The Vwf-ADAMTS13 Axis in Acute Ischaemic Brain Injury: a Prospective Study

Background:

Acute ischaemic brain injury is associated with raised von Willebrand factor (vWF) and decreased ADAMTS13. Mouse data suggested manipulation of either factor has a direct impact on infarct volume, impacting functional outcome. Preliminary clinical data supports a role in arterial thrombosis severity and recurrence risk. We investigate the VWF: ADAMTS axis in acute stroke and impact on follow up.

Methods:

A prospective study in adults of vWF-ADAMTS13 in acute ischaemic brain injury, recruited from regional hyperacute stroke unit referrals and TIA (transient ischaemic attack) clinic. Exclusion included secondary precipitating causes such as known active malignancy. The control group were cases admitted with possible stroke, subsequently excluded. Blood was sampled at presentation, daily during admission, 7 -10 days post presentation and from 6 weeks post presentation. Clinical phenotype and stroke scoring parameters were documented. vWF (antigen- Ag, activity- Ac), Factor VIII, ADAMTS13- activity and thrombin generation (peak thrombin and endogenous thrombin potential-ETP) were analysed.

Results:

291 patients (140 males, 151 females), aged 23 -100 years. Patients were categorized into ischaemic stroke (IS, n=103), TIA (n=80) or controls (n=108). IS: At presentation, ADAMTS13 was lower in IS compared to controls (median 86.0IU/dL vs 95.7IU/dL, p<0.0001) and TIAs (median 94.0IU/dL, p<0.0001). vWFAg was higher in IS versus controls (median 196.9IU/dL vs 160.8 IU/dL, p=0.0007) and TIA ( median 167.8IU/dL, p=0.0194). Comparable significant findings for vWFAc were confirmed. Longer-term follow up (> 6 weeks since admission) in 62 patients, IS demonstrated increased ADAMTS13 from presentation to final follow up (86.0 to 97.4 IU/dL, p=0.01). There was a significant increase in median ADAMTS13 across all time points (p=0.0388) with median final follow up at 215 days (72- 394). The reverse was seen with vWFAg, vWFAc and Factor VIII in IS, with significant decrease over time. The vWFAg/ ADAMTS13 ratio decreased over time (2.42 to 1.53, p=0.0007) in IS as did thrombin generation (presentation vs final follow up respectively, peak: 262.6nM to 184.1nM, p=0.041; ETP: 1691nM/min to 1345nM/min, p=0.0251). Impact of thrombolysis: In IS, 38/103 were thrombolysed. Peak thrombin and endogenous thrombin generation (ETP) were raised at baseline in the thrombolysed cases compared to non-thrombolysed (p=0.0022 and 0.0012 respectively). Baseline ADAMTS13 was comparable between the groups, but the thrombolysed group showed increase at follow up (84 to 100.8 IU/dL, p=0.0005, median follow up 196 days) with no change in the non-thrombolysed group (86 to 80 IU/dL, p=0.955, median follow up 209 days). TIA : was divided between inpatient (IP, n=26) and outpatient (OP, n=54) cases. Baseline vWFAg, activity and FVIII were higher in IP compared to OP (vWFAg 229.5 vs 161.0, p=0.0029; vWFAc 199.8 vs 136.3, p=0.0173; FVIII 177.5 vs 131.3, p=0.0007). There was no difference in baseline ADAMTS13 (inpatients 95.3IU/dL vs outpatients 92.1IU/dL, p=0.505). Between baseline and follow up, the vWFAg/ ADAMTS13 ratio decreased but this was non-significant. Blood group was reviewed regarding impact on vWF. Comparing blood group O versus non-O showed significant differences in vWFAg, Ac and FVIII in the overall cohort. However, differences in vWFAg, vWFAc and ADAMTS13 were unchanged between IS and controls with adjustment for blood group (O versus non-O).

Conclusion: Our findings support decreased ADAMTS13 in acute IS compared to TIA and control, with a reciprocal increase in vWFAg and vWFAc. Comparison of TIA in-patients to out-patients showed significantly higher vWFAg, Ac and FVIII in the former, in keeping with a more severe phenotype. ADAMTS13 was not decreased in TIAs. There was resolution of VWF: ADAMTS 13 in IS at follow up, supporting increased vWF levels and consumption of ADAMTS13 in acute stroke. Thrombolysis appeared associated with recovery of ADAMTS13 activity. Contrast between IS and TIA groups suggest association with infarct volume and consequent stroke severity, and may indicate a close role between the vWF-ADAMTS13 axis and thrombogenicity in acute ischaemic brain injury. In the era of recombinant ADAMTS13, therapeutic implications of reducing raised vWF levels and normalising ADAMTS13 activity merit further investigation.