We report a child with thrombocytopenia since birth, circulating platelet agglutinates, and a tendency to bleed. A bone marrow aspirate revealed large platelet clumps within the bone marrow and ...megakaryocyte nuclei surrounded by halos of clumped platelets. Laboratory evaluation revealed type 2B von Willebrand disease. Gene sequencing revealed a G to C mutation at base 3923 of the VWF gene. This mutation was previously described in a family with circulating platelet clumps and abnormal megakaryopoiesis with release of clumped platelets in culture. This same mutation was previously described in a family with circulating platelet aggregates and abnormalities of platelet release from megakaryocytes in vitro. Presence of megakaryocytes with halos of clumped platelets in our patient suggests that platelet agglutinate occurs in the bone marrow in some type 2B von Willebrand disease patients.
The Zimmerman Program for the Molecular and Clinical Biology of VWD (ZPMCBVWD) is an NIH Program Project for the study of VWD in the USA and collaboration with ongoing studies in Canada and the ...University of Sheffield. Study subjects were recruited from 9 Primary Clinical Centers and 21 Secondary Clinical Centers across the USA and had to have the prior diagnosis of VWD on an intention to treat basis. We recruited 651 index cases, 2017 family members, and 247 normal controls. Of the index cases 152 had type 2 or 3 VWD or other variants and not part of this report. The remaining 499 represents the now completed Type 1 VWD cohort.
All 2915 study subjects underwent extensive laboratory testing including VWF:Ag, VWF:RCo, VWF multimeric analysis, FVIII activity, VWFpp, and VWF:CB (collagen binding), blood typing, and VWF linkage analysis. A detailed quantitative bleeding score (BS) was also performed on all 2915 individuals. Index cases had full length VWF sequencing with mutation confirmation and exclusion in family members. When indicated VWF:F8B (FVIII binding), VWF:PB (platelet binding to GPIb), VWF:IbCo (spontaneous binding to modified GPIb in absence of ristocetin), and repeat VWF testing in a second laboratory by different methods. When possible, historical laboratory results obtained at the time of initial diagnosis were obtained and entered into our Investig-8 Database.
Based upon clinical laboratory studies and phenotypic assignment, this cohort was found to include 232 type 1 VWD (VWF:Ag or VWF:RCo <40 IU/dL including 66 type 1C or severe type 1 VWD); 93 low-VWF (LVWF with lab studies between 40 IU/dL and the lower end of the normal range); 119 type 1H (historical levels below the normal range but not substantiated in current testing); and 55 individuals that tested within the normal range and did not have historic levels that were low. Full-length VWF sequencing was performed on all index cases and sequence variations (SVs) were identified, and where possible, compared to clinical phenotypes reported in the Sheffield Database. SVs were identified in 53% of the Type 1 VWD cohort (excluding those that were normal on testing without abnormal historic results). Of the 232 Type 1 VWD with VWF levels <40, 74% had SVs. In further analysis of this group, 100% of severe type 1, and 85% of type 1C had SVs. Looking at this in the type 1 with VWF:Ag <40 IU/dL by level of VWF:Ag, 87% of those 1 with VWF:Ag of 2-10, 93% with VWF:Ag 11-20, 71% with VWF:Ag of 21-30, 67% with VWF:Ag of 31-40, and 52% with VWF:Ag of >40 had SVs. The milder phenotypes demonstrate SVs in 39% of the LVWF subjects and 30% of the Type 1H subjects. In the individuals entered into the study as VWD subjects that on central testing had normal levels of VWF on entry into the study and did not have an abnormal historic VWF determination, only 22% had SVs.
A similar approach was undertaken to compare the quantitative BS using the ISTH Bleeding Assessment Tool. For this analysis, a score of 5 or greater was considered abnormal without regard to age or sex. Abnormal BS were identified in 63% of those with VWF:Ag of 2-10, 66% of those 11-20, 64% of those 21-30, 48% of those 31-40, and 58% of those >40. In LVWF subjects, 52% had abnormal BS and in Type 1H subjects 57% were abnormal.
Based upon a similar laboratory analysis, all 2017 family members underwent phenotypic assignment and were found to either be affected or unaffected family members. 713 were phenotyped as being an affected family member and 1296 as unaffected family members. Abnormal bleeding scores were identified in 38% of affected family members and 19% of unaffected family members.
