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Factor VIIa (factor + viia)
Kinds of Factor VIIa Selected AbstractsThe Efficacy of Factor VIIa in Emergency Department Patients With Warfarin Use and Traumatic Intracranial HemorrhageACADEMIC EMERGENCY MEDICINE, Issue 3 2010Daniel K. Nishijima MD Abstract Objectives:, The objective was to compare outcomes in emergency department (ED) patients with preinjury warfarin use and traumatic intracranial hemorrhage (tICH) who did and did not receive recombinant activated factor VIIa (rFVIIa) for international normalized ratio (INR) reversal. Methods:, This was a retrospective before-and-after study conducted at a Level 1 trauma center, with data from 1999 to 2009. Eligible patients had preinjury warfarin use and tICH on cranial computed tomography (CT) scan. Patients before (standard cohort) and after (rFVIIa cohort) implementation of a protocol for administering 1.2 mg of rFVIIa in the ED were reviewed. Glasgow Coma Scale (GCS) score, Revised Trauma Score (RTS), Injury Severity Score (ISS), INR, and Marshall score were collected. Outcome measures included mortality, thromboembolic complications, and INR normalization. Results:, Forty patients (median age = 80.5 years, interquartile range [IQR] = 63.5,85) were included (20 in each cohort). Age, GCS score, ISS, RTS, initial INR, and Marshall score were similar (p > 0.05) between the two cohorts. Survival was identical between cohorts (13 of 20, or 65.0%, 95% confidence interval [CI] = 40.8% to 84.6%). There were no differences in rate of thromboembolic complications in the standard cohort (1 of 20, 5.0%, 95% CI = 0.1% to 24.9%) than the rFVIIa cohort (4 of 20, 20.0%, 95% CI = 5.7% to 43.7%; p = 0.34). Time to normal INR was earlier in the rFVIIa cohort (mean = 4.8 hours, 95% CI = 3.0 to 6.7 hours) than in the standard cohort (mean = 17.5 hours, 95% CI = 12.5 to 22.6; p < 0.001). Conclusions:, In patients with preinjury warfarin and tICH, use of rFVIIa was associated with a decreased time to normal INR. However, no difference in mortality was identified. Use of rFVIIa in patients on warfarin and tICH requires further study to demonstrate important patient-oriented outcomes. ACADEMIC EMERGENCY MEDICINE 2010; 17:244,251 © 2010 by the Society for Academic Emergency Medicine [source] Factor VIIa for ICH: behind the scenes of an academic,industry collaborative trialINTERNATIONAL JOURNAL OF STROKE, Issue 3 2007Stephan A. Mayer First page of article [source] Acute intestinal obstruction due to intramural haemorrhage in small intestine in a patient with severe haemophilia A and inhibitorEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 2 2005Khaled M. A. Ramadan Abstract:, Patients with severe haemophilia A usually present with joint, gastrointestinal and urinary tract haemorrhage. Bleeding elsewhere is often precipitated by pre-existing pathology or trauma. We report a patient with severe haemophilia A, who presented with symptoms of acute intestinal obstruction. He has a factor VIII inhibitor and receives recombinant factor VIIa on demand at home. The CT scan of abdomen showed dilated small intestine with fluid filled loops and a long segment in the jejunum with marked transmural thickening. There was no other pathology in the small intestine. These appearances were consistent with intramural haemorrhage in the small intestine as the cause of acute obstruction. He was managed conservatively with recombinant factor VIIa and this resulted in resolution of his symptoms. This case highlights an unusual presentation of bleeding in a haemophilia patient. Intestinal obstruction due to haemorrhage in the small intestinal wall is extremely rare and only previously reported in a few haemophilia patients. It also highlights the effectiveness of conservative management with recombinant factor VIIa as opposed to immediate exploratory surgery. [source] Activation loop 3 and the 170 loop interact in the active conformation of coagulation factor VIIaFEBS JOURNAL, Issue 11 2009Egon Persson The initiation of blood coagulation involves tissue factor (TF)-induced allosteric activation of factor VIIa (FVIIa), which circulates in a zymogen-like state. In addition, the (most) active conformation of FVIIa presumably relies on a number of intramolecular interactions. We have characterized the role of Gly372(223) in FVIIa, which is the sole residue in activation loop 3 that is capable of forming backbone hydrogen bonds with the unusually long 170 loop and with activation loop 2, by studying the effects of replacement with Ala [G372(223)A]. G372A-FVIIa, both in the free and TF-bound form, exhibited reduced cleavage of factor X (FX) and of peptidyl substrates, and had increased Km values compared with wild-type FVIIa. Inhibition of G372A-FVIIa·sTF by p -aminobenzamidine was characterized by a seven-fold higher Ki than obtained with FVIIa·sTF. Crystallographic and modelling data suggest that the most active conformation of FVIIa depends on the backbone hydrogen bond between Gly372(223) and Arg315(170C) in the 170 loop. Despite the reduced activity and inhibitor susceptibility, native and active site-inhibited G372A-FVIIa bound sTF with the same affinity as the corresponding forms of FVIIa, and burial of the N-terminus of the protease domain increased similarly upon sTF binding to