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Marcel Levi - One of the best experts on this subject based on the ideXlab platform.
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efficacy and safety of Recombinant Factor VIIa for treatment of severe bleeding a systematic review
Critical Care Medicine, 2005Co-Authors: Marcel Levi, Marjolein Peters, Harry R. BüllerAbstract:Background:Recombinant activated Factor VII (Factor VIIa) is a prohemostatic agent that can be used for patients with complicated coagulation disorders. Recombinant Factor VIIa is, however, increasingly used for several other indications, including patients with a preexistent normal coagulation syst
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effect of Recombinant Factor VIIa on melagatran induced inhibition of thrombin generation and platelet activation in healthy volunteers
Thrombosis and Haemostasis, 2004Co-Authors: Michael Wolzt, Ulf G. Eriksson, Stig L. Boström, Marcel Levi, Troy C Sarich, Maria Erikssonlepkowska, Mia Svensson, Jeffrey I Weitz, Karin WahlanderAbstract:The objectives were to investigate whether activation of the extrinsic coagulation cascade by Recombinant Factor VIIa (rFVIIa) reverses the inhibition of thrombin generation and platelet activation by melagatran, the active form of the oral direct thrombin inhibitor ximelagatran. In a single-blind, ran-domized, parallel-group study, volunteers (20 per group) received a 5-hour intravenous (iv) infusion to achieve steady-state melagatran plasma concentrations of approximately 0.5 µmol/L, with a single iv bolus of rFVIIa (90 µg/kg) or placebo at 60 minutes. Prothrombin fragment 1+2, thrombin-anti-thrombin complex, fibrinopeptide A, β -thromboglobulin, and thrombin-activatable fibrinolysis inhibitor were quantified for venous and shed blood. Activated partial thromboplastin time (APTT), prothrombin time (PT), endogenous thrombin poten-tial, thrombus precursor protein (TpP), and plasmin-α2 -antiplas-min complex concentrations were determined in venous blood. Shed blood volume was measured. Melagatran reduced markers of thrombin generation and platelet activation in shed blood and prolonged APTT. rFVIIa increased FVIIa activity, PT, and TpP in venous blood. All other parameters were unaffected. In conclusion, rFVIIa did not reverse the anticoagulant effects of high constant concentrations of melagatran. However, the potential value of higher, continuous or repeated doses of rFVIIa or its use with lower melagatran concentrations has not been excluded.
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Recombinant Factor VIIa reverses the anticoagulant effect of the long-acting pentasaccharide idraparinux in healthy volunteers.
British journal of haematology, 2004Co-Authors: Nick R. Bijsterveld, Roel Vink, Benien E. Van Aken, Hein Fennema, Ron J.g. Peters, Joost C. M. Meijers, Harry R. Büller, Marcel LeviAbstract:Summary We investigated whether the anticoagulant effect of idraparinux, a selective long-acting Factor Xa inhibitor, could be neutralized by Recombinant Factor VIIa (rFVIIa) in healthy male volunteers. We performed a randomized, placebo-controlled trial, comparing idraparinux [7·5 mg subcutaneous (s.c.)] followed at 3 h by rFVIIa [90 μg/kg intravenous (i.v.)] (n = 6), or idraparinux (7·5 mg s.c) followed after 1 week by rFVIIa (90 μg/kg i.v.)(n = 6). rFVIIa, given 3 h after idraparinux, significantly reversed the increased thrombin generation time (TGT), the increased activated partial thromboplastin time (aPTT) and prothrombin time (PT), and the reduced prothrombin fragment 1+2 (F1+2) levels caused by idraparinux, although no clear effect of rFVIIa on the endogenous thrombin potential (ETP) was observed. One week after idraparinux, injection of rFVIIa resulted in a similar relative reduction of the remaining increased aPTT, PT and TGT, with correction to pre-idraparinux values. A clear increase of F1+2 was observed, together with a small increase in ETP. We conclude that rFVIIa has significant effects on the idraparinux-inhibited thrombin generation and clotting parameters. These results suggest that rFVIIa may be useful in serious bleeding complications in idraparinux treated patients.
