Population Pharmacokinetics of Recombinant Factor VIIa in Volunteers Anticoagulated with Acenocoumarol

1998 ◽  
Vol 80 (07) ◽  
pp. 109-113 ◽  
Author(s):  
Patrice Nony ◽  
Elisabeth Erhardtsen ◽  
Sylvie Delair ◽  
Patrick Ffrench ◽  
Marc Dechavanne ◽  
...  
Keyword(s):  
Factor Viia ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
Individual Variability ◽  
Factor Vii ◽  
Recombinant Activated Factor Vii ◽  
Activated Factor Vii ◽  
Dose Ranging ◽  
Endogenous Activity ◽  
Dose Dependent

SummaryThis study establishes a population PK model for FVII clotting activity (FVII:C) after injection of recombinant activated factor VII (rFVIIa) to healthy volunteers. Twenty eight volunteers, anticoagulated with acenocoumarol, received one or two rFVIIa injections, with dose ranging from 5 to 320 μg/kg. The FVII:C kinetic was fitted to a 2 compartment model, with continuous “endogenous perfusion” mimicking endogenous activity. Estimated clearance was 2.4 l/h (20% inter-individual variability and 9% inter-period variability). The volume of distribution at steady-state appeared to be significantly dose dependent: 78 ml/kg for doses ≤20 μg/kg and 88 ml/kg for doses >20 μg/kg respectively, with 16% inter-individual variability. The dose producing 50% of the maximum drop of INR was estimated to be 2.2 μg/kg. The model will be used to better define the dosage regimen for future clinical developments.

Continuous infusion of recombinant factor VIIa for surgery in patients with deficiency of factor VII

2005 ◽  
Vol 94 (12) ◽  
pp. 1177-1180 ◽  
Author(s):  
Geir E. Tjønnfjord ◽  
Richard Wallensten ◽  
Uri Martinowitz ◽  
Gili Kenet ◽  
Sam Schulman
Keyword(s):  
Continuous Infusion ◽  
Recombinant Factor Viia ◽  
Factor Viia ◽  
Single Case ◽  
Thromboembolic Complication ◽  
Factor Vii ◽  
Recombinant Activated Factor Vii ◽  
Activated Factor Vii ◽  
Different Types ◽  
Fvii Deficiency

SummaryThe administration of recombinant activated factor VII (rFVIIa) by continuous infusion has provided a safe and convenient alternative to bolus injections in haemophiliacs with inhibitors, but it has only been reported in a single case with congenital factorVII (FVII) deficiency. The results of 12 consecutive surgical procedures in 7 patients with congenital FVII deficiency are reported here. rFVIIa was always given in continuous infusion, aiming at plasma FVII activity of 0.5 IU/mL. Treatment was given for 2 to 7 days with a mean total dose of 7.8 mg rFVIIa. Blood loss was as expected from the different types of procedures and the only thromboembolic complication was a superficial thrombophlebitis at the infusion site. This mode of substitution was therefore safe, effective and well tolerated.

Recombinant factor VIIa

2005 ◽  
Vol 93 (06) ◽  
pp. 1027-1035 ◽  
Author(s):  
Marco Zaffanello ◽  
Dino Veneri ◽  
Massimo Franchini
Keyword(s):  
Recombinant Factor Viia ◽  
Factor Viia ◽  
Current Knowledge ◽  
Coagulation Factors ◽  
Factor Vii ◽  
Recombinant Activated Factor Vii ◽  
Activated Factor Vii ◽  
Viii And Ix ◽  
Bleeding Episodes ◽  
Uncontrolled Bleeding

SummaryRecombinant activated factor VII (rFVIIa, Novo Seven®) has been successfully used to treat bleeding episodes in patients with antibodies against coagulation factors VIII and IX. In recent years, rFVIIa has also been employed for the management of uncontrolled bleeding in a number of congenital and acquired haemos- tatic abnormalities. Based on a literature search, this review examines the current knowledge on therapy with rFVIIa, from the now well-standardized uses to the newer and less well-characterised clinical applications.

