Journal of Neuroscience Nursing:
Recombinant Factor VIIa and the Patient With Neurologic Bleeding: Separating Fact From Fiction
Criddle, Laura M.
Questions or comments about this article may be directed to Laura M. Criddle, PhD RN ACNS-BC CNRN CCNS FAEN, at email@example.com. She is a clinical nurse specialist at The Laurelwood Group, Scappoose, OR, and a clinical nurse at Oregon Health & Science University, Portland, OR.
Despite advances in care, the morbidity and the mortality associated with intracranial hemorrhage remain high (Hanley, 2003). Unlike bleeding in most other areas of the body, simple hemorrhage control measures such as applying tourniquets or direct pressure are not feasible options. Even surgical and interventional radiologic management of intracranial bleeding offer limited benefit. Although the actual amount of blood lost may be insignificant, the damage to adjacent neurological tissue caused by direct pressure, brain displacement, and toxic secondary effects can be devastating. This has prompted the search for a hemostatic agent capable of limiting intracranial hemorrhage expansion.
In the 1980s, the proclotting drug aminocaproic acid (Amicar) was administered to patients with aneurysmal subarachnoid hemorrhage, but this treatment was abandoned when thrombotic complications proved to exceed benefits (Liu-DeRyke & Rhoney, 2008). More recently, recombinant factor VIIa has been used investigationally in individuals with a variety of hemorrhagic disorders, including neurologic bleeding. Despite optimistic case reports, a small number of clinical trials, and significant media attention, this drug has yet to clearly demonstrate its efficacy.
Recombinant Factor VIIa
Recombinant activated factor VII, made from cloned baby hamster kidney cells (Welsby, Monroe, Lawson, & Hoffman, 2005), is variously referred to in the literature as factor VII, rFVIIa, rFVII, FVIIa, or activated factor VII. It is also known by the brand name NovoSeven® (Novo Nordisk, Denmark). Factor VIIa is a naturally occurring protein that plays an important role in the coagulation cascade. Given in pharmacologic doses, rFVIIa provides the body with supraphysiologic concentrations of clotting factor (Uhlmann & Eby, 2004).
What makes this drug attractive as a hemostatic agent is its mechanism of action. rFVIIa works primarily via a tissue factor (TF)-dependent effect. Coagulation is largely limited to the site of bleeding, thus avoiding generalized thrombosis (Barletta, Ahrens, Tyburski, & Wilson, 2005; Stein & Dutton, 2004). Although controversy exists as to the exact mechanisms involved, TF is exposed in traumatized vessels. Factor VIIa is attracted to the site of vascular damage where it binds with TF to produce high concentrations of TF/FVIIa complex (Hartmann & Sucker, 2007). In combination with FVa and FXa, this process ultimately results in thrombin generation. rFVIIa may also enhance platelet aggregation and make formed clots more resistant to fibrinolysis (Pusateri & Park, 2005).
Food and Drug Administration-Approved Indications and Off-Label Applications
Currently, the only Food and Drug Administration-approved indication for recombinant factor VIIa is the treatment of spontaneous, traumatic, or surgical bleeding episodes in patients with congenital factor VII deficiency and acquired hemophilia and those with hemophilia A or B who have inhibitors to factor VIII or IX (Uhlmann & Eby, 2004). rFVIIa has been shown to be safe and effective in this small population. Yet, despite limited approved indications, the drug has gained widespread use in nonhemophiliacs with acute bleeding episodes. In fact, in 2001-2 years after the drug's introduction-less than 1000 persons in the United States received rFVIIa. By 2005, annual use had soared to approximately 5000 persons (O'Connell, Wood, Wise, Lozier, & Braun, 2006). It seems unlikely that this fivefold increase was related to an escalating number of persons with congenital or acquired factor VII deficiency.
Off-label, rFVIIa has been administered to patients with an assortment of hemorrhagic conditions ranging from gunshot wounds to amniotic fluid embolus. Unfortunately, the administration of rFVIIa as a universal hemostatic agent for hemorrhage is not as straightforward as it is for bleeding associated with hemophilia. At best, rFVIIa can be viewed as a nonspecific coagulation enhancer (Erhardtsen, 2002; Uhlmann & Eby, 2004).
