Dataset Information

Genetic Drivers of von Willebrand Factor Levels in an Ischemic Stroke Population and Association With Risk for Recurrent Stroke.

ABSTRACT: von Willebrand factor (vWF) plays an important role in thrombus formation during cerebrovascular damage. We sought to investigate the potential role of circulating vWF in recurrent cerebrovascular events and identify genetic contributors to variation in vWF level in an ischemic stroke population.We analyzed the effect of circulating vWF on risk of recurrent stroke using survival models in the VISP trial (Vitamin Intervention for Stroke Prevention) and the use of vWF in reclassification over traditional factors. We conducted a genome-wide association study) with imputation, based on 1000 Genomes Project data, for circulating vWF levels and then interrogated loci previously associated with vWF levels. We performed expression quantitative trait locus analysis for vWF across different tissues.Elevated vWF levels were associated with increased risk for recurrent stroke in VISP. Adding vWF to traditional clinical parameters also improved recurrent stroke risk prediction. We identified single-nucleotide polymorphisms significantly associated with circulating vWF at the ABO locus (P<5×10-8) and replicated findings from previous genetic associations of vWF levels in humans. Expression quantitative trait locus analyses demonstrate that most associated ABO single-nucleotide polymorphisms were also associated with vWF gene expression.Elevated vWF levels are associated with recurrent stroke in VISP. In the VISP population, genetic determinants of vWF levels that impact vWF gene expression were identified. These data add to our knowledge of the pathophysiologic and genetic basis for recurrent stroke risk and may have implications for clinical care decision making.

SUBMITTER: Williams SR

PROVIDER: S-EPMC5536245 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Genetic Drivers of von Willebrand Factor Levels in an Ischemic Stroke Population and Association With Risk for Recurrent Stroke.

Williams Stephen R SR Hsu Fang-Chi FC Keene Keith L KL Chen Wei-Min WM Dzhivhuho Godfrey G Rowles Joe L JL Southerland Andrew M AM Furie Karen L KL Rich Stephen S SS Worrall Bradford B BB Sale Michèle M MM

Stroke 20170511 6

<h4>Background and purpose</h4>von Willebrand factor (vWF) plays an important role in thrombus formation during cerebrovascular damage. We sought to investigate the potential role of circulating vWF in recurrent cerebrovascular events and identify genetic contributors to variation in vWF level in an ischemic stroke population.<h4>Methods</h4>We analyzed the effect of circulating vWF on risk of recurrent stroke using survival models in the VISP trial (Vitamin Intervention for Stroke Prevention) a ...[more]

PMID: 28495826

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Project description:Introduction:Plasma factor VIII (FVIII) and von Willebrand factor (VWF) levels have been associated with the rate and severity of arterial thrombus formation and have been linked to outcomes following thrombolytic therapy in acute myocardial infarction patients. Here, we aimed to investigate FVIII and VWF levels during the course of thrombolysis in acute ischemic stroke (AIS) patients and to find out whether they predict long-term outcomes. Materials and methods:Study population included 131 consecutive AIS patients (median age: 69?years, 60.3% men) who underwent i.v. thrombolysis with recombinant tissue plasminogen activator (rt-PA). Blood samples were taken on admission, 1 and 24?h after rt-PA administration to measure FVIII activity and VWF antigen levels. Neurological deficit of patients was determined according to the National Institutes of Health Stroke Scale (NIHSS). ASPECT scores were assessed using computer tomography images taken before and 24?h after thrombolysis. Intracranial hemorrhage was classified according to the European Cooperative Acute Stroke Study (ECASS) II criteria. Long-term functional outcome was determined at 90?days after the event by the modified Rankin scale (mRS). Results:VWF levels on admission were significantly elevated in case of more severe AIS [median and IQR values: NIHSS <6:189.6% (151.9-233.2%); NIHSS 6-16: 199.6% (176.4-250.8%); NIHSS >16: 247.8% (199.9-353.8%), p?=?0.013]; similar, but non-significant trend was observed for FVIII levels. FVIII and VWF levels correlated well on admission (r?=?0.748, p?<?0.001) but no significant correlation was found immediately after thrombolysis (r?=?0.093, p?=?0.299), most probably due to plasmin-mediated FVIII degradation. VWF levels at all investigated occasions and FVIII activity before and 24?h after thrombolysis were associated with worse 24?h post-lysis ASPECT scores. In a binary backward logistic regression analysis including age, gender, high-sensitivity C-reactive protein, active smoking, diabetes, and NIHSS >5 on admission, elevated FVIII and VWF levels after thrombolysis were independently associated with poor functional outcomes (mRS???3) at 90?days (immediately after thrombolysis: FVIII: OR: 7.10, 95% CI: 1.77-28.38, p?=?0.006, VWF: OR: 6.31, 95% CI: 1.83-21.73, p?=?0.003; 24?h after thrombolysis: FVIII: OR: 4.67, 95% CI: 1.42-15.38, p?=?0.011, VWF: OR: 19.02, 95% CI: 1.94-186.99, p?=?0.012). Conclusion:Elevated FVIII activity and VWF antigen levels immediately after lysis and at 24?h post-therapy were shown to have independent prognostic values regarding poor functional outcomes at 90?days.

Dataset Information

Genetic Drivers of von Willebrand Factor Levels in an Ischemic Stroke Population and Association With Risk for Recurrent Stroke.

Publications

Genetic Drivers of von Willebrand Factor Levels in an Ischemic Stroke Population and Association With Risk for Recurrent Stroke.

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