Reversal of Warfarin-Induced Excessive Anticoagulation with Recombinant Human Factor VIIa Concentrate

Context Traditional treatments (fresh-frozen plasma, prothrombin complex concentrate) for rapid reversal of excessive anticoagulation from warfarin are limited by inconvenience and potentially serious side effects. Contribution This prospective case series showed that a single infusion of human recombinant factor VIIa concentrate (rFVIIa) immediately reduced international normalized ratios without adverse effects in 13 patients who needed rapid reversal of excessive warfarin-induced anticoagulation for various reasons. Cautions Before changing treatment policy on the basis of these preliminary findings, physicians should watch for controlled studies that compare outcomes, side effects, and costs in patients treated with rFVIIa versus traditional therapies. The Editors Warfarin, the most widely prescribed oral anticoagulant therapy in North America (1), is administered to treat or prevent primary and secondary venous and arterial thromboembolic complications. Prolonged use for many years may be necessary, particularly for treating symptomatic hypercoagulability, chronic atrial fibrillation, maintaining mechanical prosthetic heart valves, and preventing acute myocardial infarction and stroke (2). Warfarin therapy has a narrow risk-to-benefit profile. Its complex pharmacokinetics are influenced by concurrent medications, ethanol ingestion, variability of vitamin K intake and absorption, and hepatic disease (3). Therefore, it is not surprising that the most common complication of warfarin use is adverse bleeding (4). For patients receiving warfarin, estimated yearly risks are 0.6% for fatal bleeding, 3.0% for major hemorrhage, and 9.6% for minor events (5). The incidence of bleeding complications is directly proportional to the intensity of anticoagulation (6) and time spent at a high international normalized ratio (INR) (7). Various strategies have been implemented to reverse warfarin-induced excessive anticoagulation. In a patient with a prolonged INRs without active bleeding but with an anticipated high risk for bleeding, the INR can be decreased slowly by administering an exogenous source of vitamin K1 (8). The reversal of active bleeding or excessively elevated INRs in patients with a high risk for bleeding requires rapid replacement of vitamin Kdependent coagulation proteins. This replacement has traditionally been achieved by transfusing fresh-frozen plasma (9) or prothrombin complex concentrates (10). Problems associated with transfusing fresh-frozen plasma are the long time necessary to administer large volumes, a patient's inability to tolerate increases in intravascular volumes, and the potential for transmission of pathogenic blood-borne viruses (11) or prions. Prothrombin complex concentrates work very rapidly but may be thrombogenic (12) and may transmit nonlipid-enveloped pathogens. Therefore, it is important to identify alternative agents that are safe, reliable, and rapidly acting. We describe the successful use of recombinant factor VIIa (rFVIIa) concentrate in 13 adults receiving warfarin who required rapid reversal of a critically prolonged INR and excessive anticoagulation. Methods Recombinant FVIIa NovoSeven (Novo Nordisk, Princeton, New Jersey) is a genetically engineered concentrate of human coagulation FVIIa, which is structurally similar to native human plasmaderived FVIIa. The FVII zymogen is synthesized in vitro by a baby hamster kidney-cell line, which is then auto-activated through sequential ion exchange chromatography. This process also enhances eradication of any contaminating murine viruses. No exogenous human serum proteins are used in the manufacturing procedure (13). The rFVIIa product was developed to achieve hemostasis in persons with hemophilia who have allogeneic antibody inhibitors directed against factor VIII or IX. Essentially, rFVIIa, complexed with tissue factor on phospholipid-rich membranes of activated platelets, mediates conversion of coagulation factor IX to IXa and factor X to Xa. Subsequently, the prothrombinase complex (factors Xa and Va and phospholipid) produces a procoagulant burst, which is derived from prothrombin conversion to thrombin (14). Thrombin then proteolyzes fibrinogen to fibrin, which is essential for thrombus formation and cross-linking. Clot stability is further promoted by rFVIIa-induced activation of thrombin-activated fibrinolytic inhibitor. Patients Between 1 September 1999 and 31 October 2001, we considered administration of rFVIIa concentrate in patients referred to the Hematology Service of Georgetown University, Washington, DC, for evaluation and rapid reversal of anticoagulation effects produced by warfarin. Recombinant factor VIIa was prescribed when clinically significant bleeding was precipitated or exacerbated by anticoagulation; when persons assessed to be at high risk for bleeding (INR > 10) could not tolerate infusions of fresh-frozen plasma because of intravascular volume