Summary
The objective of this retrospective study was to evaluate the potential ability of diluted Russell viper-venom time (dRVVT) to identify antiphospholipid syndrome (APS) in a lupus ...anticoagulant (LA)-positive patient population, already selected by other LA clotting tests. Our cohort of positive LA patients was first identified in our outpatients population by the following sensitive LA-detecting tests: Rosner index, diluted prothrombin time (dPT) and Rosove index. Then the 227 consecutive LA-positive patients were tested for dRVVT with the same blood sample. Anticardiolipin (aCL) and anti-β2-glycoprotein-I (β2GPI) autoantibodies assays were also performed. APS using Sapporo clinical criteria revised at Sydney, was found in 116 of these 227 consecutive LA-positive patients. Results of the different tests were analysed statistically. Using univariate analysis, dRVVT, dPT, IgG aCL and IgG anti-β2GPI autoantibodies were significantly associated with APS. The receiver operating-characteristics (ROC) curve defined the best cut-off value for dRVVT ratio at 1.61 with a good specificity (78%) and a lower sensitivity (53%). A multivariate analysis using a binary logistic procedure, retained the dRVVT ratio (≥ 1.61) and IgG anti-β2GPI autoantibodies (> 15 USG) as being associated with APS (p = 0.018; odds ratio OR 2.39; 95% confidence interval CI 1.2–4.7, and p = 0.0001; OR 3.2; 95% CI 1.5–6.5, respectively). To conclude, these results agree with the need for LA criteria favouring specificity over sensitivity. The use of a threshold around 1.6 for dRVVT ratio should help discriminate APS from non-APS patients.
von Willebrand disease (VWD) is a genetic bleeding disease due to a defect of von Willebrand factor (VWF), a glycoprotein crucial for platelet adhesion to the subendothelium after vascular injury. ...VWD include quantitative defects of VWF, either partial (type 1 with VWF levels <50 IU/dL) or virtually total (type 3 with undetectable VWF levels) and also qualitative defects of VWF (type 2 variants with discrepant antigenic and functional VWF levels). The most bleeding forms of VWD usually do not concern type 1 patients with the mildest VWF defects (VWF levels between 30 and 50 IU/dL). The French reference center for VWD performed a laboratory phenotypic and genotypic analysis in 1167 VWD patients (670 families) selected by their basic biologic phenotype: type 3, type 2, and type 1 with VWF levels <30 IU/dL. In these patients indeed, to achieve an accurate diagnosis of VWD type and subtype is crucial for the management (treatment and genetic counseling). A phenotype/genotype correlation was present in 99.3% of cases; 323 distinct VWF sequence variations (58% of novel) were identified (missense 67% versus truncating 33%). The distribution of VWD types was: 25% of type 1, 8% of type 3, 66% of type 2 (2A: 18%, 2B: 17%, 2M: 19%, 2N: 12%), and 1% of undetermined type. Type 1 VWD was related either to a defective synthesis/secretion or to an accelerated clearance of VWF. In type 3 VWD, bi-allelic mutations of VWF were found in almost all patients. In type 2A, the most frequent mechanism was a hyper-proteolysis of VWF. Type 2B showed 85% of patients with deleterious mutations (distinct from type 2B New York). Type 2M was linked to a defective binding of VWF to platelet glycoprotein Ib or to collagen. Type 2N VWD included almost half type 2N/3. This biologic study emphasizes the complex mechanisms for both quantitative and qualitative VWF defects in VWD. In addition, this study provides a new epidemiologic picture of the most bleeding forms of VWD in which qualitative defects are predominant.
The prevalence of anticardiolipin antibodies (aCL) and of vascular diseases increases with age, and aCL may be associated with various diseases in the elderly. So the significance of aCL in the ...elderly remains difficult to determine. We sought to determine the significance of persistent antiphospholipid antibodies (aPL) in the elderly.
We retrospectively analyzed the files of 327 patients 149 patients with antiphospholipid syndrome (APS); 64 patients age >or= 65 yrs with 2 positive aPL lupus anticoagulant (LAC) and/or aCL.
The frequency of APS was 40.8% (n = 134) in our 263 young patients (< 65 yrs) and 23.4% (n = 15) in our 64 elderly patients (>or= 65 yrs). The clinical characteristics of patients with persistent aPL were the same in those under and over 65 years. LAC was positive in all but one elderly patient with APS, and occurred in this group more frequently than in the young patients (93.3% vs 44.6%; p < 0.006). The presence of LAC allowed to discriminate APS patients in our elderly population (93.3% in APS vs 48.9% in non-APS patients; p < 0.009).
