Evaluation of Off-Label Recombinant Activated Factor VII for Multiple Indications in Children

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1 Evaluation of Off-Label Recombinant Activated Factor VII for Multiple Indications in Children Pamela D. Reiter, PharmD, * Robert J. Valuck, PhD, RPh, and Ruston S. Taylor, PharmD * Pediatric ICU and Trauma, The Children s Hospital; * The University of Colorado at Denver and Health Sciences Center, School of Pharmacy, Denver, Colorado; and Department of Pharmacy Christus Santa Rosa Hospital, San Antonio, Texas Despite a paucity of safety and efficacy data, the use of recombinant activated factor VII in children for off-label indications has now surpassed its use in hemophilia. A retrospective chart review was conducted of 46 subjects (age, 6.7 ± 6 years; weight, 26 ± 20 kg) who received recombinant activated factor VII for nonhemophiliac indications between January 1, 2004, and September 1, Indications for use included prevention (n = 6) or treatment (n = 40) of bleeding due to general surgery, hepatic failure, gastrointestinal bleeding, severe traumatic brain injury, bone marrow transplant, cardiac, acetaminophen overdose, and multiorgan system failure. Decreases in prothrombin time, partial thromboplastin time, and international normalized ratio were observed. No inappropriate thrombotic events were noted. Administration of recombinant activated factor VII was associated with a reduction in coagulation markers without obvious adverse thrombotic events at cost of $4189 per dose. These findings should be confirmed in a prospective trial. Key Words: NovoSeven Recombinant activated factor VII Bleeding Child. Coagulation disturbances resulting in clinically significant bleeding are common in critically ill children. These disturbances may be the result of congenital deficiencies such as hemophilia, trauma, liver failure, disseminated intravascular coagulation secondary to sepsis, shock, or closed head injury; or dilution of coagulation factors secondary to cardiopulmonary bypass surgery. Conventional treatment of these coagulation disturbances that present with bleeding episodes includes the administration of blood products such as packed red blood cells (RBC), cryoprecipitate, fresh frozen plasma (FFP), and platelet concentrates. Despite the success of these blood products, a number of problems and risks are associated with their use, including transmission of infectious diseases, anaphylactoid reactions, and alteration in serum calcium. 1-3 Address correspondence to: Pamela D. Reiter, PharmD, 1056 E. 19th Ave. Department of Pharmacy, Center for Pediatric Medicine, Campus Box 375, Denver, CO 80218; reiter.pam@tchden.org. Clinical and Applied Thrombosis/Hemostasis Vol. 13, No. 3, July DOI: / Sage Publications As an adjunct in the control of major hemorrhage, many practitioners are now using recombinant activated factor VII (rfviia; NovoSeven, Novo Nordisk Pharmaceutical, Inc, Princeton, NJ). Historically, the major clinical application of rfviia, and the only approved indication by the United States (US) Food and Drug Administration (FDA), has been in hemophiliac patients with acquired coagulation factor inhibitors. However, the use of off-label rfviia in nonhemophiliac patients has been gaining interest. To date, only small cases series and single-patient anecdotal reports have described the use of rfviia in nonhemophiliac children Administration of rfviia produces supratherapeutic concentrations of factor VIIa and promotes hemostasis by activating the extrinsic pathway of the coagulation cascade. It replaces deficient activated coagulation factor VII, which complexes with tissue factor, and may activate coagulation factor X to Xa and factor IX to IXa on the surface of activated platelets. When complexed with other factors, coagulation factor Xa converts prothrombin to thrombin, a key step in the formation of a fibrin-platelet hemostatic plug. Recombinant factor VIIa has many advantages, including fast onset 233