Redistribution of Recombinant Activated Factor VIIA into Platelets and Vascular Bed: Implications on Bioavailability and Hemostatic Mechanisms.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3957-3957
Author(s):  
Ana Maria Galan ◽  
Irene Lopez-Vilchez ◽  
Juan Gracia ◽  
Gines Escolar
Keyword(s):  
Flow Cytometry ◽  
Cross Sections ◽  
Factor Viia ◽  
Platelet Rich Plasma ◽  
Thrombus Formation ◽  
Factor Vii ◽  
Recombinant Activated Factor Vii ◽  
Activated Factor Vii ◽  
Perfusion Studies ◽  
Subendothelial Matrix

Abstract Background: Clinical evidence suggests that hemostatic action of recombinant activated factor VII (rFVIIa) exceeds its predicted plasma half life (around 3 hours). Mechanisms involved in the long lasting effects of rFVIIa for prophylactic treatment of patients with hemophilia and inhibitors have not been fully elucidated. Previous studies from our group have demonstrated that platelets internalize tissue factor preparations containing small amounts of FVII. We have investigated the possible redistribution of rFVIIa in different intracellular compartments focussing more specifically on platelets, endothelium and subendothelial matrix. Methods: We exposed platelet rich plasma, isolated platelets, human umbilical veins and endothelial cells in culture (HUVECs) to rFVIIa. Samples were incubated for up to 2 hours at rFVIIa concentrations from 2-60 mg/ml (normal plasma concentration: 0.5 mg/ml). Flow cytometry techniques were applied to detect surface and intracellular antigens, including FVIIa, in platelets before and after exposure to membrane permeabilizing agents. Immunocytochemical techniques were applied to detect FVIIa in cross sections of umbilical veins and confocal microscopy was used to detect FVIIa in HUVECs. In additional studies, aliquots of washed platelets previously exposed to rFVIIa were incorporated into whole blood anticoagulated with low molecular weight heparin (LMWH) and perfused through a collagen rich damaged vascular surface at a shear rate equivalent to 600/sec. Results: Flow cytometry studies revealed a significantly enhanced presence of intracellular FVIIa in platelets previously exposed to rFVIIa. Fluorescence intensity related to FVIIa was dependent on the concentration of rFVIIa used during the incubation. A more intense labeling for FVIIa was observed in the subendothelial matrix of umbilical veins exposed to rFVIIa. In perfusion studies, presence of platelets previously exposed to rFVIIa improved platelet thrombus formation and enhanced fibrin generation with respect to parallel experiments using platelets not exposed to rFVIIa. Conclusion: Our results indicate that rFVIIa can be internalized into platelets and redistributed into subendothelial compartments. Redistribution of rFVIIa into other cellular compartments may explain the prolonged prophylactic action of rFVIIa in some clinical conditions. The existence of extravascular sources of FVIIa may provide new insights into the physiological and pathological implications of FVIIa on hemostasis mechanisms.

Recombinant Factor VIIa for the Prophylaxis of Perioperative Hemorrhage in a Patient With Congenital Factor XI Deficiency Undergoing Brain Tumor Neurosurgery

2007 ◽  
Vol 14 (4) ◽  
pp. 472-475 ◽  
Author(s):  
Christoph Sucker ◽  
Michael Sabel ◽  
Walter Stummer ◽  
Rainer B. Zotz ◽  
Ruediger E. Scharf ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Factor Viia ◽  
Factor Vii ◽  
Bleeding Complications ◽  
Factor Xi ◽  
Recombinant Activated Factor Vii ◽  
Promising Alternative ◽  
Factor Xi Deficiency ◽  
Activated Factor Vii ◽  
Perioperative Hemorrhage

The authors report on the first successful use of recombinant activated factor VII for the prophylaxis of bleeding during brain tumor neurosurgery in a patient suffering from inherited factor XI deficiency. Using the agent, surgery was performed without any bleeding complications. In this setting, off-label use of recombinant activated factor VII appears to be a promising alternative for patients suffering from this rare hemostatic defect with hitherto limited therapeutic options.

scholarly journals Increased volume of distribution for recombinant activated factor VII and longer plasma-derived factor VII half-life may explain their long lasting prophylactic effect

2013 ◽  
Vol 132 (2) ◽  
pp. 256-262 ◽  
Author(s):  
Natascha C.J. Mathijssen ◽  
Rosalinde Masereeuw ◽  
Pal Andre Holme ◽  
Marian G.J. van Kraaij ◽  
Britta A.P. Laros-van Gorkom ◽  
...  
Keyword(s):  
Half Life ◽  
Volume Of Distribution ◽  
Factor Vii ◽  
Prophylactic Effect ◽  
Recombinant Activated Factor Vii ◽  
Activated Factor Vii