G372A-FVIIa and FVIIa. Thus Gly372(223) in FVIIa appears to play a critical role in maturation of the S1 pocket and adjacent subsites, but does not appear to be of importance for TF binding and the ensuing allostery. [source] Peri-interventional control of haemostasis in a patient with combined coagulation factor V- and factor VIII-deficiency and anaphylaxis to fresh frozen plasma , a rare indication for recombinant factor VIIaHAEMOPHILIA, Issue 4 2010D. LECHNER No abstract is available for this article. [source] Cost minimization analysis to compare activated prothrombin complex concentrate (APCC) and recombinant factor VIIa for haemophilia patients with inhibitors undergoing major orthopaedic surgeriesHAEMOPHILIA, Issue 5 2009P. O. BONNET Summary., Benefits of bypassing agents for maintaining haemostasis in major surgeries have been described in the literature; however, their use has a substantial economic impact. This study assessed the cost of FEIBA, an activated prothrombin complex concentrate and recombinant factor VIIa (rFVIIa) when used in inhibitor patients undergoing major surgeries. After reviewing published literature, a cost minimization model was developed describing dosing regimens recommended and used during major surgeries for FEIBA (pre-operative: 75,100 U kg,1; postoperative: 75,100 U kg,1 q 8,12 h days 1,5 and 75,100 U kg,1 q 12 h days 6,14) and rFVIIa (pre-operative: 90 ,g kg,1; intra-operative: 90 ,g kg,1 q 2 h; postoperative: 90 ,g kg,1 q 2,4 h days 1,5 and 90 ,g kg,1 q 6 h days 6,14). Using a 75 kg patient and US prices, total drug cost was calculated for three scenarios: use of FEIBA or rFVIIa alone and a third case combining rFVIIa pre- and intra-operative and FEIBA throughout a 14-day postoperative period. Dosage amounts of modelled bypassing agents were similar to cases in the literature. Using FEIBA instead of rFVIIa would decrease total drug cost by >50% and save over $400 000 per surgery. Sequential use of both bypassing agents would increase total drug cost by 9% when compared with FEIBA alone, but would remain >40% lower than rFVIIa alone. Univariate sensitivity analyses confirmed robustness of results. As large amounts of bypassing agents are necessary for patients with inhibitors to undergo major surgeries, cost is a major consideration. Use of FEIBA alone or in combination with rFVIIa has emerged as a cost-saving approach. [source] Safety update on the use of recombinant factor VIIa and the treatment of congenital and acquired deficiency of factor VIII or IX with inhibitorsHAEMOPHILIA, Issue 5 2008T. ABSHIRE Summary., Recombinant factor VIIa (rFVIIa, NovoSeven®) has been licensed for treatment of haemophilia with inhibitors in Europe since 1996 and in North America since 1999. Overall, approximately 1.5 million doses have since been administered. Safety data from licensure to April 2003 revealed 25 thromboembolic (TE) adverse events (AE) from over 700 000 doses given, a remarkably low incidence of TE events. Recent reports have cited a higher prevalence of TE events with rFVIIa use, especially when used off-label. This report reviews the TE and fatal events with use of rFVIIa for congenital and acquired haemophilia A or B from May 2003 to December 2006. Approximately 800 000 standard doses of rFVIIa have been administered during this time frame. All clinical trials, spontaneous and solicited reports, as well as a detailed literature review, were included in the data analysis. There were a total of 30 TE events and 6 TE-associated fatal events. Spontaneous reports captured 14/71 (20%) TE/AE and 2/34 TE-associated/total fatal events. From solicited reports, 5/40 (12.5%) were associated with a TE and 1/32 TE-associated fatal events. Literature review revealed 11/19 (58%) TE events and 3/6 TE-associated fatal events. Despite the use of high-dose rFVIIa (270 ,g kg,1) in some clinical trials and registries, rFVIIa appears safe, when used for congenital and acquired haemophilia. The prevalence of TE associated with rFVIIa use is less than 4/100 000 and a TE-associated fatal event is also extremely rare. However, use of rFVIIa for off-label indications should continue to be monitored closely via clinical trials and carefully designed registries. [source] Prophylaxis with recombinant factor VIIa for the management of bleeding episodes during immune tolerance treatment in a boy with severe haemophilia A and high-response inhibitorsHAEMOPHILIA, Issue 5 2008J. BLATNY No abstract is available for this article. [source] Prophylactic effect of recombinant factor VIIa with congenital factor VII deficiencyHAEMOPHILIA, Issue 4 2008M. KARIMI No abstract is available for this article. [source] A randomized, double-blind trial demonstrating bioequivalence of the current recombinant activated factor VII formulation and a new robust 25°C stable formulationHAEMOPHILIA, Issue 5 2007B. V. BYSTED Summary., Recombinant activated factor VIIa (rFVIIa) is a well-established treatment for bleeding episodes in patients with congenital or acquired haemophilia A or B with inhibitors to factors VIII and IX and patients with FVII deficiency. The aim of this trial was to demonstrate bioequivalence between the currently marketed (rFVIIa/NovoSeven®) and a new rFVIIa formulation (VII25) stable at up to 25°C. Furthermore, short-term safety and tolerability