2 234 P. D. REITER ET AL of 10 to 20 minutes, moderate duration of effect (>6 hours), absence of coagulation system activation, no effect from circulating inhibitors, and no risk of transfusion-transmissible infections. Despite these advantages, rfviia carries the risk of inappropriate thrombotic events and is very expensive: the average wholesale price in 2006 US$ is $3000 to $4000 per dose and up to $ per treatment course. Consensus recommendations for off-label use of rfviia therapy in adults have recently been published 20 ; yet treatment strategies and guidelines in the pediatric population remain elusive. No randomized controlled trials are currently available to determine how to best use rfviia in nonhemophiliac children. We present the results of our case series, the largest pediatric series reported to date, and characterize indications, dosing schema, clinical outcomes, cost of therapy, and assessment of predictors of therapy success. METHODS This was a retrospective medical chart review of all children younger than 21 years old who required rfviia for off-label (nonhemophiliac) indications between January 1, 2004, and September 1, Subjects were identified from the pharmacy billing database at The Children s Hospital (TCH), Denver Colorado, Department of Pharmacy, Center for Pediatric Medicine. TCH is a private, nonprofit, level I regional trauma center located in a metropolitan area that serves a multistate geographic area. This study protocol was reviewed and approved by the Colorado Multiple Institutional Review Board, and informed consent from parents and subjects was not required. Data collection included patient demographics, indications for rfviia administration, dose of rfviia, interval between repeat doses of rfviia, arterial ph, and baseline platelet count and concentrations of serum creatinine, fibrinogen, and lactate. The rfviia dosing regimen was determined by the attending physician and rounded to the nearest vial size within 20% of the prescribed dose. Repeat doses were at the discretion of the attending physician(s). If available, serum concentrations of factors V, VII, and VIII were documented. To describe treatment efficacy, we compared changes in coagulation parameters, described as change from baseline to end-of-treatment, in prothrombin time (PT), partial thromboplastin time (PTT), and international normalized ratio (INR). We also attempted to calculate the change in blood volume loss after therapy. To describe adverse treatment effects, we noted any description of inappropriate thromboses within 48 hours of rfviia administration. Mortality rate was calculated at 48 hours posttherapy. Direct cost of therapy was expressed using the average wholesale price in 2006 US$. To identify the influence of age and underlying disease on treatment course(s) and outcomes, we categorized patients into subgroups of indication for rfviia administration, and neonate, infant/child, or adolescent. For the purpose of this study, neonate was defined as younger than 30 days old, an infant/ child as 30 days to 15 years old, and an adolescent as older than 15 years of age. A 2-tailed, paired Student t test was used to analyze the change in coagulation parameters from baseline to the end of rfviia therapy. Linear regression analysis was performed to determine the extent to which variation in INR and PT could be explained by selected measures, including levels of fibrinogen, whole blood lactate, arterial ph, and platelet count at start of therapy, as well as dose (expressed in micrograms, micrograms/kilogram, and number of doses administered). Forced entry regression models that included all of the above measures as predictors and stepwise regression models (in which only significant independent