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1.  Effects of In vitro hemodilution, hypothermia and rFVIIa addition on coagulation in human blood 
Introduction
Coagulopathy can occur after hemorrhage, trauma and resuscitation, and has been associated with dilution of coagulation factors and hypothermia. Recombinant activated Factor VII (rFVIIa) has been used, often as a last resort, to improve hemostasis in trauma/hemorrhage patients with coagulopathy. The aim of this study was to further characterize the effects of rFVIIa on various coagulation parameters and the influence of temperature and hemodilution.
Methods
Whole blood from healthy human volunteers was incubated in a combination of three conditions: undiluted or diluted 40% with either lactated Ringer’s solution or Hextend, at 37°C or 34°C, and with and without rFVIIa (1.26 μg/ml, final concentration). Blood or plasma, as appropriate, was measured for coagulation by thrombin generation, thromboelastography (TEG), prothrombin Time (PT) and activated partial thromboplastin (aPTT).
Results
Incubation of plasma at 34°C significantly elevated thrombin generation, and prolonged PT and aPTT. Dilution of blood or plasma with 40% Hextend, but not lactated Ringer’s, had a significant effect on TEG parameters, and prolonged PT and aPTT. In control conditions (37°C, 0 dilution), the addition of rFVIIa to human plasma or whole blood led to a significant change in all TEG parameters, and Lagtime for thrombin generation, but not to PT or aPTT.
Conclusion
Theses data show that thrombin generation is affected by hypothermia, but not 40% dilution. TEG is affected by 40% dilution with Hextend, but not by hypothermia. PT and aPTT are significantly affected by both hypothermia and dilution. Recombinant FVIIa caused a greater change in thrombin generation at 34°C as compared to 37°C, and a greater change in PT at 40% dilution, suggesting that the effect of rFVIIa on coagulation is both temperature and dilution dependant.
PMCID: PMC3415967  PMID: 22928166
TEG; thrombin generation; PT; aPTT
2.  Acidosis and correction of acidosis does not affect rFVIIa function in swine 
Background: Hemorrhagic shock and trauma are associated with acidosis and altered coagulation. A fall in pH has been reported to attenuate the activity of recombinant activated Factor VII (rFVIIa) in vitro. However, it is not known if acidosis induced by hemorrhagic shock or infusion of HCl attenuates FVIIa activity in vivo. The purpose of this study was to determine if acidosis, induced by two methods, affects recombinant FVIIa (rFVIIa) activity in swine, and if correction of the pH restores rFVIIa activity to normal. Methods: Acidosis was induce in anesthetized swine in two separate models: 1) HCl infusion (n=10) and 2) hemorrhage/hypoventilation (n=8). Three groups per model were used: Control (pH7.4), Acidosis (arterial pH7.1) and Acidosis-Corrected (bicarbonate infusion to return pH from 7.1 to 7.4). Pigs were then injected with rFVIIa (90 μg/kg) or vehicle (saline) at target pH and arterial blood samples were taken for measurement of coagulation function, including Thromboelastography -TEG, Thrombin Generation, Activated Clotting Time, Prothrombin Time, activated Partial Thromboplastin Time, Fibrinogen Concentration and Platelet count before and 5min after injection of rFVIIa. Results: Acidosis led to a hypocoagulation as measured by almost all coagulation parameters in both models. Furthermore, the change in coagulation function produced after infusion of rFVIIa was not different between control, acidosis and acidosis-corrected groups for all coagulation parameters measured. Conclusion: Acidosis associated with hemorrhagic shock or HCl infusion led to a hypocoagulation that was not corrected with bicarbonate infusion. Furthermore, acidosis did not affect rFVIIa function, and correction of the acidosis with bicarbonate had no effect on rFVIIa function in these models. This suggests that in vivo acidosis did not diminish rFVIIa function.
PMCID: PMC3523398  PMID: 23272296
Hemorrhage; acidosis; hypoventilation; hypocoagulation; thromboelastography; thrombin generation; rotational thromboelastogram; fibrinogen; platelets; coagulation parameters; recombinant factor VIIa
3.  Impact of experimental haemodilution on platelet function, thrombin generation and clot firmness: effects of different coagulation factor concentrates 
Blood Transfusion  2013;11(3):391-399.
Background
Haemodilution during resuscitation after massive haemorrhage may worsen the coagulopathy and perpetuate bleeding.
Materials and methods
Blood samples from healthy donors were diluted (30 and-60%) using crystalloids (saline, Ringer’s lactate, PlasmalyteTM) or colloids (6% hydroxyethylstarch [HES130/0.4], 5% human albumin, and gelatin). The effects of haemodilution on platelet adhesion (Impact R), thrombin generation (TG), and thromboelastometry (TEM) parameters were analysed as were the effects of fibrinogen, prothrombin complex concentrates (PCC), activated recombinant factor VII (FVIIa), and cryoprecipates on haemodilution.
Results
Platelet interactions was already significantly reduced at 30% haemodilution. Platelet reactivity was not improved by addition of any of the concentrates tested. A decrease in TG and marked alterations of TEM parameters were noted at 60% haemodilution. HES130/0.4 was the expander with the most deleterious action. TG was significantly enhanced by PCC whereas rFVIIa only caused a mild acceleration of TG initiation. Fibrinogen restored the alterations of TEM parameters caused by haemodilution including those caused by HES 130/0.4. Cryoprecipitates significantly improved the alterations caused by haemodilution on TG and TEM parameters; the effects on TG disappeared after ultracentrifugation of the cryoprecipitates.