of VII25 and pharmacokinetics of both formulations were investigated. In this single-centre, randomized, double-blind, two-way cross-over trial, healthy male subjects received one intravenous bolus injection of rFVIIa and one of VII25, both at 90 ,g kg,1, in a randomized order 2,3 weeks apart. Mean VII25/rFVIIa ratio for area under the plasma activity-time curve from time 0 to last quantifiable activity (primary bioequivalence endpoint), was 0.93, 90% confidence interval (CI) (0.89,0.96), within the predefined bioequivalence range (0.80,1.25). Secondary pharmacokinetic parameters were comparable between formulations. No serious adverse events were observed. Six mild or moderate treatment-emergent adverse events were reported in five subjects. Coagulation-related parameter profiles were similar between rFVIIa and VII25. No clinically abnormal changes were observed for laboratory parameters and no subjects developed FVIIa antibodies. This trial demonstrated bioequivalence between the currently available rFVIIa and VII25 stable at up to 25°C. VII25's ,user-friendly' formulation removes the inconvenience of storing/transporting at 2,8°C, and as the drug substance is the same, the activity and safety established for rFVIIa is maintained. [source] Effect of recombinant factor VIIa variant (NN1731) on platelet function, clot structure and force onset time in whole blood from healthy volunteers and haemophilia patientsHAEMOPHILIA, Issue 5 2007D. F. BROPHY Summary., NN1731 is a novel variant of recombinant factor VIIa (rFVIIa) that binds to activated platelets, but has greater enzymatic activity than rFVIIa in generating FXa and thrombin. The effect of NN1731 on clot structure and platelet function was characterized ex vivo in whole blood from healthy volunteers and haemophilic patients. Blood samples from six healthy volunteers, nine haemophilia A patients with and without inhibitors and one acquired haemophilia A patient, were spiked with increasing concentrations (0.32, 0.64 and 1.28 ,g mL,1) of rFVIIa and NN1731. Platelet contractile force (PCF) or platelet function, clot elastic modulus (CEM) or clot structure, and force onset time (FOT) or the thrombin generation time (TGT) were determined using the Hemodyne Hemostasis Analysis System (HASÔ). Baseline PCF, CEM and FOT values in patients were abnormal compared to healthy volunteers' baseline values. Overall, haemophilia blood samples with or without inhibitors spiked with NN1731 had significantly greater PCF, CEM and shorter FOT values relative to samples spiked with corresponding doses of rFVIIa. The variability in response to treatment between patients was greater with rFVIIa compared to NN1731. At 1.28 ,g mL,1 (90 ,g kg,1), NN1731 normalized PCF, CEM and FOT in nine of 10 patients, while rFVIIa normalized these parameters in four of 10 patients. Increasing in vitro concentrations of NN1731 normalized platelet function, clot structure and thrombin generation consistently in haemophilia blood with or without inhibitors. NN1731 may be a promising haemostatic agent for patients with bleeding disorders. These results should be confirmed in an in vivo study. [source] Prophylactic recombinant factor VIIa in haemophilia patients with inhibitorsHAEMOPHILIA, Issue 3 2005G. Young Summary., Prevention of bleeding, especially into joints, with prophylactic factor infusions is the most effective treatment for severe haemophilia patients. Approximately 15,30% of patients with factor VIII deficiency and 3,5% of patients with factor IX deficiency develop neutralizing antibodies (inhibitors) to factor precluding their use. Such patients often have significant bleeding complications including life- and limb-threatening bleeds and severe joint disease. Prophylaxis for such patients is not generally considered because of the fact that the standard (bypassing) agents for such patients are not as effective as natural factor replacement, because of concerns for thrombotic complications and also because of the very high cost of bypassing agents. We treated two patients with high titre inhibitors with prophylactic recombinant factor VIIa (rFVIIa). The first patient was treated as a result of development of a target joint and to reduce the use of agents that can lead to anamnesis of his inhibitor. The second patient had multiple severe bleeds and was hospitalized 20% of the time over a 2-year period. He had a very poor quality of life. Both patients had shown good responses previously to rFVIIa for treatment of bleeds. Both patients had an outstanding response to prophylaxis albeit at a very high cost. Prophylaxis with rFVIIa can be an effective approach in select inhibitor patients with severe complications related to bleeding. [source] Management of oral bleedings with recombinant factor VIIa in children with haemophilia A and inhibitorHAEMOPHILIA, Issue 1 2005P. Laguna Summary., Dental extraction in patients with haemophilia A and high-titre inhibitor is always a high-risk procedure, which often presents a lot of problems associated with bleeding. Prothrombin complex concentrates or recombinant activated factor VII (rFVIIa) has been used to control bleeding. rFVIIa was administered to five boys with severe haemophilia A complicated with inhibitor, who underwent seven dental extractions. The age of the patients ranged