The medical literature contains abundant case reports of rFVIIa administration leading to hemostasis in patients undergoing hepatic, cardiovascular, obstetric, or gynecologic surgery when standard hemorrhage control measures and aggressive blood transfusion have failed (Grounds, 2003; Hardy, 2002; Khan et al., 2005; Ranucci, Isgro, Soro, Conti, & De Toffol, 2008; van Veen et al., 2008; Warren et al., 2007). A number of retrospective reports describe bleeding control after rFVIIa administration to exsanguinating trauma patients (Hardy, 2002; Lynn, Jeroukhimov, Klein, & Martinowitz, 2002; Martinowitz, Kenet, Lubetski, Luboshitz, & Segal, 2002; Martinowitz et al., 2001). More recently, U.S. healthcare providers in Iraq have published accounts of achieving hemostasis in cases of life-threatening hemorrhage because of combat injuries (Perkins, Schreiber, Wade, & Holcomb, 2007; Spinella et al., 2008). Off-label use of rFVIIa has also been documented in bleeding Jehovah's Witnesses who have refused transfusion (Veneri & Franchini, 2005).
The State of the Evidence
The idea that a universal cure for hemorrhage could be found in a drug vial is extremely alluring. Unfortunately, despite hopeful case reports, randomized, prospective, controlled studies of rFVIIa for off-label use are scarce. Moreover, clinical trials to date have demonstrated limited benefits. The absence of uniform dosing regimens, the multiple uncontrolled variables, the lack of control groups, the ill-defined clinical end points, and the risk of reporting bias have all made it difficult to draw comparisons between published studies (Criddle, 2006). In 2007, the Cochrane Collaboration reviewed seven placebo-controlled, double-blind, randomized clinical trials and concluded that patients who received rFVIIa showed a trend toward reduced mortality (risk ratio = 0.82) but demonstrated an increase risk of thromboembolic events (risk ratio = 1.50; Stanworth, Birchall, Doree, & Hyde, 2007). Despite these less-than-optimistic results, rFVIIa has been trialed in patients with intracranial bleeding from traumatic, surgical, spontaneous, and coagulopathic causes (Ilyas, Beyer, Dutton, Scalea, & Hess, 2008; Kapapa et al., 2009; Kluger et al., 2007).
rFVIIa and the Neurotrauma Patient
The effects of rFVIIa have been investigated in patients with a variety of traumatically induced neurologic insults. Individuals anticoagulated with warfarin experience grim outcomes after head injury. In-hospital mortality in this population approaches 50% compared with approximately 10% in non-anticoagulated but otherwise matched controls (Karni et al., 2001; Lavoie et al., 2004; Mina, Bair, Howells, & Bendick, 2003). Hence, there has been much interest in the potential benefits of rFVIIa therapy in this population. Ilyas et al. (2008) studied 54 warfarin anticoagulated individuals with traumatic intracranial hemorrhage, primarily due to subdural hematomas. Twenty-four subjects received conventional therapy only (vitamin K, fresh frozen plasma), whereas 30 were treated with rFVIIa as well. The authors concluded that patients treated with rFVIIa required significantly less plasma (4 vs. 7 U) to correct their prothrombin time-international normalized ratio (PT-INR) and corrected in a much shorter period (4 vs. 10 hours). Unfortunately, no information about patient survival or other outcome measures was included.
Kluger et al. (2007) examined the safety of rFVIIa in 30 hemodynamically unstable severe blunt trauma patients with brain injuries. Subjects were randomized to receive either 400 μg/kg of rFVIIa or placebo. There were no significant differences between the groups in the number of adverse events or in-hospital mortality, but no other patient outcome data were reported (Kluger et al., 2007). The study of rFVIIa by Stein, Dutton, Alexander, Miller, and Scalea (2009) focused on 148 potential organ donors, all of whom had suffered devastating neurologic injuries. Twenty-nine of these subjects received rFVIIa. Analysis indicated that there were no differences between the two groups with respect to the number of transplantable organs per donor or early graft function. The researchers concluded that rFVIIa facilitated organ harvesting in severely brain-injured patients who otherwise might have been ineligible for donation (Stein et al., 2009).
rFVIIa and the Neurosurgical Patient
A Medline search of the literature identified a handful of case series but failed to produce any published prospective, randomized clinical trials of rFVIIa administration in neurosurgical patients. A descriptive study by researchers at the National Brain Aneurysm Center reported the perioperative use of rFVIIa to prevent intraoperative aneurysm rupture in 18 high-risk subarachnoid hemorrhage patients undergoing craniotomy for aneurysm clipping. None of the subjects experienced aneurysm rupture. The group had a total of eight postoperative venous thrombotic events identified on Doppler screening exam, but there were no significant immediate or long-term adverse effects attributable to rFVIIa use (Nussbaum, Janjua, Defillo, Sinner, & Zelensky, 2009).