Discussion
The haemostatic alterations caused by haemodilution are multifactorial and affect both blood cells and coagulation. In our in vitro approach, HES 130/0.4 had the most deleterious effect on haemostasis parameters. Coagulation factor concentrates did not improve platelet interactions in the Impact R, but did have favourable effects on coagulation parameters measured by TG and TEM. Fibrinogen notably improved TEM parameters without increasing thrombin generation, suggesting that this concentrate may help to preserve blood clotting abilities during haemodilution without enhancing the prothrombotic risk.
doi:10.2450/2012.0034-12
PMCID: PMC3729130  PMID: 23058866
haemodilution; coagulation factor concentrates; platelet function; thrombin generation; thromboelastometry
4.  Cost effectiveness of recombinant factor VIIa for treatment of intracerebral hemorrhage 
BMC Neurology  2008;8:17.
Background
Phase I/II placebo-controlled clinical trials of recombinant Factor VIIa (rFVIIa) suggested that administration of rFVIIa within 4 hours after onset of intracerebral hemorrhage (ICH) is safe, limits ICH growth, and improves outcomes. We sought to determine the cost-effectiveness of rFVIIa for acute ICH treatment, using published Phase II data. We hypothesized that rFVIIa would have a low marginal cost-effectiveness ratio (mCER) given the poor neurologic outcomes after ICH with conventional management.
Methods
We performed an incremental cost-effectiveness analysis from the societal perspective, considering conventional management vs. 80 ug/kg rFVIIa treatment for acute ICH cases meeting Phase II inclusion criteria. The time frame for the analysis was 1. 25 years: data from the Phase II trial was used for 90 day outcomes and rFVIIa complications – arterial thromboembolic events (ATE). We assumed no substantial cost differences in care between the two strategies except: 1) cost of rFVIIa (for an 80 mcg/kg dose in an 80 kg patient, assumed cost of $6,408); 2) cost of ATE side effects from rFVIIa (which also decrease quality of life and increase the chance of death); and 3) differential monetary costs of outcomes and their impact on quality of life, including disposition (home vs. nursing home), and outpatient vs. inpatient rehabilitation. Sensitivity analyses were performed to explore uncertainty in parameter estimates, impact of rFVIIa cost, direct cost of neurologic outcomes, probability of ATE, and outcomes after ATE.
Results
In the "base case", treating ICH with rFVIIa dominates the usual care strategy by being more effective and less costly. rFVIIa maintained a mCER < $50,000/QALY over a wide range of sensitivity analyses. Sensitivity analyses showed that the cost of rFVIIa must exceed $14,500, or the frequency of ATE exceed 29%, for the mCER to exceed $50,000/QALY. Varying the cost and/or reducing the utility of health states following ATE did not impact results.
Conclusion
Based on data from preliminary trials, treating selected ICH patients with rFVIIa results in lower cost and improved clinical outcomes. This potential cost-effectiveness must be considered in light of the Phase III trial results.
doi:10.1186/1471-2377-8-17
PMCID: PMC2397434  PMID: 18489750
5.  An in vitro evaluation of standard rotational thromboelastography in monitoring of effects of recombinant factor VIIa on coagulopathy induced by hydroxy ethyl starch 
Background
Rotational thromboelastography (ROTEG) has been proposed as a monitoring tool that can be used to monitor treatment of hemophilia with recombinant factor VIIa (rFVIIa). In these studies special non-standard reagents were used as activators of the coagulation. The aim of this study was to evaluate if standard ROTEG analysis could be used for monitoring of effects of recombinant factor VIIa (rFVIIa) on Hydroxy Ethyl Starch-induced dilutional coagulopathy.
Methods
The study was performed in vitro on healthy volunteers. Prothrombin time (PT) and ROTEG analysis were performed after dilution with 33% hydroxy ethyl starch and also after addition of rFVIIa to the diluted blood.
Results
PT was impaired with INR changing from 0.9 before dilution to 1.2 after dilution while addition of rFVIIa to diluted blood lead to an overcorrection of the PT to an International Normalized Ratio (INR) value of 0.6 (p = 0.01). ROTEG activated with the contact activator ellagic acid was impaired by hemodilution (p = 0.01) while addition of rFVIIa had no further effects. ROTEG activated with tissue factor (TF) was also impaired by hemodilution (p = 0.01) while addition of rFVIIa lead to further impairment of the coagulation (p = 0.01).
Conclusions
The parameters affected in the ROTEG analysis were Clot Formation Time and Amplitude after 15 minutes while the Clotting Time was unaffected. We believe these effects to be due to methodological problems when using standard activators of the coagulation in the ROTEG analysis in combination with rFVIIa.
doi:10.1186/1471-2326-5-3
PMCID: PMC551614  PMID: 15713229
6.  Bio-distribution of pharmacologically administered recombinant factor VIIa (rFVIIa) 
Summary
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.
doi:10.1111/j.1538-7836.2009.03696.x
PMCID: PMC2849270  PMID: 19943873
bio-distribution; endothelial cell protein C receptor; hemophilia; prophylaxis; rFVIIa; tissue factor
7.  Recombinant coagulation factor VIIa—a novel haemostatic agent in scoliosis surgery? 
European Spine Journal  2005;15(6):944-952.
