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SummaryTissue factor pathway inhibitor (TFPI) plays an important role in inhibiting tissue factor-induced coagulation by a factor Xadependent pathway of the activated tissue-factor VIIa complex. Decreased values of the latter inhibitor have been recently reported in adult patients with venous thrombosis (VT) or ischaemic stroke (IS). The present case-control study was therefore performed to evaluate whether a decreased TFPI concentration is also involved in paediatric symptomatic thromboembolism (ST). Total TFPI concentrations were measured along with established prothrombotic risk factors six to twelve months after the acute thrombotic onset in 144 Caucasian children aged 0.6 to 18 years (VT: n=80; IS: n=64). The cut-off values defined as age-dependent 10th percentiles were obtained from 244 healthy controls. Median (range) values of TFPI were significantly lower in patients compared with control subjects [50.0(20.0-132.3) ng/ml vs. 59.5(25.4-117.4) ng/ml; p-value < 0.0001]. In addition, 42 of the 144 patients (29.2%) compared with 25 of the 244 controls (10.2%) showed TFPI concentrations below the 10th age-dependent percentiles. Compared to baseline values 78.6% of children with total TFPI Ag < 10th percentiles showed a low response to enoxaparin administration, whereas in children with normal baseline TFPI values 30% show a low TFPI release (p= 0.007). Multivariate analysis adjusted for the presence of established prothrombotic risk factors showed a significantly increased odds ratio (OR) and 95% confidence interval (CI) for patients with ST [OR/CI: 3.8/2.2-6.6; p< 0.0001]. Data shown here give evidence that total TFPI concentrations below the 10th age-dependent percentiles independently increase the risk of ST in Caucasian children 3.8-fold.

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It has been recently shown that the first bleeding onset in children with severe hemophilia A (HA) carrying prothrombotic risk factors is significantly later in life than in non-carriers.1 The present multicenter study was performed to determine whether the factor (F) V G1691A or the F II G20210A are associated with decreased annual bleeding episodes (ABE) in 106 pediatric PUP patients with severe HA (Intron 22 58.6%) consecutively admitted to German pediatric hemophilia treatment centers. Treatment was initiated according to the frequency of bleedings, and most patients received on demand therapy with a switch over to prophylactic therapy 3x/week (40–60 IU/kgKG factor VIIII concentrate) when more than three bleedings (range 2–6) had occurred into the same joint (n=49). Prospective median(range) patient follow-up was 14(4–35) years. Heterozygosity of the FV mutation was found in 8 subjects, homozygosity in one, and 5 children carried the FII mutation once combined with protein C-deficiency. Carriers of the FV and FII mutations had significantly fewer ABE than non-carriers (p=0.004). 66 of 106 PUP patients developed at least one target joint with a median(range) Pettersson score of 1(0–12) available in 57 patients clearly dependent on age (p=0.039) as well as ABE (p=0.037). The “Nuss” joint score available in 33 subjects highly correlated with the Pettersson score (p=0.007). Data presented here give evidence that the clinical expression of severe HA in children is influenced by the co-expression of the FV and FII mutation.

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