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superactive analogs of Factor VIIa superglue for bleeding patients
Blood, 2003Co-Authors: Marcel LeviAbstract:Recombinant Factor VIIa was introduced in clinical medicine 20 years ago and has been shown to be a highly effective prohemostatic agent. Primarily, Recombinant Factor VIIa was used in patients with congenital or acquired hemophilia and inhibiting antibodies toward Factor VIII or IX, for which it
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effect of Recombinant activated Factor vii on perioperative blood loss in patients undergoing retropubic prostatectomy a double blind placebo controlled randomised trial
The Lancet, 2003Co-Authors: Philip W Friederich, Harry R. Büller, Christiaan P Henny, Embert J Messelink, Mark G Geerdink, Tymen T Keller, K H Kurth, Marcel LeviAbstract:Summary Background Recombinant activated Factor VII (Factor VIIa) has prohaemostatic effects in bleeding patients with coagulation abnormalities. We aimed to test the hypothesis that Recombinant Factor VIIa could reduce perioperative blood loss in patients with normal coagulation systems. Therefore, we assessed safety and efficacy of this drug in patients undergoing retropubic prostatectomy, which is often associated with major blood loss and need for transfusion. Methods In a double-blind, randomised placebo-controlled trial, we recorded blood loss and transfusion requirements in 36 patients undergoing retropubic prostatectomy, who were randomised to receive an intravenous bolus of Recombinant Factor VIIa (20 μg/kg or 40 μg/kg) or placebo in the early operative phase. Findings Median perioperative blood loss was 1235 mL (IQR 1025–1407) and 1089 mL (928–1320) in groups given Recombinant Factor VIIa 20 μkg and 40 μg/kg, respectively, compared with 2688 mL (1707–3565) in the placebo group (p=0·001). Seven of twelve placebo-treated patients were transfused, whereas no patients who received 40 μkg Recombinant Factor VIIa needed transfusion. The odds ratio for receiving any blood product in patients treated with Recombinant Factor VIIa compared with control patients was 0 (95% CI 0·00–0·33) No adverse events arose. Interpretation An injection of Recombinant Factor VIIa can reduce perioperative blood loss and eliminate the need for transfusion in patients undergoing major surgery.
Harry R. Büller - One of the best experts on this subject based on the ideXlab platform.
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efficacy and safety of Recombinant Factor VIIa for treatment of severe bleeding a systematic review
Critical Care Medicine, 2005Co-Authors: Marcel Levi, Marjolein Peters, Harry R. BüllerAbstract:Background:Recombinant activated Factor VII (Factor VIIa) is a prohemostatic agent that can be used for patients with complicated coagulation disorders. Recombinant Factor VIIa is, however, increasingly used for several other indications, including patients with a preexistent normal coagulation syst
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Recombinant Factor VIIa reverses the anticoagulant effect of the long-acting pentasaccharide idraparinux in healthy volunteers.
British journal of haematology, 2004Co-Authors: Nick R. Bijsterveld, Roel Vink, Benien E. Van Aken, Hein Fennema, Ron J.g. Peters, Joost C. M. Meijers, Harry R. Büller, Marcel LeviAbstract:Summary We investigated whether the anticoagulant effect of idraparinux, a selective long-acting Factor Xa inhibitor, could be neutralized by Recombinant Factor VIIa (rFVIIa) in healthy male volunteers. We performed a randomized, placebo-controlled trial, comparing idraparinux [7·5 mg subcutaneous (s.c.)] followed at 3 h by rFVIIa [90 μg/kg intravenous (i.v.)] (n = 6), or idraparinux (7·5 mg s.c) followed after 1 week by rFVIIa (90 μg/kg i.v.)(n = 6). rFVIIa, given 3 h after idraparinux, significantly reversed the increased thrombin generation time (TGT), the increased activated partial thromboplastin time (aPTT) and prothrombin time (PT), and the reduced prothrombin fragment 1+2 (F1+2) levels caused by idraparinux, although no clear effect of rFVIIa on the endogenous thrombin potential (ETP) was observed. One week after idraparinux, injection of rFVIIa resulted in a similar relative reduction of the remaining increased aPTT, PT and TGT, with correction to pre-idraparinux values. A clear increase of F1+2 was observed, together with a small increase in ETP. We conclude that rFVIIa has significant effects on the idraparinux-inhibited thrombin generation and clotting parameters. These results suggest that rFVIIa may be useful in serious bleeding complications in idraparinux treated patients.