Astract
Spinal fusion surgery in children and adolescents with idiopathic scoliosis is often associated with severe haemorrhage. Recombinant coagulation factor VIIa (rFVIIa) has previously been shown to be an effective haemostatic treatment for severe bleeding associated with a variety of coagulopathic and non-coagulopathic indications. The aim of this retrospective study was to assess the safety and haemostatic efficacy of rFVIIa in a series of 26 consecutive adolescent patients with scoliosis (22 females; mean age 16.6 years) undergoing correctional surgery. A second series of 26 consecutive patients (20 females; mean age 16.2 years) who received standard therapy during surgery, represented historical controls. Blood loss, transfusion requirements, duration of surgery, and peri-operative measurements of coagulation parameters were compared between the two groups. Intra-operative and combined intra-operative and post-operative blood losses were significantly smaller in the rFVIIa-treatment group than in the historical controls (P=0.003 and 0.032, respectively); rFVIIa-treated patients also demonstrated significantly reduced blood loss per vertebral segment fused (P=0.032) and per hour of surgery (P<0.001). Intra-operative requirements for packed red blood cells were also significantly lower in the treatment group (P=0.042). Patients in the treatment group demonstrated rapid and maintained reduction of prothrombin time and international normalised ratio; values among rFVIIa-treated patients remained significantly lower than those in the control group at all time points evaluated (P<0.001). There were no deaths and no adverse events. These results suggest that rFVIIa is a safe and effective haemostatic agent for use during spinal fusion surgery in adolescent patients with idiopathic scoliosis; however, further research and randomised, placebo-controlled trials are needed to confirm these findings.
doi:10.1007/s00586-005-1004-5
PMCID: PMC3489422  PMID: 16133083
Bleeding; Haemostasis; Scoliosis; Surgery; RFVIIa
8.  Recombinant Factor VIIa Analog NN1731 (V158D/E296V/M298Q-FVIIa) Enhances Fibrin Formation, Structure and Stability in Lipidated Hemophilic Plasma 
Thrombosis research  2011;128(6):570-576.
SUMMARY
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.
Methods
We used calibrated automated thrombography and plasma clotting assays to compare effects of bypassing agents (rFVIIa, NN1731) on hemophilic clot formation, structure, and ability to resist fibrinolysis.
Results
Both rFVIIa and NN1731 shortened the clotting onset and increased the maximum rate of fibrin formation and fibrin network density in hemophilic plasma clots. In the presence of tissue plasminogen activator, both rFVIIa and NN1731 shortened the time to peak turbidity (TTPeaktPA) and increased the area under the clot formation curve (AUCtPA). Phospholipids increased both rFVIIa and NN1731 activity in a lipid concentration-dependent manner. Estimated geometric mean concentrations of rFVIIa and NN1731 producing similar onset, rate, TTPeaktPA, and AUCtPA as seen with 100% factors VIII and IX were: 24.5, 74.3, 29.7, and 37.1 nM rFVIIa, and 8.6, 31.2, 9.0, and 11.3 nM NN1731, respectively. In each case, the NN1731 concentration was significantly lower than rFVIIa.
Conclusions
These findings suggest that like rFVIIa, NN1731 improves the formation, structure, and stability of hemophilic clots. Higher lipid concentrations may facilitate assessment of both rFVIIa and NN1731 activity. NN1731 appears likely to support rapid clot formation in tissues with high endogenous fibrinolytic activity.
doi:10.1016/j.thromres.2011.04.009
PMCID: PMC3156970  PMID: 21561645
hemophilia; recombinant factor VIIa; fibrinogen; fibrinolysis; NN1731
9.  Recombinant Factor VIIa: Hemostatic Adjunct in the Coagulopathic Burn Patient 
Eplasty  2009;9:e27.
Introduction: Recombinant factor VIIa (rFVIIa; NovoSeven) is well recognized as an effective hemostatic agent in the management and prophylaxis of patients with hemophilia. We report here the successful use of rFVIIa in a coagulopathic burn patient. Methods: A 63-year-old man was admitted with significant upper-body burns in a total body surface area of 60%. Initial management included early intubation and escharotomies, with subsequent admission to the burn unit. Fascial excision was carried out with allograft placement. During a complicated hospital course, decline in platelet function was noted and was associated with the development of a generalized coagulopathy with elevated international normalized ratio. Following a routine follow-up debridement and autografting, extensive bleeding was noted from donor sites. A period of increasing hemodynamic instability followed in the burn unit, with serial hematocrit measurements pointing toward ongoing bleeding from the surgical sites. Following administration of significant amounts of blood product, it was decided to administer rFVIIa per pharmacy protocol. Results: Within 4 hours of administration of rFVIIa, the patient was noted to be hemodynamically stable with unchanging serial hematocrit measurements. Hemostasis was attributed to the use of rFVIIa with prior administration of platelets. Conclusions: Our case demonstrates the successful use of rFVIIa in the severely coagulopathic burn patient.
PMCID: PMC2705287  PMID: 19649159
10.  The interaction of factor VIIa with rehydrated, lyophilized platelets 
Platelets  2008;19(3):182-191.
The experiments presented here were undertaken to determine if factor VIIa (rFVIIa, the Novo Nordisk product NovoSeven™) will directly bind to rehydrated, lyophilized (RL) platelets for the formation of a catalytic surface with an enhanced ability to generate thrombin. The interaction between rFVIIa and the RL platelet surface was examined by measuring equilibrium and non-equilibrium binding of the coagulation factor to the cells and by following the effects of the surface modification on the kinetics of thrombin generation. The association of rFVIIa with RL platelets was rapid with saturation occurring within minutes. Disassociation was slow, with over half of the coagulation factor remaining bound after two hours. Densities of over one million molecules of rFVIIa per RL platelet were obtained when high concentrations of rFVIIa were incubated with RL platelets. Thrombin generation measurements showed that RL platelet-bound rFVIIa was catalytically active. Thus we can expect that RL platelets, which have been shown to effectively bind to sites of vascular injury, will localize rFVIIa to wounds for an increase in therapeutic index. These studies indicate that rFVIIa-RL platelets are worthy of preclinical and clinical development as an infusion agent for severe bleeding.
doi:10.1080/09537100701493794
PMCID: PMC3925421  PMID: 18432519
Platelet; factor VIIa; coagulation; thrombin; lyophilized
11.  The Australian and New Zealand Haemostasis Registry: ten years of data on off-licence use of recombinant activated factor VII 
Blood Transfusion  2015;13(1):86-99.