This report summarizes some of the results on the completed Type 1 VWD cohort that was part of the ZPMCBVWD. All 2915 subjects (including index cases, family members, affected family members and normal controls) underwent extensive laboratory testing and phenotype assignment. Of the 499 subjects in the Type 1 VWD cohort, 325 had low VWF and 232 had VWF levels <40 IU/dL. Based on the drop of SV frequency, the level of VWF <40 may provide a possible demarcation to define VWD. In this study the frequency of abnormal bleeding score was not helpful in further defining this critical level for diagnosis - possibly because the bleeding score was ascertained at the entry into the study rather than at the time of diagnosis as done in earlier studies. Further analysis of this cohort can be expected to shed further understanding of the molecular and clinical biology of VWD.
No relevant conflicts of interest to declare.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
493.
Age and Racial Disparities in Dialysis Survival Kucirka, Lauren M.; Grams, Morgan E.; Lessler, Justin ...
JAMA : the journal of the American Medical Association,
08/2011, Volume:
306, Issue:
6
Journal Article
Intravascular infection due to Staphylococcus aureus requires colonization of subendothelium in the presence of shear forces. von Willebrand factor (VWF) is a large multimeric glycoprotein playing a ...key role in platelet adhesion to subendothelium. To determine whether VWF may also play a role in adhesion of S. aureus to endovascular sites, binding of VWF to S. aureus and adhesion of S. aureus to VWF-adsorbed substrates was examined. Binding isotherms revealed a dose-dependent reaction of purified VWF with S. aureus Cowan 1 as well as VWF binding to other S. aureus strains. On solid phase, VWF showed saturable adsorption kinetics to polymethylmethacrylate and promoted S. aureus adhesion up to 67-fold in a trypsin-sensitive reaction. Similar adhesion promotion was observed when recombinant VWF was used. These results show that VWF interacts with S. aureus in suspension and promotes S. aureus adhesion to surfaces, suggesting a role of VWF in the pathogenesis of intravascular S. aureus infections.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Parkinson disease (PD) is a late-onset neurodegenerative disorder. The mean age at onset is 61 years, but the disease can range from juvenile cases to cases in the 8th or 9th decade of life. The ...parkin gene on chromosome 6q and loci on chromosome 1p35-36 and 1p36 are responsible for some cases of autosomal recessive early-onset parkinsonism, but they do not appear to influence susceptibility or variability of age at onset for idiopathic PD. We have performed a genomewide linkage analysis using variance-component methodology to identify genes influencing age at onset of PD in a population of affected relatives (mainly affected sibling pairs) participating in the GenePD study. Four chromosomal loci showed suggestive evidence of linkage: chromosome 2p (maximum multipoint LOD MaxLOD = 2.08), chromosome 9q (MaxLOD = 2.00), chromosome 20 (MaxLOD = 1.82), and chromosome 21 (MaxLOD = 2.21). The 2p and 9q locations that we report here have previously been reported as loci influencing PD affection status. Association between PD age at onset and allele 174 of marker D2S1394, located on 2p13, was observed in the GenePD sample (P=.02). This 174 allele is common to the PD haplotype observed in two families that show linkage to PARK3 and have autosomal dominant PD, which suggests that this allele may be in linkage disequilibrium with a mutation influencing PD susceptibility or age at onset of PD.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
There is a need for empirical studies to define criteria for vascular cognitive impairment (VCI) subtypes. In this paper, we report the predictive validity of a subtype classification scheme based on ...clinical and radiographic features.
Nine Canadian memory clinics participated in the Consortium to Investigate Vascular Impairment of Cognition. This cohort consisted of 1347 patients, of whom 324 had VCI, and was followed for up to 30 months.
Clinical and neuroimaging features defined three subtypes: vascular cognitive impairment, no dementia, (
n
=
97), vascular dementia (
n
=
101) and mixed neurodegenerative/vascular dementia (
n
=
126). Any ischemic lesion on neuroimaging increased the odds (odds ratio
=
9.31; 95% confidence interval 6.46, 13.39) of a VCI diagnosis. No VCI subtype, however, was associated with a specific neuroimaging abnormality. Compared to those with no cognitive impairment, patients with each VCI subtype had higher rates of death and institutionalization (hazard ratio for combined adverse events
=
6.08,
p
<
0.001).
Both clinical features and radiographic features help establish a diagnosis of VCI. The outcomes of VCI subtypes, however, are more strongly associated with clinical features than with radiographic ones.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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