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Antithrombin deficiency and pediatric thrombosis
studies, restricted to cases with antithrombin deficiency, showed also lower mortality rates.32,33 Two of the six deceased patients in our cohort were carrying the p.Leu131Phe variant, Antithrombin Budapest III, in homozygous state. The occurrence of pediatric thrombo- sis associated with this variant present in homozygosity has been described earlier,14,15,34 but, as far as we know, never with fatal outcome.
The frequency of thrombosis in patients with type I vs. type II deficiency was significantly higher with an OR of 2.3 (95%CI: 1.26-4.18; P=0.007). Interestingly, the preva- lence of type II HBS deficiency was low in our cohort with the majority of patients carrying this specific subtype in homozygous state or having an additional thrombophilic defect. This finding supports the fact that isolated heparin binding site deficiency in heterozygous state is less throm- bogenic in children than type I or the other type II defi- ciencies. There was a remarkable number of patients car- rying genetic variants associated with formation of disul- phide-linked dimers (14 of 73: 19.2%). The presence of these dimeric forms indicates that the causative mutation has a major impact on the correct folding of antithrombin.35 These results reinforce the hypothesis that mutations with conformational consequences have severe clinical implications and might also increase the risk of pediatric thrombosis.36
It is still a matter of debate whether it is useful to test for thrombophilia in children with a first venous thrombotic event or in asymptomatic children from families with thrombophilia.37,38 The identification of an inherited thrombophilic defect does not alter the acute antithrom- botic management in children,39 and it is not common practice to administer thromboprophylaxis in children in high-risk situations such as immobilization, surgery, or trauma.40 However, a recent study suggests that throm- bophilia care in children should be individualized.41 Our study has shown a high incidence of severe thrombotic events in children with antithrombin deficiency, most of them in high-risk situations, supporting the recent recom- mendation on the screening of thrombophilia in children with positive family history of VTE and/or severe throm- bophilia.41 Thus, we recommend testing for antithrombin
deficiency in children of affected families, particularly for those carrying type I deficiency. These carriers might have benefited from preventive strategies like thromboprophy- laxis in high-risk situations,42-46 and from counseling con- cerning risk factors such as oral contraceptive use. We also propose to test for antithrombin deficiency in pediatric cases with cerebral sinovenous thrombosis or thrombosis occurring at unusual sites. Although this may not change directly the treatment of the thrombotic event, it may pro- vide valuable information for future management of these patients and their family members. In selected cases, antithrombin concentrate could be a valuable treatment option, although this should be validated in clinical trials. Given the high frequency of CSVT in neonates with antithrombin deficiency, we recommend avoiding inva- sive procedures, like forceps or vacuum extraction, during delivery if one of the parents has antithrombin deficiency.
Our study has certain limitations, some of them due to its retrospective design. For example, in some cases, data on additional thrombophilic factors were lacking. Additionally, although anti-FXa is the method currently recommended for the diagnosis of antithrombin deficiency, there are some specific mutations that can only be detected by anti-FIIa or molecular methods.47,48 Accordingly, as the screening method used to identify the patients in our cohorts was anti-FXa, our study could have missed some cases of antithrombin deficiency, whose role in pediatric thrombo- sis has not been evaluated. Similarly, pediatric patients with asymptomatic thrombosis have not been included in our study. Nevertheless, this study represents the largest cohort of pediatric patients with antithrombin deficiency with thrombotic complications reported to date. Our results emphasize the severity of the disorder in the pediatric pop- ulation and reveal age-dependent differences in thrombotic manifestations and risk factors.
Acknowledgments
We thank Antonia Miñano, José Padilla, Ann De Reuse and Hilde Wauters for their excellent technical assistance, and Dr. Nuria Revilla for critical reading of the manuscript. A complete list of contributors and their institutions is provided in the Online Supplementary Appendix.
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