Impact of Reduced Von Willebrand Factor-Cleaving Protease [ADAMTS13] In Pediatric Stroke: A Nested Case-Control Study
Authors: Nowak-Gottl Ulrike , Lambers Moritz , Thedieck Sabine , Manner Daniela , Mesters Rolf M. , Junker Ralf , Stoll Monika 
Published: October 2019

Abstract
Abstract 805

Background:
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.

Methods:
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 <10th percentiles were compared to those >10th percentiles. Second: ADAMTS13 levels were distributed into quartiles. The number of patients versus controls in the lowest quartile [1st: 16–86%] was compared to the 2nd [87-101%], 3rd [102-112%] and 4th [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].

Results:
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 <10th 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: 1st vs. 2nd [2.17/1.04-4.53], 1st vs. 3rd [2.35/1.11-4.94] and 1st vs. 4th [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.

Conclusions:
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.

Disclosures:
No relevant conflicts of interest to declare.