Recombinant factor VIIa

Human coagulation factor (F) VII is a single chain protease that circulates in the blood as a weakly active zymogen at concentrations of approximately 10 nmol/L. When converted to the active 2 chain form (FVIIa), it is a powerful initiator of haemostasis. Recombinant factor VIIa (rFVIIa, eptacog alfa, NovoSeven) is a genetically engineered product that was first introduced in 1988 for the treatment of patients with haemophilia A and B with high inhibitory antibody titres to factors VIII and IX. Recent reports in the form of case studies and series, and early trial data, have suggested a role for rFVIIa across a diverse range of indications including bleeding associated with trauma, surgery, thrombocytopaenia, liver disease and oral anticoagulant toxicity. This review describes the physiology of the coagulation pathway and in particular the role of recombinant factor VIIa. It will also focus on the emerging role of rFVIIa in both trauma and non-trauma bleeding and its potential use in the ED.     

Recombinant factor VIIa use in refractory ulcer bleeding in uremic patient

Peptic ulcer bleeding is thought to be a major cause of bleeding in patients with end-stage renal disease and is more complicated in uremic patients. We described a 41-year-old man with end-stage renal disease who underwent hemodialysis with refractory ulcer bleeding, failure to all traditional peptic ulcer treatments, and correction of uremic component, who has been successfully treated by using recombinant factor VIIa. There have been few case reports in dealing refractory upper gastrointestinal bleeding in uremic patients in the literature; and in this case report, we demonstrates that recombinant factor VIIa could be used as a rescue therapy in these high–surgical risk patients when medical therapy fails.     

Recombinant factor VIIa in the treatment of non-hemophiliac bleeding

OBJECTIVE: To review the clinical evidence for the use of recombinant factor VIIa (rFVIIa) in the prevention and/or treatment of bleeding in non-hemophiliac patients. DATA SOURCES: A MEDLINE search (1966-December 2004) was conducted to identify pertinent literature. Results were limited to English-language reports and clinical trials. References of relevant articles and selected abstracts presented at scientific meetings were also reviewed. STUDY SELECTION AND DATA EXTRACTION: Human data from prospective and retrospective studies that examined the hemostatic effect of rFVIIa in non-hemophiliac patients were reviewed, with a focus on surgical prophylaxis, liver disease, intractable bleeding associated with trauma and surgery, and anticoagulation reversal. DATA SYNTHESIS: Results from limited controlled trials on the use of rFVIIa as an adjunct for prevention of bleeding in surgery and liver diseases have not been consistent. For treatment of intractable bleeding, earlier use of rFVIIa in one trauma trial was shown to decrease the number of blood transfusions, but no differences in terms of clinical outcomes were observed in all trials. Controlled trials do not suggest an increased risk of thrombotic events. Optimal dosing and timing of administration have yet to be defined. CONCLUSIONS: Until further prospective controlled data are available, it is recommended that conventional intervention for prevention and control of hemorrhage in non-hemophiliac patients should remain the standard of care. Close monitoring of coagulation parameters is recommended before, during, and after therapy, especially in high-risk patients. Pharmacoeconomic analysis may be useful to help control costs and maximize clinical benefits.     

Uses of recombinant factor VIIa in trauma

PURPOSE OF REVIEW: Despite advances in the care of the injured, the morbidity and mortality of traumatic hemorrhage remain a significant problem. Traumatologists continue to look for ways to treat bleeding and prevent the sequelae of hemorrhagic shock. Recombinant factor VIIa, developed for the treatment of patients with hemophilia, has been used with some success in acute bleeding associated with injuries. RECENT FINDINGS: The mechanism of action is via a tissue factor-dependent effect and/or platelet activation. Coagulation occurs at the site of tissue injury, where tissue factor is exposed. Case series have described the beneficial effects of recombinant factor VIIa in the treatment of acute hemorrhage, early treatment of traumatic brain injury, and reversal of premorbid anticoagulation. In addition, there have been numerous reports of recombinant factor VIIa use in acute bleeds secondary to other causes as well as some evidence that recombinant factor VIIa may be efficacious when used prophylactically in high-risk patients and for high-risk procedures. Typical doses range from 50 to 100 microg/kg as a single bolus. Although there has been concern over the risk of inappropriate thrombosis with recombinant factor VIIa administration, this complication has seldom been described in published series. SUMMARY: Although case experience is encouraging, no level 1 evidence has been published that demonstrates clinical or economic benefit of the use of recombinant factor VIIa in trauma patients. Many questions remain to be answered, ideally through randomized, prospective clinical trials. In particular, the issues of patient selection, ideal dosing, and factors associated with futile administration need to be elucidated.     

