In patients undergoing transcatheter aortic-valve replacement, defects in high-molecular-weight von Willebrand factor multimers and the closure time with adenosine diphosphate (a measure of ...hemostasis) were closely correlated with postprocedural aortic regurgitation.
Postprocedural aortic regurgitation, usually due to paravalvular leak, occurs in 10 to 20% of patients with aortic stenosis who undergo transcatheter aortic-valve replacement (TAVR).
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Patients with aortic regurgitation that is more than mild after TAVR have poorer outcomes than those without aortic regurgitation, including increased rates of rehospitalization, death from cardiac causes, and death from any cause at 1 year.
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Ideally, aortic regurgitation after TAVR should be detected at the time of the procedure, because correction maneuvers can be undertaken immediately. However, despite the combined use of angiography, echocardiography, and hemodynamic evaluation, it is very difficult to identify and . . .
The main risk factor for bleeding in patients with continuous-flow mechanical circulatory support (CF-MCS) is the acquired von Willebrand factor (VWF) defect related to the high shear-stress forces ...developed by these devices. Although a higher bleeding rate has been reported in CF-MCS recipients who had reduced pulsatility, the relation between pulsatility and the VWF defect has never been studied.
The purpose of this study was to investigate the relation between pulsatility and VWF under CF-MCS.
We assessed the effect of 2 CF-MCS on VWF multimer degradation in a mock circulatory loop (model 1). Using these devices, we investigated in a dose-effect model (model 2) 3 levels of pulsatility in 3 groups of swine. In a cross-over model (model 3), we studied the effects of sequential changes of pulsatility on VWF. We reported the evolution of VWF multimerization in a patient undergoing serial CF-MCS and/or pulsatile-MCS.
We demonstrated the proteolytic degradation of VWF multimers by high shear CF-MCS in a circulatory loop without pulsatility. We observed both in swine models and in a patient that the magnitude of the VWF degradation is modulated by the pulsatility level in the high shear-stress level condition, and that the restoration of pulsatility is a trigger for the endothelial release of VWF.
We demonstrated that the VWF defect reflects the balance between degradation induced by the shear stress and the endothelial release of new VWF triggered by the pulsatility. This modulation of VWF levels could explain the relationship between pulsatility and bleeding observed in CF-MCS recipients. Preservation of pulsatility may be a new target to improve clinical outcomes of patients.
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RATIONALE:Percutaneous aortic valve procedures are a major breakthrough in the management of patients with aortic stenosis. Residual gradient and residual aortic regurgitation are major predictors of ...midterm and long-term outcome after percutaneous aortic valve procedures. We hypothesized that (1) induction/recovery of high molecular weight (HMW) multimers of von Willebrand factor defect could be instantaneous after acute changes in blood flow, (2) a bedside point-of-care assay (platelet function analyzer-closure time adenine DI-phosphate PFA-CADP), reflecting HMW multimers changes, could be used to monitor in real-time percutaneous aortic valve procedures.
OBJECTIVE:To investigate the time course of HMW multimers changes in models and patients with instantaneous induction/reversal of pathological high shear and its related bedside assessment.
METHODS AND RESULTS:We investigated the time course of the induction/recovery of HMW multimers defects under instantaneous changes in shear stress in an aortic stenosis rabbit model and in patients undergoing implantation of a continuous flow left ventricular assist device. We further investigated the recovery of HMW multimers and monitored these changes with PFA-CADP in aortic stenosis patients undergoing transcatheter aortic valve implantation or balloon valvuloplasty. Experiments in the aortic stenosis rabbit model and in left ventricular assist device patients demonstrated that induction/recovery of HMW multimers occurs within 5 minutes. Transcatheter aortic valve implantation patients experienced an acute decrease in shear stress and a recovery of HMW multimers within minutes of implantation which was sustained overtime. In patients with residual high shear or with residual aortic regurgitation, no recovery of HMW multimers was observed. PFA-CADP profiles mimicked HMW multimers recovery both in transcatheter aortic valve implantation patients without aortic regurgitation (correction) and transcatheter aortic valve implantation patients with aortic regurgitation or balloon valvuloplasty patients (no correction).
CONCLUSIONS:These results demonstrate that variations in von Willebrand factor multimeric pattern are highly dynamic, occurring within minutes after changes in blood flow. It also demonstrates that PFA-CADP can evaluate in real time the results of transcatheter aortic valve procedures.
We report a 38-year-old woman who presented with a subdural hematoma after minor facial trauma in a stressful situation. The laboratory data showed a subnormal platelet count (166×10
/L), VWF:RCo ...activity was 45% and VWF:Ag was 53% with a VWF:RCo/VWF Ag ratio of 0.79. Hemostasis results and gene analysis revealed von Willebrand disease (VWD) type 2B with normal multimers and a novel mutation c.4136 G>T (R1379L), which appears to be a novel mutation of VWD type 2B that is mainly diagnosed with hypersensitivity to ristocetin and an hyperfixation of platelet Willebrand to a recombinant Gp1b. SIMILAR CASES PUBLISHED: None.
