[en] BACKGROUND: To date, clinical experience with recombinant factor VIIa (rFVIIa) in neonates is rather limited because of the lack of controlled studies. AlphaIM: The objective of this study was to present further experience from our center with regard to the use of rFVIIa in newborns with severe bleeding or coagulopathy resistant to conventional therapy and to determine factors affecting the clinical outcome. METHODOLOGY: We performed a retrospective data analysis of 29 neonates with intractable bleeding or severe coagulation disturbances. All patients received 100 mug/kg of rFVIIa per dose bolus intravenously (maximum of 23 doses), as rescue procedure after other interventions had failed to achieve hemostasis. RESULTS: Fourteen neonates survived (group A), whereas 15 died (group B). There was no difference in birth weight, gestational age, and bleeding site and causes between the 2 groups. In the neonates who survived, rFVIIa had been administered earlier in the disease process (<24 h of beginning of bleeding) compared with those who died (P=0.009). In all 29 neonates, international normalized ratio was directly restored (from 2.99+/-1.4 before rFVIIa administration to 1.6+/-1.1 afterward, P<0.001) and prothrombin time and activated partial thromboplastin time were significantly decreased after administration of rFVIIa (from 28 to 16.4 and from 180 to 67, respectively; P=0.001 and 0.05, respectively). Blood products administered were significantly less in group A than in group B, as time from the beginning of bleeding to the administration of rFVIIa was significantly less in group A than in group B. Neither acute adverse events nor thromboembolic complications were observed. CONCLUSIONS: In this neonatal group with intractable bleeding and/or severe coagulation disturbances, rFVIIa was more effective in early intervention as rescue therapy, without any adverse events in all neonates. Upon failure to achieve hemostasis with initial administration of blood products, fast intervention with rFVIIa could be considered in neonates with serious bleeding and coagulation disorders.
Disciplines :
Hematology Pediatrics
Author, co-author :
GKIOUGKI, Evangelia ; Centre Hospitalier Universitaire de Liège - CHU > Pédiatrie
Mitsiakos, Georgios; Aristotle University of Thessaloniki > Neonatal > Neonatal Intensive Care Unit
Chatziioannidis, Elias; Aristotle University of Thessaloniki > Neonatal > Neonatal Intensive Care Unit
Hedner U, Kisiel W. Use of human factor VIIa in the treatment of two hemophilia a patients with high-titer inhibitors. J Clin Invest. 1983;71: 1836-1841.
Novoseven Scientific Discussion EMA 2005. Available at: http://www.ema.europa.eu/docs/en-GB/document-library/EPAR- Scientific- Discussion/human/000074/WC500030713.pdf. Accessed 29 January 2013.
Guzzetta NA, Huch S, Fernandez JD, et al. Use of recombinant factor VIIa for uncontrolled bleeding in neonates after cardiopulmonary bypass. Paediatr Anaesth. 2009;19: 364-370.
Young G, Wicklund B, Neff P, et al. Off-label use of rFVIIa in children with excessive bleeding: a consecutive study of 153 off-label uses in 139 children. Pediatr Blood Cancer. 2009;53: 179-183.
ten Cate H, Bauer KA, Levi M, et al. The activation of factor X and prothrombin by recombinant factor VIIa in vivo is mediated by tissue factor. J Clin Invest. 1993;92: 1207-1212.
Lisman T, De Groot PG. Mechanism of action of recombinant factor VIIa. J Thromb Haemost. 2003;1: 1138-1139.
Aitken MG. Recombinant factor VIIa. Emerg Med Australas. 2004;16: 446-455.
Hedner U. Mechanism of action of recombinant activated factor VII: an update. Semin Hematol. 2006;43(suppl 1): S105-S107.
Monroe DM, Hoffman M, Allen GA, et al. The factor VIIplatelet interplay: effectiveness of recombinant factor VIIa in the treatment of bleeding in severe thrombocytopathia. Semin Thromb Hemost. 2000;26: 373-377.
Warren OJ, Alcock EM, Choong AM, et al. Recombinant activated factor VII: a solution to refractory haemorrhage in vascular surgery? Eur J Vasc Endovasc Surg. 2008;35: 145-152.
Duchesne JC, Mathew KA, Marr AB, et al. Current evidence based guidelines for factor VIIa use in trauma: the good, the bad, and the ugly. Am Surg. 2008;74: 1159-1165.
