Our data indicate that AVWS is a typical disorder in patients with ECLS. We hypothesize that AVWS could contribute to aggravation of bleeding tendencies in ECLS patients.

The AVWS is present already in the early postoperative phase after VAD implantation. Therefore, reduced shear stress has to be an important feature of newly developed assist devices in the future.

Aims: Acquired Von Willebrand syndrome (AVWS) is an acquired bleeding disorder that has been reported to aggravate bleeding complications in patients with ventricular assist devices or aortic stenosis. AVWS is characterized by the loss of the high-molecular-weight (HMW) multimers of Von Willebrand factor (VWF) with consequent impaired VWF binding to platelets and collagen. The aim of this study was to investigate the development of AVWS in patients treated with veno-venous ECMO (extracorporeal membrane oxygenation) support. Methods: We examined the presence of AVWS in adult patients receiving ECMO support (n 18) and control subjects treated without ECMO support (n 18). The diagnosis of AVWS was made based on the ratio of collagen-binding capacity to VWF-antigen (VWF:CB/VWF:Ag) and a VWF multimeric analysis. In addition, bleeding episodes were monitored. Results: All patients supported with ECMO developed AVWS. AVWS was identified in the early period after ECMO implantation, i.e. within 24 hours after ECMO implantation. In 17 patients, the VWF:CB/VWF:Ag ratio was significantly reduced and HMW multimers were severely missing, and 17 of the 18 patients developed bleeding complications and required transfusions of blood, FFP and/ or platelet concentrates. In addition, nine patients without an ECMO device were investigated (prior to ECMO implantation: n 2, after ECMO explantation: n 7). Conclusions: In this study, all patients treated with ECMO support developed AVWS, and AVWS was detectable within 24 hours after ECMO implantation. However, the AVWS was reversible after ECMO explantation. Making an early diagnosis of AVWS and providing appropriate treatment may reduce the incidence of life-threatening bleeding. See

No abstract

According to our data, platelet aggregation is often impaired in LVAD patients even without an implanted LVAD. Additionally, appearance of AVWS seems to be closely linked to LVAD implantation.

Key Points• Two patients with bleeding diathesis had dysfunctional platelet P2Y 12 R for ADP, attributable to homozygous His187Gln mutation.• These studies delineate a region of transmembrane 5 of P2Y 12 R that is required for normal function after ADP binding.Defects of the platelet P2Y 12 receptor (P2Y 12 R) for adenosine diphosphate (ADP) are associated with increased bleeding risk. The study of molecular abnormalities associated with inherited qualitative defects of the P2Y 12 R protein is useful to unravel structurefunction relationships of the receptor. We describe the case of 2 brothers, sons of first cousins, with lifelong history of abnormal bleeding, associated with dysfunctional P2Y 12 R and a previously undescribed missense mutation in the encoding gene. ADP (4-20 mM)-induced aggregation of patients' platelets was markedly reduced and rapidly reversible. Other agonists induced borderline-normal aggregation. Inhibition of vasodilator-stimulated phosphoprotein phosphorylation and prostaglandin E 1 -induced increase in cyclic adenosine monophosphate (cAMP) by ADP was impaired, whereas inhibition of cAMP increase by epinephrine was normal.[ 3 H]PSB-0413, a selective P2Y 12 R antagonist, bound to a normal number of binding sites; however, its affinity, and that of the agonists ADP and 2-methylthio-adenosine-59-diphosphate, was reduced. Patients' DNA showed a homozygous c.847T>A substitution that changed the codon for His-187 to Gln (p.His187Gln). Crystallographic data and molecular modeling studies indicated that His187 in transmembrane 5 is important for agonist and nucleotide antagonist binding and located in a region undergoing conformational changes. These studies delineate a region of P2Y 12 R required for normal function after ADP binding. (Blood. 2015; 125(6):1006-1013

AVWS is detected in half of the children with high intra- or extracardiac stenoses and resolves completely after surgical or interventional repair. Even when undergoing surgery on cardiopulmonary bypass, excessive surgical site bleeding was not detected in our study patients.

Multilineage dysplasia was detected in 32 cases (25%), a frequency similar to that reported by Falini, and was associated with a higher proportion of normal karyotype (93% vs 60%; P Ͻ .001), lower leukocyte count at diagnosis (32 ϫ 10 9 /L vs 69 ϫ 10 9 /L; P ϭ .01), and lower bone marrow infiltration (51% vs 72% blast cells, P Ͻ .001). Interestingly, the frequency of NPM1 and FLT3 internal tandem duplication (FLT3-ITD) mutations did not differ between patients with and without MLD (59% vs 50%, and 31% vs 38%, respectively). NPM1 mutations were found in 68 patients (52%). MLD was observed in 19 patients (28%) with mutated NPM1 and in 13 (21%) with wild-type NPM1. Outcomes in patients with mutated NPM1 were similar for those with and without MLD; response rate was 95% and 85%, 5-year relapse incidence was 35% Ϯ 26% and 47% Ϯ 16%, and 5-year survival was 56% Ϯ 23% and 46% Ϯ 14%, respectively. In contrast in patients with wildtype NPM1, those patients with MLD showed an inferior response rate to induction chemotherapy (53% vs 85%; P ϭ .02). When the analysis was restricted to younger patients (Յ 60 years) those with MLD showed a lower 5-year survival (0% vs 40% Ϯ 16%, P ϭ .012; Figure 1). The unfavorable prognostic value of MLD on response rate (P ϭ .034; relative risk, 4.8; 95% confidence interval, 1.1-20) and survival (P ϭ .036; hazard ratio ϭ 2.5; 95% confidence interval, 1.1-6) was confirmed in a multivariate analysis.These results confirm that, although dysplastic features are a common trait in NPM1-mutated AML, they do not confer a worse prognosis. Falini et al found that gene expression profiling did not identify any distinctive MLD-associated gene signature in the mutated NPM1 cohort. 6 The correlation found in the present study between an unfavorable outcome and dysplastic features in wildtype NPM1 IR-AML patients leads us to suggest that a search for novel genetic or epigenetic markers in this AML subgroup might reveal a specific biologic identity.In conclusion, the prognostic relevance of MLD in IR-AML might be dependent on NPM1 mutational status. Whereas MLD predicts an adverse outcome in patients with wild-type NPM1, it lacks prognostic value in NPM1-mutated AML. Nonetheless, this observation requires further confirmation in a larger series of patients. Contribution: M.D.-B. updated the database of patients included in the analysis, performed all statistical analysis, and wrote the manuscript; M.R. performed morphologic review of all cases and reviewed the article; M.P. updated the database, performed molecular analysis, and reviewed the article; M.T. and M.C. performed molecular analysis and reviewed the article; J.Ll.A. performed morphologic review of all cases and reviewed the article; and J.E. designed the study, supervised statistical analysis, and reviewed the manuscript. Marina Díaz-Beyá Conflict-of-interest disclosure:The authors declare no competing financial interests.