between 8 and 13 years (median 10 years). The concentrate was administered in doses of 90,100 ,g kg,1 body weight. Duration in the therapy and intervals between rFVIIa doses depended on the severity of bleeding. rFVIIa was proven to be highly effective and no side-effects of the product were observed. [source] Successful use of recombinant factor VIIa in a patient with inhibitor secondary to severe factor XI deficiencyHAEMOPHILIA, Issue 2 2002P. LAWLER Factor XI (FXI) inhibitors are a rare complication of inherited FXI deficiency. We report the successful use of recombinant factor VIIa (FVIIa) in a patient with a high-responding inhibitor undergoing cataract extraction. At the time of surgery there were limited available data on the optimal management of patients with FXI deficiency. A 62-year-old Ashkenazi Jewish woman had a lifelong history of excessive bleeding secondary to severe FXI deficiency (2 U dL,1), and received FXI concentrate (FXI:C) when she underwent a colposuspension procedure. She was subsequently diagnosed with a FXI inhibitor of 16 Bethesda units (BU) when she developed a poor response to FXI:C at the time of total hip replacement. Two months later she was admitted for cataract extraction. The FXI level was < 1 U dL,1 with an inhibitor titre of 48 BU. She received 90 ,g kg,1 of FVIIa immediately preoperatively followed by continuous infusion at a rate of 20 ,g kg,1 h,1 for 24 h. The cataract extraction was successful and there was no excess bleeding during surgery or in the postoperative period. Mutation analysis of the FXI gene showed that the patient was homozygous for the type II genotype [exon 5, Glu117,Ter]. The reason for the low prevalence of inhibitor formation in patients with FXI deficiency is unclear but may reflect a number of factors including reporting bias, the rarity of absent circulating FXI:C activity, and the infrequent use of FXI replacement therapy. [source] Successful outcome of a cirrhotic patient with postoperative haematuria treated with a single high dose of recombinant factor VIIaHAEMOPHILIA, Issue 6 2001J. F. Lucía Recombinant factor VIIa (rfVIIa) has been widely used for the treatment and prevention of bleeding episodes in haemophiliacs with high-titre inhibitors. High single doses are the treatment of choice for joint and muscle bleeds in those patients. There are only a few reports on the value of rfVIIa in cirrhotic patients with haemostatic impairment but this drug can consistently correct the prothrombin time in these individuals. We report a case of a good response to a single high dose of rfVIIa in a patient with advanced liver disease who suffered from severe refractory postoperative haematuria. [source] Effects of fibrinogen concentrate administration during severe hemorrhageACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 9 2010H. R. THORARINSDOTTIR Background: Fibrinogen concentrate has been shown to improve coagulation in dilutional coagulopathy in experimental studies, but clinical experience is still scarce. The aim of this study was to evaluate laboratory data and the clinical outcome of fibrinogen administration in patients suffering from severe hemorrhage. Materials and methods: A retrospective study over a 3-year observation period of consecutive patients who received a single dose of fibrinogen concentrate but not recombinant factor VIIa as part of their treatment of severe hemorrhage, defined as >6 U of packed red blood cells (PRBCs). Results: Thirty-seven patients were included, most of them suffering from severe hemorrhage following open heart surgery (68%). After a median fibrinogen dose of 2 g (range 1,6 g), an absolute increase in the plasma fibrinogen concentration of 0.6 g/l was observed (P<0.001). The activated partial thromboplastin time (APTT) decreased significantly (P<0.001), from 52 to 43 s and the prothrombin time (PT) decreased from 20 to 17 s, respectively. The transfusion requirement for PRBCs decreased from 6 to 3 U (P<0.01) in the 24 h after fibrinogen administration, but fresh-frozen plasma and platelet concentrate transfusions did not change significantly. Eight patients (22%) died in intensive care unit and the pre-operative fibrinogen concentration was not significantly different in these patients. Conclusion: Administration of fibrinogen for severe hemorrhage was associated with an increased fibrinogen concentration and a significant decrease in APTT, PT and the requirement for PRBCs. [source] Immediate haemostasis with recombinant factor VIIa for haemorrhage following Hickman line insertion in acute myeloid leukaemiaINTERNATIONAL JOURNAL OF LABORATORY HEMATOLOGY, Issue 3 2004W. Osborne Summary Bleeding following Hickman line insertion is not uncommon but can be life threatening, especially in the presence of coagulopathy and thrombocytopenia following chemotherapy. Treatment to control the bleeding can be challenging and treatment options are limited. We present our experience of a patient who had persisting haemorrhage immediately following Hickman line insertion for administration of chemotherapy for relapsed acute myeloid leukaemia. Haemostasis could not be achieved after FFP and platelet administration. A single dose of recombinant factor VIIa (rhFVIIa) stopped the bleeding immediately, avoiding the need for surgical intervention or line