constraints or comorbid conditions; when very rapid warfarin reversal was required; or when interruption of anticoagulation was deemed risky but temporary moderation of warfarin was indicated (for example, for invasive therapeutic or diagnostic procedures). The dose of rFVIIa to be administered was based on the patient's weight, rounded off to the closest vial size (1.2 mg and 4.8 mg). The first patient received 90 g/kg of body weight, the recommended dose for persons with hemophilia and alloantibody inhibitors. Subsequent patients were treated with progressively lower doses as it became apparent that even doses in the 15 to 20 g/kg range (Table) provided adequate hemostasis. Recombinant factor VIIa was administered intravenously over 3 to 5 minutes. Prothrombin time and INR were obtained before and after treatment in all persons in order to monitor the effects on coagulation. In addition, factors II, VII, IX, and X activity levels were concurrently measured in four patients. One patient received rFVIIa on two separate occasions. Table. Characteristics of 13 Patients Treated with Recombinant Factor VIIa Results Thirteen adult patients received decreasing single doses of rFVIIa concentrate as our experience and confidence in the product increased (Table). In all patients, the INR was immediately reduced after a single infusion (Figure). Prothrombin times and INRs slowly increased with time after administration of rFVIIa but remained below baseline levels for all patients. Subsequent management of patients after rFVIIa administration was individualized according to clinical situation and treatment goals. Most patients resumed warfarin therapy at appropriately adjusted doses within 12 hours after the INR normalized. Patients with an INR greater than 10 also received supplemental vitamin K1 for long-term protection against relapse. Figure. The international normalized ratios ( INRs ) of 13 patients relative to treatment with recombinant factor VIIa. Four vitamin Kdependent coagulation proteins (factors II, VII, IX, and X) were assayed in four patients 1 hour before and 1 hour after rFVIIa infusion. The activity of these proteins was markedly deficient, which is consistent with the effects of warfarin. Of interest, the activity level of factors II, IX, and X did not appreciably increase after rFVIIa treatment. However, FVII activity increased dramatically (by more than 500%) (data not shown). The clinical scenarios in this series varied but were typical of a large hospital experience. Four patients presented with clinically significant hemorrhage, consisting of retroperitoneal bleeding, severe protracted epistaxis, tongue laceration, and an expanding facial and soft palate hematoma. Immediate cessation of bleeding was clinically apparent after rFVIIa administration. Five patients required rapid reversal of anticoagulation effects before invasive, diagnostic, or surgical interventions. These included removal of an arterial femoral sheath, removal of epidural and central venous catheters, closed fixation of a femoral neck fracture, and electrophysiologic studies with pacemaker placement. No adverse bleeding occurred in any persons during or after surgery. In several patients who had recurrent hypercoagulable events or had previous episodes of heparin-induced thrombocytopenia, the risk for bleeding was reduced without complete reversal of anticoagulation effects. Hemorrhagic complications were averted in patients with significant comorbid conditions (Table) and a high risk for bleeding, including an INR greater than 10, recent upper gastrointestinal bleeding or history of peptic ulcer disease, quantitative and qualitative platelet dysfunction, hemodialysis, and congestive heart failure. All patients had indications for chronic or lifelong use of warfarin before treatment with rFVIIa (Table). Most patients had received anticoagulation for at least 3 months. In one patient, initiation of warfarin therapy after surgery produced excessive anticoagulation effects within 3 days. Discussion This series represents the first substantial experience with rFVIIa concentrate to reverse the effects of excessive warfarin-induced anticoagulation. Thirteen persons who had been taking warfarin received rFVIIa to treat active, symptomatic bleeding; to ameliorate high risks for bleeding; or to reverse anticoagulation preceding invasive diagnostic or therapeutic interventions. The regimen was safe, rapidly acting, and effective in all patients. Substantially lower doses than those recommended for persons with hemophilia and alloantibody inhibitors were used to achieve hemostasis, perhaps reflecting the otherwise normal coagulation mechanism in patients with warfarin-induced anticoagulation. Preclinical studies in rats (15) and normal humans who ingested acenocoumarol (16) have demonstrated the safety and feasibility of rFVIIa use in the clinical setting. Recent anecdotal reports have supported the potential effectiveness of rFVIIa for reversing warfarin-induced excessive anticoagulation