Blatt J, Gold SH, Wiley JM, et al. Off-label use of recombinant factor VIIa in patients following bone marrow transplantation. Bone Marrow Transplant. 2001;28: 405-407.
Mathew P. The use of rFVIIa in non-haemophilia bleeding conditions in paediatrics. a systematic review. Thromb Haemost. 2004;92: 738-746.
Ghorashian S, Hunt BJ. "Off-license" use of recombinant activated factor VII. Blood Rev. 2004;18: 245-259.
MacLaren R, Weber LA, Brake H, et al. A multicenter assessment of recombinant factor VIIa off-label usage: clinical experiences and associated outcomes. Transfusion. 2005;45: 1434-1442.
Mathew P, Young G. Recombinant factor VIIa in paediatric bleeding disorders - a 2006 review. Haemophilia. 2006;12: 457-472.
Mallarkey G, Brighton T, Thomson A, et al. An evaluation of eptacog alfa in nonhaemophiliac conditions. Drugs. 2008;68: 1665-1689.
Heller M, Lau W, Pazmino-Canizares J, et al. A comprehensive review of rFVIIa use in a tertiary care pediatric center. Pediatr Blood Cancer. 2008;50: 1013-1017.
Alten JA, Benner K, Green K, et al. Pediatric off-label use of recombinant factor VIIa. Pediatrics. 2009;123: 1066-1072.
Puetz J, Darling G, Brabec P, et al. Thrombotic events in neonates receiving recombinant factor VIIa or fresh frozen plasma. Pediatr Blood Cancer. 2009;53: 1074-1078.
Chuansumrit A, Nuntnarumit P, Okascharoen C, et al. The use of recombinant activated factor VII to control bleeding in a preterm infant undergoing exploratory laparotomy. Pediatrics. 2002;110: 169-171.
Chuansumrit A, Visanuyothin N, Puapunwattana S, et al. Outcome of intracranial hemorrhage in infants with congenital factor VII deficiency. J Med Assoc Thai. 2002;85(suppl 4): S1059-S1064.
Veldman A, Fischer D, Voigt B, et al. Life-threatening hemorrhage in neonates: management with recombinant activated factor VII. Intensive Care Med. 2002;28: 1635-1637.
Olomu N, Kulkarni R, Manco-Johnson M. Treatment of severe pulmonary hemorrhage with activated recombinant factor VII (rFVIIa) in very low birth weight infants. J Perinatol. 2002;22: 672-674.
Brown JB, Emerick KM, Brown DL, et al. Recombinant factor VIIa improves coagulopathy caused by liver failure. J Pediatr Gastroenterol Nutr. 2003;37: 268-272.
Greisen G, Andreasen RB. Recombinant factor VIIa in preterm neonates with prolonged prothrombin time. Blood Coagul Fibrinolysis. 2003;14: 117-120.
Fontaine MJ, Lazarchick J, Taylor S, et al. Use of recombinant factor VIIa in infants with severe coagulopathy. J Perinatol. 2004;24: 310-311.
Girisch M, Rauch R, Carbon R, et al. Refractory bleeding following major surgery of a giant sacrococcygeal teratoma in a premature infant: successful use of recombinant factor VIIa. Eur J Pediatr. 2004;163: 118-119.
Tancabelic J, Haun SE. Management of coagulopathy with recombinant factor VIIa in a neonate with echovirus type 7. Pediatr Blood Cancer. 2004;43: 170-176.
Velik-Salchner C, Sergi C, Fries D, et al. Use of recombinant factor VIIa (Novoseven) in combination with other coagulation products led to a thrombotic occlusion of the truncus brachiocephalicus in a neonate supported by extracorporal membrane oxygenation. Anesth Analg. 2005;101: 924.
Filan PM, Mills JF, Clarnette TD, et al. Spontaneous liver hemorrhage during laparotomy for necrotizing enterocolitis: a potential role for recombinant factor VIIa. J Pediatr. 2005; 147: 857-859.
Grizelj R, Vukovic J, Filipovic-Grcic B, et al. Successful use of recombinant activated FVII and aminocaproic acid in four neonates with life-threatening hemorrhage. Blood Coagul Fibrinolysis. 2006;17: 413-415.