German researchers related the cases of five neurosurgical patients who received rFVIIa for the treatment (n = 3) or prevention (n = 2) of severe intraoperative bleeding. In all five cases, the operation was successfully completed after drug administration, and all patients achieved normalization of their coagulation status (Kapapa et al., 2009). In a similarly small case series, a group of French researchers described their use of rFVIIa in pediatric neurosurgical patients experiencing massive intraoperative hemorrhage. Three of the four subjects achieved a good recovery (Uhrig et al., 2007).
rFVIIa and the Hemorrhagic Stroke Patient
Although individuals with a hemorrhagic etiology constitute only 8-15% of the stroke population, this form of stroke is the least treatable and the most devastating. One-year mortality is approximately 50%, and associated morbidity is extremely high (Hanley, 2003). Not only do patients suffer the initial bleeding event, but early hematoma expansion is the natural course of the disease. Thirty-eight percent of patients will demonstrate hemorrhage progression within 3 hours; 60% of this subgroup experience hematoma growth in the first 60 minutes (Brott et al., 1997). Because hematoma expansion is an independent risk factor for poor outcome and high mortality, timely hemorrhage control is desirable. This goal ha sgenerated much interest in the potential role of rFVIIa in the management of spontaneous intracerebral hemorrhage (ICH).
In a study published in 2005, Mayer et al. (2005) randomly assigned 399 ICH patients to receive either placebo or one of three doses of rFVIIa within 1 hour of their initial computed tomography scan. Patients were rescanned 24 hours later, and the percent change in ICH volume was calculated. Clinical outcomes at 90 days were also measured. Researchers concluded that despite a small increase in the frequency of thromboembolic adverse events, treatment with rFVIIa within 4 hours of ICH onset limited hematoma growth, reduced mortality, and improved functional outcome at 90 days (Mayer et al., 2005). Although this work generated much enthusiasm in the neuroscience community, the sample size was too small to make statistically valid determinations about the effect of treatment on outcome.
Undaunted, Mayer's group conducted a confirmatory study with more than double the sample size. This time, the findings were much less positive: "hemostatic therapy with rFVIIa reduced hematoma growth but did not improve survival or functional outcome after ICH" (Mayer et al., 2008). Most recently, these same researchers have reanalyzed their results in an attempt to identify whether specific ICH subpopulations demonstrated benefits from rFVIIa therapy. In particular, the data suggest that hemostatic therapy was effective in patients less than 70 years old, in patients with small ICH and intraventricular hemorrhage volumes, and in patients who received the drug within 2.5 hours of symptom onset. However, the study authors caution that a prospective trial will be necessary before drawing any definitive conclusions (Mayer et al., 2009).
Individuals with the worst prognosis after ICH are those who are anticoagulated at the time of insult. Hemorrhagic stroke is 8 to 10 times more common in patients taking warfarin than in the general population. Because in-hospital mortality in this group has been reported to be as high as 67%, clinicians have been eager to find anything that might improve outcome (Appelboam & Thomas, 2009). In a very small case series, Freeman et al. (2004) reviewed the records of seven consecutive ICH patients who had spontaneous, symptomatic, nontraumatic, warfarin-related acute intracranial bleeds. All seven subjects (mean age = 87 years) were treated with intravenous rFVIIa. Patients' PT-INR decreased from a mean of 2.7 before drug administration to a mean of 1.08 afterward. However, two of seven subjects died during hospitalization, and the remainder were discharged with severe disability (Freeman et al., 2004). Researchers in two additional studies of patients taking warfarin before hemorrhagic stroke have documented similar reductions in anticoagulant reversal time in subjects who received rFVIIa. (Brody, Aiyagari, Shackleford, & Diringer, 2005; Da'as, Misgav, Kalish, & Varon, 2006). Unfortunately, both studies were retrospective, sample sizes were small, and each lacked postdischarge outcome data.
Besides basic safety and efficacy concerns, several other questions regarding rFVIIa administration in theneuroscience population remain to be answered. Guidelines for patient selection, ideal dosing, timing of drug administration, and determining a point at which administration becomes futile all have yet to be established.