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effect of Recombinant activated Factor vii on perioperative blood loss in patients undergoing retropubic prostatectomy a double blind placebo controlled randomised trial
The Lancet, 2003Co-Authors: Philip W Friederich, Harry R. Büller, Christiaan P Henny, Embert J Messelink, Mark G Geerdink, Tymen T Keller, K H Kurth, Marcel LeviAbstract:Summary Background Recombinant activated Factor VII (Factor VIIa) has prohaemostatic effects in bleeding patients with coagulation abnormalities. We aimed to test the hypothesis that Recombinant Factor VIIa could reduce perioperative blood loss in patients with normal coagulation systems. Therefore, we assessed safety and efficacy of this drug in patients undergoing retropubic prostatectomy, which is often associated with major blood loss and need for transfusion. Methods In a double-blind, randomised placebo-controlled trial, we recorded blood loss and transfusion requirements in 36 patients undergoing retropubic prostatectomy, who were randomised to receive an intravenous bolus of Recombinant Factor VIIa (20 μg/kg or 40 μg/kg) or placebo in the early operative phase. Findings Median perioperative blood loss was 1235 mL (IQR 1025–1407) and 1089 mL (928–1320) in groups given Recombinant Factor VIIa 20 μkg and 40 μg/kg, respectively, compared with 2688 mL (1707–3565) in the placebo group (p=0·001). Seven of twelve placebo-treated patients were transfused, whereas no patients who received 40 μkg Recombinant Factor VIIa needed transfusion. The odds ratio for receiving any blood product in patients treated with Recombinant Factor VIIa compared with control patients was 0 (95% CI 0·00–0·33) No adverse events arose. Interpretation An injection of Recombinant Factor VIIa can reduce perioperative blood loss and eliminate the need for transfusion in patients undergoing major surgery.
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ability of Recombinant Factor VIIa to reverse the anticoagulant effect of the pentasaccharide fondaparinux in healthy volunteers
Circulation, 2002Co-Authors: Nick R. Bijsterveld, Benien E. Van Aken, Hein Fennema, Ron J.g. Peters, Joost C. M. Meijers, Harry R. Büller, Arno H.m Moons, Matthijs S Boekholdt, Marcel LeviAbstract:Background— The novel anticoagulant fondaparinux proved to be effective and safe in the postoperative prevention of venous thrombosis. Current phase III trials with this synthetic selective Factor Xa inhibitor focus on its use in the treatment of patients with venous and arterial thrombosis. As with any anticoagulant therapy, there is a risk of bleeding complications; hence, a strategy to reverse the effects of fondaparinux is desirable. The aim of this study was to investigate whether Recombinant Factor VIIa (rFVIIa) could neutralize the anticoagulant effects of subcutaneously administered fondaparinux. Methods and Results— In a randomized, placebo-controlled design, 16 healthy male subjects received either a single subcutaneous dose of fondaparinux (10 mg) and a single intravenous bolus of rFVIIa (90 μg/kg; n=8), fondaparinux and placebo (n=4), or placebo and rFVIIa (n=4). Fondaparinux (or placebo) was administered 2 hours before rFVIIa (or placebo). Injection of rFVIIa after fondaparinux normalized the...
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ability of Recombinant Factor VIIa to generate thrombin during inhibition of tissue Factor in human subjects
Circulation, 2001Co-Authors: Philip W Friederich, Marcel Levi, Kenneth A. Bauer, S Barzegar, George P Vlasuk, William E Rote, Daan Breederveld, Tijmen Keller, Marco Spataro, Harry R. BüllerAbstract:Background—In view of the central role of the tissue Factor–Factor VIIa pathway in the initiation of blood coagulation, novel therapeutic strategies aimed at inhibiting this catalytic complex are currently being evaluated. A limitation of this new class of anticoagulants may be the lack of an appropriate strategy to reverse the effect if a bleeding event occurs. The aim of this study was to investigate the in vivo potential of Recombinant Factor VIIa (rVIIa) to induce thrombin generation in healthy subjects pretreated with Recombinant nematode anticoagulant protein c2, a specific inhibitor of the tissue Factor–Factor VIIa complex, in a double-blind randomized crossover study. Methods and Results—Administration of nematode anticoagulant protein c2 (3.5 μg/kg) caused a prolongation of the prothrombin time from 13.7±0.6 to 16.9±1.2 seconds. The subsequent injection of rVIIa (90 μg/kg) resulted in an immediate and complete correction of the prothrombin time and a marked generation of thrombin, reflected by in...
Ulla Hedner - One of the best experts on this subject based on the ideXlab platform.
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Recombinant Factor VIIa analog nn1731 v158d e296v m298q fVIIa enhances fibrin formation structure and stability in lipidated hemophilic plasma
Thrombosis Research, 2011Co-Authors: Laura D Gray, Ulla Hedner, Michael A Hussey, Brittany Larson, Kellie R Machlus, Robert A Campbell, Gary G Koch, Mirella Ezban, Alisa S WolbergAbstract:Introduction The bypassing agent Recombinant Factor VIIa (rFVIIa) is efficacious in treating bleeding in hemophilia patients with inhibitors. Efforts have focused on the rational engineering of rFVIIa variants with increased hemostatic potential. One rFVIIa analog (V158D/E296V/M298Q-FVIIa, NN1731) improves thrombin generation and clotting in purified systems, whole blood from hemophilic patients and Factor VIII-deficient mice.
