VWF:ADAMTS13 ratio is associated with white matter hyperintensity

Abstract Background: ADAMTS13 exerts an antithrombotic effect by cleaving highly prothrombotic high molecular weight Von Willebrand Factor (VWF) multimers. Severe deficiency of ADAMTS13 causes thrombotic thrombocytopenic purpura (TTP). Elevated VWF and low ADAMTS13 have been associated with ischemic stroke in the general population (PMID: 26511134, 20798373). population. No study has investigated a corresponding association between ADAMTS13 and VWF and the presence of white matter hyperintensities (WMH), which are precursor lesions to ischemic stroke and associated with stroke, cardiovascular mortality, and cognitive decline (PMID: 20660506). We investigated whether the ratio of VWF antigen to ADAMTS13 activity (VWF:ADAMTS13 ratio) is associated with presence of WMH, particularly large WMH, on brain magnetic resonance imaging (MRI) in a cohort enriched for risk factors for early vascular disease. Methods: Healthy relatives of probands with early-onset cardiovascular disease were enrolled in the Genetic Study for Atherosclerosis Risk (GeneSTAR) cohort. We included individuals who completed brain MRI and had citrated plasma samples available for VWF and ADAMTS13 testing. MRIs were performed on a Phillips 3T scanner and an expert neuroradiologist adjudicated the presence of WMH and large (≥3 mm) WMH. Volumetric analysis of WMH was also performed. Mixed effects logistic regression accounting for family membership was used to examine the association of the VWF:ADAMTS13 ratio with any WMH and large WMH, adjusting for other clinical risk factors including age, sex, race, and the presence of hypertension, diabetes mellitus, current smoking, total cholesterol, high-density lipoprotein (HDL) cholesterol, and aspirin use. Results: A total of 287 participants met inclusion criteria. The majority (60.6%) were female and median age at assessment was 50 years (IQR: 41-59). Most self-identified as white (55.1%) or black (43.9%). Vascular risk factors were common; 31.7% had hypertension, 12.9% had diabetes, and 15.3% reported active smoking. The median ADAMTS13 activity was 109.14% (IQR 93.31%-128%) and the median VWF antigen level was 64.29% (44.07%-97.34%). The vWF:ADAMTS13 ratio was higher in those with WMH (median 0.623, IQR: 0.434 - 0.926), compared to those without WMH (median 0.509, IQR: 0.373 - 0.804) (p = 0.013). Similarly, the vWF:ADAMTS13 ratio was higher in those with large WMH (median: 0.702, IQR: 0.468 - 1.083) compared to those without large WMH (median: 0.514, IQR: 0.373 - 0.836) (p=0.003). The VWF:ADAMTS13 ratio was significantly associated with large WMH [OR 2.03 (95% CI 1.16 – 3.55) (p = 0.013)] in a model adjusted for age (OR: 1.11, 95% CI: 1.07 – 1.15), sex (female OR: 1.76, 95% CI: 0.92 - 3.37 ), race (black OR: 1.58, 95% CI 0.84 – 2.95; other OR: 9.89 95% CI 0.63 – 154.87, reference white), diabetes mellitus (OR 0.61, 95% CI 0.24 – 1.54), current smoking (OR: 0.47, 95% CI 0.21 – 1.05), total cholesterol (OR 0.99, 95% CI 0.99 – 1.01) high-density cholesterol (OR 0.99, 95% CI 0.98 – 1.01), hypertension (OR 0.82, 95% CI 0.41 – 1.63), and aspirin use (OR 1.17, 95% CI 1.16 – 3.55). Conclusion: In conclusion, we demonstrate an association between ADAMTS13 and VWF with a stroke precursor lesion, WMH. This provides further evidence to the growing body of literature that disruption of the ADAMTS13 - VWF axis may play a role in the pathogenesis of ischemic cerebrovascular disease. Our results may have implications for risk stratification in the general population as well as for patients with TTP in whom silent infarct and cognitive impairment remain prevalent in remission.