Interpretation of a positive determination of APL is difficult in the elderly; persistent LAC may be the most valuable biological marker of APS in the elderly.
von Willebrand disease (VWD) is a genetic bleeding disease due to a defect of von Willebrand factor (VWF), a glycoprotein crucial for platelet adhesion to the subendothelium after vascular injury. ...VWD include quantitative defects of VWF, either partial (type 1 with VWF levels <50 IU/dL) or virtually total (type 3 with undetectable VWF levels) and also qualitative defects of VWF (type 2 variants with discrepant antigenic and functional VWF levels). The most bleeding forms of VWD usually do not concern type 1 patients with the mildest VWF defects (VWF levels between 30 and 50 IU/dL). The French reference center for VWD performed a laboratory phenotypic and genotypic analysis in 1167 VWD patients (670 families) selected by their basic biologic phenotype: type 3, type 2, and type 1 with VWF levels <30 IU/dL. In these patients indeed, to achieve an accurate diagnosis of VWD type and subtype is crucial for the management (treatment and genetic counseling). A phenotype/genotype correlation was present in 99.3% of cases; 323 distinct VWF sequence variations (58% of novel) were identified (missense 67% versus truncating 33%). The distribution of VWD types was: 25% of type 1, 8% of type 3, 66% of type 2 (2A: 18%, 2B: 17%, 2M: 19%, 2N: 12%), and 1% of undetermined type. Type 1 VWD was related either to a defective synthesis/secretion or to an accelerated clearance of VWF. In type 3 VWD, bi-allelic mutations of VWF were found in almost all patients. In type 2A, the most frequent mechanism was a hyper-proteolysis of VWF. Type 2B showed 85% of patients with deleterious mutations (distinct from type 2B New York). Type 2M was linked to a defective binding of VWF to platelet glycoprotein Ib or to collagen. Type 2N VWD included almost half type 2N/3. This biologic study emphasizes the complex mechanisms for both quantitative and qualitative VWF defects in VWD. In addition, this study provides a new epidemiologic picture of the most bleeding forms of VWD in which qualitative defects are predominant.
Acquired von Willebrand syndrome is described in patients with Waldenström macroglobulinemia (WM). Assessment of ristocetin cofactor activity (VWF:RCo) and von Willebrand factor (VWF) antigen ...(VWF:Ag) in 72 consecutive patients with WM showed a negative relation between VWF levels < 130 U/dL and both monoclonal immunoglobulin M concentration (mIgMC) and viscosity. Ten patients with VWF:RCo < 50 U/dL (< 40 for patients with blood group O) fulfilled the acquired von Willebrand syndrome criteria. They had higher mIgMC and viscosity. Reduction in mIgMC was associated with increase in VWF levels. The low VWF:RCo/VWF:Ag ratio suggested that high viscosity might be associated with increased shear force and cleavage of multimers. Surprisingly, 43 patients (59%) presented with high VWF:Ag (> 110 U/dL). They had higher bone marrow microvessel density and vascular endothelial growth factor expression on bone marrow mast cells. Five-year survival rates of patients with VWF:Ag < 110, between 110 and 250, and more than 250 U/dL were 96%, 71%, and 44%, respectively (P < .0001). High VWF:Ag was also a significant adverse prognostic factor for survival after first-line therapy (P < .0001), independently of the international scoring system. These results support systematic assessment of VWF in patients with WM. The adverse prognostic value of high VWF levels raises issues on interactions between lymphoplasmacytic cells, mast cells, and endothelial cells in WM.
Background/Purpose
Long-term anticoagulation is the standard treatment for thrombotic antiphospholipid syndrome (APS). However, in daily practice, the question of withdrawing anticoagulation may ...arise, without any evidence-based recommendations. This study aimed to assess outcomes in APS patients after anticoagulation withdrawal.
Methods
Thrombotic APS patients followed in our centre, whose anticoagulation was withdrawn after APS diagnosis, were retrospectively selected, and were match-controlled with patients under anticoagulation, based on sex, age, APS clinical phenotype and disease duration.
Results
Thirty cases with anticoagulation withdrawal were included. Median follow-up was 51 months (12–124). The risk of thrombotic relapse was higher in cases compared to controls (7.3% versus 1.5% patient-year (p = 0.01); hazard ratio 4.8; 95% confidence interval (1.4–16.7)). Male gender, anti-β2GP1 and triple positivity at inclusion were predictive factors for thrombotic relapse. Conversely, aspirin prescription was a protective factor against relapses. Persistence of LA, anti-β2GP1 and triple positivity over time were associated with a higher risk of thrombosis and aPL disappearance with a lower risk.
Conclusion
In our study, anticoagulation withdrawal was associated with an increased risk of thrombotic relapse. Our findings emphasize the influence of anti-β2GP1 and triple positivity persistence over time on the risk of relapse and the benefit of aspirin prescription when anticoagulation has been withdrawn.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Le catalogue des oeuvres de Pierre Mercure reste des plus énigmatiques ; manuscrits introuvables et bandes magnétiques perdues seraient en cause. Tourné vers les spectacles de danse lors desquels ses ...oeuvres ont été diffusées – entre 1948 et 1964, Pierre Mercure compose onze musique de danse – , cet article propose d’en retracer l’histoire à partir des photographies, des programmes de spectacles et des articles de presse. Nous verrons par ce corpus comment Mercure repense la composition au fil des années en explorant des trajectoires originales dans son écriture, en utilisant des outils et des techniques des studios de musique électroacoustique et en revisitant le cadre du concert conventionnel avec, d’une part, des danseurs, de l’équipement technologique en lieu et place des interprètes et, d’autre part, un éclairage spécialisé et la participation de collaborateurs en arts visuels. Pierre Mercure aura certes été un grand créateur aux côtés des artistes de Refus global et ceux-ci auront naturellement contribué à la diffusion et à la réception de la musique contemporaine au Québec.
