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B. de la Morena-Barrio et al.
patients from two unrelated families presented p.Arg161* mutation. Finally, we identified two families where more than one member developed pediatric thrombosis: three carriers of p.Pro112Ser from the same family developed thrombosis during childhood, but this is a large family with 14 affected members; and two twins carrying p.Ser223Pro developed VTE at 12 and 15 years old. Genetic variants associated with the presence of unusual disulphide-linked dimers in plasma were identified in 14 children: p.Gly456Arg, p.Pro112Ser, p.Pro112Leu, c.1154- 14G>A, p.Ser114Asn and p.Ser381Pro.The remaining mutations were predominantly distinct missense or non- sense mutations responsible for type I deficiency (Online Supplementary Table S1).
Discussion
The low prevalence of severe thrombophilic disorders like deficiencies of the natural anticoagulants antithrom- bin, protein C and protein S renders it difficult to estimate the thrombotic risk in patients affected by these condi- tions. This limitation is even more prominent when con- sidering pediatric thrombosis. In particular, for antithrom- bin deficiency very few data are available about the occur- rence of thrombosis in the first two decades and most information results from case reports or small case series,13-15 as well as from reports on thrombophilia in large cohorts of pediatric patients.16,20
Our results, obtained from the largest series of pediatric antithrombin deficient patients world-wide, emphasize the severity of this condition and suggest that more strict recommendations on the management of families with antithrombin deficiency should be considered.
The incidence of pediatric thrombosis among our antithrombin deficient patient cohort was as high as 7.5%, 4.32 cases/1,000-patient years, or 300-fold higher than described in the general population (0.0014%/year).4
We observed more thrombotic complications in males than females (male-to-female ratio 1.2:1), consistent with previous studies in children.5,16,20-22 Thrombosis in
antithrombin deficient children also seems to be age- dependent. In accordance with other studies,23 we observed a fairly consistent pattern with an initial peak incidence of thrombosis during the neonatal period and a second increment occurring in adolescence. During ado- lescence, the localization of the thrombosis and the trig- gering risk factors were similar to those seen in adults, notably estrogen-related conditions (oral contraceptives, pregnancy and puerperium). The reason for the high inci- dence of thrombosis in neonatal period could be attrib- uted to the labile hemostatic system in newborns with reduced levels of many coagulation factors and inhibitors, including antithrombin. Antithrombin levels are known to be 60% reduced at birth and to reach adult values around three months of age.24,25 We speculate that the physiologi- cal antithrombin deficiency at birth is exacerbated by the addition of a congenital defect of this protein, making the neonate more sensitive to any other prothrombotic trig- gering factor like acidosis, hypoxia, thermal changes, release of tissue factor, and a frequent exposure to trauma and manipulation. Indeed, in half of the neonates with thrombosis, one of these conditions was present. It is worth mentioning that only one of the initial thrombosis in the neonates from our cohort was catheter-related, while this is the main overall cause of thrombosis in new- borns.26 We note a strikingly high prevalence (17.8%) of cerebral sinovenous thrombosis in our pediatric cohort. This finding is not consistent with prior reports of single cases or small case series.27,28 It is plausible that the devel- opment of the skull (with fontanels) makes the newborn vulnerable to cerebral thrombosis during this period, par- ticularly if associated with thrombophilia and/or localized trauma.29 Three of the events in our study occurred after assisted delivery, a procedure known to be associated with 60% of the cases of CSVT.30
Of interest is the severe outcome and mortality in our pediatric antithrombin deficient patients. Directly attrib- utable mortality was 4-fold higher compared to children with thrombosis from the Canadian Childhood Thrombophilia registry (8.2% vs. 2.2%, respectively),31 including different types of thrombophilia. Other small
Figure 3. Kaplan-Meier survival curves of thrombosis-free survival between male and female patients with pediatric thrombosis.
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haematologica | 2019; 104(12)