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Anesthesiology:
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Intraoperative Use of Recombinant Activated Coagulation Factor VII

Weiskopf, Richard B. M.D., Professor

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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). 1–3 The 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. 1 These 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. 4 Subsequent reports have described the successful treatment of patients who sustained severe trauma, 5 absence of blood loss from laparoscopic liver biopsy in patients with cirrhosis, 6 and 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. 8 Under the initiation and direction of Dr. Ulla Hedner, 9 rFVIIa 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 10,11 and safe, and is now an approved and accepted therapy. The theoretical possibility of induction of systemic pathologic thrombosis could not be found in rabbits, 12 and 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, 8 and 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. 13 Thrombin formation is impaired in thrombocytopenia and some types of platelet dysfunction. 14 rFVIIa increases thrombin generation in thrombocytopenia. 15 Thus, it is not surprising that there have been case reports of success in achieving hemostasis after administration of rFVIIa for thrombocytopenia, 16 thrombocytopenia refractory to platelet transfusion owing to antibodies to platelet antigens, 17 or in some states of platelet dysfunction. 18 Inasmuch as FVII is the first coagulation factor to decrease in hepatic dysfunction, 19 rFVIIa 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−1 in adults and greater in children, 21 requiring 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.
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References

1. Tobias JD: Synthetic factor VIIa to treat dilutional coagulopathy during posterior spinal fusion in two children. A nesthesiology 2002; 96: 1522–5

2. Slappendel R, Huvers FC, Benraad B, Novàkova I, van Hellemondt GG: Use of recombinant factor VIIa (NovoSeven®) to reduce postoperative bleeding after total hip arthroplasty in a patient with cirrhosis and thrombocytopenias. A nesthesiology 2002; 96: 1525–7

3. Svartholm E, Annerhagen V, Länne T: Treatment of bleeding in severe necrotizing pancreatitis with recombinant factor VIIa (letter). A nesthesiology 2002; 96: 1528

4. Kenet G, Walden R, Eldad A, Martinowitz U: Treatment of traumatic bleeding with recombinant factor VIIa (letter). Lancet 1999; 354: 1879

5. Martinowitz U, Kenet G, Segal E, Luboshitz J, Lubetsky A, Ingerslev J, Lynn M: Recombinant activated factor VII for adjunctive hemorrhage control in trauma. J Trauma 2001; 51: 431–8

6. Jeffers L, Bernstein DE, Erhardtsen E, Reddy KR, Glazer S, Squiban P, Bech R, Hedner U, Schiff ER: The use of recombinant factor VIIa in laparoscopy liver biopsy: A pilot trial (abstract). Gastroenterology 1998; 114: L0275

7. Martinowitz U, Holcomb JB, Pusateri AE, Stein M, Onaca N, Freidman M, Macaitis JM, Castel D, Hedner U, Hess JR: Intravenous rFVIIa administered for hemorrhage control in hypothermic coagulopathic swine with grade V liver injuries. J Trauma 2001; 50: 721–9

8. Wildgoose P, Nemerson Y, Hansen LL, Nielsen FE, Glazer S, Hedner U: Measurement of basal levels of factor VIIa in hemophilia A and B patients. Blood 1992; 80: 25–8

9. Hedner U: Recombinant coagulation factor VIIa: From the concept to clinical application in hemophilia treatment in 2000. Semin Thromb Hemost 2000; 26: 363–6

10. Shapiro AD, Gilchrist GS, Hoots WK, Cooper HA, Gastineau DA: Prospective, randomised trial of two doses of rFVIIa (NovoSeven) in haemophilia patients with inhibitors undergoing surgery. Thromb Haemost 1998; 70: 773–8

11. Key NS, Aledort LM, Beardsley D, Cooper HA, Davignon G, Ewenstein BM, Gilchist GS, Gill JC, Glader B, Hoots WK, Kisker CT, Lusher JM: Home treatment of mild to moderate bleeding episodes using recombinant factor VIIa (Novoseven) in haemophiliacs with inhibitors. Thromb Haemost 1998; 80: 912–8

12. Diness V, Bregengaard C, Frhardtsen F, Hedner U: Recombinant human factor VIIa (rFVIIa) in a rabbit stasis model. Thromb Haemost 1992; 67: 233–41

13. Monroe DM, Hoffman M, Oliver JA, Rogerts HR: Platelet activity of high-dose factor VIIa is independent of tissue factor. Br J Haematol 1997; 1997: 542–7

14. Béguin S, Keularts I: On the coagulation of platelet-rich plasma. Haemostasis 1999; 29: 50–7

15. Kjalke M, Ezban M, Monroe DM, Hoffman M, Roberts HR, Hedner U: High-dose factor VIIa increases initial thrombin generation and mediates faster platelet activation in the thrombocytopenia-like conditions in a cell-based model system. Br J Haematol 2001; 114: 114–20

16. Kristensen J, Killander A, Hippe E, Hellegerg C, Ellegard J, Holm M, Kutti J, Mellqvist U, Johansson J, Glazer S, Hedner U: Clinical experience wtih recombinant factor VIIa in patients with thrombocytopenia. Haemostasis 1996;(suppl 1): 26

17. Vidarsson B, Onundarson PT: Recombinant factor VIIa for bleeding in refractory thrombocytopenia (letter). Thromb Haemost 2000; 83: 634–635

18. Tengborn L, Petruson B: A patient with Glanzmann thrombastenia and epistaxis successfully treated with recombinant factor VIIa. Thromb Haemost 1996; 75: 981–2

19. Manzano ML, Arocena D, Tomás JA, Hedner U, Quiroga JA, Carreno V: Measurement of the procoagulant activity of factor VII in patients with liver cirrhosis and normal prothrombin activity: evaluation of the bleeding risk, Blood Coagul Fibrinolysis 2000; 1(suppl 1): S95–9

20. Bernstein DE, Jeffers L, Erhardtsen E, Reddy KR, Glazer S, Squiban P, Bech R, Hedner U, Schiff ER: Recombinant factor VIIa corrects prothrombin time in cirrhotic patients: a preliminary study. Gastroenterology 1997; 113: 1930–7

21. Erhardtsen E: Pharmacokinetics of recombinant activated factor VII (rFVIIa). Semin Thromb Hemost 2000; 26: 385–91

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