- Email: [email protected]
Recombinant factor VIIa for intraoperative bleeding in a child with hepatoblastoma and review of recombinant activated factor VIIa use in children undergoing surgery
Journal of Pediatric Surgery (2008) 43, E15–E19
www.elsevier.com/locate/jpedsurg
Recombinant factor VIIa for intraoperative bleeding in a child with hepatoblastoma and review of recombinant activated factor VIIa use in children undergoing surgery Khoula Al-Said a,⁎, Ronald Anderson b , Andrew Wong c , Doan Le b a
Department of Pediatrics, Alberta Children's Hospital, University of Calgary, Calgary, Alberta, Canada T3B 6A8 Division of Hematology/Oncology, Alberta Children's Hospital, University of Calgary, Calgary, Alberta, Canada T3B 6A8 c Division of Surgery, Alberta Children's Hospital, University of Calgary, Calgary, Alberta, Canada T3B 6A8 b
Key words: Recombinant factor VIIa; Hepatoblastoma; Massive bleeding
Abstract We report a case of a child with a large liver mass who underwent an open liver biopsy and had massive bleeding intraoperatively. Recombinant activated factor VII (rFVIIa) given intraoperatively was successful in stopping the bleeding. We also reviewed the literature on the use of rFVIIa in pediatric surgery. © 2008 Published by Elsevier Inc.
Recombinant factor VIIa (rFVIIa) use in children has been a relatively new emergent therapy. It was first introduced to clinical medicine 2 decades ago. It gained approval by the American Food and Drug Association in 1999 to be used solely for the treatment of patients with congenital or acquired hemophilia who develop inhibitors [1]. However, the offlabel uses of the drug have been increasing. Factor VIIa initiates hemostasis by binding to tissue factor (TF) [2]. Tissue factor is produced secondary to tissue injury. The VIIa/TF complex activates other coagulation factors and platelets. As a consequence of this, thrombin is formed that then activates fibrinogen to fibrin, and a clot is formed (Fig. 1). Another proposed mechanism of action is that factor VII binds activated platelets and induces a thrombin burst. The use of rFVIIa in nonhemophilic patients has been reported in the adult literature with promising outcomes; examples are liver disease, massive blood loss because of trauma or surgery [2], Glanzmann's thrombasthenia and Bernard-Soulier syndrome, and thrombocytopenia [3]. ⁎ Corresponding author. Tel.: +1 403 955 7211; fax: +1 403 955 3055. E-mail address: [email protected] (K. Al-Said). 0022-3468/$ – see front matter © 2008 Published by Elsevier Inc. doi:10.1016/j.jpedsurg.2008.01.002
However, its use in nonhemophilic children, without preexisting coagulopathy, is seldom reported. We report a case of a child with no preexisting coagulopathy who received rFVIIa intraoperatively for uncontrollable bleeding.
1. Case A previously healthy 2.5-year-old boy, with no personal or family history of bleeding, presented with abdominal distension. On examination, he had an enlarged liver of 8 cm below the costal margin and a span of 13 cm. An abdominal ultrasound showed a large heterogeneous mixed echogenic mass encompassing a large portion of the right hepatic lobe with high vascularity. He had an elevated α-fetoprotein of 91,906 μg/L. The international normalized ratio (INR, 1.0 second) and partial thromboplastin time (PTT, 27.3 seconds) were both normal. Abdominal computed tomographic scan demonstrated a mass occupying the entire right lobe of the liver with extension to the caudate lobe and right portal vein thrombosis (Fig. 2).
E16
K. Al-Said et al. (90 μg/kg). The patient remained stable until chemotherapy started on postoperative day 7 for the diagnosis of hepatoblastoma. He was discharged home 5 days later with no complications.
2. Discussion
Fig. 1 Activated factor VII initiates the coagulation cascade by binding to TF.