Timing appears to play a significant role in the success or failure of rFVIIa therapy. Given to moribund patients, the probability of benefit is slim (Clark, Gordon, Walker, & Tait, 2004). However, can prophylactic use (e.g., preoperative administration to high-risk surgical patients) be justified? Under what circumstances? And when in the course of hemorrhage, should the decision to administer the medication be made? A retrospective review of rFVIIa use in patients with combat wounds found that subjects who received the drug before the infusion of 8 U of blood products required significantly fewer units during the first 24-hour period than did those who did not receive rFVIIa until after 8 U had been transfused. Nevertheless, mortality among the two groups was identical (Perkins et al., 2007).
The standard rFVIIa dose in hemophiliacs is 90 μg/kg every 2 hours until hemostasis is achieved. In the hemophiliac population, doses as high as 120 μg/kg have been used preoperatively and during serious bleeding episodes. Some authors have even recommended "megadoses" of up to 240 μg/kg, and single boluses of 300 μg/kg have been given to hemophiliac children and adolescents. In fact, there is evidence to suggest that the continuous infusion of rFVIIa may be beneficial in hemorrhaging hemophiliac patients (Stein & Dutton, 2004).
The goal of rFVIIa therapy is to give enough drug to generate a thrombin burst that will form a stable clot, but the optimal drug quantity in the patient with intracranial bleeding is currently unknown, and widely varying dosing regimens have been trialed. For example, in a review of five small warfarin-induced ICH studies, doses as low as 10 μg/kg and as high as 120 μg/kg were reported (Da'as et al., 2006).
Objective information regarding the off-label dosing of rFVIIa is beginning to appear as some prospective randomized trials are completed. In their original study of rFVIIa and ICH, Mayer et al. (2005) randomized patients to receive placebo, 40, 80, or 160 μg/kg doses. Because there were no dose-related differences in 90-day mortality or thromboembolic events among subjects who received the drug, the 2008 study by the same researchers limited dosing options to 0 (placebo), 20, or 80 μg/kg (Mayer et al., 2008).
A therapeutic dose of recombinant factor VIIa produces serum concentrations 100 to 1000 times greater than basal levels, warranting concern about the potential for inappropriate thrombosis (Pusateri & Park, 2005; Uhlmann & Eby, 2004). Post rFVIIa administration, clotting in deep extremity veins, lungs, coronary arteries, cerebral arteries, and cerebral venous sinuses and in various vascular access devices have all been described (O'Connell et al., 2006; Siegel et al., 2004). Because thrombotic events are not uncommon in critically ill patients, it has been difficult to establish the role of rFVIIa in inadvertent thrombus formation.
Between 1996 and 2001, an estimated 480,000 90 μg/kg doses of rFVIIa were administered to bleeding hemophiliacs, with only 17 documented thrombotic events. Seven of these were myocardial infarctions, five of which occurred in patients over the age of 70 years, suggesting that coexisting risk factors contributed to the thrombotic complications. Nevertheless, four younger hemophiliac patients-ages 27 to 57 years-experienced venous thromboembolic events within 1 week of rFVIIa infusion (Uhlmann & Eby, 2004). The drug's duration of action, however, is short. In adult hemophiliacs, plasma half-life is under 3 hours, less in children. Duration of action is further reduced in the presence of ongoing blood loss and transfusion (Da'as et al., 2006; Gibbs, 2006). Just how long after injection can thrombus formation be attributed to rFVIIa administration?
In the largest series of rFVIIa use in neuroscience patients, the ICH trial of Mayer et al. (2005) documented a 2% incidence of serious thromboembolic events in placebo patients and a 7% incidence among those receiving rFVIIa (Mayer et al., 2005). The 2008 follow-up study recorded no difference in venous thrombotic events between subjects and controls, but there was a 4%, 5%, and 8% incidence of arterial thrombotic episodes in patients respectively receiving placebo, 20 μg/kg, and 80 μg/kg doses (Mayer et al., 2008).
In addition to safety and efficacy questions, much of the controversy surrounding rFVIIa use concerns the drug's cost. Currently, recombinant factor VIIa is one of the most expensive medications available. The average wholesale price in the United States is $4,500 per 4.8-mg vial. For an 80-kg patient, the cost of a single 90 μg/kg dose is approximately $6,750 (Fishman, Drumheller, Dubon, & Slesinger, 2008). Arguably, shock, surgery, medical complications, extended hospitalization, rehabilitation, disability, and death are expensive as well. In fact, conventional therapy with blood product replacement is also associated with substantial expense. In a retrospective review of transfusion at one trauma center, the average total cost of blood products in patients who required 50 or more units in the first 24 hours was over $49,000 per survivor and $51,000 per nonsurvivor (Criddle, Eldredge, & Walker, 2005). In relation to massive transfusion costs, the high price of rFVIIa appears more reasonable, provided it can indeed reduce blood product requirements and hemorrhagic complications.