predictors of response are included, as determined by the statistical software) were used to fit to the data for INR and PT outcomes, and variables reaching statistical significance as predictors were identified. Pearson s correlation was used to identify any baseline factors that were associated with a lower posttreatment INR. P <.05 was considered indicative of statistically significant predictive ability or association for any given measure. All analyses were performed using SPSS 14.0 software (SPSS Inc, Chicago, IL). RESULTS During the study period, 54 patients received rfviia. Two were excluded because they received rfviia for hemophilia, leaving 52 charts for review. Six subjects were then excluded from analysis because of disparities between medication billing and drug administration documentation, leaving 46 patients for final analysis (24 girls, 22 boys). The mean age of these patients was 6.7 ± 6 years (range, 4 days 18 years), including 4 neonates, 25 infants/children, and 7 adolescents. Their mean

3 FACTOR RVIIA IN CHILDREN 235 weight was 26 ± 22 kg (range, 2-88 kg). Of these patients, 87% received rfviia as therapy for active bleeding, and 13% received therapy as prophylaxis before an invasive procedure. The underlying disease process was used to categorize patients into 9 groups: general surgery, gastrointestinal (GI) bleed, postoperative cardiac surgery, nontoxin-related hepatic failure, severe traumatic brain injury (TBI), acetaminophen (APAP) overdose, bone marrow transplantation (BMT), multiple organ failure (MOF), and prophylaxis. The clinical characteristics of the study population, as a whole and as subgroups, are summarized in Table 1. At the time of rfviia administration, all patients who were actively bleeding and half of the patients who received prophylactic therapy were coagulopathic. The provision of conventional transfusion therapy, consisting of any or all of fresh frozen platelets (FFP), red blood cells (RBC), or cryoprecipitate, was under way in 42 of 46 patients. A summary of transfusion and hemostatic treatment, along with hematologic status of the study population, is presented in Table 2. Blood loss was so perfuse in 13 patients that quantification was not possible. Subjects in the neonate and infant/child subgroups had a much higher blood loss compared with the older subjects. Patients in the GI bleed, TBI, postoperative cardiac surgery, BMT, and general surgery groups had the highest blood volume loss, whereas patients in the prophylaxis, nontoxin hepatic failure, MOF, and APAP overdose group had little to no blood loss recorded. We were not able to accurately calculate change in blood loss associated with rfviia therapy owing to inadequate documentation. Serum concentrations of factors V, VII, or VIII were available in 14 patients and were 319% ± 21.5% in 3 (normal, 63%-116%), 48% ± 50% in 14 (normal, 51%-120%), and 271.6% ± 65% in 3 (normal, 58%-132%), respectively. The dose of rfviia varied with underlying disease process (Table 3). Although the mean dose of rfviia provided to the entire study population was 111 μg/kg, the variability was wide (SD, 114 μg/kg), with between 1 and 9 doses provided per patient. Provision of additional doses was determined entirely by the attending physician. Almost half of the patients (22/46) received more than 1 rfviia dose during the study period. The time interval between doses varied from 1 hour to 6 months. When further analyzed using data during a discrete episode (within 48 hours), the interval between repeat doses was 16.8 hours (range, 1-48 hours). Laboratory markers of coagulation were documented at baseline and again at the completion of rfviia therapy for a discrete episode, except for the patient with a GI hemorrhage, whose predose coagulation markers were not obtained. A reduction in INR was observed across all groups, with statistical