Background
Recombinant activated factor VII (rFVIIa) has been widely used as an off-licence pan-haemostatic agent in patients with critical bleeding. However, outside the trauma setting, there is relatively little high quality evidence on the risks and benefits of this agent. The Haemostasis Registry was established to investigate the extent of use, dosing, safety and outcomes of patients after off-licence rFVIIa treatment of critical bleeding.
Materials and methods
The Registry recruited non-haemophiliac patients treated with rFVIIa from 2000–2009 (inclusive) in Australia and New Zealand. Detailed information was gathered on patients’ demographics, context of bleeding, rFVIIa administration, laboratory results, blood component and other therapies, and outcomes. Outcome measures included subjectively assessed effect of rFVIIa on bleeding (response), adverse events (thromboembolic and other) and 28-day mortality.
Results
The registry included 3,446 cases in 3,322 patients (median [IQR] age 56 [33–70] years, 65% (n=2,147) male). Clinical indications included cardiac surgery (45%), other surgery (18%), trauma (13%), medical bleeding (6%), liver disease (6%), and obstetric haemorrhage (5%). The median [IQR] dose was 91 [72–103] μg/kg and 77% received a single dose. Reduction or cessation of bleeding was reported in 74% and 28-day survival was 71% but outcomes varied depending on clinical context. pH strongly correlated with outcome measures; 81% of patients with pH <7.1 died. Approximately 11% of patients had thromboembolic adverse events. In multivariate analysis, pH prior to administration and bleeding context were independently associated with reported response to rFVIIa and 28-day mortality.
Discussion
The Haemostasis Registry is the largest dataset of its kind and provides observational data on the off-licence use of rFVIIa over a 10-year period. It has been an invaluable resource for rigorously tracking adverse events and helping to inform clinical practice.
doi:10.2450/2014.0260-13
PMCID: PMC4317095  PMID: 24960661
Haemostasis Registry; rFVIIa; NovoSeven®; critical bleeding; haemostasis
12.  Newly diagnosed congenital factor VII deficiency and utilization of recombinant activated factor VII (NovoSeven®) 
This case report presents a newly diagnosed congenital factor VII deficiency treated with recombinant activated factor VII (rFVIIa). Congenital factor VII deficiency is a rare autosomal-recessive bleeding disorder that occurs in fewer than 1/500,000 persons. Its presentation can vary from epistaxis to hemarthroses and severe central nervous system bleeding, and correlates poorly with factor VII levels. Our patient had not had a significant hemostatic challenge prior to his presentation and therefore never had any symptomatology suggestive of this disease. He was treated with rFVIIa, and was able to undergo repair of his fractures without bleeding.
Case report
A 19-year-old African-American male presented to the emergency room after an altercation that resulted in significant trauma. He sustained bilateral mandibular angle fractures and orbital floor fractures, requiring urgent surgical correction. On initial evaluation, he was noted to have a prolonged prothrombin time of 40.1 seconds, with an International Normalized Ratio of 4.0, a normal activated partial thromboplastin time of 29.9 seconds, and a platelet count of 241. After receiving vitamin K and fresh frozen plasma, he was taken to the operating room for a temporary rigid maxillomandibular fixation. A 1:1 mixing study with normal plasma corrected the prothrombin time (decreasing from 40.7 to 14.7 seconds) and a factor VII assay revealed 5% of the normal factor VII level. The patient was diagnosed with congenital factor VII deficiency. Due to his coagulopathy and the extensive surgical correction needed, rFVIIa was administered and surgery was accomplished without hemorrhagic sequelae.
Conclusion
This case report and review describes a rare congenital disease, the history of rFVIIa use, and its mechanism. rFVIIA use in our patient provided a treatment option that allowed the necessary surgical correction, but further prospective studies on dose optimization would ensure adequate dosing with minimal risk of severe side effects.
doi:10.2147/CPAA.S39772
PMCID: PMC3601647  PMID: 23516010
factor VII deficiency; recombinant activated factor VII; coagulation cascade
13.  Hemostatic and neuroprotective effects of human recombinant activated factor VII therapy after traumatic brain injury in pigs 
Experimental neurology  2008;210(2):645-655.
Human recombinant activated factor-VII (rFVIIa) has been used successfully in the treatment of spontaneous intracerebral hemorrhage. In addition, there is increasing interest in its use to treat uncontrolled bleeding of other origins, including trauma. The aim of this study was to evaluate the safety and potential effectiveness of rFVIIa to mitigate bleeding using a clinically relevant model of traumatic brain injury (TBI) in the pig. A double injury model was chosen consisting of (1) an expanding cerebral contusion induced by the application of negative pressure to the exposed cortical surface and (2) a rapid rotational acceleration of the head to induce diffuse axonal injury (DAI). Injuries were performed on 10 anesthetized pigs. Five minutes after injury, 720 μg/kg rFVIIa (n = 5) or vehicle control (n = 5) was administered intravenously. Magnetic resonance imaging (MRI) studies were performed within 30 min and at 3 days post-TBI to determine the temporal expansion of the cerebral contusion. Euthanasia and histopathologic analysis were performed at day 3. This included observations for hippocampal neuronal degeneration, axonal pathology and microclot formation. The expansion of contusion volume over the 3 days post-injury period was reduced significantly in animals treated with rFVIIa compared to vehicle controls. Surprisingly, immunohistochemical analysis demonstrated that the number of dead/dying hippocampal neurons and axonal pathology was reduced substantially by rFVIIa treatment compared to vehicle. In addition, there was no difference in the extent of microthrombi between groups. rFVIIa treatment after TBI in the pig reduced expansion of hemorrhagic cerebral contusion volume without exacerbating the severity of microclot formation. Finally, rFVIIa treatment provided a surprising neuroprotective effect by reducing hippocampal neuron degeneration as well as the extent of DAI.
doi:10.1016/j.expneurol.2007.12.019
PMCID: PMC3979422  PMID: 18291370
Traumatic brain injury; TBI; rFVIIa; Cerebral contusion; Recombinant Activated Factor VII; Hemostasis; Diffuse axonal injury; Neuroprotection
14.  Recombinant activated factor VII in controlling bleeding in non-hemophiliac patients 
Annals of Saudi Medicine  2010;30(3):198-202.
