IMAJ • VOL 11 • october 2009 Case Communications

Rescue Recombinant Activated Factor VII for Neonatal Subgaleal Hemorrhage Tzipora Strauss MD1,2,3, Gili Kenet MD2,3, Irit Schushan-Eisen MD1,3, Ram Mazkereth MD1,3 and Jacob Kuint MD1,3

1Department of Neonatology, Safra Medical Center and 2Thrombosis Unit and Israeli National Hemophilia Center, Sheba Medical Center, Tel Hashomer, Israel 3Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel

investigational data on the use of rFVIIa file disclosed a prothrombin ratio of 33% Key words: neonate, subgaleal , in children, and the reports generally (normal 70–120%), international normal- recombinant activated factor VII, involve small numbers of patients. The ized ratio 1.94, partial thromboplastin vacuum delivery, , literature on the use of rFVIIa in non- time >130 seconds (normal 25–30 sec), autopsy hemophilic neonates is anecdotal and fibrinogen 95 mg/dl (normal 200–400 mg/ IMAJ 2009;11:639–640 limited to post‑cardiac surgery, liver dl), thrombin time 17 seconds (normal failure, necrotizing enterocolitis and 14–18 sec) and D-dimer > 10,000 ng/ml pulmonary hemorrhage. To date there is (normal < 250). The hematocrit decline only one case report of the use of rFVIIa continued to a nadir of 29% despite con- eonatal subgaleal hematoma often in infant subgaleal hematoma [3], and we tinuous blood transfusions. A neurosur- N occurs after instrumental delivery add another report, presented below. geon consultant had been involved, but (vacuum, forceps) or in infants with since a surgical option is rarely helpful congenital disorders after and the literature recommends conser- normal spontaneous delivery [1]. This Patient Description vative treatment [4], it was decided not major blood loss causes severe coagu- A male infant (birth weight 2548 g) was to operate at that point. Dopamine and lopathy, especially in neonates since delivered at 37 weeks gestation to a 36 dobutamin, 20 µg/kg/min each, were their coagulation system is deficient year old woman with no family history of started due to hypotension. Three doses in vitamin K-dependent and contact hemophilia or any other bleeding disor- of tranexamic acid (Hexakapron®, Teva, factors [2]. Massive acute bleeding der. Vacuum delivery was initiated in the Israel), 20 mg/kg (50 mg) per dose, were into the subgaleal space may cause delivery room due to slow progression of administered every 8 hours starting from extremely serious complications, such delivery and onset of fetal bradycardia. the age of 12 hours. Cranial ultrasound as shock and death. Thus, infants born After several unsuccessful attempts with confirmed a huge subgaleal hematoma after instrumental delivery require close the vacuum, a cesarean section was per- with normal brain structures and no evi- monitoring of vital signs, hematocrit, formed. The newborn's Apgar score was 2, dence of intracranial bleeding. The head blood gases, head circumference, and 3 and 5 at 1, 5 and 10 minutes, respectively. circumference increased to 40 cm during signs of tissue hypoperfusion. Early The baby was immediately intubated and the first hours of life and the hematocrit recognition of symptoms is crucial to transferred to the neonatal intensive care continued to drop. avoid a fatal outcome. unit. No medications were required at this A rescue treatment with rFVIIa was Recombinant activated factor VII stage. The infant’s first hematocrit mea- suggested. After the rFVIIa treatment (NovoSeven®, Novo Nordisk A/S, surement was 36%, blood pressure 66/53 was explained to the parents, including Bagsvaerd, Denmark) was first intro- and head circumference 33 cm. its advantages and disadvantages, and duced for the treatment of bleeding epi- The initial physical examination approval was obtained from our risk sodes in patients with hemophilia A or revealed subgaleal hematoma (enlarged management committee, rescue treat- B with inhibitors. RFVIIa is increasingly head with fluid wave and pale appearance) ment with rFVIIa (NovoSeven®) was being used as a potent procoagulant for whereupon emergency O RH-negative started. A total of four doses of rFVIIa the treatment of acute hemorrhage in packed cells were promptly administered 100 µg/kg/dose were given at intervals of situations other than hemophilia. These and continued with 400 ml (156 ml/kg) 2 hours (total dose 1.2 mg) starting from include trauma, general surgery, cardiac packed cells, 130 ml (50 ml/kg) fresh fro- the age of 12 hours. Bleeding slowed surgery and obstetrics. There are scarce zen plasma, 365 ml (144 ml/kg) platelets and PC transfusion was required only and 80 ml (30 ml/kg) cryoprecipitate over RFVIIa = recombinant activated factor VII the next 6 hours. His first coagulation pro- PC = packed cells