significance (P.05) detected in the APAP, MOF, postoperative cardiac, and prophylaxis groups (Figure 1). Likewise, a reduction in PT was observed, with significance detected in the MOF, postoperative cardiac, and prophylaxis groups (Figure 2). While a reduction in PTT was observed, it was less robust (Figure 3). There were no reports of inappropriate thromboses in any patient within 48 hours of rfviia therapy. Overall 48-hour post-rfviia therapy mortality was 35%. Mortality was the highest (at 100%) in the severe TBI and GI bleed subgroups. All deaths occurred in the treatment subgroups. Medical support was withdrawn in the each of the 3 patients in the severe TBI group because of catastrophic brain injury without likelihood of recovery. The patient in the GI bleed group was transported to TCH in extremis and died shortly after arrival. Of the 16 patients who died within 48 hours of rfviia therapy, 3 (19%) died as a direct result of acute hemorrhage and 13 (81%) from their injuries or underlying disease processes. Stepwise linear regression analysis identified whole blood lactate as a statistically significant independent predictor of posttreatment PT. That is to say, a lower whole blood lactate concentration could explain a lower (more successful) posttreatment PT (standardized coefficient β =0.502; P <.05). Variability in INR could not be predicted by any measurement tested. Pearson correlation analyses identified baseline arterial ph and baseline platelet count as factors associated with a lower posttreatment INR (see Table 4). The overall cost of rfviia therapy was $4189 ± $3106 per dose (range, $1908 $15 264) and $8574 ± $9462 (range, $1908 $50 978) per course. The patient who received the highest number of doses was in fulminate nontoxin-mediated hepatic failure and received 9 doses over 6 days. This patient ultimately received a liver transplant and survived to discharge. DISCUSSION Off-label use of rfviia in the United States has now surpassed its official FDA-approved use. In the present evaluation, 96% of subjects screened

4 TABLE 1. Baseline Characteristics of Study Population, Categorized by Indication and Patient Age a Entire General Hepatic GI APAP Study Surgery Failure Prophylaxis Bleed TBI BMT Cardiac OD MOF Neonate Infant/Child Adolescent Characteristic (n = 46) (n = 2) (n = 9) (n = 6) (n = 1) (n = 3) (n = 5) (n = 11) (n = 3) (n = 6) (n = 4) (n = 35) (n = 7) Age (yr) 6.7 (6) 13.5 (3.5) 4.6 (5) 5.8 (5.3) (1.3) 8.6 (6.6) 4.6 (5.7) 15 (1) 9.5 (7.2) 0.03 (0.01) 5.6 (5) 15.7 (1.1) Weight (kg) 26 (22) 28.7 (14) 25 (27) 22.6 (17) (5) 24.5 (14) 21.7 (26) 58.4 (20) 30.2 (24) 2.99 (0.97) 22.3 (18) 57 (20) Vitamin K % Receiving Dose (mg) 2.8 (3) (1.7) 4.9 (2.8) NA 3 b 2 (2.2) 1.6 (3) 6.7 (2.9) 2.6 (2.3) 1.3 (0.6) 2.6 (2.7) 5.2 (4.3) Arterial ph c 7.3 (0.2) 7.29 (0.16) 7.3 (1.3) 7.4 (0.1) (0.27) 7.4 (0.1) 7.45 (0.1) 7.36 (0.04) 7.28 (0.14) 7.38 (0.13) 7.35 (0.18) 7.32 (0.18) WB lactate d 5.6 (6.7) NA 5.2 (3.9) 5.3 (5.2) NA NA 1.6 b 3.8 (2.8) 9 b 0.94 b 9.36 (0.48) 3.5 (2.8) NA GI = gastrointestinal; TBI = traumatic brain injury; BMT = bone marrow transplant; APAP OD = acetaminophen overdose; MOF = multiple organ failure; WB = whole blood; NA = not available. a. Data are presented as mean (standard deviation). b. Single data point. c. Normal reference range, d. Normal reference range,