He underwent an open liver biopsy that revealed an inoperable liver mass because of involvement of right and left lobe of the liver with extension into the portal vein. During the surgery, a small tear in the capsule resulted in severe bleeding with a total of 1 L of blood loss. The patient was transfused with 900 mL of packed red blood cells (PRBC). Despite ligation of the tear and constant pressure, the bleeding continued for another 1.5 hours. Coagulation tests drawn intraoperatively (after PRBC transfusion and before rFVIIa) were all normal including INR, 1.2 seconds; PTT, 28.6 seconds; fibrinogen, 1.6 g/L; platelet count, 517 × 109; factor V, 0.66 μ/mL; factor VII, 0.64 μ/mL; factor VIII, 1.57 μ/mL; and normal closure time. Because of the normal INR, PTT, fibrinogen, and platelet count, no other blood products besides PRBC were given. Capillary gas showed a pH of 7.15. Recombinant factor VIIa was administered at a dose of 90 μg/kg as bleeding continued. Cessation of bleeding was noted intraoperatively, and this enabled the surgeon to close the abdomen within 45 minutes after the administered dose. A second dose of rFVIIa (90 μg/kg) was given 2 hours later. The patient was observed in the pediatric intensive care unit for 24 hours and remained hemodynamically stable. On postoperative day 4, a significant drop in the patient's hemoglobin level was noted (from 139 to 79 g/L); 200 mL PRBC was transfused along with a third dose of rFVIIa
Recombinant VIIa is increasingly being used in the pediatric population as an off-label drug [4]. It has been used to treat factor VII deficiency, liver disease, platelet dysfunction (Glanzmann thrombasthenia and Bernard-Soulier), bleeding in trauma, and surgery [4]. Most of the literatures on rFVIIa use in nonhemophilic children are case reports or case series. This factor is given in an attempt to achieve hemostasis in surgical life-threatening bleeding. In many of the cases, rFVIIa was administered after platelets and/or fresh frozen plasma (FFP) transfusions. In our patient, intraoperative testing revealed normal platelet count, fibrinogen, coagulation profile, and closure time. Given this situation, rFVIIa was given intraoperatively. The dose was repeated 2 hours postoperatively to help maintain hemostasis. Recombinant factor VIIa has a short half-life with an average of 2.7 hours for adults and 1.3 hours for children less than 15 years. The clearance is faster for pediatric patients (67 mL/kg per hour) compared to adults (33 mL/kg per hour) [5]. Barro et al [6] reported a case of a 5 month old with severe surgical bleeding from an open liver biopsy to diagnose hepatoblastoma. The patient required massive amounts of circulatory support with PRBC, platelets, and FFP. On postoperative day 4, a second surgery for right hepatectomy
Fig. 2 Abdominal computed tomographic scan showing the hepatoblastoma occupying most of the right lobe of the liver.
Recombinant factor VIIa for intraoperative bleeding in a child was required. Four hours after this surgery, a single dose of 90 μg/kg of rFVIIa was given with fibrinogen concentrate infusion. Bleeding ceased shortly after the dose of rFVIIa. Our case differs from that of Barro in that our patient did not have preexisting coagulopathy, and rFVIIa was the sole hemostatic agent given intraoperatively. Intraoperative use of rFVIIa is reported in cardiac and brain surgery. Aldouri [7] described a 2.5-year-old boy with transposition of the great vessels who received a single dose of rFVIIa (30 μg/kg) during cardiac surgery after 4.5 L of blood loss. A dramatic decrease in intraoperative blood loss was observed within 1 hour. Hartmann and colleagues [8] reported 2 pediatric cases of rFVIIa use intraoperatively to stop bleeding during brain tumor surgery. The amount of bleeding reported in these 2 cases was large (27.5 L in case 1 and 5 L in case 2). Both patients received transfusions with blood, platelets, FFP, and aprotinin. Unfortunately, the first patient developed vasospasms and died of cerebral infarction. The coagulation profile was normal in both cases, and bleeding ceased within 10 to 15 minutes at doses of 100 to 120 μg/kg rFVIIa. Tobias [9] used rFVIIa to treat 2 pediatric patients undergoing posterior spinal fusion for neuromuscular scoliosis who developed massive bleeding. Both patients had dilutional coagulopathy that did not respond to FFP. Recombinant factor VIIa was then administered. In both patients, a dose of 90 μg/kg was given intraoperatively and another dose postoperatively to obtain hemostasis. A recent study compared 26 adolescents undergoing scoliosis surgery who received approximately 23 μg/kg rFVIIa 30 minutes before surgery with 26 historical controls who did not receive rFVIIa. It showed that rFVIIa-treated patients had significantly reduced blood loss per vertebral segment fused per hour of surgery [10]. All patients survived, and no adverse events were reported. The use of rFVIIa has been reported in premature babies. The first is a 29-week gestational age preterm infant [11]. The infant was bleeding profusely from a ruptured umbilical artery. After an exploratory laparotomy and ligation of the artery, he received massive amounts of PRBC, cryoprecipitate, FFP, and platelets to control bleeding from the surgical wound. Postoperatively, a dose of 40 μg/kg of rFVIIa was administered that slowed down the bleeding in 10 minutes, and a second dose of rFVIIa was given in 7 hours with complete cessation of bleeding by 18 hours. Recently, Abdullah et al [12] used rFVIIa for the treatment of massive liver fracture in a 25-week gestational age infant during surgery for resection of a large sacrococcygeal teratoma. Kalicinski and colleagues [13] reported 2 children undergoing orthotopic liver transplantation for fulminant liver failure. Their coagulopathy and bleeding was not corrected by FFP, cryoprecipitate, platelet, and PRBC transfusions. The INR preoperatively was 5.7 and 6.9 in these patients. In both patients, a dose of 100 μg/kg rFVIIa was given 5 minutes before surgery. This resulted in correction of the INR to the normal range within 15 minutes.
