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Joshua R. Canter - One of the best experts on this subject based on the ideXlab platform.
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Activated Prothrombin Complex Concentrate Versus 4-Factor Prothrombin Complex Concentrate for Vitamin K-Antagonist Reversal.
Critical care medicine, 2018Co-Authors: A. Shaun Rowe, Scott K Dietrich, John W. Phillips, Kaci E. Foster, Joshua R. CanterAbstract:OBJECTIVES To compare the international normalized ratio normalization efficacy of Activated Prothrombin Complex concentrates and 4-factor Prothrombin Complex concentrates and to evaluate the thrombotic complications in patients treated with these products for warfarin-associated hemorrhage. DESIGN Retrospective, Multicenter Cohort. SETTING Large, Community, Teaching Hospital. PATIENTS Patients greater than 18 years old and received either Activated Prothrombin Complex concentrate or 4-factor Prothrombin Complex concentrate for the treatment of warfarin-associated hemorrhage. We excluded those patients who received either agent for an indication other than warfarin-associated hemorrhage, pregnant, had a baseline international normalized ratio of less than 2, received a massive transfusion as defined by hospital protocol, received plasma for treatment of warfarin-associated hemorrhage, or were treated for an acute warfarin ingestion. INTERVENTIONS Patients in the Activated Prothrombin Complex concentrate group (enrolled from one hospital) with an international normalized ratio of less than 5 received 500 IU and those with an international normalized ratio greater than 5 received 1,000 IU. Patients in the 4-factor Prothrombin Complex concentrate (enrolled from a separate hospital) group received the Food and Drug Administration approved dosing algorithm. MEASUREMENTS AND MAIN RESULTS A total of 158 patients were included in the final analysis (Activated Prothrombin Complex concentrate = 118; 4-factor Prothrombin Complex concentrate = 40). Those in the 4-factor Prothrombin Complex concentrate group had a higher pretreatment international normalized ratio (2.7 ± 1.8 vs 3.5 ± 2.9; p = 0.0164). However, the posttreatment international normalized ratio was similar between the groups. In addition, even when controlling for differences in the pretreatment international normalized ratio, there was no difference in the ability to achieve a posttreatment international normalized ratio of less than 1.4 (odds ratio, 0.753 [95% CI, 0.637-0.890]; p = 0.0009). Those in the Activated Prothrombin Complex concentrate group did have higher odds of achieving a posttreatment international normalized ratio of less than 1.2 (odds ratio, 3.23 [95% CI, 1.34-7.81]; p = 0.0088). There was only one posttreatment thrombotic complication reported. CONCLUSIONS A low, fixed dose of Activated Prothrombin Complex concentrate was as effective as standard dose 4-factor Prothrombin Complex concentrate for normalization of international normalized ratio. In addition, we did not see an increase in thrombotic events.
Joshua M Demott - One of the best experts on this subject based on the ideXlab platform.
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Reversal of Warfarin-Associated Major Hemorrhage: Activated Prothrombin Complex Concentrate versus 4-Factor Prothrombin Complex Concentrate.
Thrombosis and haemostasis, 2019Co-Authors: Gary D Peksa, Robert K Mokszycki, Megan A Rech, Brian Maynard, Nicholas G Panos, Rolla T Sweis, Joshua M DemottAbstract:Warfarin-associated major hemorrhage is frequently treated with Prothrombin Complex concentrates to correct international normalized ratio (INR). This article aims to investigate the efficacy of Activated Prothrombin Complex concentrate (aPCC) versus 4-factor Prothrombin Complex concentrate (4PCC) for vitamin K antagonist reversal in patients with warfarin-associated major hemorrhage. This was a multicenter, retrospective cohort study. Patients included were age ≥ 18 years with pretreatment INR of > 1.5. Exclusion criteria were patients treated for urgent procedures without hemorrhage, treated but not taking warfarin, unavailable INR values, and pregnant patients. Patients were stratified into two groups: aPCC or 4PCC. The primary outcome was achievement of INR ≤ 1.5 at the posttreatment INR sampling. Secondary outcomes focused on thrombotic events and mortality. Of 342 patients, 237 patients received aPCC and 105 patients received 4PCC. After 1:1 propensity score matching, 86 patients remained in each group. In the matched cohort, the proportion of patients who achieved target INR ≤ 1.5 was greater with 4PCC (aPCC = 61 [70.9%] vs. 4PCC = 76 [88.4%]; 95% confidence interval [CI] -29.2% to -5.7%) and groups had comparable in-hospital thrombotic events and mortality. In the unmatched cohort, achievement of target INR ≤ 1.5 was greater with 4PCC (aPCC = 151 [63.7%] vs. 4PCC = 92 [87.6%]; 95% CI -32.7% to -15.1%). In the treatment of warfarin-associated major hemorrhage, 4PCC compared with aPCC was associated with greater achievement of INR ≤ 1.5 with comparable thrombotic events and mortality. Further controlled studies are needed to confirm these findings and determine the optimal dosing strategy that maximizes efficacy and safety. Georg Thieme Verlag KG Stuttgart · New York.
