von Willebrand factor/ADAMTS13 ratio at presentation of acute ischemic brain injury is predictive of outcome

Abstract

Acute ischemic stroke (IS) and transient ischemic attack (TIA) are associated with raised von Willebrand factor (VWF) and decreased ADAMTS13 activity (ADAMTS13Ac). Their impact on mortality and morbidity is unclear. We conducted a prospective investigation of the VWF-ADAMTS13 axis in 292 adults (acute IS, n = 103; TIA, n = 80; controls, n = 109) serially from presentation until >6 weeks. The National Institutes of Health Stroke Score (NIHSS) and modified Rankin scale (mRS) were used to assess stroke severity. Presenting median VWF antigen (VWF:Ag)/ADAMTS13Ac ratios were: IS, 2.42 (range, 0.78-9.53); TIA, 1.89 (range, 0.41-8.14); and controls, 1.69 (range, 0.25-15.63). Longitudinally, the median VWF:Ag/ADAMTS13Ac ratio decreased (IS, 2.42 to 1.66; P = .0008; TIA, 1.89 to 0.65; P < .0001). The VWF:Ag/ADAMTS13Ac ratio was higher at presentation in IS patients who died (3.683 vs 2.014; P < .0001). A presenting VWF:Ag/ADAMTS13Ac ratio >2.6 predicted mortality (odds ratio, 6.33; range, 2.22-18.1). Those with a VWF:Ag/ADAMTS13Ac ratio in the highest quartile (>3.091) had 31% increased risk mortality. VWF:Ag/ADAMTS13Ac ratio at presentation of ischemic brain injury was associated with higher mRS (P = .021) and NIHSS scores (P = .029) at follow-up. Thrombolysis resulted in prompt reduction of the VWF:Ag/ADAMTS13Ac ratio and significant improvement in mRS on follow-up. A raised VWF:Ag/ADAMTS13Ac ratio at presentation of acute IS or TIA is associated with increased mortality and poorer functional outcome. A ratio of 2.6 seems to differentiate outcome. Prompt reduction in the ratio in thrombolysed patients was associated with decreased mortality and morbidity. The VWF:Ag/ADAMTS13Ac ratio is a biomarker for the acute impact of an ischemic event and longer-term outcome.

Graphical abstract

Figure 1.

Comparison of hemostatic markers among groups at presentation demonstrated significant differences between groups. (A) VWF:Ag. (B) VWF:Ac. (C) FVIII. (D) ADAMTS13Ac. IS demonstrates the highest median VWF:Ag (196.9IU/dl), VWF:Ac (188.8IU/dL) and FVIII (178.6IU/dL), followed by TIA (VWF:Ag 167.8, VWF:Ac 159.8, FVIII 149.7 IU/dL) and controls (VWF:Ag 160.1, VWF:Ac 140.4, FVIII 142.6IU/dL). The reverse trend was seen for ADAMTS13Ac, as illustrated in panel D (IS median 86.0, TIA 94.0, controls 95.6IU/dL). KW, Kruskal-Wallis.

Figure 2.

Longitudinal patterns in ischemic stroke. Longitudinal changes in all haemostatic markers were measured at presentation (t0), 24 hours later (t1), 48 hours post presentation (t2), 5-7 days post presentation (t3) and final follow up from 6 weeks post presentation (t4). Median follow up time for ischaemic stroke specifically was 257 days (range 48-889). (A) Decrease in VWFAg from presentation (median 196.9 IU/dL) to final follow up (median 157.7 IU/dL) was observed (P = .0093 on matched paired testing). The same trend was seen with VWFAc from presentation (median 188.7 IU/dL) to final follow up (median 143.7IU/dL; P = .0289) (B), and FVIII (presentation median 178.6 to final follow up 137.7 IU/dL; P = .0149) (C). (D) A clear reverse trend was seen with ADAMTS13Ac in ischaemic stroke, demonstrating a significant increase in ADAMTS13Ac from presentation (median 85.9 IU/dL) to final follow up (median 96.8IU/dL, P = .0092).

Figure 3.

Mortality outcome: difference in baseline hemostatic markers in IS and TIA groups combined. Significant differences were seen in all haemostatic markers at baseline between those patients whom had subsequently died at final follow up (n =2 4) vs those whom survived (n = 156) at a median follow up time of 152 days post initial presentation (minimum 6 weeks from first presentation). Differences were as follows (died vs survived): VWF:Ag (269.1 vs 171.2IU/dL, P < .0001) (A), VWF:Ac (210.5 vs 159.8IU/dL, P = .0019) (B), ADAMTS13 activity (79.1 vs 90.3IU/dL, P = .0126) (C), and mean VWF:Ag/ ADAMTS13Ac ratio (3.683 vs 1.988, P < .0001) (D).