Recombinant factor VIIa (NovoSeven) as a hemostatic agent

Recombinant activated factor VII (rFVIIa; NovoSeven, Novo Nordisk, Denmark) induces hemostasis in life- and limb-threatening bleeds and in major surgery of hemophilia A and B patients, regardless of inhibitor titer. A total of more than 6,500 patients have been treated, and NovoSeven has been administered in more than 180,000 standard doses. Experience gained from these clinical situations suggests that NovoSeven should be administered as a 90- to 110-microg/kg bolus dose every second hour. Hemophilia patients with mild to moderate bleeding episodes require two to three doses to achieve complete hemostasis, whereas patients with severe bleeding episodes may require more doses. For major surgery and in cases of life-threatening bleeding, dosing every second hour for the first 24 hours may be required. Thereafter, the same dose, but with longer intervals between doses, is recommended. Recent in vitro experiments indicate that even higher doses of NovoSeven may be needed to achieve full thrombin generation in the absence of factor VIII (FVIII), factor IX (FIX), and factor XI (FXI).     

Recombinant factor VIIa for refractory bleeding following orthotopic heart transplantation

OBJECTIVE: To report a case of successful use of recombinant factor VIIa (rFVIIa) for the treatment of refractory bleeding in a patient undergoing orthotopic heart transplantation. CASE SUMMARY: A 57-year-old white male with idiopathic cardiomyopathy was taken to the operating room for explantation of his left-ventricular assist device and orthotopic heart transplantation. He experienced excessive generalized oozing that required transfusions of multiple units of blood products and significant amounts of Cellsaver (washed red blood cells via autotransfusion) without achieving adequate hemostasis. After ruling out any obvious surgical sources of bleeding and attempting to correct all coagulation deficiencies, the clinicians administered rFVIIa 90 microg/kg. The oozing rapidly declined to a negligible level, chest tubes and sternal wires were placed, and the chest was closed. The patient was on minimal inotropic support and was transferred to the intensive care unit in stable condition. DISCUSSION: Cardiac surgery is often associated with significant disruption of the coagulation system, particularly in high-risk patients, such as those undergoing removal of a ventricular assist device and subsequent orthotopic heart transplantation. This can lead to life-threatening bleeding that can require multiple hemostatic agents and significant transfusions to restore hemostasis. Recently, rFVIIa has been utilized as an alternative to massive transfusion for treatment of refractory bleeding in several patient populations, including some cardiac surgery patients. CONCLUSIONS: rFVIIa appears to be a viable option as rescue therapy for treatment of refractory bleeding following orthotopic heart transplantation. Despite the anecdotal success of rFVIIa in this setting, further clinical research is needed.     

Recombinant factor VIIa in patients with platelet function disorders or thrombocytopenia

Apart from on-label indications, recombinant factor VIIa (rFVIIa) is increasingly administered for treatment of life threatening bleeding events when appropriate standard therapy fails. Case reports and short treatment series document the efficacy and safety of rFVIIa to achieve haemostasis in patients with platelet function disorders and thrombocytopenias of various origin. An established on-label indication for the use of rFVIIa is given in patients with Glanzmann thrombasthenia with refractoriness to transfusions of platelet concentrates. Bolus applications of rFVIIa at dosages between 80 and 120 microg/kg body weight every 1.5 to 3 h are also administered successfully in patients with Bernard-Soulier syndrome, platelet storage pool defects, and other acquired platelet function disorders. In patients with Glanzmann thrombasthenia, at least three bolus injections are required to achieve effective haemostasis. In approximately half of the patients with thrombocytopenias, a single bolus of rFVIIa has been shown to be sufficient in managing otherwise untreatable bleeding complications. In these patients, haemostasis was achieved even at platelet counts <20,000/microl, although the efficacy of rFVIIa increases at higher platelet concentrations.     

Recombinant human factor VIIa (rFVIIa) can activate factor FIX on activated platelets

The studies reported here show that factor (F)VIIa can activate factor (F)IX on activated platelets in the absence of tissue factor. Both FIX and FIXa bind to the activated platelet surface with a K(d) of 8 nM and 2 nM, respectively. With factor (F)VIIIa, FIXa binds more tightly to platelets (K(d) 0.6 nM). At rFVIIa concentrations < 100 nm, no direct binding to the activated platelet surface can be detected with electrophoretic light scattering. However, in the presence of FIX, rFVIIa binding to platelets at concentrations as low as 10 nm rFVIIa can be detected. This is reflected by a decrease in the FIX K(d) from 8 to 1.6 nM. When rFVIIa is added to activated platelets in the presence of both FIX and FVIIIa, the K(d) for FIX decreases to 0.6, suggesting that rFVIIa activates FIX on the surface of activated platelets in the absence of tissue factor. The activation of FIX by FVIIa on activated platelets can also be demonstrated by a functional assay for FIXa. These data show that pharmacological doses of rFVIIa result in the direct activation of FIX by rFVIIa to form additional tenase complexes ultimately resulting in improved thrombin generation. These results may explain, at least in part, the mechanism of action of rFVIIa in hemorrhagic conditions seen in otherwise normal patients who develop an acquired coagulopathy due to trauma, surgery or a variety of other events in which rFVIIa has been found to be effective.     