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bio distribution of pharmacologically administered Recombinant Factor VIIa rfVIIa
Journal of Thrombosis and Haemostasis, 2010Co-Authors: Ramakrishnan Gopalakrishnan, Ulla Hedner, Samit Ghosh, Ramesh C Nayak, T C Allen, Usha R Pendurthi, L V M RaoAbstract:Background: Recent clinical studies suggest that the prophylactic use of Recombinant Factor VIIa (rFVIIa) markedly reduces the number of bleeding episodes in hemophilic patients with inhibitors. Given the short biological half-life of rFVIIa, it is unclear how rFVIIa could be effective in prophylactic treatment. Objectives: To examine the extravascular distribution of pharmacologically administered rFVIIa to obtain clues on how rFVIIa could work in prophylaxis. Methods: Recombinant mouse FVIIa tagged with AF488 fluorophore (AF488-FVIIa) was administered into mice via the tail vein. At different time intervals following the administration, mice were exsanguinated and various tissues were collected. The tissue sections were processed for immunohistochemistry to evaluate distribution of rFVIIa. Results: rFVIIa, immediately following the administration, associated with the endothelium lining of large blood vessels. Within 1 h, rFVIIa bound to endothelial cells was transferred to the perivascular tissue surrounding the blood vessels and thereafter diffused throughout the tissue. In the liver, rFVIIa was localized to sinusoidal capillaries and accumulated in hepatocytes. In bone, rFVIIa was accumulated in the zone of calcified cartilage and some of it was retained there for a week. The common finding of the present study is that rFVIIa in extravascular spaces was mostly localized to regions that contain TF expressing cells. Conclusions: The present study demonstrates that pharmacologically administered rFVIIa readily associates with the vascular endothelium and subsequently enters into extravascular spaces where it is likely to bind to TF and is retained for extended time periods. This may explain the prolonged pharmacological effect of rFVIIa. (Less)
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the effect of Recombinant Factor VIIa on coagulopathic pigs with grade v liver injuries
Journal of Trauma-injury Infection and Critical Care, 2002Co-Authors: Martin A Schreiber, Ulla Hedner, John B Holcomb, Susan I Brundage, Joseph M Macaitis, Keith HootsAbstract:BACKGROUND: Recombinant Factor VIIa (rFVIIa) has been used to decrease bleeding in a number of settings including hemophilia, liver transplantation, intractable bleeding, and cirrhosis. Experience in the trauma setting is limited. This study was performed to determine whether rFVIIa would reduce bleeding after a grade V liver injury in hypothermic, dilutionally coagulopathic pigs when used as an adjunct to abdominal packing and to determine whether increasing the dose of the drug increased its hemostatic efficacy. METHODS: Thirty animals were randomized to receive 180 microg/kg of rFVIIa, 720 microg/kg of rFVIIa, or vehicle buffer control. After laparotomy and splenectomy, animals underwent a 60% blood volume isovolemic exchange transfusion with 5% human albumin. The animals' temperature was maintained at 33 degrees C and a standardized grade V liver injury was made with a liver clamp. Thirty seconds after injury, the abdomen was packed with laparotomy sponges, resuscitation was initiated, and blinded therapy was given. Animals were resuscitated to their baseline mean arterial pressure and the study was continued for 2 hours. Serial coagulation parameters were measured at the temperature they were drawn. After the study period, surviving animals were killed, posttreatment blood loss was measured, and an autopsy was performed. RESULTS: Ten animals were randomized to each group. After administration of study drug, Factor VII clotting activity (FVII:C) was higher in the 720 microg/kg group than in the 180 microg/kg group (p < 0.01). FVII:C was higher in both treatment groups than in the control group (p < 0.01). The mean prothrombin time was shorter in the treatment groups than in the control group (p < 0.05). Mean arterial pressure was lower in the control group than in the treatment groups throughout the study (p < 0.01). Mean blood loss was less in the treatment groups than in the control group (p = 0.03). Mortality was not different between groups. There were no differences between the groups that received rFVIIa in any measured parameters except for FVII:C. Liver injuries were similar between groups and there was no evidence of microthrombosis on lung histology. CONCLUSION: rFVIIa reduces blood loss in hypothermic, dilutionally coagulopathic pigs with grade V injuries when used as an adjunct to packing. Increasing the dose does not enhance the hemostatic effect.