Midori Shima - One of the best experts on this subject based on the ideXlab platform.
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tissue factor pathway inhibitor in Activated Prothrombin Complex concentrates apcc moderates the effectiveness of therapy in some severe hemophilia a patients with inhibitor
International Journal of Hematology, 2014Co-Authors: Kenichi Ogiwara, Keiji Nogami, Tomoko Matsumoto, Midori ShimaAbstract:Some hemophilia A patients who have developed inhibitors are poorly responsive to Activated Prothrombin Complex concentrates (aPCC) after daily dosage, but the mechanism(s) underlying this remain unknown. We examined two representative cases. In case 1, we found that changing to recombinant factor VIIa (rFVIIa) therapy was more effective, and the response to aPCC was restored within ~2 weeks. Tissue factor (TF)-triggered thrombin generation demonstrated a prolonged lag-time and decreased peak thrombin, and this impairment was focused on TF pathway inhibitor (TFPI). Plasma-free TFPI was elevated post-infusion of aPCC, while this was unaffected by rFVIIa. TFPI returned to normal range within 2–3 weeks. Plasmas obtained from patients with poor or good response to aPCC (aPCC-poor or aPCC-good), and good response to rFVIIa (FVIIa-good) demonstrated that free TFPI levels are increased in both aPCC groups, but not in FVIIa-good. TFPI levels pre- and post-infusion in aPCC-poor were significantly higher than those in aPCC-good. Addition of anti-TFPI antibody to the reaction samples demonstrated a greater increase of peak thrombin in aPCC-poor compared to aPCC-good, showing the higher TFPI activity in aPCC-poor. Free TFPI contained in aPCC corresponded to the increasing levels in plasma. In conclusion, TFPI in aPCC attenuated thrombin generation, and the reduced effectiveness of therapy in these circumstances appeared to be related to TFPI activity.
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Activated Prothrombin Complex concentrate apcc mediated activation of factor f viii in mixtures of fviii and apcc enhances hemostatic effectiveness
Journal of Thrombosis and Haemostasis, 2013Co-Authors: Koji Yada, Kenichi Ogiwara, Keiji Nogami, Midori ShimaAbstract:Summary Background and objectives Activated Prothrombin Complex concentrates (APCCs), utilized in bypassing therapy for hemophiliacs with inhibitor, contain factors (Fs) VII, FII, FIX and FX, and their active forms. A recent report has demonstrated that mixtures of APCC and FVIII potentiated thrombin generation, in vitro, in plasma from patients with severe hemophilia A, but the mechanism(s) involved remains unknown. Results APCC (0.05 U mL−1) increased FVIII activity ~ 4-fold within 1 min in one-stage clotting assays, followed by a return to initial levels within 10 min. This reaction was dependent on the presence of tissue factor and phospholipid. Thrombin generation produced from APCC was ~ 3.5-fold greater in the presence of FVIII than that in its absence. SDS-PAGE analysis revealed that APCC sequentially proteolyzed the heavy chain of FVIII at Arg372 and Arg740, followed by cleavage at Arg336. Proteolysis was prevented by FVIIa inhibitor, but not by hirudin, supporting the concept that APCC itself possessed the potential to activate FVIII in early coagulation phases, and that FVIIa in APCC contributed mainly to this reaction. APCC-mediated FVIII activation was unaffected by the addition of anti-FVIII inhibitor antibodies, irrespective of epitope specificity. Anti-C2 type 1 inhibitors, however, diminished the inactivation phase of the APCC reaction by inhibiting cleavage at Arg336. Conclusion Small amounts of APCC, relative to the standard concentration used for clinical purposes, could activate FVIII directly, even in the presence of anti-FVIII antibodies. Combination therapy based on mixtures of APCC and FVIII could have significant beneficial implications for the treatment of hemophilia A patients with inhibitors.