E17
Tranexamic acid was also given with the first dose of rFVIIa. Recombinant factor VIIa was repeated 2 hours later in one patient. In both cases, no postoperative bleeding or thrombosis occurred. Kulkarni et al [14] reported on the use of rFVIIa in 2 pediatric patients with large liver lacerations after blunt abdominal trauma. The first patient received rFVIIa 50 μg/kg intravenous every 2 hours for 2 doses for 3 days. The patient required one PRBC transfusion, and surgery was avoided. The second patient sustained a grade IV lacerated liver and an avulsed kidney. Despite multiple transfusions with PRBC, FFP, and cryoprecipitate during surgery, he experienced hemorrhagic shock. Recombinant factor VIIa 50 μg/kg was then given every 2 hours, and bleeding visibly ceased. Postoperatively, rFVIIa was continued every 2 hours for 18 hours, then every 4 hours for 16 hours, then every 6 hours for 3 days. No thrombotic complications occurred. Postoperative use of rFVIIa has been reported as well. Most of case reports are from the cardiothoracic literature. Multiple authors [15-17] have reported few cases of successful use of rFVIIa for bleeding postrepair of congenital heart disease in children and for patients on extracorporeal membrane oxygenation [18,19]. However, a recent randomized, double-blind, placebo-controlled trial using prophylactic 40 μg/kg rFVIIa in infants undergoing cardiopulmonary bypass surgery for congenital heart disease did not shorten time-to-chest closure, reduce blood loss, or need for transfusions [20]. This is the largest reported pediatric study with 76 infants (40 in rFVIIa group and 36 in placebo group). The children were all younger than 1 year with the mean of 4 months. There were no thrombotic complications in either group. Different authors have used different doses, with doses ranging between 30 to 180 μg/kg. The highest dose reported in the pediatric literature was 180 μg/kg followed by a continuous infusion of 16.5 to 33 μg/kg per hour by Chuansumrit et al [21]. However, it seems that the desirable effects are achievable with doses between 40 to 90 μg/kg. Few large adult double-blind, randomized placebo controlled trials using rFVIIa have reported mixed results. Factor VIIa was found to limit the growth of intracerebral hematoma, reduce mortality, and improve functional outcomes despite a small increase in thromboembolic events [22]. In another trial, there was no overall effect of rFVIIa when used in patients with upper gastrointestinal bleeding because of cirrhosis [23]. In noncirrhotic patient undergoing partial hepatectomy, rFVIIa did not result in a statistically significant reduction in either the number of patients transfused or the volume of blood products administered [24]. The main concerns with the use of this factor are the risk of thrombosis and lack of controlled trials. The incidence of thrombotic events with the use of rFVIIa at the standard dose of 90 μg/kg was reported to be less than 1% in hemophilia patients with inhibitors, or patients with acquired inhibitors between 1996 to 2002 [25]. O'Connell and colleagues [26] reviewed thromboembolic complications after rFVIIa use as
E18 reported to the US Food and Drug Administration adverse event reporting system from 1999 to 2004. During this time, 168 reports described 185 thromboembolic events of a total of 431 reported adverse events. The median age of these patients was 52 years with a range from 1 month to 91 years. Most reported events followed the use of rFVIIa for off-label indications. The analysis from the reporting system is hindered by preexisting medical conditions, concomitant medications, and various indications. Thus, authors concluded that randomized controlled trials are needed to better define these risks. This year, Vincent et al [27], published recommendations on the use of rFVIIa as an adjunctive treatment of massive bleeding. This European group reviewed the literature and developed consensus guidelines for use of rFVIIa as an adjunct to conventional therapies and surgical control of bleeding. They recommend an attempt to achieve the following before rFVIIa: platelet, more than 50, 000 × 109/L; fibrinogen, 0.5 to 1.0 g/L; pH, higher than 7.20; and hematocrit, more than 24%. They also concluded that there is a rationale for the use of rFVIIa in blunt trauma, uncontrolled bleeding in surgical patients, and bleeding after cardiac surgery. However, they did not recommend the use of rFVIIa as prophylaxis in elective surgery or liver surgery or in penetrating trauma. At the current time, there is no national registry collecting cases involving the off-label use of rFVIIa in children. Recombinant factor VIIa is being used “off-label” in children undergoing surgery. Its use in our patient with uncontrolled intraoperative bleeding eliminated the need for platelet and FFP transfusions. This minimizes transfusion risks such as volume overload and infectious risks from blood products. In an emergency, rFVIIa is easy to reconstitute and infuses in a small volume by intravenous push within minutes. The main limitations to its use are lack of controlled trials, thrombotic events, and high cost (approximately $1200 per 1200-μg vial). There is a need for well-designed clinical studies to determine the optimal dosing regimen, the appropriate time to give rFVIIa, either alone or in combination with other hemostatic agents, and the side effect profile in children. Until further studies and guidelines are established, hematology should be involved when rVIIa use is being considered.
References [1] http://www.fda.gov/CBER/approvltr/viianov032599L.htm. [2] Lloyd JV, Joist JH. Recombinant factor VIIa: a universal hemostatic agent. Curr Hematol Rep 2002;1(1):19-26. [3] Poon MC. Management of thrombocytopenic bleeding: is there a role for recombinant coagulation factor VIIa. Curr Hematol Rep 2003;2(2): 139-47. [4] Mathew P. The use of rFVIIa in non hemophilia bleeding conditions in pediatrics: a systemic review. Thromb Haemost 2004;92(4): 738-46. [5] Erthadtsen E. Pharmacokinetics of recombinant activated factor VIIa (rFVIIa). Semin Thromb Hemost 2000;26:385-91.