BACKGROUND:
There have been recent reports on the successful use of recombinant factor VIIa (rFVIIa) in non-hemophiliac patients who have experienced heavy blood loss due to trauma with extensive organ damage and who have received multiple blood transfusions with hemostatic changes without success. The timing of administration, dosage, mortality, units of blood transfusion saved, risk of thrombotic events, and the risk/benefit ratio are still poorly defined.
PATIENTS AND METHODS:
We conducted a retrospective review of all medical records of patients who received rFVIIa between January 2003 and March 2008. Data collection included demographic characteristics, diagnosis, indications, comorbidities, and amount of blood products used with rFVIIa, dose of rFVIIa, mortality, and adverse events.
RESULTS:
We identified 45 patients, 27 (60%) males and 18 (40%) females, with a median age of 52 years. The median dose of rFVIIa was 40 μg/kg (range, 20-120 μg/kg). Five (11.1%) patients needed a second dose of rFVIIa (dose range of 20-85 μg/kg) whereas three patients (6.7%) needed a third dose of rFVIIa (dose range of 40-60 μg/kg). There was a marked and significant reduction in transfusion requirements for packed red blood cells (P=.0078). Overall transfusion requirements significantly decreased after the infusion of rFVIIa (P=.0323). Nineteen patients (42.2%) died and thrombosis was documented in 3 patients (6.7%).
CONCLUSION:
Use of rFVIIa should be based on sound clinical evidence to balance the risks, benefits, and cost if used among non-hemophiliacs. Prospective randomized studies are needed to investigate the efficacy and cost-effectiveness of rFVIIa for this indication and to allow a final assessment of the importance of this treatment.
doi:10.4103/0256-4947.62830
PMCID: PMC2886869  PMID: 20427935
15.  Haemostatic drugs for traumatic brain injury 
Background
Traumatic brain injury (TBI) is a leading cause of death and disability. Intracranial bleeding is a common complication of TBI, and intracranial bleeding can develop or worsen after hospital admission. Haemostatic drugs may reduce the occurrence or size of intracranial bleeds and consequently lower the morbidity and mortality associated with TBI.
Objectives
To assess the effects of haemostatic drugs on mortality, disability and thrombotic complications in patients with traumatic brain injury.
Search methods
We searched the electronic databases: Cochrane Injuries Group Specialised Register (3 February 2009), CENTRAL (The Cochrane Library 2009, Issue 1), MEDLINE (1950 to Week 3 2009), PubMed (searched 3 February 2009 (last 180 days)), EMBASE (1980 to Week 4 2009), CINAHL (1982 to January 2009), ISI Web of Science: Science Citation Index Expanded (SCI-EXPANDED) (1970 to January 2009), ISI Web of Science: Conference Proceedings Citation Index - Science (CPCI-S) (1990 to January 2009).
Selection criteria
We included published and unpublished randomised controlled trials comparing haemostatic drugs (antifibrinolytics: aprotinin, tranexamic acid (TXA), aminocaproic acid or recombined activated factor VIIa (rFVIIa)) with placebo, no treatment, or other treatment in patients with acute traumatic brain injury.
Data collection and analysis
Two review authors independently examined all electronic records, and extracted the data. We judged that there was clinical heterogeneity between trials so we did not attempt to pool the results of the included trials. The results are reported separately.
Main results
We included two trials. One was a post-hoc analysis of 30 TBI patients from a randomised controlled trial of rFVIIa in blunt trauma patients. The risk ratio for mortality at 30 days was 0.64 (95% CI 0.25 to 1.63) for rFVIIa compared to placebo. This result should be considered with caution as the subgroup analysis was not pre-specified for the trial. The other trial evaluated the effect of rFVIIa in 97 TBI patients with evidence of intracerebral bleeding in a computed tomography (CT) scan. The corresponding risk ratio for mortality at the last follow up was 1.08 (95% CI 0.44 to 2.68). The quality of the reporting of both trials was poor so it was difficult to assess the risk of bias.
Authors’ conclusions
There is no reliable evidence from randomised controlled trials to support the effectiveness of haemostatic drugs in reducing mortality or disability in patients with TBI. New randomised controlled trials assessing the effects of haemostatic drugs in TBI patients should be conducted. These trials should be large enough to detect clinically plausible treatment effects.
doi:10.1002/14651858.CD007877.pub2
PMCID: PMC4066582  PMID: 20091656
16.  Failure of recombinant factor VIIa in a patient with severe polymicrobial sepsis and postoperative uncontrolled intraabdominal bleeding 
Background
This report discusses a case of unsuccessful treatment with recombinant factor VIIa (rFVIIa) in off-label use. The need for international guidelines concerning the off-label use of rFVIIa is outlined as well as the need for methods to control the efficacy of rFVIIa objectively.