removal. Our experience indicates rhFVIIa may be an effective option for bleeding related to Hickman line insertion. [source] The Efficacy of Factor VIIa in Emergency Department Patients With Warfarin Use and Traumatic Intracranial HemorrhageACADEMIC EMERGENCY MEDICINE, Issue 3 2010Daniel K. Nishijima MD Abstract Objectives:, The objective was to compare outcomes in emergency department (ED) patients with preinjury warfarin use and traumatic intracranial hemorrhage (tICH) who did and did not receive recombinant activated factor VIIa (rFVIIa) for international normalized ratio (INR) reversal. Methods:, This was a retrospective before-and-after study conducted at a Level 1 trauma center, with data from 1999 to 2009. Eligible patients had preinjury warfarin use and tICH on cranial computed tomography (CT) scan. Patients before (standard cohort) and after (rFVIIa cohort) implementation of a protocol for administering 1.2 mg of rFVIIa in the ED were reviewed. Glasgow Coma Scale (GCS) score, Revised Trauma Score (RTS), Injury Severity Score (ISS), INR, and Marshall score were collected. Outcome measures included mortality, thromboembolic complications, and INR normalization. Results:, Forty patients (median age = 80.5 years, interquartile range [IQR] = 63.5,85) were included (20 in each cohort). Age, GCS score, ISS, RTS, initial INR, and Marshall score were similar (p > 0.05) between the two cohorts. Survival was identical between cohorts (13 of 20, or 65.0%, 95% confidence interval [CI] = 40.8% to 84.6%). There were no differences in rate of thromboembolic complications in the standard cohort (1 of 20, 5.0%, 95% CI = 0.1% to 24.9%) than the rFVIIa cohort (4 of 20, 20.0%, 95% CI = 5.7% to 43.7%; p = 0.34). Time to normal INR was earlier in the rFVIIa cohort (mean = 4.8 hours, 95% CI = 3.0 to 6.7 hours) than in the standard cohort (mean = 17.5 hours, 95% CI = 12.5 to 22.6; p < 0.001). Conclusions:, In patients with preinjury warfarin and tICH, use of rFVIIa was associated with a decreased time to normal INR. However, no difference in mortality was identified. Use of rFVIIa in patients on warfarin and tICH requires further study to demonstrate important patient-oriented outcomes. ACADEMIC EMERGENCY MEDICINE 2010; 17:244,251 © 2010 by the Society for Academic Emergency Medicine [source] Recombinant factor VIIa and fibrinogen display additive effect during in vitro haemodilution with crystalloidsACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 3 2009C. FENGER-ERIKSEN Background: Major blood loss requires fluid resuscitation for maintaining hemodynamic stability. Excessive volume infusions predispose to dilutional coagulopathy through loss, consumption and dilution of cells and proteins involved in haemostasis. Further treatment with fibrinogen concentrate and/or recombinant activated factor VII (rFVIIa) may be initiated, although the haemostatic effects in a situation with haemodilution are not fully detailed. The present study evaluates haemostatic effect of fibrinogen and rFVIIa and their combination in an in vitro model of haemodiluted whole blood with two commonly used crystalloids. Methods: Eight healthy, male volunteers were enrolled. Outcome variables were clot initiation, propagation and strength assessed by thrombelastographic parameters: clotting time, clot formation time, maximum velocity, time until maximum velocity, maximum clot firmness evaluated at dilution levels of 0% (control), 10%, 30% and 50% with isotonic saline and Ringer's lactate in a model of tissue factor-activated whole blood. Fibrinogen and rFVIIa were additional final reaction concentrations, reflecting commonly used clinically therapeutic dosages. Results: Dose-dependent coagulopathy developed following haemodilution with isotonic saline and Ringer's lactate, characterised by a prolonged clot initiation, reduced clot propagation and reduced clot strength. Fibrinogen improved clot strength and propagation phase while rFVIIa shortened clot initiation, both with a positive dose dependency. Conclusions: The combination of fibrinogen and rFVIIa displays an additive effect and improves overall in vitro whole blood clot formation in a model of in vitro crystalloid-induced haemodilution. [source] Dynamical view of membrane binding and complex formation of human factor VIIa and tissue factorJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 5 2010Y. Z. OHKUBO Summary.,Background:,The molecular mechanism of enhancement of the enzymatic activity of factor VIIa by tissue factor (TF) is not fully understood, primarily because of the lack of atomic models for the membrane-bound form of the TF,FVIIa complex. Objectives:,To construct the first membrane-bound model of the TF,FVIIa complex, and to investigate the dynamics of the complex in solution and on the surface of anionic membranes by using large-scale molecular dynamics (MD) simulations in full atomic detail. Methods:,Membrane-bound models of the TF,FVIIa complex and the individual factors were constructed and subjected to MD simulations, in order to characterize protein,protein and protein,lipid interactions, and to investigate the dynamics of TF and FVIIa. Results:,The MD trajectories reveal that isolated FVIIa undergoes large structural fluctuation, primarily due to the hinge motions between its domains, whereas soluble TF (sTF) is structurally stable. Upon complex formation, sTF restricts the motion of FVIIa significantly. The results also show that, in the membrane-bound form, sTF directly interacts with the lipid headgroups, even in the absence of FVIIa. Conclusion:,The first atomic models of membrane-bound sTF,FVIIa, FVIIa and sTF are presented, revealing that sTF forms direct contacts with the lipids, both in the isolated form and in complex with FVIIa. The main effect of sTF binding to FVIIa is spatial stabilization of the catalytic site of FVIIa, which ensures optimal interaction with the substrate, FX. [source] Active site inhibited factor VIIa attenuates myocardial ischemia/reperfusion injury in miceJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 2 2009S. T. B. G. LOUBELE Summary.,Background:,Inhibition of specific coagulation pathways such as the factor VIIa-tissue factor complex has been shown to attenuate ischemia/reperfusion (I/R) injury, but the cellular mechanisms have not been explored. Objectives:,To determine the cellular mechanisms involved in the working mechanism of active site inhibited factor VIIa (ASIS) in the protection against myocardial I/R injury. Methods:,We investigated the effects of a specific mouse recombinant in a mouse model of myocardial I/R injury. One hour of ischemia was followed by 2, 6 or 24 h of reperfusion. Mouse ASIS or placebo was administered before and after induction of reperfusion. Results:,ASIS administration reduced myocardial I/R injury by more than 40% at three reperfusion times. Multiplex ligation dependent probe amplification (MLPA) analysis showed reduced mRNA expression in the ischemic myocardium of CD14, TLR-4, interleukin-1 (IL-1) receptor-associated kinase (IRAK) and I,B, upon ASIS administration, indicative of inhibition of toll-like receptor-4 (TLR-4) and subsequent nuclear factor-,B (NF-,B) mediated cell signaling. Levels of nuclear activated NF-,B and proteins influenced by the NF-,B pathway including tissue factor (TF) and IL-6 that were increased after I/R, were attenuated upon ASIS administration. After 6 and 24 h of reperfusion, neutrophil infiltration into the area of infarction was decreased upon ASIS administration. There was, however, no evidence of an effect of ASIS on apoptosis (Tunel staining and MLPA analysis). Conclusions:,We conclude that the diminished amount of myocardial I/R injury after ASIS administration is primarily due to attenuated inflammation-related lethal I/R injury, probably mediated through the NF-,B mechanism. [source] Activity and regulation of glycoPEGylated factor VIIa analogsJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 9 2008S. GHOSH Summary.,Background:,Recombinant coagulation factor VIIa (rFVIIa) has proven to be a safe and effective drug for treatment of bleeding episodes in hemophilic patients with inhibitors. However, rFVIIa is cleared from the circulation relatively quickly. Protein modification with poly(ethylene glycol) (PEG) can prolong the circulatory lifetime of proteins but it could also impair protein function by molecular shielding of the protein surface. Objectives:, To characterize the interaction of glycoPEGylated rFVIIa , rFVIIa-10K PEG and rFVIIa-40K PEG , with tissue factor (TF), factor X (FX) and plasma inhibitors, tissue factor pathway inhibitor (TFPI) and antithrombin (AT). Methods:, The amidolytic and FX activation assays were employed to investigate the interaction of glycoPEGylated rFVIIa with its macromolecular substrate and inhibitors. Results:, Both the glycoPEGylated rFVIIa analogs exhibited similar amidolytic activity as that of rFVIIa in the absence or the presence of relipidated TF. The analogs were as effective as rFVIIa in activating FX in the absence of TF. In the presence of TF, the glycoPEGylated rFVIIa variants, relative to rFVIIa, were slightly less effective at lower concentrations, but no significant differences were found among them in activating FX at saturating concentrations. Both AT/heparin and TFPI effectively inhibited the glycoPEGylated rFVIIa bound to relipidated TF or TF on stimulated endothelial cells. In contrast to their normal interaction with TF, the glycoPEGylated rFVIIa variants appeared to interact poorly with phospholipids. Conclusions:, The glycoPEGylated rFVIIa variants retained their catalytic activity and interacted efficiently with TF, FX and the plasma inhibitors. Further work with appropriate in vitro and in vivo model systems is needed to determine the feasibility of using glycoPEGylated rFVIIa to improve therapeutic options for bleeding disorders. [source] Tissue factor-dependent blood coagulation is enhanced following delivery irrespective of the mode of deliveryJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 12 2007K. BOER Summary. Background:,The risk of thrombosis is clearly increased in the postpartum period. Mice with a targeted deletion of the transmembrane domain of tissue factor (TF) develop serious activation of blood coagulation and widespread thrombosis after delivery. Objective and methods:,We hypothesized that TF, abundantly present in placental tissue, is released during delivery, resulting in the activation of blood coagulation. We measured sensitive markers for TF-dependent activation of coagulation before and after induction of labor in two groups: a vaginal