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Von Willebrand factor variant p.Arg924Gln marks an allele associated with reduced von Willebrand factor and factor VIII levels.

ABSTRACT: von Willebrand factor (VWF) variant c.2771G>A; p.R924Q has been described as a benign polymorphism or a possible marker for a null allele and been associated with mild bleeding phenotypes. It was identified in several patients in recent type 1 von Willebrand disease (VWD) studies.To determine whether the p.R924Q allele contributes to reduced VWF levels and type 1 VWD.One thousand one hundred and fifteen healthy controls and 148 index cases from the MCMDM-1VWD study were genotyped for c.2771G>A; VWF and FVIII levels were analyzed in ABO blood group stratified individuals and the p.R924Q variant was expressed in 293 EBNA cells.c.2771G>A was present in six index cases, five of whom had a second VWF variant which probably contributed to the phenotype. A common core haplotype identified in families, which included the rare G allele of c.5843-8C>G, was present in the majority of 35 c.2771G>A heterozygous controls. c.2771G>A contributed about 10% variance in VWF and FVIII levels in controls and 35% variance when co-inherited with blood group O. Recombinant p.R924Q VWF had no effect on in vitro expression and heterozygous family members had normal VWF-FVIII binding and normal clearance of VWF and FVIII.The allele bearing c.2771A leads to reductions in VWF and FVIII levels particularly in combination with blood group O. Its inheritance alone may be insufficient for VWD diagnosis, but it appears to be associated with a further VWF level reduction in individuals with a second VWF mutation and it contributes to population variance in VWF and FVIII levels.

SUBMITTER: Hickson N

PROVIDER: S-EPMC3856360 | biostudies-literature | 2010 Sep

REPOSITORIES: biostudies-literature

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von Willebrand factor variant p.Arg924Gln marks an allele associated with reduced von Willebrand factor and factor VIII levels.

Hickson N N Hampshire D D Winship P P Goudemand J J Schneppenheim R R Budde U U Castaman G G Rodeghiero F F Federici A B AB James P P Peake I I Eikenboom J J Goodeve A A

Journal of thrombosis and haemostasis : JTH 20100901 9

<h4>Background</h4>von Willebrand factor (VWF) variant c.2771G>A; p.R924Q has been described as a benign polymorphism or a possible marker for a null allele and been associated with mild bleeding phenotypes. It was identified in several patients in recent type 1 von Willebrand disease (VWD) studies.<h4>Objectives</h4>To determine whether the p.R924Q allele contributes to reduced VWF levels and type 1 VWD.<h4>Methods</h4>One thousand one hundred and fifteen healthy controls and 148 index cases fr ...[more]

PMID: 20492463

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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

Von Willebrand factor variant p.Arg924Gln marks an allele associated with reduced von Willebrand factor and factor VIII levels.

Publications

von Willebrand factor variant p.Arg924Gln marks an allele associated with reduced von Willebrand factor and factor VIII levels.

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