IN the current issue of Anesthesiology, two case reports and a letter describe the perioperative use of recombinant activated coagulation factor VII (rFVIIa; NovoSeven®, NovoNordisk, Copenhagen). 1–3The letter by Svartholm et al . reports that rFVIIa diminished intraoperative bleeding associated with severe necrotizing pancreatitis after standard therapeutic measures had failed 3; the case report by Slappendel et al . reports that rFVIIa appears to have decreased postoperative bleeding after hip arthroplasty in a patient with alcohol-induced cirrhosis 2; while Tobias appears to have used rFVIIa during dilutional coagulopathy. 1These are not the first anecdotal reports of using rFVIIa to control bleeding for disorders for which rFVIIa is not approved; indeed, several others have been published. One such report details the dramatic cessation of bleeding in a victim of major trauma with apparently irremediable hemorrhage and coagulopathy, which had caused the clinicians to cease further attempts to achieve hemostasis. 4Subsequent reports have described the successful treatment of patients who sustained severe trauma, 5absence of blood loss from laparoscopic liver biopsy in patients with cirrhosis, 6and reduction of blood loss in a swine model of liver trauma. 7
Coagulation factor VII is an integral component of the coagulation system, and normally small amounts of the activated form (FVIIa) are present in the circulation. 8Under the initiation and direction of Dr. Ulla Hedner, 9rFVIIa was developed for the prevention of spontaneous bleeding episodes and for diminution of intraoperative blood loss for the 15–25% of patients with hemophilia who have inhibitors (antibodies) of clotting factors VIII or IX. The development of these inhibitors can occur as a consequence of therapy with replacement coagulation factors, or in patients with previously normal coagulation (acquired hemophilia). For these indications rFVIIa has been shown to be efficacious 10,11and safe, and is now an approved and accepted therapy. The theoretical possibility of induction of systemic pathologic thrombosis could not be found in rabbits, 12and has thus far not been a clinically important problem. The research and development of rFVIIa for its approved indication has expanded our knowledge about normal and abnormal coagulation paradigms. Progress in knowledge and therapy of coagulation disorders is planned to be the subject of a forthcoming article in the “Clinical Concepts and Commentary” section of Anesthesiology.
Circulating FVIIa accounts for approximately 1% of circulating FVII, 8and is enzymatically inactive until a complex with tissue factor (TF) is formed. Coagulation factor VII initiates hemostasis by combining with tissue factor (a membrane-bound glycoprotein expressed by subendothelial cells) at the site of injury, forming a TF–FVIIa complex at the local site. The complex activates other factors, which eventually results in limited thrombin generation, which activates platelets. Activated platelets are essential, together with factors II, IX, and X for the development of a full thrombin burst, which is necessary for the development of a stable, solid fibrin plug; one that is resistant to fibrinolysis. Therapy with doses of rFVIIa that achieve supraphysiologic concentrations saturate TF binding sites, provide for platelet activation and development of clinically significant thrombin production despite an absence of coagulation factors VIII or IX, or in the presence of antibodies to these factors. 13Thrombin formation is impaired in thrombocytopenia and some types of platelet dysfunction. 14rFVIIa increases thrombin generation in thrombocytopenia. 15Thus, it is not surprising that there have been case reports of success in achieving hemostasis after administration of rFVIIa for thrombocytopenia, 16thrombocytopenia refractory to platelet transfusion owing to antibodies to platelet antigens, 17or in some states of platelet dysfunction. 18Inasmuch as FVII is the first coagulation factor to decrease in hepatic dysfunction, 19rFVIIa has been used in patients with cirrhosis, with normalization of prothrombin time. 20
However, rFVIIa should not be regarded as the universal solution for disorders of coagulation; there are limitations to its rational use. Each dose of the protein is currently exceedingly expensive. The clearance of rFVIIa is approximately 30–35 ml·kg−1·h−1in adults and greater in children, 21requiring repeated dosing approximately every 2 h for maintenance of efficacy. Furthermore, availability of this recombinant protein is limited.
Although rFVIIa has been reportedly used to treat a wide variety of coagulation defects, it is important to note that its only clinically proven efficacy, by double-blinded, randomized clinical trials, has been for hemophilia. Trials of the use of rFVIIa for treating several clinical conditions are in progress. Indeed, a recent National Institutes of Health (NIH) request for applications (RFA) specifically expressed interest in clinical trials with rFVIIa. Efficacy for rFVIIa has not been demonstrated for patients without a preoperative coagulation disorder, in whom abnormal intraoperative bleeding develops, such as that resulting from a dilutional coagulopathy. Diagnosis of the specific defect, and therapy with specific coagulation factors, plasma, or platelets, remain the appropriate therapies for these patients. It would not be appropriate, at this time, to attempt to replace standard diagnostic measures and standard accepted therapy with use of rFVIIa. When these measures truly fail, it may be reasonable to use rFVIIa as an attempted “rescue” therapy. However, as with any new therapeutic agent, rational use should follow appropriate demonstration of efficacy and safety.