Croatian experience in treatment with recombinant activated factor VII in pediatric liver transplantations

The process of liver transplantation is connected with a high risk of blood loss resulting from portal hypertension, collateral circulation, vascularised adhesions and coagulation disorder associated with liver dysfunction (1-5). The loss of active liver parenchymal cells is the reason for the reduced production of coagulation factors dependent on vitamin K and the proteins C and S. During liver transplantation surgical bleeding is one of the major problems. Massive blood loss causes high morbidity, mortality and carries a risk of postoperative multiorgan dysfunction (6), reduced graft survival (7), increased infection rates (6-8), as well as prolonged stay in the intensive care unit (9). Conventional therapy (fresh frozen plasma, cryoprecipitate or fibrinogen concentrate, platelet concentrate, vitamin K) has a limited and often a short term effect and leads to volume overload with the infunded blood products. In our patients, despite conventional therapy, as well as surgical hemostasis, the bleeding did not stop. That was the reason for recombinant activated factor VII (rFVIIa) administration.
Recombinant activated factor VII (NovoSeven, Novo Nordisk) is a hemostatic agent working by enhancing localized thrombin formation at the site of vascular injury by binding to the surface of activated platelets (10). Its ability to initiate coagulation cascade at the site of bleeding without inducing systemic coagulation makes rFVIIa treatment useful in liver transplantation process.
MATERIALS AND METHODS
Recombinant activated factor VII was administered in nine children before and/or during liver transplantation before graft reperfusion. The patients were between nine months and 14 years of age, five boys and four girls. Four of the children were scored by Child-Pugh classification with B degree, and five children with C degree of liver damage. Indications for liver transplantation were biliary atresia after unsuccessful Kasai operation (3), choledochal cyst with cirrhosis (2), cryptogenic hepatal cirrhosis (1), alfa- 1-antitripsine deficiency (1), progressive familiar intrahepatic cholestasis (PFIC) type I (1) and Crigler-Najjar syndrome type I (1). Five cadaveric transplants and four live donor transplants were used (eight segment and one whole liver trans- 1 Department of Anesthesiology, Reanimathology and Intensive care, Childrens’ Hospital Zagreb
2 School of Public Health “Andrija Štampar”, Department for Statistics and Informatics Correspondence to:
Ljiljana Popović, M. D., Ph. D., Department of Anesthesiology, Reanimathology and Intensive care, Childrens’ Hospital Zagreb, Klaićeva 16, 10 000 Zagreb, e-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it. plantation). Few postoperative surgical interventions were indicated. The indications were various – from obstructive ileus to stenosis of biliodigestive anastomosis. Recombinant activated factor VII was administered when bleeding could not be stopped by surgical hemostasis, repeated treatment with fresh frozen plasma (in the dose of 10-20 mL/kg of body weight), cryoprecipitate or fibrinogen concentrate and platelet concentrate (in the dose of 1-2 units per 10 kg of body weight). Fresh frozen plasma was administered when hemostasis was clinically insufficient and PT and/or APTT were 1,5 times higher than their upper normal values or when fibrinogen level was below 1.0g/L. Cryoprecipitate or fibrinogen concentrate were administered when fibrinogen level fell bellow 1.0g/L despite fresh frozen plasma administration. Platelet concentrate was administered when hemostasis was insufficient and the platelet count was less than 50x109/L. Administration of hemostatic agents was performed along with the correction of metabolic acidosis and maintenance of body temperature. An intravenous injection of rFVIIa in a dose of 90 μg/kg of body weight was administered pre- and/or intraoperatively before graft reperfusion. In seven children one dose was used intraoperatively, two doses were used in one child (preoperatively – invasive upper endoscopy for hemathemesis and intraoperatively) and three doses also in one child (one dose preoperatively for same indication as former and two doses intraoperatively in two hour intervals). Administered intraoperative doses were used before graft reperfusion. The use of this medication was approved by the Drug Committee of the Clinical Hospital Center Zagreb. The main indicators for coagulation function assessment were prothrombin time (PT; normal range 12-14 seconds) and activated partial thromboplastin time (APTT; normal range 18-40 seconds), as well as platelet count (PC; normal range 100-400 x 109/L). PT was measured by the optical coagulation detection method; Ca 500 device, Date Behring. APTT was measured by the optical coagulation detection method (turbidimethric method); BCT, Date Behring device. PC in peripheral blood was determined by measuring the electric resistance and by direct counting of the thrombocites using the counting chamber (Cocain method by Ludin Fleissl) or a Sysmex K 4500 electronic counter. Laboratory parameters were measured before and 15 minutes after the administration of rFVIIa. The coagulation parameters were measured in the Clinical department for laboratory diagnostics of the Department for hematology and coagulation of the Clinical Hospital Center Zagreb.
Statistical analysis was made using the Students t-test for related measures. The Kolmogorov-Smirnov test was used for testing the distribution normality.
RESULTS
The results are shown in the tables 1, 2 and 3.
Fifteen minutes after the intravenous administration of rFVIIa in a dose of 90 μg/kg of body weight, PT and APTT values significantly improved to normal range (tables 1 and 2). PC also changed significantly (table 3).
DISCUSSION
In children with end-stage liver disease the number of active liver cells is reduced resulting in impaired coagulation function. In these patients the synthesis of the coagulation factors dependent on vitamin K (factors II, VII, IX and X) and proteins C and S is significantly disturbed. In patients with end-stage liver disease the most common manifestation is gastrointestinal bleeding. The risk of bleeding in these patients exists during diagnostic procedures (liver biopsy), as well as during surgery (liver transplantation). The common pre-, intra- or postoperative correction includes the use of blood products, which contributes to volume overload of the circulation and can cause deterioration of portal hypertension and bleeding (11).
Liver transplantation in children is often the only therapeutic approach to treatment of some liver diseases. The most common reason for liver transplantation is liver cirrhosis caused by unsuccessful surgical treatment of biliary atresia by Kasai portoenterostomy. The new operation causes additional overload because of major blood loss compensation and the problems connected with massive blood transfusion.
Massive blood transfusion during liver transplantation increases the risk of infectious disease transmission, dilutional coagulopathy, activation of fibrinolysis, difficulties in preserving sufficient tissue perfusion and normothermia resulting in metabolic acidosis. It is well known that a smaller child undergoing transplantation has more severe consequences of any intra- and postoperative complications. Recombinant activated factor VII was administered in a single dose of 90 μg/kg of body weight, when it was not possible to correct the coagulation disorder and achieve clinically sufficient hemostasis by conventional and/or surgical methods. Fifteen minutes after rFVIIa administration PT and APTT values significantly improved to normal ranges, PC also changed significantly. During this time patients did not receive any other medication for coagulation disorder correction.
No thromboembolic event occurred during the perioperative period. This could be explained by the short lasting activity of rFVIIa (especially in pediatric patients) (12-14), as well as by the fact that it was administered before the completion of vascular anasthomosis.
Our results confirm that PT and APTT values shortened to normal range 15 minutes after a single dose of rFVIIa and verify the therapeutic effect of rFVIIa in treatment of coagulation disorders in children with end-stage liver disease. Past literature data, regarding the verification of rFVIIa therapeutic effect, point to the need for large multicentric studies based on which it will be possible to widen the indications for its use in the anesthesiological practice (15).
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