RECOMBINANT FACTOR VIIa

Recombinant factor VIIa (rFVIIa) has been approved for treatment of bleeding in hemophilia patients with inhibitors. It has also been successfully used in non-hemophilia patients with acquired antibodies against factor VIII (acquired hemophilia). Pharmacological doses of rFVIIa have been found to enhance the thrombin

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To date, case reports, anecdotal experience, and limited clinical trials describe these uses; data from randomized clinical trials are limited. Because of the recent trends in rFVIIa use in non-approved settings among physicians from various disciplines, significant concerns about its safety, efficacy, and costs have arisen. Additionally, dosing of rFVIIa for these potentially broad clinical applications is not standardized. Currently, the decision on when and where to use rFVIIa for patients with uncontrolled bleeding continues to be one that must be made by individual physicians.

A retrospective review of 40 patients with coagulopathic bleeding in a variety of medical and surgical settings from 13 hospitals in a web-based database (excluding prior history of coagulopathy and trauma patients) who received rFVIIa (15 to 180 µg/kg, with 38 patients receiving fewer than five doses) found that 32 (80%) achieved complete (18 patients) or partial (14 patients) cessation of bleeding. ^[112] Responses occurred in all dose ranges, without any evidence of a dose-response effect; the percentages of complete, partial, or no response were not different at doses of <70 µg/kg, 70 to 90 µg/kg, or >90 µg/kg. Significantly fewer blood products were administered after rFVIIa therapy. Twenty-three patients (58%) died, reflecting the unstable clinical status of the patients at the decision point for considering rFVIIa therapy. An editorial accompanying this review concluded that dose and timing of rFVIIa therapy have yet to be defined in this diverse patient population, and formal prospective trials are needed; in the meantime, the decision on when and where to use rFVIIa for patients with uncontrolled bleeding continues to be one that must be made by individual physicians, assisted by their hospital pharmacotherapeutic or transfusion committees.^[113]

Of the more than 170,000 standard doses of rFVIIa given after its approval (almost all to patients with hemophilia and inhibitors), only rare (<1:11,300) thrombotic events have been reported.^[103] Six patients developed acute myocardial infarction in association with rFVIIa treatment (three patients with hemophilia, two with acquired hemophilia, and one with uremic thrombocytopenia). Five of the six patients were over 70 years old, and two of the hemophilia patients had a history of cardiovascular disease, which also was the case in the two patients with acquired hemophilia. Cerebrovascular disorders were reported in four patients, three of whom were more than 55 years old, one with hemophilia, and the others having acquired hemophilia.

Thrombotic complications have also been reported with rFVIIa therapy in patients without inhibitors to factor VIII or IX. A review of patients with factor XI deficiency reported a serious adverse event in a clinical trial of rFVIIa (90 µg/kg) before and after minor surgery or dental procedures.^[114] This occurred is an elderly male patient with a history of acute myocardial infarction who experienced an acute cerebral vascular accident and who subsequently died during treatment. The last of ten patients enrolled in an open label, dose-escalation trial to prevent rebleeding after subarachnoid hemorrhage developed middle cerebral artery thrombosis after receiving rFVIIa.^[115] In a high-risk trauma population, 3 of 40 (7.5%) patients who were deemed at high risk for thrombosis developed thrombotic complications after receiving rFVIIa.^[116]

We reported a patient who had a fatal thrombosis after administration of activated prothrombin complex concentrate (APCC), who had also received two doses of rFVIIa more than 6 hours earlier, while supported by extracorporeal membrane oxygenation. ^[117] Because of this experience, we recommend that patients should not receive combination therapy with both APCC and rFVIIa, and that clinicians confirm the adequacy of anticoagulation for patients on extracorporeal membrane oxygenation (ECMO) or ventricular assist device (VAD). Because the thrombotic potential of rFVIIa is currently felt to be less than that for APCC, the use of rFVIIa in this setting is indicated for patients that satisfy the following criteria: life-threatening bleeding, with no identifiable surgical source, that has failed to respond to blood component therapy and has no demonstrable coagulation factor deficiencies.

On the basis of these reports, use of activated factor concentrates should be used with caution in patients with known hypercoagulability (e.g., a history of thrombotic complications, established thrombotic disorders such as factor V Leiden, antiphospholipid syndrome) or who have excessive bleeding in the setting of disseminated intravascular coagulation (DIC) or other states of generalized activation of the hemostatic system (e.g., after cardiac surgery, patients on ECMO or ventricular assist devices) based on the potential for development of localized or systemic intravascular thrombosis.^[118]

Because of concerns regarding use of this drug in the context not only of costs but also for potential adverse events such as unwanted thrombosis, our transfusion committee set forth two conditions for approval of rFVIIa therapy: (1) the initial dose released must be approved by the transfusion medicine service, and (2) subsequently a hematology consult is recommended for assistance in managing the patient and for assessment of the effect of rFVIIa on clinical outcomes. An educational newsletter summarizing these elements was published in our Laboratory Medicine Newsletter in 2003.^[119]