K. Al-Said et al. [6] Barro C, Wrobleski I, Piolat C, et al. Successful use of recombinant factor VIIa for severe surgical liver bleeding in a 5-month-old baby. Haemophilia 2004;10(2):183-5. [7] Aldouri M. The use of recombinant factor VIIa in controlling surgical bleeding in non-haemophiliac patients. Pathophysiol Haemost Thromb 2002;32(Suppl 1):41-6. [8] Hartmann M, Suker C, Messing M. Recombinant activated factor VII in the treatment of near-fatal bleeding during pediatric brain tumor surgery. Report of two cases and review of the literature. J Neurosurg 2006;104(1 Suppl):55-8. [9] Tobias JD. Synthetic factor VIIa to treat dilutional coagulopathy during posterior spinal fusion in two children. Anesthesiology 2002;96(6): 1522-5. [10] Kolban M, Balachowska-Kosciolek I, Chmielniki M. Recombinant coagulation factor VIIa–a novel haemostatic agent in scoliosis surgery. Eur Spine J 2006;15(6):944-52 [Epub 2005 Aug 17]. [11] 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(1 Pt 1): 169-71. [12] 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(10):1764-7. [13] Kalicinski P, Kaminski A, Drewniak T, et al. Quick correction of hemostasis in two patients with fulminant liver failure undergoing liver transplantation by recombinant activated factor VII. Transplant Proc 1999;31:378-9. [14] Kulkarni R, Danesshmand A, Guertin S, Fath J, et al. Successful use of activated recombinant factor VII in traumatic liver injuries in children. J Trauma 2004;56(6):1348-52. [15] Razon Y, Erez E, Vidne B, et al. Recombinant factor VIIa (NovoSeven) as a hemostatic agent after surgery for congenital heart disease. Paediatr Anaesth 2005;15(3):235-40. [16] Tobias JD, Simsic JM, Weinstein S, et al. Recombinant factor VIIa to control excessive bleeding following surgery for congenital heart disease in pediatric patients. J Intensive Care Med 2004;19(5): 270-3. [17] Pychynska-Pokorsa M, Moll JJ, Krajewski W, et al. The use of recombinant coagulation factor VIIa in uncontrolled postoperative bleeding in children undergoing cardiac surgery with cardiopulmonary bypass. Pediatr Crit Care Med 2004;5(3):246-50. [18] Wittenstein B, Ng C, Ravn H, et al. Recombinant factor VII for severe bleeding during extracorporeal membrane oxygenation following open heart surgery. Pediatr Crit Care Med 2005;6(4): 473-6. [19] Dominguez TE, Mitchell M, Friess SH, et al. Use of recombinant factor VIIa for refractory hemorrhage during extracorporeal membrane oxygenation. Pediatr Crit Care Med 2005;6(3):348-51. [20] Ekert H, Brizard C, Eyers R, et al. Elective administration in infants of low-dose recombinant activated factor VII (rFVIIa) in cardiopulmonary bypass surgery for congenital heart disease does not shorten time to chest closure or reduce blood loss and need for transfusions: a randomized, double-blind, parallel group, placebo-controlled study of rFVIIa and standard haemostatic replacement therapy versus standard haemostatic replacement therapy. Blood Coagul Fibrinolysis 2006;17(5):389-95. [21] Chuansumrit A, Chantarojanasiri T, Isarangkura P, et al. Recombinant activated factor VII in children with acute bleeding resulting from liver failure and disseminated intravascular coagulation. Blood Coagul Fibrinolysis 2000;11(Suppl 1):S101-5. [22] Mayer SA, Brun NC, Begtrup K, et al. Recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med 2005;352(8): 777-85. [23] Bosch J, Thabut D, Bendtsen F, et al. Recombinant factor VIIa for upper gastrointestinal bleeding in patients with cirrhosis: a randomized, double-blind trial. Gastroenterology 2004;127(4): 1123-30.
Recombinant factor VIIa for intraoperative bleeding in a child [24] Lodge JP, Jonas S, Oussoultzoglou E, et al. Recombinant coagulation factor VIIa in major liver resection: a randomized, placebocontrolled, double-blind clinical trial. Anesthesiology 2005;102(2): 269-75. [25] Roberts HR, Monroe III, Dougald M, et al. Safety profile of recombinant factor VIIA. Semin Hematol 2004;41(1, Suppl 1):101-8.