Summary
Interaction between von Willebrand factor (VWF) and platelet GPIbα is required for primary haemostasis. Lack or loss-of-function in the ligand-receptor pair results in bleeding complications. ...Paradoxically, gain-of-function mutations in VWF or GPIbα also result in bleeding complications as observed in type 2B von Willebrand disease (VWD) and platelet-type- (PT-) VWD, respectively. A similar phenotype is observed with increased ristocetin-induced platelet agglutination and disappearance of the highest molecular weight multimers of VWF. We evaluated a patient with a bleeding disorder and a biological presentation compatible with type 2B VWD. VWF and platelet functional assays, sequencing of the
VWF
and
GP1BA
genes, and expression studies in HEK cells were performed. Sequencing of the
VWF
gene in the propositus revealed a heterozygous p.Pro1266Leu mutation previously found in type 2B VWD Malmö/New York. These variants are characterised by a mild phenotype and a normal VWF multimer composition suggesting the presence of a second mutation in our propositus. Sequencing of the
GP1BA
gene revealed a heterozygous c.765G>A substitution changing Met at position 255 of GPIbα to Ile. This new mutation is located in the β-switch domain where five other gain-of-function mutations have been reported in PT-VWD. Expression of GPIbα Ile255 in HEK GPIb-IX cells resulted in enhanced VWF binding compared to wild-type, similar to known PT-VWD mutations (p.Val249, p.Ser249 and p.Val255) indicating that it contributes to the propositus defects. This first report associating PT-with type 2B VWD illustrates the importance of combining biological assays with genetic testing to better understand the clinical phenotype.
Summary
Von Willebrand disease-type 2A (VWD-2A) and acquired von Willebrand syndrome (AVWS) due to aortic stenosis (AS) or left ventricular assist device (LVAD) are associated with an increased ...proteolysis of von Willebrand factor (VWF). Analysis of VWF multimeric profile is the most sensitive way to assess such increased VWF-proteolysis. However, several technical aspects hamper a large diffusion among routine diagnosis laboratories. This makes early diagnosis and early appropriate care of increased proteolysis challenging. In this context of unmet medical need, we developed a new ELISA aiming a quick, easy and reliable assessment of VWF-proteolysis. This ELISA was assessed successively in a LVAD-model, healthy subjects (n=39), acquired TTP-patients (n=4), VWD-patients (including VWD-2A(IIA), n=22; VWD-2B, n=26; VWD-2A(IIE), n=21; and VWD-1C, n=8) and in AVWS-patients (AS, n=9; LVAD, n=9; and MGUS, n=8). A standard of VWF-proteolysis was specifically developed. Extent of VWF-proteolysis was expressed as relative percentage and as VWF proteolysis/VWF:Ag ratio. A speeddependent increase in VWF-proteolysis was assessed in the LVAD model whereas no proteolysis was observed in TTP-patients. In VWDpatients, VWF-proteolysis was significantly increased in VWD-2A(IIA) and VWD-2B and significantly decreased in VWD-2A(IIE) versus controls (p< 0.0001). In AVWS-patients, VWF-proteolysis was significantly increased in AS- and LVAD-patients compared to controls (p< 0.0001) and not detectable in MGUS-patients. A significant increase in VWFproteolysis was detected as soon as three hours after LVAD implantation (p< 0.01). In conclusion, we describe a new ELISA allowing a rapid and accurate diagnosis of VWF-proteolysis validated in three different clinical situations. This assay represents a helpful alternative to electrophoresis-based assay in the diagnosis and management of AVWS with increased VWF-proteolysis.
Supplementary Material to this article is available online at www.thrombosis-online.com.
Background
Bleeding originating in the gastrointestinal (
GI
) tract is one of the most common adverse events after left ventricular assist device (
LVAD
) implantation. In these patients,
GI
...bleeding appears to be the consequence of altered hemostasis on the one hand and alterations of the
GI
microvasculature on the other.
Case Report
We report the case of a patient who suffered repeated, severe
GI
bleeding early after implantation of a
HeartMate II
continuous‐flow
LVAD
.
Results
After failure of conventional treatment strategies,
GI
bleeding was controlled using repeated transfusions of a purified von
W
illebrand factor (
VWF
) concentrate, almost devoid of
F
actor
VIII
(
W
ilfactin,
LFB
). No episodes of pump thrombosis were noted. Subsequent to
VWF
transfusions, we observed a progressive normalization of circulating vascular endothelial growth factor levels.
Conclusions
Our data raise the possibility that, in addition to its hemostatic properties, transfusions of
VWF
might have acted as an antiangiogenic factor.
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