Anti-ADAMTS13 autoantibodies are the main cause of acquired thrombotic thrombocytopenic purpura. Binding of these antibodies to ADAMTS13 eventually results in the formation of antigen-antibody immune ...complexes. Circulating ADAMTS13-specific immune complexes have been described in patients with acquired thrombotic thrombocytopenic purpura, although the prevalence and persistence of these immune complexes over time have hitherto remained elusive. Here, we analyzed a large cohort of patients with acquired thrombotic thrombocytopenic purpura for the presence of free and complexed anti-ADAMTS13 antibodies. In the acute phase (n=68), 100% of patients had free IgG antibodies and 97% had ADAMTS13-specific immune complexes. In remission (n=28), 75% of patients had free antibodies (mainly IgG) and 93% had ADAMTS13-specific immune complexes. Free antibodies were mainly of subclasses IgG1 and IgG4, whereas IgG4 was by far the most prevalent in ADAMTS13-specific immune complexes. Comparison of ADAMTS13 inhibitor and anti-ADAMTS13 IgG (total and subclasses) antibody titers in acute phase and in remission samples showed a statistically significant decrease in all parameters in remission. Although non-significant, a trend towards reduced or undetectable titers in remission was also observed for ADAMTS13-specific immune complexes of subclasses IgG1, IgG2 and IgG3. No such trend was discernible for IgG4; IgG4 immune complexes persisted over years, even in patients who had been treated with rituximab and who showed no features suggesting relapse.
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 Willebrand factor (VWF) concentrate, almost devoid of Factor VIII (Wilfactin, 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.
Two unrelated families were recruited in the French Reference Center for von Willebrand Disease with moderate bleeding symptoms associated with low von Willebrand factor (VWF) antigen levels, ...decreased collagen binding assay, and no or partial response to desmopressin. Genetic analysis showed the presence of heterozygous mutations in the A3 domain away from the collagen-binding surface: 1 never reported previously (p.L1696R) and another (p.P1824H) described in a Spanish family. The mutations were reproduced by site-directed mutagenesis and mutant VWF was expressed in different expression systems, COS-7 cells, baby hamster kidney cells, and in VWF-deficient mice through hydrodynamic injection. p.L1696R and p.P1824H were associated with very low expression levels both in vitro and in vivo, with intracellular retention for p.P1824H. Both homozygous mutants displayed decreased binding to collagen types I and III but also decreased binding to platelet glycoproteins Ib and IIbIIIa. Co-transfections with wild-type VWF partially corrected these defects, except that collagen binding remained abnormal. The in vivo thrombosis response was severely reduced for both heterozygous mutants. In conclusion, we report 2 VWF A3 domain mutations that induce a combined qualitative and quantitative defect.
•VWF A3 domain mutations inducing defective collagen binding and impaired protein production.
We evaluated the use of the turbidimetric HemosIL von Willebrand Factor (VWF) Activity assay (VWF:Act) on the STA-R automated coagulometer (Stago, Asnières, France) for the diagnosis of von ...Willebrand disease (VWD). For this, we prospectively screened 268 patients. As a second part, we retrospectively assayed 111 patients with well-defined VWD subtype. In the first prospective study, we demonstrate that in most cases of VWD, VWF ristocetin cofactor activity (VWF:RCo) and VWF:Act are highly correlated but that they both cannot be considered a good screening assay when used alone, since they could miss about 25% of VWF abnormalities. However, the association of VWF:Act analysis and the Platelet Function Analyzer-100 (PFA-100) test constitutes an excellent screening strategy. In our second retrospective study concerning VWD subtypes, VWF:RCo and VWF:Act were well correlated but could be very discrepant, especially for some cases of type 2M VWD. We consider that VWF:RCo remains the “reference assay” for VWD subtype classification.
Summary
Type 2N von Willebrand disease (VWD) is characterized by a markedly decreased affinity of von Willebrand factor (VWF) for factorVIII (FVIII) and is caused by mutations in the D’ or D3 domain ...of mature VWF. We now report a French patient with an atypical 2N VWD phenotype associating FVIII deficiency with plasmaVWF unable to bind FVIII (undetectableVWF:FVIIIB) but with an abnormal multimeric profile. This patient is heterozygous for both the frequent R854Q type 2NVWD mutation and a novel R763G mutation at the cleavage site betweenVWF propeptide and mature VWF. Four children of the patient displayed moderately decreased VWF:FVIIIB of plasma VWF and were heterozygous for either the R763G or the R854Q mutation. Children with the R763G mutation displayed the same abnormal multimeric profile as their father. Recombinant VWF (rVWF) expression studies performed in COS-7 cells showed that the R763G mutation subtly affects its multimeric profile and dramatically impairs its FVIII binding function. Furthermore, the characteristics of hybrid G763/Q854 rVWF resulting from cotransfection experiments were in agreement with the type 2N VWD diagnosis of the patient. We conclude that R763G is a new type 2N VWD mutation located in the VWF propeptide which alters the proteolytic processing of VWF and consequently its binding to FVIII.
Type 2N von Willebrand disease encompasses all patients with factor VIII deficiency caused by a markedly decreased affinity of von Willebrand factor for factor VIII. It is recessively inherited and ...clinically similar to mild haemophilia. The differential biological diagnosis is of major importance for providing the optimal treatment and relevant genetic counselling. This accurate diagnosis is based on an evaluation of the factor VIII-binding capacity of plasma von Willebrand factor. Furthermore, molecular biology techniques allow the identification of missense mutations in the von Willebrand factor gene. All of these induce the substitution of amino acid residues located in the N terminal part of the mature von Willebrand factor molecule, which contains the factor VIII binding site. Most of them induce a classical type 2N von Willebrand disease phenotype with factor VIII deficiency but a normal level and multimeric pattern of von Willebrand factor.
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