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tissue factor pathway inhibitor causes unresponsiveness to Activated Prothrombin Complex concentrates for hemophilia a patients with inhibitors
Blood, 2010Co-Authors: Kenichi Ogiwara, Keiji Nogami, Ichiro Tanaka, Katsumi Nishiya, Nobuyuki Tsujii, Midori ShimaAbstract:Abstract Abstract 3663 Bypassing agents such as Activated Prothrombin Complex concentrates (APCC, FEIBA®) and recombinant Activated factor VII (rFVIIa, NovoSeven®) are effective for most hemophiliac patients with inhibitors. While, some patients exhibit unresponsiveness to the treatment with APCC and/or rFVIIa, but their mechanisms remain unknown. We had a severe hemophilia A patient with inhibitor whose bleeding worsened despite of consecutive infusion of APCC. Switching from APCC to rFVIIa was very effective for his bleeding symptoms, and one-week cessation of bypassing agents had restored good response for APCC. Comprehensive coagulation assay such as thromboelastometry and thrombin generation test (TGT) provided us clear evidence of unresponsiveness to APCC. In particular, tissue factor (TF)-triggered TGT showed two significant features, the prolonged lag time and reduced peak thrombin level even after APCC infusion. Although FII, FVII(a), FIX, FX(a) and protein C contained in APCC were elevated in his plasmas after APCC infusion, increased amounts of these factors did not affect the parameters of TGT described above in vitro. We focused on a natural anticoagulant, tissue factor pathway inhibitor (TFPI), since the prolonged lag time in TF-triggered TGT might result from the impairment of FVII/TF-induced initial reaction of blood coagulation. In vitro experiment on the addition of TFPI to FVIII-deficient plasma with APCC showed similar inhibitory pattern in TGT. TFPI antigen levels (total and free forms) in his plasma actually increased above normal range after APCC infusion, whilst these levels unchanged after rFVIIa infusion and returned to the normal range after one-week cessation, speculating that TFPI might contributes to unresponsiveness to APCC. To confirm this, plasmas from several hemophiliac patients with APCC and/or rFVIIa infusion, including 4 patients with poor response pattern in TGT, were prepared. Among 12 pairs of plasmas (a pair; pre and post bypassing agents), each of 4 pairs were for APCC-poor response (APCC-PR), APCC-good response (APCC-GR), and rFVIIa-good response (FVIIa-GR). Free form TFPI antigen levels (normal; 15–35 ng/ml) increased after infusion in APCC-PR (pre/post; 38±4/51±3 ng/ml, p 0.05). Post-infusion levels in APCC-PR were significantly higher than those in APCC-GR (p Disclosures: Ogiwara: Baxter Hemophilia Scientific Research and Education Fund in Japan 2009: Research Funding. Nogami: Bayer Hemophilia Award Program 2009: Research Funding.
A. Shaun Rowe - One of the best experts on this subject based on the ideXlab platform.
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Activated Prothrombin Complex Concentrate Versus 4-Factor Prothrombin Complex Concentrate for Vitamin K-Antagonist Reversal.
