Frederic Perez-Alvarez, Cristina Serra, Jaume Macia and Lluis Mayol rFVII for Pediatric Acute Intracranial Hemorrhage Print ISSN: 0039-2499. Online ISSN: 1524-4628 Copyright © 2007 American Heart Association, Inc. All rights reserved. is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Stroke doi: 10.1161/STROKEAHA.107.484493 2007;38:e63-e64; originally published online May 17, 2007;Stroke. http://stroke.ahajournals.org/content/38/7/e63 World Wide Web at: The online version of this article, along with updated information and services, is located on the http://stroke.ahajournals.org//subscriptions/ is online at: Stroke Information about subscribing to Subscriptions: http://www.lww.com/reprints Information about reprints can be found online at: Reprints: document. Permissions and Rights Question and Answer process is available in the Request Permissions in the middle column of the Web page under Services. 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Include a fax number for the corresponding author and a completed copyright transfer agreement form (published in every issue). rFVII for Pediatric Acute Intracranial Hemorrhage To the Editor: A recent interesting phase IIB randomized, double-blind, placebo-controlled, dose-ranging “proof-of-concept” trial on recom- binant activated factor VII (rFVIIa) for acute intracranial hemor- rhage in adult patients has been reported. 1 A lacking of similar experience in the pediatric population is noted. rFVIIa has been anecdotally reported as effective for profound bleeding episodes in children. In the pediatric literature, case reports have been made with apparent clinical improvement seen after the use of rFVIIa for acute life-threatening bleeding; however, there are limited data regarding its use in infants younger than 4 months of age, regardless of whether it is a congenital or acquired condition. 2–3 We report on a case of acute intracranial hemorrhage in a newborn with congenital factor VII deficiency treated with rFVIIa and given a prophylactic program during a follow-up of 36 months. A full-term newborn boy, the first child of nonrelated black parents, was born to his mother aged 29, and the father was 28 years old. The family history was unremarkable. The preg- nancy was uneventful. Her birth weight was 2800 g, height was 47.0 cm, and cranial perimeter was 33 cm. Apgar scores were 5 and 6 at 1 and 5 minutes, respectively. Multifocal seizures occurred on the second day postpartum. The fontanelle was tense, and the cerebrospinal was bloody. Cranial CT did not show abnormal parenchymal images. Subarachnoid hemorrhage was diagnosed. Posthemorrhagic hydrocephalus occurred later, and she required shunt placement. Tests for coagulopathies reveled factor VII deficiency. rFVIIa was given 150 g/kg. The patient received a prophylactic treatment with an infusion pro- gram every 3 days in which she received rFVIIa using multiple doses from a single reconstituted vial over a 72-hour period. Since then, coagulation has been tested every 3 months and 80 g/kg intravenous rFVIIa is given if prothrombin time is Ͻ30%. At the age of 4 months, he was admitted because of increased intracranial pressure and a temporoparietal hematoma was iden- tified on CT of the brain, with the prothrombin time being of 30%. After a follow-up of 30 months, rFVIIa was required twice according to this scheme. No further hemorrhagic complications have occurred, with no change in prophylactic program. Devel- opmental retardation is present. At 36 months old, MRI shows residual parenchymal lesion. Family study was uneventful. Factor VII deficiency is the least rare among uncommon congen- ital coagulation disorders. The majority of cases are isolated defi- ciencies. Curiously, we remark that subarachnoid hemorrhage in adults has been previously reported. 4 Some practical questions are raised. First, we report on rFVIIa treatment and prophylaxis of bleeding in congenital deficiency. However, conclusions and hypotheses can be drawn from it independently of the congenital or acquired bleeding condition. Recombinant FVIIa has been reported to provide effective hemo- stasis in patients of all ages and in a range of bleeding situations, including acute central nervous system/life-threatening bleeding episodes, nonlife-threatening bleeding episodes, surgery, and childbirth. It may also promote hemostasis in patients with normal coagulation. rFVa acts locally at the bleeding site without activating systemic coagulation. Reports suggest that it may also be effective prophylactically. However, the risk of thrombosis in FVII-deficient patients treated with rFVIIa is unknown, as is the occurrence of inhibiting antibodies. 