5 TABLE 2. Transfusion Requirements, Hemostatic Therapy, and Hematologic Status of Study Population a Entire General Hepatic GI APAP Study Surgery Failure Prophylaxis Bleed TBI BMT Cardiac OD MOF Neonate Infant/Child Adolescent (n = 46) (n = 2) (n = 9) (n = 6) (n = 1) (n = 3) (n = 5) (n = 11) (n = 3) (n = 6) (n = 4) (n = 35) (n = 7) FFP (ml/kg) 50 (59) 17 (11) 48 (44) (15) 11 (21) 107 (21) 42 (51) 23 (25) 123 (82) 48 (55) 12 (8) FFP doses/ patient (n) 1.8 (1.5) (2.3) 1.5 (0.5) (0.6) 0.5 (1) 1.5 (0.7) 2.3 (1.5) 1.5 (1.9) 2 (1) 1.7 (1.6) 1.8 (1.7) Hct (mg/dl) At baseline 31.3 (9.4) 35.5 (3.5) 32.6 (8) 28.5 (6.5) (10.2) 27.3 (7.8) 36.9 (9.8) 42.8 (7.5) 25 (5.9) 30.1 (9.5) 30.7 (9.3) 34.7 (10.8) At end of therapy 31.3 (7) 31 b 30.8 (9.7) 29.3 (7.2) NA 28.8 (1) 26.3 (3) 34.6 (5.8) 38.1 (4) 31.2 (7.5) 35.2 (1.8) 30.2 (6.7) 36.6 (9) Cryo (ml/kg) 2.6 (5.3) b 2.4 (4) (11) 6.2 (7) ( (8.9) 2.54 (5.2) 0.8 (1.9) Fibrinogen before 276 (166) 245 (248) 207 (106) 234 (40) 250 b 122 (90) 377 (192) 320 (105) 275 (180) 359 (306) 220 (66) 265 (149) 404 (233) rfviia therapy Platelet count ( 10 mm 3 ) 150 (102) 85.5 (22) 138 (124) 164 (54) (50) 63 (43) 198 (101) 222 (144) 68 (39) 229 (91) 136 (94) 177 (131) RBC Loss (ml) TMTC (n = 13) (138) 18.3 (28) b TMTC TMTC 0 5 b TMTC TMTC 0 (n = 4) 754 (1192) (2121) n = 3 n = 2 (n = 3) (n = 10) (n = 9) b 1485 b 604 (529) (2505) Infused (ml/kg) 72 (101) 71 (78) 37 (47) 13 (20) (12) 61 (55) 176 (144) 4 (7) 14 (15) 176 (142) 74 (96) 4.78 (6.4) GI = gastrointestinal; TBI = traumatic brain injury; BMT = bone marrow transplant; APAP OD = acetaminophen overdose; MOF = multiple organ failure; FFP = fresh frozen plasma; Hct = hematocrit; Cryo = cryoprecipitate; rfviia = recombinant activated factor VII; RBC = red blood cell; TMTC = too much to count; NA = not available. a. Data presented as mean (standard deviation). b. Single data point. 237

6 238 P. D. REITER ET AL TABLE 3. Summary of Recombinant Activated Factor VII Dosing a Entire General Hepatic GI APAP Study Surgery Failure Prophylaxis Bleed TBI BMT Cardiac Overdose MOF (n = 46) (n = 2) (n = 9) (n = 6) (n = 1) (n = 8) (n = 5) (n = 11) (n = 3) (n = 6) Dose (μg) (2082) (2546) (2151) (1533) (693) (1368) (2968) (794) (2169) Dose (μg/kg) 111 (114) 94 (43.8) 89 (22) 74 (15) (30) 141 (42) 160 (225) 73 (28) 89 (7) Doses per 2.1 (1.7) (2.3) 1.2 (0.4) (0.6) 3.4 (1.8) 1.6 (1.5) 2.3 (1.5) 1.3 (0.5) patient (n) GI = gastrointestinal; TBI = traumatic brain injury; BMT = bone marrow transplant; APAP= acetaminophen; MOF = multiple organ failure. a. Dosing data are presented as mean (standard deviation). FIG. 1. Effect of recombinant activated factor VII (rfviia) on the international normalized ratio (INR). BMT = bone marrow transplantation; MOF = multiple organ failure; APAP = acetaminophen overdose; TBI = traumatic brain injury. *P <.05. FIG. 3. Effect of recombinant activated factor FVII (rfviia) on partial thromboplastin time (PTT). BMT = bone marrow transplantation; MOF = multiple organ failure; APAP = acetaminophen overdose; TBI = traumatic brain injury. *P <.05. for study inclusion received rfviia for off-label (nonhemophiliac) indications. This study highlights the indications, clinical outcomes, predictive factors of therapy success, and cost associated with FIG. 2. Effect of recombinant activated factor FVII (rfviia) on prothrombin time (PT). BMT = bone marrow transplantation; MOF = multiple organ failure; APAP = acetaminophen overdose; TBI = traumatic brain injury. *P <.05. off-label use of rfviia in children. Previous anecdotal case reports and small studies of rfviia in nonhemophiliac infants and children have demonstrated efficacy in cardiac surgery, BMT, 13 inherited platelet function disorders, 4,8,14 Burkitt s lymphoma, 18 life-threatening hemorrhage in Dengue shock syndrome 6 and in neonates, 15,19 global coagulation dysfunction, 9 and liver failure. 7 With the exception of a report 5 in which 28 patients were followed up, all the reports consisted of 1 to 15 patients. These early reports were critical in establishing a role for rfviia outside of hemophilia. We now report data from the largest pediatric case series to date and underscore the increased use of rfviia for bleeding triggered by trauma, surgery, MOF, BMT, and liver disease. The 2 largest subgroups described in this report included children with acute or chronic liver failure and postcardiopulmonary bypass patients. Treatment algorithms, under the premise of goal-directed therapy, for bleeding after pediatric cardiopulmonary bypass