Recombinant factor VIIa reverses the in vitro and ex vivo anticoagulant and profibrinolytic effects of fondaparinux

Summary.  Background : Fondaparinux is a synthetic pentasaccharide, which selectively inhibits coagulation factor (F) Xa, and is registered for prevention of venous thromboembolism following hip fracture, hip replacement, and knee replacement surgery. Recently, it was shown that recombinant FVIIa (rFVIIa) reverses anticoagulant effects of fondaparinux in healthy volunteers. Objectives : In this study, we have explored the in vitro and ex vivo effects of rFVIIa on clot formation and thrombin-activatable fibrinolysis inhibitor (TAFI)-mediated down-regulation of fibrinolysis after fondaparinux administration. Methods :  In vitro clot lysis assays were performed in pooled normal plasma from healthy volunteers to which fondaparinux was added, and in serial samples from healthy volunteers who received a single bolus dose of fondaparinux, a single bolus dose of rFVIIa, or both. Results and conclusions : Fondaparinux significantly delayed clot formation, and clot lysis was significantly increased due to decreased activation of TAFI. Addition of recombinant FVIIa corrected the inhibited clot formation induced by fondaparinux, and the acceleration of clot lysis was partially reversed. In vivo administration of fondaparinux (10 mg) to healthy volunteers similarly resulted in accelerated plasma clot lysis. Subsequent administration of rFVIIa (90 µg kg⁻¹) normalized the clot lysis time up to 6 h postadministration. rFVIIa might be a good therapeutic option in patients treated with fondaparinux who develop bleeding complications, since both clot formation as well as fibrinolytic resistance are improved.     

Recombinant factor VIIa enhances platelet adhesion and activation under flow conditions at normal and reduced platelet count.

BACKGROUND: Recombinant factor VIIa (rFVIIa), which was developed for treatment of inhibitor-complicated hemophilia, appears suitable as prohemostatic agent in other clinical disorders including patients with thrombocytopenia. It is generally accepted that rFVIIa functions by enhancement of thrombin generation at the site of injury. It is, however, unknown if and how this affects platelet adhesion and aggregation. OBJECTIVES: To determine the effect of rFVIIa-mediated thrombin generation on platelet adhesion and aggregation under flow conditions at normal and reduced platelet counts. METHODS: Washed platelets and red cells were combined to obtain plasma-free blood with different platelet counts. The reconstituted blood was perfused over a collagen- or fibrinogen-coated surface in the absence or presence of a thrombin generating system consisting of purified coagulation factors rFVIIa, factor (F)X and prothrombin. RESULTS: Addition of coagulation factors rFVIIa, FX and prothrombin to washed platelets and red cells enhanced platelet adhesion and aggregation to collagen and adhesion and spreading to fibrinogen at normal platelet count and at platelet numbers as low as 10 000 microL(-1). rFVIIa-mediated thrombin generation enhanced the activation state of platelets as measured by intracellular calcium fluxes, and enhanced the exposure of procoagulant phospholipids as measured by annexin A5 binding. CONCLUSIONS: Taken together, increased platelet adhesion and aggregation by rFVIIa-mediated thrombin formation may explain the therapeutic effects of rFVIIa in thrombocytopenic conditions and in patients with a normal platelet count by (i) enhancement of primary hemostasis and (ii) enhancement of procoagulant surface leading to elevated fibrin formation.     

Recombinant factor VIIa for rapid reversal of warfarin anticoagulation in acute intracranial hemorrhage

OBJECTIVE: To assess the effects of recombinant factor VIIa (rFVIIa) on hemorrhage volume and functional outcomes in warfarin-related acute intracranial hemorrhage (ICH), which has a 30-day mortality of more than 50%. PATIENTS AND METHODS: We reviewed the clinical, laboratory, and radiographic features of a consecutive series of 7 patients (median age, 87 years; 5 women) with symptomatic, nontraumatic warfarin-related acute ICH treated with intravenous rFVIIa at St. Luke's Hospital in Jacksonville, Fla, between December 2002 and September 2003. Prestroke baseline functional status was assessed with the modified Rankin Scale. Outcome was assessed with the Glasgow Outcome Scale. RESULTS: The international normalized ratio decreased from a mean of 2.7 before administration of rFVIIa to 1.08 after administration of rFVIIa. The median prestroke score on the modified Rankin Scale was zero. The median presenting score on the Glasgow Coma Scale was 14 (range, 4-15). The mean time from onset to treatment was 6.2 hours. The mean initial dose of rFVIIa was 62.1 microg/kg. One patient underwent placement of an external ventricular drain, and another underwent craniotomy and hematoma evacuation. Five of the 7 patients survived and were dismissed from the hospital with severe disability (Glasgow Outcome Scale, 3); 2 patients died during hospitalization. CONCLUSIONS: Intravenous bolus administration of rFVIIa can rapidly lower the international normalized ratio and appears to be safe for patients with warfarin-related ICH. Prospective controlled studies are needed to determine whether rFVIIa can prevent hematoma expansion and improve neurologic outcomes in patients with warfarin-related ICH.