Low ADAMTS13 activity is associated with an increased risk of ischemic stroke

Abstract

ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin motif repeats 13) has antithrombotic properties because it cleaves von Willebrand factor (VWF) in smaller, less active multimers. The aim of our study was to investigate prospectively the association between ADAMTS13 activity and ischemic stroke. We included 5941 individuals ≥55 years without a history of stroke or transient ischemic attack (TIA) of the Rotterdam Study, a population-based cohort study. ADAMTS13 activity was measured at inclusion with the FRETS-VWF73 assay and VWF antigen (VWF:Ag) levels by enzyme-linked immunosorbent assay. We assessed the association among ADAMTS13 activity, VWF:Ag levels, and ischemic stroke by Cox proportional hazard analysis. The added value of ADAMTS13 activity above the traditional risk factors for ischemic stroke risk prediction was examined by the C-statistic and the net reclassification improvement index (NRI). All individuals were followed for incident stroke or TIA. Over a median follow-up time of 10.7 years (56,403 total person-years), 461 participants had a stroke, 306 of which were ischemic. After adjustment for cardiovascular risk factors, individuals with ADAMTS13 activity in the lowest quartile had a higher risk of ischemic stroke (absolute risk, 7.3%) than did those in the reference highest quartile (absolute risk, 3.8%; hazard ratio, 1.65; 95% confidence interval [CI], 1.16-2.32). Adding ADAMTS13 to the model in prediction of ischemic stroke, increased the C-statistic by 0.013 (P = .003) and provided 0.058 (95% CI, -0.002 to 0.119) NRI. Low ADAMTS13 activity is associated with the risk of ischemic stroke and improves the accuracy of risk predictions for ischemic stroke beyond traditional risk factors.

Von Willebrand Factor: Multimeric Structure and Functional Activity in Patients With Atrial Fibrillation With and Without Oral Anticoagulation

“…15 Individuals who had both lowest ADAMTS13 activity and higher vWF levels had an increased risk of ischemic stroke, suggesting that ADAMTS13 and vWF are independent risk factors for thrombotic events. 35 Patients without OAC had lower levels of ADAMTS13, and such levels correlated with higher vWF levels, higher vWF activity, stroke risk stratification scales, and the incidence of stroke. The association between ADAMTS13 and ischemic stroke has been investigated previously in small case-control studies.…”

“…As it is well known, OAC inhibits thrombin formation and thrombin inactivates ADAMTS13, 45 and in consequence, formation of HMWMs; larger multimeric forms of vWF are more active in hemostasis, 4,34 promoting a prothrombotic state. 35 Nevertheless, this could be due to the acute response to stroke, so further studies are needed to confirm whether vWF parameters are related to an increased risk of stroke. Low ADAMTS13 activity is associated with the risk of ischemic stroke and improves the accuracy of risk predictions for ischemic stroke beyond traditional risk factors.…”

“…39 Sonneveld et al conclude that low ADAMTS13 activity was significantly associated with the risk of ischemic stroke, independent of age, sex, and established cardiovascular risk factors over a median of 10.7 years of follow-up, and addition of ADAMTS13 activity improved the accuracy of risk predictions for ischemic stroke beyond the traditional risk factors. 35 In other words, more risk is associated with lower ADAMTS13 levels. From these results, an altered vWF multimeric pattern would be expected with the presence of HMWMs because lower ADAMTS13 levels correlate with increased levels of ultralarge vWF multimers.…”

“…4,34 This results in larger procoagulant vWF multimer concentrations and consequently a prothrombotic state that may lead to thrombus formation at sites of endothelial damage and especially at sites with a higher shear stress such as arterial circulation. 35 Further studies are needed to investigate whether the increased risk that is related to vWF antigen is in part mediated by the presence of vWF HMWMs.…”

“…10,[36][37][38] The association between low ADAMTS13 activity and ischemic stroke risk is likely to be explained by less cleavage of vWF HMWMs, which are the most prothrombotic. 4,35 Freynhofer et al affirm that vWF and its cleaving protease ADAMTS13 might play an important role in the development and perpetuation of vascular disease in patients with AF. 39 Sonneveld et al conclude that low ADAMTS13 activity was significantly associated with the risk of ischemic stroke, independent of age, sex, and established cardiovascular risk factors over a median of 10.7 years of follow-up, and addition of ADAMTS13 activity improved the accuracy of risk predictions for ischemic stroke beyond the traditional risk factors.…”