NovoSeven®, activated factor VII (recombinant), has traditionally been supplied in 1.2-, 2.4-, and 4.8-mg vials. A recently released form of rFVIIa, NovoSeven® RT, is produced in 1-, 2-, and 5-mg vials. The "RT" designation on the newer formulation of the drug indicates the product is stable at room temperature (2-25°C), although refrigeration remains an option. Both versions of the drug require reconstitution with sterile water before administration. Inject the diluent against the side of the vial; do not inject sterile water directly onto the NovoSeven powder. Gently swirl the vial until all drug is dissolved. After reconstitution with the specified amount of sterile water (amount varies by vial size), the 1.2-, 2.4-, and 4.8-mg vials will contain approximately 0.6 mg of NovoSeven per milliliter (600 μg/ml). NovoSeven RT 1-, 2-, and 5-mg vials will contain 1000, 2000, or 5000 μg per vial once reconstituted with the supplied diluent. The mixed solution should be clear and colorless.
NovoSeven contains no preservatives. After reconstitution, the refrigerated product may be used for up to 3 hours. NovoSeven is intended for bolus use only; inject the drug slowly, over 2 to 5 minutes. Because no data are available regarding intravenous line compatibility with other solutions, NovoSeven should not be administered through any line containing additional medications. Flush the tubing before and after rFVIIa administration if another agent has been infusing through the line. Consult the NovoSeven package insert or the Novo Nordisk Web site (http://www.us.novoseven.com) for additional product information. NovoSeven is contraindicated in patients with known sensitivity to mouse, hamster, or bovine proteins. Signs of hypersensitivity reactions include hives, wheezing, chest tightness, urticaria, hypotension, and anaphylaxis. Serious adverse reactions to NovoSeven are rare, but patients should be monitored for signs of venous or arterial thrombosis, which can occur anywhere in the body.
Currently, no specific laboratory assays have been identified to monitor rFVIIa therapy (Lam & Sims-McCallum, 2005). Standard laboratory coagulation parameters-PT-INR and activated partial thromboplastin time-may be used as an adjunct to the clinical evaluation of coagulopathy. However, neither these nor any other hematologic parameters have shown a direct correlation with rFVIIa-induced hemostasis.
Notwithstanding its limited Food and Drug Administration-approved indications, rFVIIa has rapidly gained widespread use for the treatment of a variety of hemorrhagic conditions, including intracranial bleeding from spontaneous, traumatic, surgical, and coagulopathic causes. Although it appears that the drug only minimally increases the risk of thromboembolic events, its efficacy remains in question. The idea of finding a universal cure for hemorrhage in a medication bottle remains highly appealing, but enthusiasm for the concept is no replacement for evidence. Neuroscience nurses, who are the interface between patients and rFVIIa, need to balance hope and hype until the facts are all in.