7 FACTOR RVIIA IN CHILDREN 239 TABLE 4. Pearson Correlation Matrix Baseline Posttreatment Posttreatment RFVIIa Dose No. Doses Arterial Whole Blood Platelet PT INR (μg/kg) Infused ph Lactate Fibrinogen Count Posttreatment PT ** Posttreatment INR ** * * rfviia dose (μg/kg) No. doses infused Baseline arterial ph * Baseline whole blood * lactate Baseline fibrinogen Baseline platelet count * * rfviia = recombinant activated factor VII. *P <.05. **P <.001. have been proposed and encourage the use of platelet transfusions, FFP, cryoprecipitate, aprotinin, and 1-desamino- 8-D-arginine vasopressin before using rfviia. All of the patients within the cardiac subgroup of the current study received FFP, cryoprecipitate, and platelets before rfviia. Efficacy in our study was measured predominately by change in PT, INR, and PTT coagulation markers from baseline to the end of rfviia therapy. All these markers of coagulation fell after therapy, with significant reductions noted in specific diagnostic subgroups. The decline in PTT was less profound and was not surprising given the mechanism of action of rfviia on the extrinsic coagulation pathway. Although attempts were made to include hemostasis or change in blood volume loss as an additional marker of therapy effectiveness, the retrospective nature (and hence incomplete documentation) of this study did not consistently allow for this type of comparison. The mortality at 48 hours post-rfviia, which was a mean 35% and varied with clinical diagnosis (range, 0%-100%), was lower than the 49% to 55% mortality rates reported in adults. 20 The most common cause of death in our study population was not hemorrhagic in nature but rather was due to the child s injuries or the underlying disease process. Because rfviia is an expensive therapy, investigators have tried to identify groups of patients in which clinical benefit is most likely. Specific factors in adults associated with a reduction in rfviia effectiveness include profound acidosis and low levels of platelets and fibrinogen. 21,22 We hoped to identify baseline predictive factors in children to help distinguish futile administration from effective administration. However, stepwise linear regression analysis identified only the variable of whole blood lactate that independently predicted a reduction in PT. Pearson correlation analyses only identified the 2 factors of platelet count and arterial ph at baseline as being associated with a lower posttreatment INR. From this data pool, it therefore appears that prediction of clinical benefit from rfviia is more difficult in children than adults. Overall cost of treatment with rfviia in this study group was $8574 ± $9462 (range, $1908- $50 978) per course. This exorbitant cost, coupled with a lack of firm pediatric prescribing guidelines, has prompted some US hospitals to create a drug gatekeeper. This gatekeeper, who is generally a medical or pharmacy director, is responsible for reviewing all orders before dispensing. After review, the gatekeeper judges the order as acceptable or unacceptable; however, this practice may require some lead time and thus may not be suitable for a medication such as rfviia owing to its urgent nature. Fortunately, overall clinical use of rfviia during the study period at our institution appeared to be appropriate, because most patients were aggressively treated with conventional therapy (RBC, cryoprecipitate, FFP, and platelet concentrates) before rfviia administration. We did identify 2 types of patient that may not benefit from the addition of rfviia. These are (1) a child who arrives at the hospital in extremis with profound acidosis and anemia due to bleeding and (2) a child who has sustained obvious catastrophic brain injury and in whom withdrawal of life support is likely.