E19
[26] O'Connell KA, Wood JJ, Wise RP, et al. Thromboembolic adverse events after use of recombinant human coagulation factor VIIa. JAMA 2006;295(3):293-8. [27] Vincent J-L, Rossaint R, Riou B, et al. Recommendations on the use of recombinant activated factor VII as an adjunctive treatment for massive bleeding—a European perspective. Crit Care 2006;10(4):R120.
www.elsevier.com/locate/jpedsurg
Recombinant factor VIIa for intraoperative bleeding in a child with hepatoblastoma and review of recombinant activated factor VIIa use in children undergoing surgery Khoula Al-Said a,⁎, Ronald Anderson b , Andrew Wong c , Doan Le b a
Department of Pediatrics, Alberta Children's Hospital, University of Calgary, Calgary, Alberta, Canada T3B 6A8 Division of Hematology/Oncology, Alberta Children's Hospital, University of Calgary, Calgary, Alberta, Canada T3B 6A8 c Division of Surgery, Alberta Children's Hospital, University of Calgary, Calgary, Alberta, Canada T3B 6A8 b
Key words: Recombinant factor VIIa; Hepatoblastoma; Massive bleeding
Abstract We report a case of a child with a large liver mass who underwent an open liver biopsy and had massive bleeding intraoperatively. Recombinant activated factor VII (rFVIIa) given intraoperatively was successful in stopping the bleeding. We also reviewed the literature on the use of rFVIIa in pediatric surgery. © 2008 Published by Elsevier Inc.
Recombinant factor VIIa (rFVIIa) use in children has been a relatively new emergent therapy. It was first introduced to clinical medicine 2 decades ago. It gained approval by the American Food and Drug Association in 1999 to be used solely for the treatment of patients with congenital or acquired hemophilia who develop inhibitors [1]. However, the offlabel uses of the drug have been increasing. Factor VIIa initiates hemostasis by binding to tissue factor (TF) [2]. Tissue factor is produced secondary to tissue injury. The VIIa/TF complex activates other coagulation factors and platelets. As a consequence of this, thrombin is formed that then activates fibrinogen to fibrin, and a clot is formed (Fig. 1). Another proposed mechanism of action is that factor VII binds activated platelets and induces a thrombin burst. The use of rFVIIa in nonhemophilic patients has been reported in the adult literature with promising outcomes; examples are liver disease, massive blood loss because of trauma or surgery [2], Glanzmann's thrombasthenia and Bernard-Soulier syndrome, and thrombocytopenia [3]. ⁎ Corresponding author. Tel.: +1 403 955 7211; fax: +1 403 955 3055. E-mail address: [email protected] (K. Al-Said). 0022-3468/$ – see front matter © 2008 Published by Elsevier Inc. doi:10.1016/j.jpedsurg.2008.01.002
However, its use in nonhemophilic children, without preexisting coagulopathy, is seldom reported. We report a case of a child with no preexisting coagulopathy who received rFVIIa intraoperatively for uncontrollable bleeding.
1. Case A previously healthy 2.5-year-old boy, with no personal or family history of bleeding, presented with abdominal distension. On examination, he had an enlarged liver of 8 cm below the costal margin and a span of 13 cm. An abdominal ultrasound showed a large heterogeneous mixed echogenic mass encompassing a large portion of the right hepatic lobe with high vascularity. He had an elevated α-fetoprotein of 91,906 μg/L. The international normalized ratio (INR, 1.0 second) and partial thromboplastin time (PTT, 27.3 seconds) were both normal. Abdominal computed tomographic scan demonstrated a mass occupying the entire right lobe of the liver with extension to the caudate lobe and right portal vein thrombosis (Fig. 2).
E16
K. Al-Said et al. (90 μg/kg). The patient remained stable until chemotherapy started on postoperative day 7 for the diagnosis of hepatoblastoma. He was discharged home 5 days later with no complications.
2. Discussion
Fig. 1 Activated factor VII initiates the coagulation cascade by binding to TF.