delivery (VAG) group and a cesarean section (CS) group.Results:,One hour after delivery, soluble TF (sTF) significantly increased in both groups [VAG group (mean ± SD) 226 ± 42 to 380 ± 42 pg mL,1 and CS group 193 ± 17 to 355 ± 44 pg mL,1]. The day after delivery, sTF was somewhat less increased. Both groups also showed an increase in factor VIIa, indicating activation of the TF pathway of coagulation. Indeed, after delivery, TF-dependent coagulation, as measured by the TF clotting time assay, was significantly enhanced. Increased plasma levels of prothrombin fragment 1 + 2 and thrombin,antithrombin complexes demonstrated thrombin generation following delivery. TF pathway-dependent activation of coagulation upon delivery was not blocked by TF pathway inhibitor and was not dependent on the mode of delivery.Conclusion:,The postdelivery increase in TF-dependent activation of coagulation is likely to be a natural mechanism to prevent excessive blood loss during and after delivery, and may also indicate a novel mechanism by which puerperal women have an increased risk of venous thromboembolism. [source] Preferential localization of recombinant factor VIIa to platelets activated with a combination of thrombin and a glycoprotein VI receptor agonistJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 4 2007M. KJALKE Summary., Background:, Activation of platelets with a combination of collagen and thrombin generates a subpopulation of highly procoagulant ,coated' platelets characterized by high surface expression of fibrinogen and other procoagulant proteins. Objectives:, To analyze the interaction of recombinant factor VIIa (rFVIIa) with coated platelets. Methods and results:, rFVIIa localized to the coated platelets in flow cytometry experiments, while minimal rFVIIa was found on platelets activated with adenosine diphosphate, thrombin or via glycoprotein VI individually, and essentially no rFVIIa was found on non-stimulated platelets. Removal of the , -carboxyglutamic acid (Gla) domain of rFVIIa, and addition of EDTA, annexin V or excess prothrombin inhibited rFVIIa localization to the coated platelets, indicating that the interaction was mediated by the calcium-dependent conformation of the Gla domain and platelet exposure of negatively charged phospholipids. A reduced level of platelet fibrinogen exposure was observed at hemophilia A-like conditions in a model system of cell-based coagulation, indicating that coated platelet formation in hemophilia may be diminished. Addition of rFVIIa dose-dependently enhanced thrombin generation and partly restored platelet fibrinogen exposure. Conclusions:, The data suggest that rFVIIa localized preferentially on platelets activated with dual agonists, thereby ensuring enhanced thrombin generation localized at the site of injury where both collagen and tissue factor are exposed, the latter ensuring the formation of thrombin necessary for coated platelet formation. [source] Efficacy and safety of recombinant factor VIIa in the treatment of bleeding episodes in patients with aplastic anemiaJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 2 2007A. M. AL HAMMADI [source] Prerequisites for recombinant factor VIIa-induced thrombin generation in plasmas deficient in factors VIII, IX or XIJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 1 2006T. LIVNAT 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. [source] Comparative thrombotic event incidence after infusion of recombinant factor VIIa versus factor VIII inhibitor bypass activityJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 10 2004L. M. Aledort Summary. Thrombosis is a rare but well-recognized potential complication of Factor VIII Inhibitor Bypass Activity (FEIBA) infusion. Recombinant factor VIIa (rFVIIa) is increasingly used as an alternative to FEIBA; however, the thrombotic safety profile of rFVIIa remains incompletely characterized. To determine the incidence rates of thrombotic adverse events (AEs) after infusion of rFVIIa and FEIBA. Data from the MedWatch pharmacovigilance program of the US Food and Drug Administration, as supplemented by published case reports, were used in conjunction with estimated numbers of infusions available from manufacturers to assess comparative incidence of thrombotic AEs in patients receiving rFVIIa or FEIBA in the period from April 1999 through June 2002. Reported thrombotic AEs were rare, with incidence rates of 24.6 per 105 infusions (CI, 19.1,31.2 per 105 infusions) for rFVIIa and 8.24 per 105 infusions (CI, 4.71,13.4 per 105 infusions) for FEIBA. Thrombotic AEs were significantly more frequent in rFVIIa than FEIBA recipients (incidence rate ratio, 2.98; CI, 1.71,5.52). The most commonly documented single type of thrombotic AE after rFVIIa infusion was cerebrovascular thrombosis, while myocardial infarction was the most frequent type in patients receiving FEIBA. Contrasting AE reporting patterns between rFVIIa and FEIBA may have contributed to the observed difference in thrombotic event incidence. Nevertheless, this comprehensive pharmacovigilance assessment does not support superior thrombotic safety of rFVIIa and suggests that thrombotic AE risk may be higher in rFVIIa than FEIBA recipients. [source] Regulation of the p21Ras-MAP kinase pathway by factor VIIaJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 