Total tissue factor pathway inhibitor is an independent risk factor for symptomatic paediatric venous thromboembolism and stroke

Abstract

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.

Familial Elevated Factor VIII in Children With Symptomatic Venous Thrombosis and Post-Thrombotic Syndrome

“…DNA extraction was performed by a spin column procedure (Qiagen) as previously described. 9,11,12,15 For the present FVIII study blood samples were drawn from otherwise healthy patients, relatives, and controls with normal hemograms and no evidence of further diseases.…”

“…Standard laboratory techniques 9,11,12,15 were used to investigate the factor V G1691A (FV) and factor II G20210A (FII) mutations, concentration of Lp (a) (intrassay-coefficient of variation [ICV], 4.5%; run-to-run coefficient of variation [RCV], 4.2%), PC (ICV, 1.6%; RCV, 5.0%), PS (ICV, 2.2%; RCV, 4.2%), AT (ICV, 3.1%; RCV, 6.5%), and tissue factor pathology inhibitor (TFPI) levels (ICV, 5.2%; RCV, 4.0%) in patients and controls. Samples from 69 patients and 181 controls were available for TFPI measurements.…”

Tissue Factor Pathway Inhibitor, Activated Protein C Resistance, and Risk of Ischemic Stroke due to Postmenopausal Hormone Therapy

“…10 Cross-sectional studies suggest that low levels of TFPI or increased APC resistance may play a role in childhood ischemic stroke, but their roles in adult strokes are unclear. 11,12,13 Higher TFPI levels in subjects with subclinical carotid and coronary atherosclerosis and with increased arterial stiffness may reflect endothelial dysfunction. 14,15, 16 …”

Novel protein ADTRP regulates TFPI expression and function in human endothelial cells in normal conditions and in response to androgen

“…TF-driven coagulation not adequately countered by TFPI seemingly underlies thrombotic complications in sepsis, atherosclerosis, lupus and cancer, [10][11][12][13][14] and could associate with increased risk of deep vein thrombosis/venous thromboembolism (DVT/VTE). [15][16][17][18] Although TFPI is a major endogenous inhibitor of coagulation, few mechanisms/factors that regulate the natural expression of TFPI have been identified so far. [19][20][21][22] Finding ways to up-regulate the cell-associated TFPI to prevent unwanted clotting and to inhibit TF-dependent pathologic effects, although being of great importance, is a still underinvestigated area.…”