639 Case Communications IMAJ • VOL 11 • october 2009

12 hours after rFVIIa administration, tic option for infants who experience the postmortem examination) probably followed by only three more PC transfu- life-threatening hemorrhages and fail due to severe DIC. sions at 12 hour intervals. The adminis- to respond to standard therapy. Since a It is not known whether earlier admin- tration of rFVIIa also led to stabilization surgical option is anecdotal [4] and the istration of rFVIIa would have been ben- of laboratory coagulation parameters and literature recommends conservative eficial. We need to consider the potential improved PTT values from > 130 to 57 treatment, it is our hope that raising the role of rFVIIa in promoting the risk for seconds 1 hour after rFVIIa administra- awareness of rFVIIa adjunct therapy for thrombotic complications; however, we tion. No deterioration in neurological subgaleal hematoma may be life saving believe that in cases that are refractory status was apparent. He continued to for other newborns. to continuous blood products infusion, respond symmetrically in reaction to At pharmacological doses, rFVIIa the benefit of using it as rescue treatment pain but without spontaneous move- binds to the surfaces of activated plate- might outweigh the disadvantages. We ment. A second ultrasound performed lets and initiates a thrombin burst, inde- propose that this approach might prevent on day 8 of life demonstrated severe pendent of the tissue factor (factor VIII further deterioration into hemorrhagic brain with anoxic damage and or factor IX), which leads to the forma- shock and death. an organized hematoma in the subgaleal tion of a stable clot. RFVIIa may also In conclusion, rFVIIa may be con- area. Further imaging, namely computed increase clot stability via enhancement sidered as a possible novel therapeutic tomography, was not an alternative due of thrombin-activatable fibrinolysis approach to be used as rescue therapy to his critical condition. inhibitor-dependent down‑regulation for patients presenting with massive The infant died from multiorgan of fibrinolysis. RFVIIa is increasingly life-threatening hemorrhage progress- failure 2 weeks later. Deterioration in being used as a potent procoagulant for ing into hemorrhagic shock. Further his neurological status was observed; the treatment of acute hemorrhage in controlled trials to elucidate the safety he became encephalopathic with no situations other than hemophilia [5]. of this treatment are warranted. response to pain and no spontaneous We administered rFVIIa after 12 movement. Extension of his severe brain hours of massive bleeding and after treat- Correspondence: Dr. T. Strauss edema seen on cranial ultrasound, renal ment with an enormous amount of Dept. of Neonatology, Safra Childrens Hospital, failure, severe metabolic acidosis and blood products following standard Sheba Medical Center, Tel Hashomer 52621, Israel cardiogenic shock were caused by his protocol. Administering rFVIIa at an Phone: (972-3) 530-2227, Fax: (972-3) 530-2215 initial severe and hypoxia. earlier stage may have been beneficial. email: [email protected] The postmortem examination re- Eventually the bleeding stopped and References vealed blood clots between the scalp the infant survived for an additional 1. Boo NY, Foong KW, Mahdy ZA, et al. Risk factors and the periosteum, pulmonary blood 2 weeks. During this time there was associated with subaponeurotic haemorrhage in full-term infants exposed to . clots, massive hemothorax and a right a slight improvement in his general Br J Obstet Gynecol 2005; 112: 1516-21. lower lobe infarct. Various clots and condition. No evidence of thrombosis 2. Kenet G. Bleeding disorders in neonates. Thromb small infarcts were seen in the spleen was found on renal or head ultrasound. Res 2005; 115 (Suppl 1): 41-4. and kidneys due to old bleeding. Unfortunately, due to the massive bleed- 3. Hünseler C, Kribs A, Eifinger F, Roth B. Recombinant activated factor seven in acute life-threatening ing and hypotension during the first bleeding in neonates: report on three cases and hours of life the infant suffered from review of literature J Perinatol 2006; 26: 706-13. Comment irreversible hypoxic ischemic dam- 4. Amar AP, Aryan HE, Meltzer HS, Levy ML. Neonatal subgaleal hematoma causing brain Despite the eventual demise of the age. His ultrasound showed significant compression: report of two cases and review of infant from complications due to severe brain edema, evidence of disseminated the literature Neurosurgery 2003; 52(6): 1470-4. blood loss and multiorgan failure, this intravascular coagulation in his labora- 5. Mathew P, Young G. Recombinant factor VIIa case represents an important therapeu- tory tests, and a hydrothorax that was in paediatric bleeding disorders – a 2006 review. Haemophilia 2006; 12: 457-72. tapped revealed serous fluid following PTT = partial thromboplastin time massive bleeding (also documented by DIC = disseminated intravascular coagulation

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