Case presentation
54 year old male with severe polymicrobial sepsis due to a perforated diverticulitis of the sigmoid colon and consecutive overt disseminated intravascular coagulation. He suffered severe intraabdominal bleeding after abdominal surgery despite conventional haemostatic support. Repeated applications of factor VIIa temporarily improved coagulation essays but did not stop clinical bleeding. The patient died in multiorgan failure due to septic and haemorrhagic shock.
Conclusion
Off-label use of rFVIIa could result in more side effects than could be expected from literature because of a publication bias. However for most off-label applications large prospective, randomised and controlled trials to confirm the positive findings are missing. For the future, not only guidelines concerning the off-label use of rFVIIa are urgently needed but also guidelines for monitoring the efficacy of rFVIIa.
doi:10.1186/1471-2334-7-34
PMCID: PMC1876232  PMID: 17462090
17.  Use of recombinant factor VIIa (rFVIIa) as pre-hospital treatment in a swine model of fluid percussion traumatic brain injury 
Context:
Recombinant factor VIIa (rFVIIa) has been used as an adjunctive therapy for acute post-traumatic hemorrhage and reversal of iatrogenic coagulopathy in trauma patients in the hospital setting. However, investigations regarding its potential use in pre-hospital management of traumatic brain injury (TBI) have not been conducted extensively.
Aims:
In the present study, we investigated the physiology, hematology and histology effects of a single pre-hospital bolus injection of rFVIIa compared to current clinical practice of no pre-hospital intervention in a swine model of moderate fluid percussion TBI.
Materials and Methods:
Animals were randomized to receive either a bolus of rFVIIa (90 μg/kg) or nothing 15 minutes (T15) post-injury. Hospital arrival was simulated at T60, and animals were euthanized at experimental endpoint (T360).
Results:
Survival was 100% in both groups; baseline physiology parameters were similar, vital signs were comparable. Animals that received rFVIIa demonstrated less hemorrhage in subarachnoid space (P = 0.0037) and less neuronal degeneration in left hippocampus, pons, and cerebellum (P = 0.00009, P = 0.00008, and P = 0.251, respectively). Immunohistochemical staining of brain sections showed less overall loss of microtubule-associated protein 2 (MAP2) and less Flouro-Jade B positive cells in rFVIIa-treated animals.
Conclusions:
Early pre-hospital administration of rFVIIa in this swine TBI model reduced neuronal necrosis and intracranial hemorrhage (ICH). These results merit further investigation of this approach in pre-hospital trauma care.
doi:10.4103/0974-2700.130880
PMCID: PMC4013725  PMID: 24812455
Coagulopathy; necrosis; pre-hospital; rFVIIa; swine; traumatic brain injury
18.  Recombinant Activated Factor VII (rFVIIa) in the Management of Major Obstetric Haemorrhage: A Case Series and a Proposed Guideline for Use 
Major obstetric haemorrhage remains a significant cause of maternal morbidity and mortality. Previous case reports suggest the potential benefit of recombinant activated factor VII (rFVIIa: NovoSevenR) as a haemostatic agent. We performed a retrospective review of the use of rVIIa in major obstetric haemorrhage in the Northern Region between July 2004 and February 2007. Fifteen women received rFVIIa. The median patient age was 34 years. Major haemorrhage occurred antepartum (5 patients), intrapartum (1), and postpartum (9). All women received an initial dose of 90 mcg/kg rFVIIa and one received 2 further doses. Bleeding stopped or decreased in 12 patients (80%). Additional measures included antifibrinolytic and uterotonic agents, Rusch balloon insertion, uterine curettage/packing, and vessel embolisation. Eight patients required hysterectomy. All women survived to discharge from hospital. No adverse events, including thrombosis, were recorded. This study provides further support for the safety and efficacy of rFVIIa as adjunct therapy in major obstetric haemorrhage.
doi:10.1155/2009/364843
PMCID: PMC2817503  PMID: 20148069
19.  Pharmacological characteristics of a novel, recombinant fusion protein linking coagulation factor VIIa with albumin (rVIIa-FP) 
Background
Recombinant factor VIIa (rFVIIa) is approved for use in controlling bleeding episodes in people with hemophilia who have developed inhibitors to replacement therapy. Due to its short half-life (t½), frequent injections are required, limiting its use as a prophylactic treatment. A novel, recombinant fusion protein linking coagulation factor VIIa with albumin (rVIIa-FP) has been developed to extend the t½ of rFVIIa.
Objectives
The aim of our studies was to investigate the pharmacokinetic/pharmacodynamic characteristics of rVIIa-FP in preclinical animal species.
Methods
Pharmacokinetic (PK) parameters were derived after single intravenous dosing in hemophilia A mice, rats, rabbits and monkeys. PK analysis was based on human FVII plasma levels determined by measuring FVII antigen levels by ELISA in mice and rats, and FVIIa activity using STACLOT® VIIa-rTF in rabbits and monkeys. Induction of thrombin generation was investigated in mice, while hemostatic activity was assessed by thrombus formation in rabbits.
Results
Compared with rFVIIa, rVIIa-FP displayed a prolonged t½, enhanced in vivo recovery and reduced clearance in all species investigated. In mice, 16 h after treatment with rVIIa-FP, thrombin levels were quantifiable, indicating prolonged efficacy, whereas values had approached baseline at this time after treatment with rFVIIa. After 12 h, hemostatic efficacy was negligible in rFVIIa-treated rabbits, but sustained in animals receiving rVIIa-FP.
Conclusions
These studies indicate that the longer t½ of rVIIa-FP compared with rFVIIa translates into extended activity. These findings suggest that rVIIa-FP has the potential to be administered less frequently than rFVIIa-containing concentrates in clinical use.
doi:10.1111/jth.12477
PMCID: PMC4166693  PMID: 24641308
half-life; hemophilia; hemostasis; inhibitors; pharmacokinetics
20.  Pharmacokinetics, pharmacodynamics and safety of recombinant canine FVIIa in a study dosing one haemophilia A and one haemostatically normal dog 
Summary
Recombinant human FVIIa (rhFVIIa) corrects the coagulopathy in hemophilia A and B as well as FVII deficiency. This is also the case in dogs until canine anti-human FVIIa antibodies develop (~2 weeks). Recombinant canine factor VIIa (rcFVIIa), successfully over-expressed by gene transfer in haemophilia dogs, has provided long-term haemostasis (>2 years). However, pharmacokinetics (PK), pharmacodynamics (PD) and safety of rcFVIIa after pharmacological administration have not been reported. We therefore wanted to explore the safety, PK and PD of rcFVIIa in dogs. A pilot study was set up to evaluate the safety as well as PK and PD of rcFVIIa after a single intravenous dose of 270 μg kg−1 to one HA and one haemostatically normal dog and to directly compare rcFVIIa with rhFVIIa in these two dogs. Single doses of rcFVIIa and rhFVIIa were well tolerated. No adverse events were observed. Pharmacokinetic characteristics including half-life (FVIIa activity: 1.2–1.8 h; FVIIa antigen 2.8–3.7 h) and clearance were comparable for rcFVIIa and rhFVIIa. Kaolin-activated thromboelastography approached normal in the HA dog with the improvement being most pronounced after rcFVIIa. This study provided the first evidence that administering rcFVIIa intravenously is feasible, safe, well tolerated and efficacious in correcting the haemophilic coagulopathy in canine HA and that rcFVIIa exhibits pharmacokinetic characteristics comparable to rhFVIIa in haemophilic and haemostatically competent dogs. This strengthens the hypothesis that rcFVIIa can be administered to dogs to mimic the administration of rhFVIIa to humans.
doi:10.1111/j.1365-2516.2011.02536.x
PMCID: PMC3925423  PMID: 21645178
animal model; haemophilia A; pharmacodynamics; pharmacokinetics; recombinant canine FVIIa; thromboelastography
21.  Evaluation of Recombinant Factor VIIa Treatment for Massive Hemorrhage in Patients with Multiple Traumas 
Annals of Laboratory Medicine  2012;32(2):145-152.
Background
Recent studies and case reports have shown that recombinant factor VIIa (rFVIIa) treatment is effective for reversing coagulopathy and reducing blood transfusion requirements in trauma patients with life-threatening hemorrhage. The purpose of this study is to evaluate the effect of rFVIIa treatment on clinical outcomes and cost effectiveness in trauma patients.
Methods
Between January 2007 and December 2010, we reviewed the medical records of patients who were treated with rFVIIa (N=18) or without rFVIIa (N=36) for life-threatening hemorrhage due to multiple traumas at the Emergency Department of Pusan National University Hospital in Busan, Korea. We reviewed patient demographics, baseline characteristics, initial vital signs, laboratory test results, and number of units transfused, and then analyzed clinical outcomes and 24-hr and 30-day mortality rates. Thromboembolic events were monitored in all patients. Transfusion costs and hospital stay costs were also calculated.
Results
In the rFVIIa-treated group, laboratory test results and clinical outcomes improved, and the 24-hr mortality rate decreased compared to that in the untreated group; however, 30-day mortality rate did not differ between the groups. Thromboembolic events did not occur in both groups. Transfusion and hospital stay costs in the rFVIIa-treated group were cost effective; however, total treatment costs, including the cost of rFVIIa, were not cost effective.
Conclusions
In our study, rFVIIa treatment was shown to be helpful as a supplementary drug to improve clinical outcomes and reduce the 24-hr mortality rate, transfusion and hospital stay costs, and transfusion requirements in trauma patients with life-threatening hemorrhage.
doi:10.3343/alm.2012.32.2.145
PMCID: PMC3289780  PMID: 22389882
Recombinant factor VIIa; Multiple trauma; Clinical outcome; Mortality rate; Treatment cost
22.  Successful pulmonary administration of activated recombinant factor VII in diffuse alveolar hemorrhage 
Critical Care  2006;10(6):R177.
Introduction
Diffuse alveolar hemorrhage (DAH) is a serious pulmonary complication seen in patients with autoimmune disorders and patients treated with chemotherapy or after hematopoietic stem cell transplantation. The clinical management of DAH is complex and the condition has a high mortality rate. Tissue factor is expressed in the lung alveoli during inflammation and therefore pulmonary administration of human recombinant activated factor VIIa (rFVIIa) could be a rational treatment option.
Methods
Six patients with acute, bronchoscopically confirmed DAH from a single intensive care unit university hospital center were included in the study of acute DAH in critically ill patients. The patients were treated with intrapulmonary administration of 50 μg/kg rFVIIa in 50 ml of sodium chloride by bronchoalveolar lavage (BAL) with 25 ml in each of the main bronchi, which was repeated after 24 hours in case of treatment failure.
Results
An excellent response, defined as complete and sustained hemostasis after a single dose of rFVIIa, was seen in three patients. A good response, meaning that sustained hemostasis was achieved by a repeated rFVIIa administration, was seen in the remaining three patients. In one of these patients, the BAL treatment was repeated twice; in another patient, the second dose of rFVIIa was administered by nebulizer after extubation after the initial BAL. The hemostatic effect was statistically significant (p = 0.031). The oxygenation capacity, as reflected by the PaO2/FiO2 (arterial oxygen pressure/inspiratory fractional oxygen content) ratio, increased significantly (p = 0.024) in all six patients following the local rFVIIa therapy.