He underwent an open liver biopsy that revealed an inoperable liver mass because of involvement of right and left lobe of the liver with extension into the portal vein. During the surgery, a small tear in the capsule resulted in severe bleeding with a total of 1 L of blood loss. The patient was transfused with 900 mL of packed red blood cells (PRBC). Despite ligation of the tear and constant pressure, the bleeding continued for another 1.5 hours. Coagulation tests drawn intraoperatively (after PRBC transfusion and before rFVIIa) were all normal including INR, 1.2 seconds; PTT, 28.6 seconds; fibrinogen, 1.6 g/L; platelet count, 517 × 109; factor V, 0.66 μ/mL; factor VII, 0.64 μ/mL; factor VIII, 1.57 μ/mL; and normal closure time. Because of the normal INR, PTT, fibrinogen, and platelet count, no other blood products besides PRBC were given. Capillary gas showed a pH of 7.15. Recombinant factor VIIa was administered at a dose of 90 μg/kg as bleeding continued. Cessation of bleeding was noted intraoperatively, and this enabled the surgeon to close the abdomen within 45 minutes after the administered dose. A second dose of rFVIIa (90 μg/kg) was given 2 hours later. The patient was observed in the pediatric intensive care unit for 24 hours and remained hemodynamically stable. On postoperative day 4, a significant drop in the patient's hemoglobin level was noted (from 139 to 79 g/L); 200 mL PRBC was transfused along with a third dose of rFVIIa
Recombinant VIIa is increasingly being used in the pediatric population as an off-label drug [4]. It has been used to treat factor VII deficiency, liver disease, platelet dysfunction (Glanzmann thrombasthenia and Bernard-Soulier), bleeding in trauma, and surgery [4]. Most of the literatures on rFVIIa use in nonhemophilic children are case reports or case series. This factor is given in an attempt to achieve hemostasis in surgical life-threatening bleeding. In many of the cases, rFVIIa was administered after platelets and/or fresh frozen plasma (FFP) transfusions. In our patient, intraoperative testing revealed normal platelet count, fibrinogen, coagulation profile, and closure time. Given this situation, rFVIIa was given intraoperatively. The dose was repeated 2 hours postoperatively to help maintain hemostasis. Recombinant factor VIIa has a short half-life with an average of 2.7 hours for adults and 1.3 hours for children less than 15 years. The clearance is faster for pediatric patients (67 mL/kg per hour) compared to adults (33 mL/kg per hour) [5]. Barro et al [6] reported a case of a 5 month old with severe surgical bleeding from an open liver biopsy to diagnose hepatoblastoma. The patient required massive amounts of circulatory support with PRBC, platelets, and FFP. On postoperative day 4, a second surgery for right hepatectomy
Fig. 2 Abdominal computed tomographic scan showing the hepatoblastoma occupying most of the right lobe of the liver.
Recombinant factor VIIa for intraoperative bleeding in a child was required. Four hours after this surgery, a single dose of 90 μg/kg of rFVIIa was given with fibrinogen concentrate infusion. Bleeding ceased shortly after the dose of rFVIIa. Our case differs from that of Barro in that our patient did not have preexisting coagulopathy, and rFVIIa was the sole hemostatic agent given intraoperatively. Intraoperative use of rFVIIa is reported in cardiac and brain surgery. Aldouri [7] described a 2.5-year-old boy with transposition of the great vessels who received a single dose of rFVIIa (30 μg/kg) during cardiac surgery after 4.5 L of blood loss. A dramatic decrease in intraoperative blood loss was observed within 1 hour. Hartmann and colleagues [8] reported 2 pediatric cases of rFVIIa use intraoperatively to stop bleeding during brain tumor surgery. The amount of bleeding reported in these 2 cases was large (27.5 L in case 1 and 5 L in case 2). Both patients received transfusions with blood, platelets, FFP, and aprotinin. Unfortunately, the first patient developed vasospasms and died of cerebral infarction. The coagulation profile was normal in both cases, and bleeding ceased within 10 to 15 minutes at doses of 100 to 120 μg/kg rFVIIa. Tobias [9] used rFVIIa to treat 2 pediatric patients undergoing posterior spinal fusion for neuromuscular scoliosis who developed massive bleeding. Both patients had dilutional coagulopathy that did not respond to FFP. Recombinant factor VIIa was then administered. In both patients, a dose of 90 μg/kg was given intraoperatively and another dose postoperatively to obtain hemostasis. A recent study compared 26 adolescents undergoing scoliosis surgery who received approximately 23 μg/kg rFVIIa 30 minutes before surgery with 26 historical controls who did not receive rFVIIa. It showed that rFVIIa-treated patients had significantly reduced blood loss per vertebral segment fused per hour of surgery [10]. All patients survived, and no adverse events were reported. The use of rFVIIa has been reported in premature babies. The first is a 29-week gestational age preterm infant [11]. The infant was bleeding profusely from a ruptured umbilical artery. After an exploratory laparotomy and ligation of the artery, he received massive amounts of PRBC, cryoprecipitate, FFP, and platelets to control bleeding from the surgical wound. Postoperatively, a dose of 40 μg/kg of rFVIIa was administered that slowed down the bleeding in 10 minutes, and a second dose of rFVIIa was given in 7 hours with complete cessation of bleeding by 18 hours. Recently, Abdullah et al [12] used rFVIIa for the treatment of massive liver fracture in a 25-week gestational age infant during surgery for resection of a large sacrococcygeal teratoma. Kalicinski and colleagues [13] reported 2 children undergoing orthotopic liver transplantation for fulminant liver failure. Their coagulopathy and bleeding was not corrected by FFP, cryoprecipitate, platelet, and PRBC transfusions. The INR preoperatively was 5.7 and 6.9 in these patients. In both patients, a dose of 100 μg/kg rFVIIa was given 5 minutes before surgery. This resulted in correction of the INR to the normal range within 15 minutes.