Recombinant Factor VIIa Is Effective for Bleeding and Surgery in Patients With Glanzmann Thrombasthenia

Blood ◽  
1999 ◽  
Vol 94 (11) ◽  
pp. 3951-3953 ◽  
Author(s):  
Man-Chiu Poon ◽  
Christine Demers ◽  
François Jobin ◽  
John W.Y. Wu
Keyword(s):  
Platelet Transfusion ◽  
Recombinant Factor Viia ◽  
Factor Viia ◽  
Factor Vii ◽  
Recombinant Activated Factor Vii ◽  
Glanzmann Thrombasthenia ◽  
Activated Factor Vii ◽  
Number Of Patients ◽  
Antifibrinolytic Drugs ◽  
Bleeding Episodes

Recombinant activated factor VII (rFVIIa) was found to be effective and safe in treating 24 bleeding episodes and to prevent bleeding during one bilateral herniorrhaphy in four children with Glanzmann thrombasthenia. One of the patients had alloantibodies to platelet membrane glycoprotein (GP) IIb/IIIa and was refractory to platelet transfusion. rFVIIa was administered at 89 to 116 μg/kg per injection every 2 hours, in association with antifibrinolytic drugs. Bleeding stopped in all cases, but platelet transfusion was required in one. Two bleeding episodes recurred 36 and 63 hours after discontinuation of rFVIIa, but were successfully treated with additional doses. No adverse effects of rFVIIa were observed. Although the number of patients is small, our study suggests that rFVIIa may be an alternative to platelet transfusions in patients with a severe congenital thrombocytopathy.

Use of recombinant factor VIIa in the perioperative period

2009 ◽  
Vol 29 (01) ◽  
pp. 68-70 ◽  
Author(s):  
M. Levi
Keyword(s):  
Blood Loss ◽  
Recombinant Factor Viia ◽  
Factor Viia ◽  
Coagulation Factor ◽  
Perioperative Period ◽  
Factor Vii ◽  
Clinical Settings ◽  
Recombinant Activated Factor Vii ◽  
Activated Factor Vii ◽  
Life Threatening

SummaryRecombinant activated factor VII (rFVIIa) is a pro-haemo -static agent that can be used for patients with haemophilia and inhibiting antibodies towards a coagulation factor. Recombinant factor VIIa is, however, increasingly used for several other indications, including patients who experience serious and life-threatening bleeding. In addition, rFVIIa has been evaluated for the prevention of major blood loss in patients undergoing surgical procedures that are known to be associated with major blood loss. In this manuscript we review the data on efficacy and safety of rFVIIa in the prevention of excessive blood loss and trans-fusion requirements in the perioperative period.We conclude that recombinant factor VIIa is a promising agent for perioperative prevention of major blood loss but that its efficacy will probably vary between specific clinical settings. Its exact place in surgery warrants further clinical trials in various situations that will also more precisely determine the safety of this intervention.

scholarly journals Recombinant activated factor VII in haemostasis after radical nephrectomy

2008 ◽  
Vol 136 (Suppl. 3) ◽  
pp. 259-262
Author(s):  
Petar Jovanovic ◽  
Dragan Ivanovic ◽  
Sladjan Timotijevic ◽  
Sladjana Trpkovic ◽  
Predrag Bojovic ◽  
...  
Keyword(s):  
Cardiac Arrest ◽  
Renal Cell ◽  
Radical Nephrectomy ◽  
Human Factor ◽  
Surgical Intervention ◽  
Factor Viia ◽  
Factor Vii ◽  
Recombinant Activated Factor Vii ◽  
Activated Factor Vii ◽  
Surgical Bleeding

INTRODUCTION. The paper presents important facts in the application of recombinant human factor VIIa (rFVIIa) and in the treatment of renal cell carcer. CASE REPORT. A 69-year old male with infiltrative renal cell carcer underwent radical nephrectomy using Hasagawa`s approach. The extirpated tumor was 35 cm in diameter. During surgery, the patient suffered cardiac arrest with 3500 ml blood loss. Twenty-four hours after operation, he lost additional 2100 ml of blood. Despite adequate blood substitution with intensive surgical attempts to treat haemostasis, bleeding did not stop until the application of rFVIIa (300 IU). The patient survived and fully recovered. CONCLUSION. To control massive non-surgical bleeding additionally complicated by paraneoplastic syndrome, extensive surgical intervention, haemodilution and massive blood substitution, the application of rFVIIa has proved to be most successful.

