day as good, moderate or poor/none, using an assessment guide. Safety outcomes were thromboembolism or death. We recruited 66 patients with major bleeding who were treated with PCC and who were receiving rivaroxaban (56%) or apixaban (44%). The effectiveness was assessed as good in 65% (95% confidence interval [CI], 53-77), moderate in 20% (95% CI, 10-30) and poor/none in 15% (95% CI, 6-24). For the 36 patients with intracranial haemorrhage, the corresponding ratings were 67, 17 and 17%, and for 16 patients with gastrointestinal bleeding they were 69, 12 and 19%, respectively. There were nine deaths (14%) by 30 days, and five (8%) major thromboembolic events. In a post hoc analysis, according to International Society on Thrombosis and Haemostasis criteria, reversal was effective in 68% and ineffective in 32%. For major bleeding associated with oral Xa inhibitors, PCC may have a beneficial effect. The risk of thromboembolism after reversal of anticoagulation in patients with a prothrombotic background has to be taken into account.
Thorsten Steiner - One of the best experts on this subject based on the ideXlab platform.
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Prothrombin Complex Concentrate versus placebo no intervention or other interventions in critically bleeding patients associated with oral anticoagulant administration a protocol for a systematic review of randomised clinical trials with meta analysis and trial sequential analysis
Systematic Reviews, 2018Co-Authors: Christian Ovesen, Jan C Purrucker, Christian Gluud, Janus Christian Jakobsen, Hanne Christensen, Thorsten SteinerAbstract:Background Acute critical bleeding is one of the most feared complications during treatment with oral anticoagulating agents. As more patients undergo treatment with anticoagulating agents, critically bleeding episodes in patients with vitamin K antagonists, thrombin inhibitor, or factor Xa inhibitor-inducted coagulopathy will be encountered frequently by physicians. Hence, an effective treatment capable of reversing the iatrogenic coagulopathy in the acute setting is needed. In randomised clinical trials and observational studies, Prothrombin Complex Concentrate has been reported to be superior to other acute interventions, and many guidelines recommend Prothrombin Complex Concentrate in treatment of critically bleeding patients. The aim of this systematic review is to synthesise the evidence of the effects of Prothrombin Complex Concentrate compared with placebo, no intervention, or other treatment options in critically bleeding patients treated with oral anticoagulants.
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Prothrombin Complex Concentrate versus placebo, no intervention, or other interventions in critically bleeding patients associated with oral anticoagulant administration: a protocol for a systematic review of randomised clinical trials with meta-analysis and trial sequential analysis
'Springer Science and Business Media LLC', 2018Co-Authors: Christian Ovesen, Jan C Purrucker, Christian Gluud, Janus Christian Jakobsen, Hanne Christensen, Thorsten SteinerAbstract:Abstract Background Acute critical bleeding is one of the most feared complications during treatment with oral anticoagulating agents. As more patients undergo treatment with anticoagulating agents, critically bleeding episodes in patients with vitamin K antagonists, thrombin inhibitor, or factor Xa inhibitor-inducted coagulopathy will be encountered frequently by physicians. Hence, an effective treatment capable of reversing the iatrogenic coagulopathy in the acute setting is needed. In randomised clinical trials and observational studies, Prothrombin Complex Concentrate has been reported to be superior to other acute interventions, and many guidelines recommend Prothrombin Complex Concentrate in treatment of critically bleeding patients. The aim of this systematic review is to synthesise the evidence of the effects of Prothrombin Complex Concentrate compared with placebo, no intervention, or other treatment options in critically bleeding patients treated with oral anticoagulants. Methods/design A comprehensive search for relevant published literature will be undertaken in Cochrane Central Register of Controlled Trials, MEDLINE, Embase, WHO International Clinical Trials Registry Platform, Science Citation Index, regulatory databases, and trial registers. We will include randomised clinical trials comparing Prothrombin Complex Concentrate versus placebo, no intervention, or other interventions in critically bleeding patients with oral anticoagulant-induced coagulopathy. Data extraction and risk of bias assessment will be handled by two independent review authors. Meta-analysis will be performed as recommended by Cochrane Handbook for Systematic Reviews of Interventions, bias will be assessed with domains, and trial sequential analysis will be conducted to control random errors. Certainty will be assessed by GRADE. Discussion As critical bleeding in patients treated with oral anticoagulants is an increasing problem, an up-to-date systematic review evaluating the benefits and harms of Prothrombin Complex Concentrate is urgently needed. It is the hope that this review will be able to guide best practice in treatment and clinical research of these critically bleeding patients. Systematic review registration PROSPERO CRD4201808437