5 2003H. H. Versteeg Summary.,Background:,In recent years it has become clear that factor (F)VIIa is not a passive mediator involved in the linear transduction of the coagulation cascade, but actively engages target cells to induce signal transduction and that this signal transduction fulfills critical functions in angiogenesis, arteriosclerosis and inflammatory processes. Objectives:,The details of coagulation factor-dependent signal transduction are among the least understood in biology and thus we set out to establish the molecular events responsible for MAP kinase activation induced by the interaction of FVIIa with its cellular binding partner tissue factor (TF). Methods:,Two different TF-expressing cell types, BHKTF and HaCaT cells, were assayed for p21Ras activation using a pull-down assay that is specific for activated Ras. This activation was visualized by means of Western blotting. In addition, the upstream pathways leading to FVIIa-induced Ras activation were characterized using phosphospecific antibodies and specific inhibitors. Results:,We observed that in both BHKTF and HaCaT cells FVIIa-induced MAP kinase activation correlates with p21Ras activation, and that this p21Ras activation is essential for FVIIa-induced MAP kinase activation. In BHKTF cells, early p21Ras activation was mediated by the activation of protein kinase C (PKC), whereas late p21Ras activation employed alternative mechanisms. In HaCaT cells, stimulation of the Src kinase family mediated FVIIa-dependent p21Ras activation. Finally, in both cell types, Raf activity was mandatory for MAP kinase activation. Conclusions:,p21Ras activation is instrumental in FVIIa signal transduction and the FVIIa-dependent activation of p21Ras involves either PKC or Src-dependent mechanisms, depending on the cell type investigated. [source] Tissue factor: a mini-reviewJOURNAL OF TISSUE ENGINEERING AND REGENERATIVE MEDICINE, Issue 3 2007Valéry Daubie Abstract Tissue factor (TF) is historically known as the trigger of the coagulation cascade. This integral membrane glycoprotein forms a ternary complex with factor VIIa (FVIIa) and zymogen factor (FX), which is then activated to factor Xa (FXa). The latter cleaves prothrombin into thrombin (FIIa), which in turn activates fibrinogen in fibrin monomers. What is less known is its additional non-haemostatic roles in inflammation, tumour growth and angiogenesis. This aspect will be developed here. TF, as a transmembrane protein, has a signalling effect requiring FVIIa. TF,FVIIa complex activates G protein-coupled receptor protease-activated receptor 2 (PAR-2) and therefore modulates various cellular processes, such as cell proliferation and survival, gene transcription and protein translation. In this review we will first highlight, using recent structural data, the ,potentially' active domain able to modulate the triggered intracellular response. We also will focus on the still emerging and promising results deciphering the diverse locations in which TF appears. We conclude with a description of an emerging and atypical use of tissue factor in platelet gel surgery for sinus augmentation. Copyright © 2007 John Wiley & Sons, Ltd. [source] Modulation of endothelial cell inflammatory integrins and stress markers with rh-factor VIIa in patients with advanced chronic hepatitis CJOURNAL OF VIRAL HEPATITIS, Issue 4 2003D. H. Van Thiel Summary. Individuals with chronic hepatitis C (CHC) progress to cirrhosis and hepatic cancer. Individuals with advanced CHC are coagulopathic and can manifest fibrinolysis. The coagulopathy is a consequence of hepatocytic dysfunction. The fibrinolysis represents a response to local endothelial cell injury, and is of a low-grade. Based upon this hypothesis, the effect of the infusion of recombinant human factor VIIa (rh-FVIIa) on endothelial cell inflammatory integrins and measures of endothelial stress were determined in 17 individuals with advanced CHC. Immediately prior to the infusion of rh-FVIIa, the plasma levels of tissue factor (TF), Thrombomodulin (TM), human soluble ICAM-1 (hs-ICAM-1), human soluble VCAM-1 (hs-VCAM-1), human soluble L-Selectin (hs-L-Selectin), the prothrombin time and the activated partial thromboplastin time were determined. The same parameters were assayed at 5, 10, 30, 120, 240 and 360 min after infusion. TF and TM levels were very high at baseline consistent with a vascular endothelial stress response. Similarly hs-ICAM-1, hs-VCAM-1 as well as L-Selectin levels were increased. Thirty minutes after the infusion, a marked reduction in ICAM-1 and VCAM-1 and to a lesser degree L-Selectin levels was observed. This reduction persisted for 360 min. No change in measures of fibrinolysis [plasminogen activator inhibitor-1 (PAI-1), total tissue factor pathway inhibitor (t-TFPI), activated tissue factor pathway inhibitor (TFPIa), d-dimers (DD), FSP and fibrinogen levels] occurred. In addition, no change in plasma Annexin-V was observed. Based upon these data it can be concluded that: (1) rh-FVIIa corrects the coagulopathy seen in advanced CHC; (2) reduces endothelial cell injury and/or stress as evidenced by the TF, TM, hs-ICAM-1 and hs-VCAM-1 levels in plasma; (3) these changes in coagulation occurred without inducing a propagated vascular thrombosis. [source] | |||||||||||||||||||||||||