8 Pediatric considerations
1 Background
The hemostatic system of a healthy newborn, while functionally adequate, can be considered “immature”. Maternal coagulation factors do not pass through the placenta; the level of the vitamin K-dependent coagulation factors including FVII in a healthy full term newborn are about half of adult values. The levels of FVII increases gradually and reach adult values by the age of 16 years, however the largest differences compared to adult levels are seen during the first 6 months of life [1]. Vitamin K is required for post-translational modification of FVII and children are vitamin K deficient at birth. Vitamin K deficiency bleeding (VKDB, hemorrhagic disease of the newborn) with deficiency of all K-dependent proteins should be considered in newborns with bleeding symptoms. This condition is rare since Vitamin K substitution (i.e. Vitamin K 1 mg IM at birth or repeated doses of Vitamin K orally the first 1-3 months) is used worldwide to prevent this condition [2].
FVII is synthesized in the liver and the levels decrease if the hepatocellular function is impaired. FVII has a short half-life and may therefore be the first coagulation factor deficiency observed in acute liver failure. Reduced levels of both pro-and anticoagulant factors are often seen in chronic liver failure. Children with cholestasis are also at increased risk for VKDB [3].
2 Diagnosis of factor VII deficiency in children
In severe inherited FVII deficiency, FVII<10%, bleeding symptoms in the neonatal period are frequent frequent but unpredictable. The correlation between FVII activity level and bleeding phenotype is poor, and a minority of patients with severe FVII deficiency may remain asymptomatic [4]. As the mode of inheritance for severe FVII is autosomal recessive, a negative family history does not exclude this bleeding disorder. Pre-and postnatal age should be considered while interpreting the FVII levels in very young children and pediatric reference ranges must be used until 16 years of age [1,5]. Low FVII values should be measured repeatedly, especially if the child is below 6 months of age, before the diagnosis of FVII deficiency can be made. Vitamin K deficiency must be ruled out by vitamin K supplementation before testing and liver disease needs to be excluded.
Prenatal diagnosis can be made in families with clinical severe FVII deficiency and known genotype.
3 Treatment in children
3.1 Treatment of bleeding episodes and at surgery
The principles of treatment are the same as for the adults. Tranexamic acid can be used safely in children, with dosing 20-25 mg/kg/per dose orally and 10mg/kg/dose given three times daily intravenously. The recommendations regarding treatment with rFVIIa, including bolus doses, repeated doses and continuous infusions, earlier in this document (section 2.2 and 3) are based on reports on adults, children and infants and can thus be applied also in children [ [6]; [7]; [8]]. However, the risk of thrombosis in children is lower than in adults while the clearance of coagulation factor concentrates is increased. Therefore, especially young children may benefit from doses in the higher dose range and more frequent administration. If available, monitoring of FVII for an individual dosing scheme is recommended.
3.2 Prophylaxis in children
Unlike hemophilia, there are no guidelines on when to initiate prophylaxis. The need for prophylaxis depends on the bleeding pattern: intracranial bleeding, recurrent hemarthroses, gastrointestinal bleeding, severe epistaxis, menorrhagia or other serious bleedings motivate prophylactic treatment. It may be necessary to start prophylaxis within the first year of life or early childhood to prevent lifelong disability. Primary prophylaxis may be considered for example in children diagnosed prenatally with a family history of early life-threatening bleeding symptoms [9]. In Israel, prophylaxis is recommended from one year of age if FVII levels are below 1%, and ultrasound post partum is applied in known severe cases (personal correspondence). The most common prophylactic regimen is rFVIIa 20-30 µg/kg 2-3 times a week [10,11].
3.3 Liver transplantation
A few case reports regarding hepatocyte transplantation, auxiliary- and orthotopic liver transplantation in pediatric patients with severe FVII deficiency have been published [12–14]. The hepatocyte transplantation only had a short-term effect. Orthotopic liver transplantation can cure FVII deficiency. However, it is a major procedure with risk of complications, need for lifelong immunosuppression and one of the transplanted patients developed antibodies against FVII [14]. Therefore, consideration of such intervention needs to be restricted to selected patients with severe FVII deficiency and complicated bleeding symptoms after careful evaluation by multidisciplinary teams in specialized centers.
4 Follow-up during childhood
Children with clear bleeding tendency or FVII levels below 25% should have regular follow-up at a pediatric coagulation center. Children with FVII deficiency not fulfilling these criteria should be informed about the FVII deficiency and instructed to contact the pediatric coagulation center before surgical interventions or in case of bleeding symptoms. A follow-up visit is also advised in adolescence to get accurate and updated information about their FVII deficiency.
4.1 Pediatric recommendations
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