5 Second, we do not know exactly the doses for both treatment and prophylaxis. Nor do we know if doses for both congenital and acquired condition are the same. Effect was reached with all 3 doses that were tested (40, 80, and 160 g/kg). 1 A phase III trial comparing 20 and 80 g/kg rFVIIa with placebo is now in progress. However, physiological differences in the hemostatic system between children and adults have been reported 6 The most commonly used dose is 90 g/kg body weight rFVIIa as bolus, and, if necessary, followed by additional injections at intervals of 2 to 3 hours. In factor VII deficiency, lower dosages of 15 to 30 g/kg body weight of rFVIIa are given every 4 to 6 hours, whereas higher doses of 150 to 200 g/kg body weight are used in neonates. We do not know the exact level of coagulability to guarantee a nonhemorrhagic diathesis condition in case of factor VII deficiency. In fact, a reported 65-year-old patient with congenital isolated factor VII deficiency and bleeding problems had not shown earlier bleeding problems, presumably because of com- pensation for the factor VII deficiency by enhanced activities of components of the extrinsic coagulation pathway, factors II, VIII, IX, and X. 7 Third, the use of rFVIIa in hemorrhagic shock in neonates and preterm infants are increasing. For instance, neonates with massive postsurgical hemorrhage after ileostomy, with severe pulmonary hemorrhage in the course of mechanical ventilation for meconium aspiration syndrome, with congenital heart dis- ease. Also, during postoperative resuscitation after cardiac sur- gery for congenital heart disease in which multiple administra- tion of rFVIIa (120 g/kg per dose) and antifibrinolytic therapy, aminocaproic acid (100 mg/kg per dose), were successfully used. 8 Prevention of intraventricular hemorrhage and its potential long-term sequelae remain one of the major challenges in the early management of preterm infants. rVIIa, a novel hemostatic agent with an ever-expanding list of potential applications, warrants consideration for use in this setting. The hypothesis that early prophylactic administration of rVIIa to extremely preterm infants (Ͻ28 weeks) would reduce the incidence of severe intraventricular hemorrhage needs to be tested. 9 Finally, intracerebral hemorrhage causes severe disability and a staggering economic burden. Because rFVIIa is a very expen- sive therapy, possible strategies for optimizing its use in these settings in the pediatric population are particularly needed. 10 Disclosures None. Frederic Perez-Alvarez, MD NeuroPediatric Unit Hospital ICS Universitari Dr J Trueta Girona, Spain (Stroke. 2007;38:e63-e64.) © 2007 American Heart Association, Inc. Stroke is available at http://www.strokeaha.org DOI: 10.1161/STROKEAHA.107.484493 e63 Letters to the Editor by guest on February 11, 2014http://stroke.ahajournals.org/Downloaded from Cristina Serra, MB Jaume Macia, MD Lluis Mayol, MD Pediatric Department Hospital ICS Universitari Dr J Trueta Girona, Spain 1. Mayer SA. Recombinant activated factor VII for acute intracerebral hemorrhage. Stroke. 2007;38:763–767. 2. Brady KM, Easley RB, Tobias JD. Recombinant activated factor VII (rFVIIa) treatment in infants with hemorrhage. Paediatr Anaesth. 2006; 16:1042–1046. 3. Abdullah F, Hunter C, Hargrove C, Arnold M, Stein J. Recombinant factor VIIa for treatment of massive liver fracture in a premature infant. J Pediatr Surg. 2006;41:1764–1767. 4. Papa ML, Schisano G, Franco A, Nina P. Congenital deficiency of factor VII in subarachnoid hemorrhage. Stroke. 1994;25:508–510. 5. Mariani G, Konkle BA, Ingerslev J. Congenital factor VII deficiency: therapy with recombinant activated factor VII—a critical appraisal. Haemophilia. 2006;12:19 –27. 6. Sosothikul D, Seksarn P, Lusher JM. Pediatric REFERENCE values for molecular Markers in Hemostasis. J Pediatr Hematol Oncol. 2007;29:19 –22. 7. Tsuda T, Okamoto Y, Sakaguchi R, Katayama N, Ota K. Isolated factor VII deficiency diagnosed after a life-threatening brain haemorrhage. J Int Med Res. 2000;28:318–323. 8. Grizelj R, Vukovic J, Filipovic-Groic B, Saric D, Luetic T. Successful use of recombinant activated FVII and aminocaproic acid in four neonates with life-threatening hemorrhage. Blood Coagul Fibrinolysis. 2006;17: 413– 415. 9. Robertson JD. Prevention of intraventricular haemorrhage: a role for recom- binant activated factor VII. J Paediatr Child Health. 2006;42:325–331. 10. Earnshaw SR, Joshi AV, Wilson MR, Rosand J. Cost-effectiveness of recombinant activated factor VII in the treatment of intracerebral hem- orrhage. Stroke. 2006;37:2751–2758. e64 by guest on February 11, 2014http://stroke.ahajournals.org/Downloaded from