Appelboam, R., & Thomas, E. O. (2009). Warfarin and intracranial haemorrhage. Blood Reviews
Barletta, J. F., Ahrens, C. L., Tyburski, J. G., & Wilson, R. F. (2005). A review of recombinant factor VII for refractory bleeding in nonhemophilic trauma patients. Journal of Trauma, Injury, Infection, and Critical Care
Brody, D. L., Aiyagari, V., Shackleford, A. M., & Diringer, M. N. (2005). Use of recombinant factor VIIa in patients with warfarin-associated intracranial hemorrhage. Neurocritical Care
Brott, T., Broderick, J., Kothari, R., Barsan, W., Tomsick, T., Sauerbeck, L., et al. (1997). Early hemorrhage growth in patients with intracerebral hemorrhage. Stroke
Clark, A. D., Gordon, W. C., Walker, I. D., & Tait, R. C. (2004). 'Last-ditch' use of recombinant factor VIIa in patients with massive haemorrhage is ineffective. Vox Sanguinis
Criddle, L. M. (2006). Recombinant factor VIIa and the trauma patient. Journal of Emergency Nursing
Criddle, L. M., Eldredge, D. H., & Walker, J. (2005). Variables predicting trauma patient survival following massive transfusion. Journal of Emergency Nursing
Da'as, N., Misgav, M., Kalish, Y., & Varon, D. (2006). Recombinant factor VIIa for rapid reversal of anticoagulant effect in patients with intracranial hemorrhage: The Israeli experience and review of the literature. Israel Medical Association Journal
Erhardtsen, E. (2002). To general haemostasis-The evidence-based route. Pathophysiology of Haemostasis and Thrombosis
Fishman, P. E., Drumheller, B. C., Dubon, M. E., & Slesinger, T. L. (2008). Recombinant activated factor VII use in the emergency department. Emergency Medicine Journal
Freeman, W. D., Brott, T. G., Barrett, K. M., Castillo, P. R., Deen, H. G. Jr., Czervionke, L. F., et al. (2004). Recombinant factor VIIa for rapid reversal of warfarin anticoagulation in acute intracranial hemorrhage. Mayo Clinic Proceedings
Gibbs, N. M. (2006). The place of recombinant activated factor VII in liver transplantation. International Anesthesiology Clinics
Grounds, M. (2003). Recombinant factor VIIa (rFVIIa) and its use in severe bleeding in surgery and trauma: A review. Blood Reviews
Hanley, D. F. (2003). Review of critical care and emergency approaches to stroke. Stroke
Hardy, J. F. (2002). Managing uncontrolled hemorrhage in trauma and surgery: A novel and promising approach. Canadian Journal of Anaesthesia
Hartmann, M., & Sucker, C. (2007). Pharmacology and clinical use of recombinant activated factor seven in neurosciences. Neurocritical Care
Ilyas, C., Beyer, G. M., Dutton, R. P., Scalea, T. M., & Hess, J. R. (2008). Recombinant factor VIIa for warfarin-associated intracranial bleeding. Journal of Clinical Anesthesia
Kapapa, T., Konig, K., Heissler, H. E., Schatzmann, C., Tschan, C. A., Perl, M., et al. (2009). The use of recombinant activated factor VII in neurosurgery. Surgical Neurology
Karni, A., Holtzman, R., Bass, T., Zorman, G., Carter, L., Rodriguez, L., et al. (2001). Traumatic head injury in the anticoagulated elderly patient: A lethal combination. American Surgeon
Khan, A. Z., Parry, J. M., Crowley, W. F., McAllen, K., Davis, A. T., Bonnell, B. W., et al. (2005). Recombinant factor VIIa for the treatment of severe postoperative and traumatic hemorrhage. American Journal of Surgery
Kluger, Y., Riou, B., Rossaint, R., Rizoli, S. B., Boffard, K. D., Choong, P. I., et al. (2007). Safety of rFVIIa in hemodynamically unstable polytrauma patients with traumatic brain injury: Post hoc analysis of 30 patients from a prospective, randomized, placebo-controlled, double-blind clinical trial. Critical Care
Lam, M. S., & Sims-McCallum, R. P. (2005). Recombinant factor VIIa in the treatment of non-hemophiliac bleeding. Annals of Pharmacotherapy
Lavoie, A., Ratte, S., Clas, D., Demers, J., Moore, L., Martin, M., et al. (2004). Preinjury warfarin use among elderly patients with closed head injuries in a trauma center. Journal of Trauma, Injury, Infection, and Critical Care
Liu-DeRyke, X., & Rhoney, D. (2008). Hemostatic therapy for the treatment of intracranial hemorrhage. Pharmacotherapy
Lynn, M., Jeroukhimov, I., Klein, Y., & Martinowitz, U. (2002). Updates in the management of severe coagulopathy in trauma patients. Intensive Care Medicine
Martinowitz, U., Kenet, G., Lubetski, A., Luboshitz, J., & Segal, E. (2002). Possible role of recombinant activated factor VII (rFVIIa) in the control of hemorrhage associated with massive trauma. Canadian Journal of Anaesthesia