E17
Tranexamic acid was also given with the first dose of rFVIIa. Recombinant factor VIIa was repeated 2 hours later in one patient. In both cases, no postoperative bleeding or thrombosis occurred. Kulkarni et al [14] reported on the use of rFVIIa in 2 pediatric patients with large liver lacerations after blunt abdominal trauma. The first patient received rFVIIa 50 μg/kg intravenous every 2 hours for 2 doses for 3 days. The patient required one PRBC transfusion, and surgery was avoided. The second patient sustained a grade IV lacerated liver and an avulsed kidney. Despite multiple transfusions with PRBC, FFP, and cryoprecipitate during surgery, he experienced hemorrhagic shock. Recombinant factor VIIa 50 μg/kg was then given every 2 hours, and bleeding visibly ceased. Postoperatively, rFVIIa was continued every 2 hours for 18 hours, then every 4 hours for 16 hours, then every 6 hours for 3 days. No thrombotic complications occurred. Postoperative use of rFVIIa has been reported as well. Most of case reports are from the cardiothoracic literature. Multiple authors [15-17] have reported few cases of successful use of rFVIIa for bleeding postrepair of congenital heart disease in children and for patients on extracorporeal membrane oxygenation [18,19]. However, a recent randomized, double-blind, placebo-controlled trial using prophylactic 40 μg/kg rFVIIa in infants undergoing cardiopulmonary bypass surgery for congenital heart disease did not shorten time-to-chest closure, reduce blood loss, or need for transfusions [20]. This is the largest reported pediatric study with 76 infants (40 in rFVIIa group and 36 in placebo group). The children were all younger than 1 year with the mean of 4 months. There were no thrombotic complications in either group. Different authors have used different doses, with doses ranging between 30 to 180 μg/kg. The highest dose reported in the pediatric literature was 180 μg/kg followed by a continuous infusion of 16.5 to 33 μg/kg per hour by Chuansumrit et al [21]. However, it seems that the desirable effects are achievable with doses between 40 to 90 μg/kg. Few large adult double-blind, randomized placebo controlled trials using rFVIIa have reported mixed results. Factor VIIa was found to limit the growth of intracerebral hematoma, reduce mortality, and improve functional outcomes despite a small increase in thromboembolic events [22]. In another trial, there was no overall effect of rFVIIa when used in patients with upper gastrointestinal bleeding because of cirrhosis [23]. In noncirrhotic patient undergoing partial hepatectomy, rFVIIa did not result in a statistically significant reduction in either the number of patients transfused or the volume of blood products administered [24]. The main concerns with the use of this factor are the risk of thrombosis and lack of controlled trials. The incidence of thrombotic events with the use of rFVIIa at the standard dose of 90 μg/kg was reported to be less than 1% in hemophilia patients with inhibitors, or patients with acquired inhibitors between 1996 to 2002 [25]. O'Connell and colleagues [26] reviewed thromboembolic complications after rFVIIa use as
E18 reported to the US Food and Drug Administration adverse event reporting system from 1999 to 2004. During this time, 168 reports described 185 thromboembolic events of a total of 431 reported adverse events. The median age of these patients was 52 years with a range from 1 month to 91 years. Most reported events followed the use of rFVIIa for off-label indications. The analysis from the reporting system is hindered by preexisting medical conditions, concomitant medications, and various indications. Thus, authors concluded that randomized controlled trials are needed to better define these risks. This year, Vincent et al [27], published recommendations on the use of rFVIIa as an adjunctive treatment of massive bleeding. This European group reviewed the literature and developed consensus guidelines for use of rFVIIa as an adjunct to conventional therapies and surgical control of bleeding. They recommend an attempt to achieve the following before rFVIIa: platelet, more than 50, 000 × 109/L; fibrinogen, 0.5 to 1.0 g/L; pH, higher than 7.20; and hematocrit, more than 24%. They also concluded that there is a rationale for the use of rFVIIa in blunt trauma, uncontrolled bleeding in surgical patients, and bleeding after cardiac surgery. However, they did not recommend the use of rFVIIa as prophylaxis in elective surgery or liver surgery or in penetrating trauma. At the current time, there is no national registry collecting cases involving the off-label use of rFVIIa in children. Recombinant factor VIIa is being used “off-label” in children undergoing surgery. Its use in our patient with uncontrolled intraoperative bleeding eliminated the need for platelet and FFP transfusions. This minimizes transfusion risks such as volume overload and infectious risks from blood products. In an emergency, rFVIIa is easy to reconstitute and infuses in a small volume by intravenous push within minutes. The main limitations to its use are lack of controlled trials, thrombotic events, and high cost (approximately $1200 per 1200-μg vial). There is a need for well-designed clinical studies to determine the optimal dosing regimen, the appropriate time to give rFVIIa, either alone or in combination with other hemostatic agents, and the side effect profile in children. Until further studies and guidelines are established, hematology should be involved when rVIIa use is being considered.
References [1] http://www.fda.gov/CBER/approvltr/viianov032599L.htm. [2] Lloyd JV, Joist JH. Recombinant factor VIIa: a universal hemostatic agent. Curr Hematol Rep 2002;1(1):19-26. [3] Poon MC. Management of thrombocytopenic bleeding: is there a role for recombinant coagulation factor VIIa. Curr Hematol Rep 2003;2(2): 139-47. [4] Mathew P. The use of rFVIIa in non hemophilia bleeding conditions in pediatrics: a systemic review. Thromb Haemost 2004;92(4): 738-46. [5] Erthadtsen E. Pharmacokinetics of recombinant activated factor VIIa (rFVIIa). Semin Thromb Hemost 2000;26:385-91.