Critical care medicine, 2018Co-Authors: A. Shaun Rowe, Scott K Dietrich, John W. Phillips, Kaci E. Foster, Joshua R. CanterAbstract:OBJECTIVES To compare the international normalized ratio normalization efficacy of Activated Prothrombin Complex concentrates and 4-factor Prothrombin Complex concentrates and to evaluate the thrombotic complications in patients treated with these products for warfarin-associated hemorrhage. DESIGN Retrospective, Multicenter Cohort. SETTING Large, Community, Teaching Hospital. PATIENTS Patients greater than 18 years old and received either Activated Prothrombin Complex concentrate or 4-factor Prothrombin Complex concentrate for the treatment of warfarin-associated hemorrhage. We excluded those patients who received either agent for an indication other than warfarin-associated hemorrhage, pregnant, had a baseline international normalized ratio of less than 2, received a massive transfusion as defined by hospital protocol, received plasma for treatment of warfarin-associated hemorrhage, or were treated for an acute warfarin ingestion. INTERVENTIONS Patients in the Activated Prothrombin Complex concentrate group (enrolled from one hospital) with an international normalized ratio of less than 5 received 500 IU and those with an international normalized ratio greater than 5 received 1,000 IU. Patients in the 4-factor Prothrombin Complex concentrate (enrolled from a separate hospital) group received the Food and Drug Administration approved dosing algorithm. MEASUREMENTS AND MAIN RESULTS A total of 158 patients were included in the final analysis (Activated Prothrombin Complex concentrate = 118; 4-factor Prothrombin Complex concentrate = 40). Those in the 4-factor Prothrombin Complex concentrate group had a higher pretreatment international normalized ratio (2.7 ± 1.8 vs 3.5 ± 2.9; p = 0.0164). However, the posttreatment international normalized ratio was similar between the groups. In addition, even when controlling for differences in the pretreatment international normalized ratio, there was no difference in the ability to achieve a posttreatment international normalized ratio of less than 1.4 (odds ratio, 0.753 [95% CI, 0.637-0.890]; p = 0.0009). Those in the Activated Prothrombin Complex concentrate group did have higher odds of achieving a posttreatment international normalized ratio of less than 1.2 (odds ratio, 3.23 [95% CI, 1.34-7.81]; p = 0.0088). There was only one posttreatment thrombotic complication reported. CONCLUSIONS A low, fixed dose of Activated Prothrombin Complex concentrate was as effective as standard dose 4-factor Prothrombin Complex concentrate for normalization of international normalized ratio. In addition, we did not see an increase in thrombotic events.
Gary D Peksa - One of the best experts on this subject based on the ideXlab platform.
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Reversal of Warfarin-Associated Major Hemorrhage: Activated Prothrombin Complex Concentrate versus 4-Factor Prothrombin Complex Concentrate.
Thrombosis and haemostasis, 2019Co-Authors: Gary D Peksa, Robert K Mokszycki, Megan A Rech, Brian Maynard, Nicholas G Panos, Rolla T Sweis, Joshua M DemottAbstract:Warfarin-associated major hemorrhage is frequently treated with Prothrombin Complex concentrates to correct international normalized ratio (INR). This article aims to investigate the efficacy of Activated Prothrombin Complex concentrate (aPCC) versus 4-factor Prothrombin Complex concentrate (4PCC) for vitamin K antagonist reversal in patients with warfarin-associated major hemorrhage. This was a multicenter, retrospective cohort study. Patients included were age ≥ 18 years with pretreatment INR of > 1.5. Exclusion criteria were patients treated for urgent procedures without hemorrhage, treated but not taking warfarin, unavailable INR values, and pregnant patients. Patients were stratified into two groups: aPCC or 4PCC. The primary outcome was achievement of INR ≤ 1.5 at the posttreatment INR sampling. Secondary outcomes focused on thrombotic events and mortality. Of 342 patients, 237 patients received aPCC and 105 patients received 4PCC. After 1:1 propensity score matching, 86 patients remained in each group. In the matched cohort, the proportion of patients who achieved target INR ≤ 1.5 was greater with 4PCC (aPCC = 61 [70.9%] vs. 4PCC = 76 [88.4%]; 95% confidence interval [CI] -29.2% to -5.7%) and groups had comparable in-hospital thrombotic events and mortality. In the unmatched cohort, achievement of target INR ≤ 1.5 was greater with 4PCC (aPCC = 151 [63.7%] vs. 4PCC = 92 [87.6%]; 95% CI -32.7% to -15.1%). In the treatment of warfarin-associated major hemorrhage, 4PCC compared with aPCC was associated with greater achievement of INR ≤ 1.5 with comparable thrombotic events and mortality. Further controlled studies are needed to confirm these findings and determine the optimal dosing strategy that maximizes efficacy and safety. Georg Thieme Verlag KG Stuttgart · New York.