Cetin H, Yalaz M, Akisu M, et al. The use of recombinant activated factor VII in the treatment of massive pulmonary hemorrhage in a preterm infant. Blood Coagul Fibrinolysis. 2006;17: 213-216.
Abdullah F, Hunter C, Hargrove C, et al. Recombinant factor VIIa for treatment of massive liver fracture in a premature infant. J Pediatr Surg. 2006;41: 1764-1767.
Hunseler C, Kribs A, Eifinger F, et al. Recombinant activated factor seven in acute life-threatening bleeding in neonates: report on three cases and review of literature. J Perinatol. 2006;26: 706-713.
Altuncu E, Berrak S, Bilgen H, et al. Use of recombinant factor VIIa in a preterm infant with coagulopathy and subdural hematoma. J Matern Fetal Neonatal Med. 2007;20: 627-629.
Agarwal HS, Bennett JE, Churchwell KB, et al. Recombinant factor seven therapy for postoperative bleeding in neonatal and pediatric cardiac surgery. Ann Thorac Surg. 2007;84: 161-168.
Fischer D, Schloesser R, Buxmann H, et al. Recombinant activated factor VII as a hemostatic agent in very low birth weight preterms with gastrointestinal hemorrhage and disseminated intravascular coagulation. J Pediatr Hematol Oncol. 2008;30: 337-342.
Faust K, Troger B, Kahl F, et al. Successful use of recombinant factor VIIa in a preterm infant with life-threatening haematuria. Blood Coagul Fibrinolysis. 2009;20: 601-604.
Poralla C, Hertfelder HJ, Oldenburg J, et al. Treatment of acute pulmonary haemorrhage in extremely preterm infants with recombinant activated factor VII. Acta Paediatr. 2010; 99: 298-300.
Dang CN, Katakam LI, Smith PB, et al. Recombinant activated factor VIIa treatment for refractory hemorrhage in infants. J Perinatol. 2011;31: 188-192.
Mitsiakos G, Papaioannou G, Giougi E, et al. Is the use of rFVIIa safe and effective in bleeding neonates? A retrospective series of 8 cases. J Pediatr Hematol Oncol. 2007;29: 145-150.
Lindley CM, Sawyer WT, Macik BG, et al. Pharmacokinetics and pharmacodynamics of recombinant factor VIIa. Clin Pharmacol Ther. 1994;55: 638-648.
Santagostino E, Morfini M, Rocino A, et al. Relationship between factor VII activity and clinical efficacy of recombinant factor VIIa given by continuous infusion to patients with factor VIII inhibitors. Thromb Haemost. 2001;86: 954-958.
Shapiro A. Inhibitor treatment: state of the art. Semin Hematol. 2001;38(suppl 12): 26-34.
Villar A, Aronis S, Morfini M, et al. Pharmacokinetics of activated recombinant coagulation factor VII (NovoSeven) in children vs. adults with haemophilia A. Haemophilia. 2004;10: 352-359.
Klitgaard T, Nielsen TG. Overview of the human pharmacokinetics of recombinant activated factor VII. Br J Clin Pharmacol. 2008;65: 3-11.
Novoseven SPC. 2012. Available at: http://www.medicines.org. uk/emc/medicine/21171/SPC/. Accessed 29 January 2013.
Chuansumrit A, Isarangkura P, Angchaisuksiri P, et al. Controlling acute bleeding episodes with recombinant factor VIIa in haemophiliacs with inhibitor: continuous infusion and bolus injection. Haemophilia. 2000;6: 61-65.
Egan JR, Lammi A, Schell DN, et al. Recombinant activated factor VII in paediatric cardiac surgery. Intensive Care Med. 2004;30: 682-685.
Millar CG, Stringer MD, Sugarman I, et al. The use of recombinant factor VIIa for bleeding in paediatric practice. Haemophilia. 2005;11: 171-174.
Brady KM, Easley RB, Tobias JD. Recombinant activated factor VII (rFVIIa) treatment in infants with hemorrhage. Paediatr Anaesth. 2006;16: 1042-1046.
Bhat S, Yadav SP, Anjan M, et al. Recombinant activated factor VII usage in life threatening hemorrhage: a pediatric experience. Indian J Pediatr. 2011;78: 961-968.
Williams MD, Chalmers EA, Gibson BE. The investigation and management of neonatal haemostasis and thrombosis. Br J Haematol. 2002;119: 295-309.