Recombinant Factor VIIa Concentrate versus Plasma-derived Concentrates for the Treatment of Acute Bleeding Episodes in Persons with Haemophilia and Inhibitors

2011 ◽  
Vol 07 (02) ◽  
pp. 140 ◽  
Author(s):  
Emanuela Marchesini ◽  
Domenico Prisco ◽  
Alfonso Iorio ◽  
◽  
◽  
...  
Keyword(s):  
Factor Viia ◽  
Tolerance Induction ◽  
Factor Vii ◽  
Induction Phase ◽  
Recombinant Activated Factor Vii ◽  
Activated Factor Vii ◽  
Activated Prothrombin Complex Concentrate ◽  
Bleeding Episodes ◽  
Randomised Controlled

The development of inhibitors remains the most challenging complication of treatment in persons with haemophilia, resulting in increased morbidity and a significant economic burden. The ultimate goal of treatment in patients with inhibitors is immune tolerance induction (ITI) therapy; however, during the induction phase of ITI, when ITI fails and where ITI is not affordable, the treatment of bleeding becomes a crucial issue. Recombinant activated factor VII (rFVIIa) and activated prothrombin complex concentrate (aPCC) have been developed to bypass the inhibitor antibody effect and have been tested in several randomised controlled trials, including two crossover head-to-head comparisons. Two systematic reviews of the literature have appraised and synthesised the available evidence. The recombinant drug seems to provide a more favourable benefit–risk ratio and may be easily administered as a single front-loaded bolus, making it a good candidate for the role of first-line treatment for bleeding in patients with inhibitors. Aggressive treatment of acute bleeds should be considered, including the use of higher and repeated-dose regimens until complete resolution of the bleed.

Clinical Usefulness of Recombinant Activated Factor VII in Patients with Liver Failure Undergoing Invasive Procedures

2011 ◽  
Vol 45 (11) ◽  
pp. 1433-1438 ◽  
Author(s):  
Jill C Krisl ◽  
Holly E Meadows ◽  
Charles S Greenberg ◽  
Joseph E Mazur
Keyword(s):  
Liver Failure ◽  
Fresh Frozen Plasma ◽  
Factor Vii ◽  
Bleeding Complications ◽  
Invasive Procedures ◽  
Recombinant Activated Factor Vii ◽  
Activated Factor Vii ◽  
Fresh Frozen ◽  
Dose Dependent ◽  
Frozen Plasma

Objective: To evaluate the use of recombinant activated factor VII (rFVIIa) in patients with liver failure undergoing invasive procedures. Methods: An OVID/MEDUNE and PubMed search (1997-June 2011) was performed to identify literature on the use of rFVIIa to reduce bleeding risk in patients with liver failure undergoing invasive procedures. Study Selection and Data Extraction: English-language data evaluating the efficacy of rFVIIa to reverse coagulopathies prior to invasive procedures in patients with liver disease were included. Data Synthesis: Following administration of rFVIIa, prothrombin time (PT) and international normalized ratio (INR) response is within 30 minutes. Doses ranging from 20 to 120 μg/kg have been studied, with a reduction in PT seen in a dose-dependent manner. One study in patients with no bleeding administered 5, 20, and 80 μg/kg sequentially during a 24-day period. All doses provided reversal of prolonged PT within 10 minutes, and the duration was dose-dependent. In a study of 15 patients with fulminant liver failure, requiring intracranial pressure monitor placement, a rFVIIa dose of 40 μg/kg was compared to fresh frozen plasma. In patients who received rFVIIa, the PT and INR normalized, compared to none of the patients in the fresh frozen plasma group. Conclusions: Retrospective and prospective data demonstrate that rFVIIa effectively reverses elevated PT and INR, reducing the risk of bleeding and safely facilitating invasive procedures. Based on available data, a dose of 20-40 μg/kg 30 minutes prior to an invasive procedure should be considered in patients with acute or chronic liver failure at risk for bleeding complications. A major limitation of rFVIIa use is the high cost of therapy. A prospective, randomized trial could help determine the appropriate dose of rFVIIa, timing of dose in relationship to procedure, and usefulness of subsequent doses.

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