Martinowitz, U., Kenet, G., Segal, E., Luboshitz, J., Lubetsky, A., Ingerslev, J., et al. (2001). Recombinant activated factor VII for adjunctive hemorrhage control in trauma. Journal of Trauma, Injury, Infection, and Critical Care
Mayer, S. A., Brun, N. C., Begtrup, K., Broderick, J., Davis, S., Diringer, M. N., et al. (2008). Efficacy and safety of recombinant activated factor VII for acute intracerebral hemorrhage. New England Journal of Medicine
Mayer, S. A., Brun, N. C., Begtrup, K., Broderick, J., Davis, S., Diringer, M. N., et al. (2005). Recombinant activated factor VII for acute intracerebral hemorrhage. New England Journal of Medicine
Mayer, S. A., Davis, S. M., Skolnick, B. E., Brun, N. C., Begtrup, K., Broderick, J. P., et al. (2009). Can a subset of intracerebral hemorrhage patients benefit from hemostatic therapy with recombinant activated factor VII? Stroke
Mina, A. A., Bair, H. A., Howells, G. A., & Bendick, P. J. (2003). Complications of preinjury warfarin use in the trauma patient. Journal of Trauma, Injury, Infection, and Critical Care
Nussbaum, E. S., Janjua, T. M., Defillo, A., Sinner, P., & Zelensky, A. (2009). Perioperative use of recombinant factor VII to prevent intraoperative aneurysm rupture in high risk patients: A preliminary safety evaluation. Neurocritical Care
O'Connell, K. A., Wood, J. J., Wise, R. P., Lozier, J. N., & Braun, M. M. (2006). Thromboembolic adverse events after use of recombinant human coagulation factor VIIa. JAMA
Perkins, J. G., Schreiber, M. A., Wade, C. E., & Holcomb, J. B. (2007). Early versus late recombinant factor VIIa in combat trauma patients requiring massive transfusion. Journal of Trauma, Injury, Infection, and Critical Care
Pusateri, A. E., & Park, M. S. (2005). Mechanistic implications for the use and monitoring of recombinant activated factor VII in trauma. Critical Care
(Suppl. 5), S15-S24.
Ranucci, M., Isgro, G., Soro, G., Conti, D., & De Toffol, B. (2008). Efficacy and safety of recombinant activated factor VII in major surgical procedures: Systematic review and meta-analysis of randomized clinical trials. Archives of Surgery
Siegel, L. J., Gerigk, L., Tuettenberg, J., Dempfle, C. E., Scharf, J., & Fiedler, F. (2004). Cerebral sinus thrombosis in a trauma patient after recombinant activated factor VII infusion. Anesthesiology
Spinella, P. C., Perkins, J. G., McLaughlin, D. F., Niles, S. E., Grathwohl, K. W., Beekley, A. C., et al. (2008). The effect of recombinant activated factor VII on mortality in combat-related casualties with severe trauma and massive transfusion. Journal of Trauma, Injury, Infection, and Critical Care
Stanworth, S. J., Birchall, J., Doree, C. J., & Hyde, C. (2007). Recombinant factor VIIa for the prevention and treatment of bleeding in patients without haemophilia. Cochrane Database of Systematic Reviews
, (2), CD005011. doi: 10.1002/14651858.CD005011.pub2
Stein, D. M., & Dutton, R. P. (2004). Uses of recombinant factor VIIa in trauma. Current Opinion in Critical Care
Stein, D. M., Dutton, R. P., Alexander, C., Miller, J., & Scalea, T. M. (2009). Use of recombinant factor VIIa to facilitate organ donation in trauma patients with devastating neurologic injury. Journal of the American College of Surgeons
Uhlmann, E. J., & Eby, C. S. (2004). Recombinant activated factor VII for non-hemophiliac bleeding patients. Current Opinion in Hematology
Uhrig, L., Blanot, S., Baugnon, T., Orliaguet, G., Carli, P. A., & Meyer, P. G. (2007). Use of recombinant activated factor VII in intractable bleeding during pediatric neurosurgical procedures. Pediatric Critical Care Medicine
van Veen, E. J., Monteban-Kooistra, W. E., Meertens, J. H., Ligtenberg, J. J., Tulleken, J. E., Zijlstra, J. G., et al. (2008). Recombinant human activated factor VII in postpartum hemorrhagic shock: The dark side. Intensive Care Medicine
Veneri, D., & Franchini, M. (2005). Successful treatment of intestinal hemorrhage in a Jehovah's Witness patient. American Journal of Hematology
Warren, O., Mandal, K., Hadjianastassiou, V., Knowlton, L., Panesar, S., John, K., et al. (2007). Recombinant activated factor VII in cardiac surgery: A systematic review. Annals of Thoracic Surgery
Welsby, I. J., Monroe, D. M., Lawson, J. H., & Hoffman, M. (2005). Recombinant activated factor VII and the anesthetist. Anesthesia
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