K. Al-Said et al. [6] Barro C, Wrobleski I, Piolat C, et al. Successful use of recombinant factor VIIa for severe surgical liver bleeding in a 5-month-old baby. Haemophilia 2004;10(2):183-5. [7] Aldouri M. The use of recombinant factor VIIa in controlling surgical bleeding in non-haemophiliac patients. Pathophysiol Haemost Thromb 2002;32(Suppl 1):41-6. [8] Hartmann M, Suker C, Messing M. Recombinant activated factor VII in the treatment of near-fatal bleeding during pediatric brain tumor surgery. Report of two cases and review of the literature. J Neurosurg 2006;104(1 Suppl):55-8. [9] Tobias JD. Synthetic factor VIIa to treat dilutional coagulopathy during posterior spinal fusion in two children. Anesthesiology 2002;96(6): 1522-5. [10] Kolban M, Balachowska-Kosciolek I, Chmielniki M. Recombinant coagulation factor VIIa–a novel haemostatic agent in scoliosis surgery. Eur Spine J 2006;15(6):944-52 [Epub 2005 Aug 17]. [11] 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(1 Pt 1): 169-71. [12] 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(10):1764-7. [13] Kalicinski P, Kaminski A, Drewniak T, et al. Quick correction of hemostasis in two patients with fulminant liver failure undergoing liver transplantation by recombinant activated factor VII. Transplant Proc 1999;31:378-9. [14] Kulkarni R, Danesshmand A, Guertin S, Fath J, et al. Successful use of activated recombinant factor VII in traumatic liver injuries in children. J Trauma 2004;56(6):1348-52. [15] Razon Y, Erez E, Vidne B, et al. Recombinant factor VIIa (NovoSeven) as a hemostatic agent after surgery for congenital heart disease. Paediatr Anaesth 2005;15(3):235-40. [16] Tobias JD, Simsic JM, Weinstein S, et al. Recombinant factor VIIa to control excessive bleeding following surgery for congenital heart disease in pediatric patients. J Intensive Care Med 2004;19(5): 270-3. [17] Pychynska-Pokorsa M, Moll JJ, Krajewski W, et al. The use of recombinant coagulation factor VIIa in uncontrolled postoperative bleeding in children undergoing cardiac surgery with cardiopulmonary bypass. Pediatr Crit Care Med 2004;5(3):246-50. [18] Wittenstein B, Ng C, Ravn H, et al. Recombinant factor VII for severe bleeding during extracorporeal membrane oxygenation following open heart surgery. Pediatr Crit Care Med 2005;6(4): 473-6. [19] Dominguez TE, Mitchell M, Friess SH, et al. Use of recombinant factor VIIa for refractory hemorrhage during extracorporeal membrane oxygenation. Pediatr Crit Care Med 2005;6(3):348-51. [20] Ekert H, Brizard C, Eyers R, et al. Elective administration in infants of low-dose recombinant activated factor VII (rFVIIa) in cardiopulmonary bypass surgery for congenital heart disease does not shorten time to chest closure or reduce blood loss and need for transfusions: a randomized, double-blind, parallel group, placebo-controlled study of rFVIIa and standard haemostatic replacement therapy versus standard haemostatic replacement therapy. Blood Coagul Fibrinolysis 2006;17(5):389-95. [21] Chuansumrit A, Chantarojanasiri T, Isarangkura P, et al. Recombinant activated factor VII in children with acute bleeding resulting from liver failure and disseminated intravascular coagulation. Blood Coagul Fibrinolysis 2000;11(Suppl 1):S101-5. [22] Mayer SA, Brun NC, Begtrup K, et al. Recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med 2005;352(8): 777-85. [23] Bosch J, Thabut D, Bendtsen F, et al. Recombinant factor VIIa for upper gastrointestinal bleeding in patients with cirrhosis: a randomized, double-blind trial. Gastroenterology 2004;127(4): 1123-30.
Recombinant factor VIIa for intraoperative bleeding in a child [24] Lodge JP, Jonas S, Oussoultzoglou E, et al. Recombinant coagulation factor VIIa in major liver resection: a randomized, placebocontrolled, double-blind clinical trial. Anesthesiology 2005;102(2): 269-75. [25] Roberts HR, Monroe III, Dougald M, et al. Safety profile of recombinant factor VIIA. Semin Hematol 2004;41(1, Suppl 1):101-8.
E19
[26] O'Connell KA, Wood JJ, Wise RP, et al. Thromboembolic adverse events after use of recombinant human coagulation factor VIIa. JAMA 2006;295(3):293-8. [27] Vincent J-L, Rossaint R, Riou B, et al. Recommendations on the use of recombinant activated factor VII as an adjunctive treatment for massive bleeding—a European perspective. Crit Care 2006;10(4):R120.