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Recombinant Factor VIIa novoseven as a hemostatic agent
Seminars in Hematology, 2001Co-Authors: Ulla HednerAbstract:Abstract Recombinant activated Factor VII (rFVIIa; NovoSeven ® , Novo Nordisk, Denmark) induces hemostasis in life- and limb-threatening bleeds and in major surgery of hemophilia A and B patients, regardless of inhibitor titer. A total of more than 6,500 patients have been treated, and NovoSeven has been administered in more than 180,000 standard doses. Experience gained from these clinical situations suggests that NovoSeven should be administered as a 90- to 110-μg/kg bolus dose every second hour. Hemophilia patients with mild to moderate bleeding episodes require two to three doses to achieve complete hemostasis, whereas patients with severe bleeding episodes may require more doses. For major surgery and in cases of life-threatening bleeding, dosing every second hour for the first 24 hours may be required. Thereafter, the same dose, but with longer intervals between doses, is recommended. Recent in vitro experiments indicate that even higher doses of NovoSeven may be needed to achieve full thrombin generation in the absence of Factor VIII (FVIII), Factor IX (FIX), and Factor XI (FXI).
Uri Seligsohn - One of the best experts on this subject based on the ideXlab platform.
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effects of Factor viii inhibitor bypassing activity feiba Recombinant Factor VIIa or both on thrombin generation in normal and haemophilia a plasma
Haemophilia, 2008Co-Authors: Tami Livnat, Ariella Zivelin, U Martinowitz, Uri SeligsohnAbstract:Factor VIII inhibitor bypass activity (FEIBA) and Recombinant Factor VIIa (rFVIIa) are the common bypassing agents for treating haemophilia A or haemophilia B patients who developed an inhibitor to Factor VIII or IX, respectively. As these preparations differ in their composition and mode of action, combined therapy, either sequential or simultaneous has recently been used for achieving haemostasis during bleeding episodes in patients who became refractory to FEIBA or rFVIIa when each was given alone. In this in vitro study, we show by a sensitive assay of thrombin generation that phospholipids present in FEIBA and other procoagulants contribute to FEIBA's activity and that exogenous phospholipids are essential for the activity of rFVIIa. We also demonstrate that the combination of FEIBA and rFVIIa has a marked synergistic effect on thrombin generation in plasma of a haemophilia A patient with a high titre of an inhibitor. It is conceivable that simultaneous administration of small doses of FEIBA and rFVIIa may be beneficial in treating haemophilia A patients, with an inhibitor to FVIII, who are resistant to conventional therapy.
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prerequisites for Recombinant Factor VIIa induced thrombin generation in plasmas deficient in Factors viii ix or xi
Journal of Thrombosis and Haemostasis, 2006Co-Authors: Tami Livnat, Ariella Zivelin, U Martinowitz, Ophira Salomon, Uri SeligsohnAbstract:Summary. Background: Recombinant Factor VIIa (rFVIIa) used for the treatment of hemophilia A or B patients with an inhibitor is hemostatically effective because it induces thrombin generation (TG), despite grossly impaired FVIII- and FIX-dependent amplification of FX activation. Tissue Factor (TF) and or activated platelets were shown to be essential for the rFVIIa activity. Objective: To evaluate the relative effects of TF and phospholipids on rFVIIa-induced TG in FVIII-, FIX- and FXI-deficient plasmas. Methods: Phospholipids had an independent effect that was augmented by TF. The contribution of blood-borne TF in FVIII-, FIX- and FXI-deficient plasma to rFVIIa-induced TG was demonstrated by removing microparticles and use of anti-TF antibodies. Results: At increasing concentrations of rFVIIa, the dependence of rFVIIa-induced TG on TF declined, but the presence of phospholipids was essential. rFVIIa was also shown to activate purified FIX and FX in the presence of phospholipids and absence of TF. rFVIIa-induced TG was dramatically augmented in FVIII- or FIX-deficient plasma in which the level of FVIII or FIX was increased to 1 or 2 U dL−1. Conclusions: The data indicate that rFVIIa-induced TG is affected by TF, phospholipids, rFVIIa concentration, and the presence of FVIII and FIX.
Raymond G Watts - One of the best experts on this subject based on the ideXlab platform.
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successful use of Recombinant Factor VIIa for emergency fasciotomy in a patient with hemophilia a and high titer inhibitor unresponsive to Factor viii inhibitor bypassing activity
American Journal of Hematology, 2005Co-Authors: Raymond G WattsAbstract:We report a patient with hemophilia A and high-titer Factor VIII inhibitor who developed compartment syndrome of his forearm following trauma. Emergency fasciotomy was performed. Initial hemostatic treatment with Factor VIII inhibitor bypassing activity (FEIBA) was unsuccessful. Bleeding was controlled with Recombinant Factor VIIa.