Impact of Reduced Von Willebrand Factor-Cleaving Protease [ADAMTS13] In Pediatric Stroke: A Nested Case-Control Study

The interaction of von Willebrand factor [VWF] and its cleaving protease ADAMTS13 for preventing thrombosis in the microvasculature has been well described in patients with thrombotic thrombocytopenic purpura [TTP]. Recently it has been hypothesized that ADAMTS13 may protect the brain from ischemia by regulating VWF-platelet interaction after reperfusion, and that lower levels are associated with cardiovascular disease in young adults. Pediatric stroke is known as a multifactorial disease: Apart from various underlying mechanisms inherited genetic traits and intra-arterial thrombus formation constitute as major risk factors. The aim of the present nested case-control study was to determine the role of reduced ADAMTS13 levels in pediatric stroke.

208 pediatric patients with confirmed stroke (6 months to 18 years) and 128 population-based control children were investigated. Patients with liver disease, sepsis or antiphospholipid antibodies were excluded. ADAMTS13 activity [AC] and antigen [Ag] levels [kit: Technoclone, Vienna, Austria] have been evaluated 6 to 12 months after first stroke onset. Non-parametric statistics was performed for descriptive analysis [median (min-max) values] and inter-group comparisons [Mann-Whitney U test]. Correlation analysis was performed using Spearman rank correlation analysis. A p-value <0.05 was considered as statistically significant. First: Age-dependent percentiles were calculated from the control cohort and the number of patients and controls <10^th percentiles were compared to those >10^th percentiles. Second: ADAMTS13 levels were distributed into quartiles. The number of patients versus controls in the lowest quartile [1^st: 16–86%] was compared to the 2^nd [87-101%], 3^rd [102-112%] and 4^th [113-156%] quartile using a multivariate statistical model [logistic regression] adjusted for VWF, factor VIIIC, blood group [BG] and age. Results are shown as odds ratios/95% confidence intervals [OR/CI].

ADAMTS13 AC levels beyond the acute stroke onset were significantly lower in patients compared to controls [98% (16-143) vs. 103% (60-156), p=0.03], and 46 of 208 patients [22%] showed values <10^th percentiles compared with 5 of 123 controls [4%: p<0.001]. The corresponding adjusted OR/CI was 7.13/2.7-19.0. In the quartile comparison adjusted for VWF, FVIIIC, BG and age the following OR/CIs were calculated: 1^st vs. 2^nd [2.17/1.04-4.53], 1^st vs. 3^rd [2.35/1.11-4.94] and 1^st vs. 4^th [2.45/1.15-5.22]. In addition, moderate positive correlations were found between ADAMTS13 AC and i) ADAMTS13 Ag [rho=0.30; p<0.001], ii), BG [rho=0.18; p=0.002] and iii) age [rho=0.16; p=0.004], but not between ADAMTS13 and VWF, or FVIIIC. VWF AG levels were higher in patients compared to controls [112 (34-453) vs.104% (50-451)] without reaching statistical significance [p=0.65]. Platelet count in patients and controls was within the normal age-dependent reference range.

Compared to healthy control children pediatric stroke survivors showed significantly reduced ADAMTS13 activities with a corresponding OR of 7.13 [percentile comparison] and 2.3 [quartile comparison]. Our findings support the concept that ADAMTS13 deficiency is associated in the pathogenesis of non TTP-dependent microangiopathy in cerebro- and cardiovascular diseases. To elucidate if this deficiency state in children with stroke beyond the acute disease onset is congenital or acquired further investigations are ongoing.

No relevant conflicts of interest to declare.