Conclusion
Symptomatic therapy of DAH after intrapulmonary administration of one or more doses of rFVIIa was found to have a good to excellent hemostatic effect in six consecutive patients with DAH. The intrapulmonary administration of rFVIIa seemed to have a high benefit-to-risk ratio. Larger series should confirm the safety of this approach.
doi:10.1186/cc5132
PMCID: PMC1794493  PMID: 17184515
23.  Intraoperative Use of Low-Dose Recombinant Activated Factor VII During Thoracic Aortic Operations 
The Annals of thoracic surgery  2012;93(6):1921-1929.
Background
Numerous studies have supported the effectiveness of recombinant activated factor VII (rFVIIa) for the control of bleeding after cardiac procedures; however safety concerns persist. Here we report the novel use of intraoperative low-dose rFVIIa in thoracic aortic operations, a strategy intended to improve safety by minimizing rFVIIa exposure.
Methods
Between July 2005 and December 2010, 425 consecutive patients at a single referral center underwent thoracic aortic operations with cardiopulmonary bypass (CPB); 77 of these patients received intraoperative low-dose rFVIIa (≤60 μg/kg) for severe coagulopathy after CPB. Propensity matching produced a cohort of 88 patients (44 received intraoperative low-dose rFVIIa and 44 controls) for comparison.
Results
Matched patients receiving intraoperative low-dose rFVIIa got an initial median dose of 32 μg/kg (interquartile range [IQR], 16–43 μg/kg) rFVIIa given 51 minutes (42–67 minutes) after separation from CPB. Patients receiving intraoperative low-dose rFVIIa demonstrated improved postoperative coagulation measurements (partial thromboplastin time 28.6 versus 31.5 seconds; p = 0.05; international normalized ratio, 0.8 versus 1.2; p < 0.0001) and received 50% fewer postoperative blood product transfusions (2.5 versus 5.0 units; p = 0.05) compared with control patients. No patient receiving intraoperative low-dose rFVIIa required postoperative rFVIIa administration or reexploration for bleeding. Rates of stroke, thromboembolism, myocardial infarction, and other adverse events were equivalent between groups.
Conclusions
Intraoperative low-dose rFVIIa led to improved postoperative hemostasis with no apparent increase in adverse events. Intraoperative rFVIIa administration in appropriately selected patients may correct coagulopathy early in the course of refractory blood loss and lead to improved safety through the use of smaller rFVIIa doses. Appropriately powered randomized studies are necessary to confirm the safety and efficacy of this approach.
doi:10.1016/j.athoracsur.2012.02.037
PMCID: PMC3718882  PMID: 22551846
24.  Evidence supporting the use of recombinant activated factor VII in congenital bleeding disorders 
Background:
Recombinant activated factor VII (rFVIIa, NovoSeven®) was introduced in 1996 for the treatment of hemophilic patients with antibodies against coagulation factor VIII or IX.
Objective:
To review the evidence supporting the use of rFVIIa for the treatment of patients with congenital bleeding disorders.
Patients and methods:
English-language databases were searched in September 2009 for reports of randomized controlled trials (RCTs) evaluating the ability of rFVIIa to restore hemostasis in patients with congenital bleeding disorders.
Results:
Eight RCTs involving 256 hemophilic patients with antibodies against coagulation factors, also known as inhibitors, were identified. The evidence supporting the use of rFVIIa in these patients was weak with regard to dose, clinical setting, mode of administration, efficacy, and adverse events, given the limited sample size of each RCT and the heterogeneity of the studies.
Conclusion:
The authors suggest that rFVIIa therapy in hemophilic patients with inhibitors should be based on the individual’s ability to generate thrombin and form a clot, and not on the patient’s weight alone. Therefore, assays for thrombin generation, such as whole-blood thromboelastography, have the potential to significantly improve the treatment of these patients.
PMCID: PMC2915535  PMID: 20689697
hemophilia; inhibitors; coagulation factor VIII; coagulation factor IX; rFVIIa; NovoSeven; FEIBA; hemostasis; RCT
25.  Recombinant-activated factor VII in patients with uncontrolled bleeding: A retrospective observational analysis 
Background:
Factor VIIa (recombinant) has an off-label use to control life-threatening bleeding that is refractory to other measures and was shown to decrease transfusion requirements.
Objective:
The primary objective of this study was to assess the safety and effectiveness of factor VIIa (recombinant) on blood transfusion requirements and coagulation parameters when used in patients whose bleeding was uncorrected by other means. The pharmacoeconomic impact for any discrepancy from our protocol was evaluated. Secondary outcomes included 4-hour and 28-day mortality, as well as safety of this agent in terms of thromboembolic complications.
Materials and Methods:
We retrospectively evaluated patients who received recombinant-activated factor VII (rFVIIa) for uncontrolled bleeding from June 2008 to April 2011. The medical records of 33 patients were evaluated. Coagulation parameters and blood products were determined 24 hours before and 24 hours after administration of rFVIIa, and the results compared. Patients were also screened for any thromboembolic complications.
Results:
Administration of rFVIIa reduced blood transfusion requirements and improved coagulation parameters significantly (P<0.05). No thromboembolic complications were reported. Most of the dosing was consistent with those recommended in our institutional protocol, with discrepancies resulting in an average cost of $56 058. Moreover, pH was reported in only 67% of patients. All patients treated with rFVIIa survived up to 4 hours after receiving this agent, while the 28-day mortality was 24% (8/33).
Conclusion:
The use of rFVIIa appears to be safe and effective in promoting hemostasis, as evident from reducing transfusion requirements and improving the coagulation variables.
doi:10.4103/0973-6247.95044
PMCID: PMC3353622  PMID: 22623836
Coagulopathy; hemorrhage; recombinant-activated factor VIIa; trauma; uncontrolled bleeding

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