8 240 P. D. REITER ET AL CONCLUSIONS The overall benefits of rfviia are difficult to estimate without the support of a randomized, prospective clinical trial. Although the results of this report do not satisfy the criteria necessary to establish unequivocal safety and efficacy recommendations, the data do reflect current clinical practice and suggest that the administration of rfviia in children for nonhemophilic indications is associated with a reduction in laboratory bleeding indices and does not appear to result in inappropriate thrombotic events. In an effort to further elucidate the best role of rfviia in children, we believe that prospective clinical trials should be performed and reported, and that ultimately, a consensus guideline with specific administration criteria should be developed for children. REFERENCES 1. Dodd RY. Emerging infections, transfusion safety, and epidemiology. N Engl J Med. 2003;349: Pealer LN, Marfin AA, Petersen LR, et al; West Nile Transmission Investigation Team. Transmission of West Nile virus through blood transfusion in the United States in N Engl J Med. 2003;349: Taylor RW, O Brien J, Trottier SJ, et al. Red blood cell transfusions and nosocomial infections in critically ill patients. Crit Care Med. 2006;34: Hennewig U, Laws HJ, Eisert S, Gobel U. Bleeding and surgery in children with Glanzman thrombasthenia with and without the use of recombinant factor VIIa. Klin Padiatr. 2005;217: Kalicinski P, Markiewicz M, Kaminski A, et al. Single pretransplant bolus of recombinant activated factor VII ameliorates influence of risk factors for blood loss during orthotopic liver transplantation. Pediatr Transplant. 2005; 9: Chuansumrit A, Tangnararatchakit K, Lektakul Y, et al. The use of recombinant activated factor VII for controlling lifethreatening bleeding in Dengue shock syndrome. Blood Coagul Fibrinolysis. 2004;15: Brown JB, Emerick KM, Brown DL, Whitington PF, Alonso EM Recombinant factor VIIa improves coagulopathy caused by liver failure. J Pediatr Gastroenterol Nutr. 2003;37: Almeida AM, Khair K, Hann I, Liesner R. The use of recombinant factor VIIa in children with inherited platelet function disorders. Br J Haematol. 2003;121: Tobias JD, Groeper K, Berkenbosch JW. Preliminary experience with the use of recombinant factor VIIa to treat coagulation disturbances in pediatric patients. South Med J. 2003;96: Pychynska-Pokorska M, Moll JJ, Krajewski W, Jarosik P. The use of recombinant coagulation factor VIIa in uncontrolled postoperative bleeding in children undergoing cardiac surgery with cardiopulmonary bypass. Pediatr Crit Care. 2004; 5: Tobias JD, Berkenbosch JW, Russo P. Recombinant factor VIIa to treat bleeding after cardiac surgery in an infant. Pediatr Crit Care Med. 2003;4: Egan JR, Lammi A, Schell DN, Gillis J, Nunn GR. Recombinant activated factor VII in paediatric cardiac surgery. Intensive Care Med. 2004;30: Blatt J, Gold SH, Wiley JM, Monahan PE, Cooper HC, Harvey D. Off-label use of recombinant factor VIIa following bone marrow transplantation. Bone Marrow Transplant. 2001;28: Yilmaz BT, Alioglu B, Ozyurek E, Akay HT, Mercan S, Ozbek N.. Sucessful use of recombinant factor VIIa (NovoSeven) during cardiac surgery in a pediatric patient with Glanzmann thrombasthenia. Pediatr Cardiol. 2005; 26: Veldman A, Fischer D, Voigt B, et al. Life-threatening hemorrhage in neonates: management with recombinant activated factor VII. Intensive Care Med. 2002;28: 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: Cetin H, Yalaz M, Akisu M, Karapinar DY, Kavakli K, Kultursay N. The use of recombinant activated factor VII in the treatment of massive pulmonary hemorrhage in a preterm infant, Blood Coagul Fibrinolysis. 2006;17: Culic S. Kuljis D, Armanda V, Jankovic S. Successful management of bleeding with recombinant factor VIIa (NovoSeven ) in a patient with Burkitt lymphoma and thrombosis of the left femoral and left common iliac veins. Pediatr Blood Cancer Mar2; Epub ahead of print. 19. Tancabelic J, Haun SE. Management of coagulopathy with recombinant factor VIIa in a neonate with echovirus type 7. Pediatr Blood Cancer. 2004;43: Shander A, Goodnough LT, Ratko T, et al. Consensus recommendations for the off-label use of recombinant human factor VIIa (NovoSeven ) therapy. Pharma Ther. 2005;30: Stein DM, Dutton RP, O Connor J, et al. Determinants of futility of administration of recombinant factor VIIa in trauma. J Trauma. 2005:59; Meng ZH, Wolberg AS, Monroe DM, Hoffman M. The effect of temperature and ph on the activity of factor VIIa: implications for the efficacy of high-dose factor VIIa in hypothermic and acidotic patients. J Trauma. 2003;55: