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Evaluation of targeted exome sequencing for 28 protein-based blood group systems, including the homologous gene systems, for blood group genotyping.
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Evaluation of targeted exome sequencing for 28 protein-based blood group systems, including the homologous gene systems, for blood group genotyping.

Transfusion. 2017 Mar 24;:

Authors: Schoeman EM, Lopez GH, McGowan EC, Millard GM, O'Brien H, Roulis EV, Liew YW, Martin JR, McGrath KA, Powley T, Flower RL, Hyland CA

Abstract
BACKGROUND: Blood group single nucleotide polymorphism genotyping probes for a limited range of polymorphisms. This study investigated whether massively parallel sequencing (also known as next-generation sequencing), with a targeted exome strategy, provides an extended blood group genotype and the extent to which massively parallel sequencing correctly genotypes in homologous gene systems, such as RH and MNS.
STUDY DESIGN AND METHODS: Donor samples (n = 28) that were extensively phenotyped and genotyped using single nucleotide polymorphism typing, were analyzed using the TruSight One Sequencing Panel and MiSeq platform. Genes for 28 protein-based blood group systems, GATA1, and KLF1 were analyzed. Copy number variation analysis was used to characterize complex structural variants in the GYPC and RH systems.
RESULTS: The average sequencing depth per target region was 66.2 ± 39.8. Each sample harbored on average 43 ± 9 variants, of which 10 ± 3 were used for genotyping. For the 28 samples, massively parallel sequencing variant sequences correctly matched expected sequences based on single nucleotide polymorphism genotyping data. Copy number variation analysis defined the Rh C/c alleles and complex RHD hybrids. Hybrid RHD*D-CE-D variants were correctly identified, but copy number variation analysis did not confidently distinguish between D and CE exon deletion versus rearrangement.
CONCLUSION: The targeted exome sequencing strategy employed extended the range of blood group genotypes detected compared with single nucleotide polymorphism typing. This single-test format included detection of complex MNS hybrid cases and, with copy number variation analysis, defined RH hybrid genes along with the RHCE*C allele hitherto difficult to resolve by variant detection. The approach is economical compared with whole-genome sequencing and is suitable for a red blood cell reference laboratory setting.

PMID: 28338218 [PubMed - as supplied by publisher]




A national French noninterventional study to assess the long-term safety and efficacy of reformulated nonacog alfa.
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A national French noninterventional study to assess the long-term safety and efficacy of reformulated nonacog alfa.

Transfusion. 2017 Mar 24;:

Authors: Lambert T, Rothschild C, Volot F, Borel-Derlon A, Trossaërt M, Claeyssens-Donadel S, Attal S

Abstract
BACKGROUND: Nonacog alfa, the recombinant Factor IX (F IX) used for the treatment of hemophilia B, was approved in Europe in 1998. A reformulated version was approved for European use in 2007.
STUDY DESIGN AND METHODS: This postmarketing study, as recommended by the risk management plan, was conducted to confirm the safety of reformulated nonacog alfa in a usual care setting in France. This open-label, noninterventional, prospective, longitudinal postmarketing study comprised 19 French hemophilia centers. Patients with hemophilia B receiving reformulated nonacog alfa for prophylaxis or on-demand treatment were followed up on usual care schedule.
RESULTS: A total of 58 subjects were enrolled, of whom 29 (50%) were less than 18 years of age. Hemophilia was severe (baseline F IX activity < 1%) in 47 (81%) patients. All subjects except one were already treated with reformulated nonacog alfa before enrollment. One subject was receiving reformulated nonacog alfa as immune tolerance induction at time of enrollment. At enrollment, treatment regimen was mainly prophylactic in subjects less than 18 years and on-demand in subjects 18 years or older. Median duration of follow-up in the survey was 3.3 (2.3-3.8) years. The median annualized bleeding rate was 3.9 (1.5-5.2) for prophylaxis regimen and 12.2 (3.9-22.1) for on-demand regimen. One subject, a previously untreated patient, developed F IX inhibitors during follow-up. No allergic reaction, no blood cell agglutination, no lack of efficacy or recovery, and no thrombotic events were reported.
CONCLUSION: Reformulated nonacog alfa was shown to be safe in a usual care setting.

PMID: 28337764 [PubMed - as supplied by publisher]




Depression and cognitive deficits as long-term consequences of thrombotic thrombocytopenic purpura.
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Depression and cognitive deficits as long-term consequences of thrombotic thrombocytopenic purpura.

Transfusion. 2017 Mar 24;:

Authors: Falter T, Schmitt V, Herold S, Weyer V, von Auer C, Wagner S, Hefner G, Beutel M, Lackner K, Lämmle B, Scharrer I

Abstract
BACKGROUND: Thrombotic thrombocytopenic purpura (TTP) is an acute life-threatening microangiopathy with a tendency of relapse characterized by consumptive thrombocytopenia, microangiopathic hemolytic anemia, and spontaneous von Willebrand factor-induced platelet clumping leading to microthrombi. The brain is frequently affected by microthrombi leading to neurologic abnormalities of varying severity.
STUDY DESIGN AND METHODS: The aim of this observational cohort study was to investigate the prevalence of depression and cognitive deficits in 104 patients having survived acute TTP. TTP survivors were repeatedly assessed by means of different standardized questionnaires to evaluate depression (IDS-SR) and mental performance (FLei). We received answers of 104 individual TTP patients and 55 of them participated in both surveys.
RESULTS: Seventy-one of the 104 responding TTP patients (68%) suffered from depression and the severity of depression was similar in both surveys performed 1 year apart. Furthermore, TTP patients had considerably lower cognitive performance than controls. There was no correlation between prevalence of depression and cognitive deficits and the number and the severity of acute episodes. Impairment of mental performance correlated with the severity of depression (rs  = 0.779).
CONCLUSION: The prevalence of depression and cognitive deficits was significantly higher in TTP patients. Cognitive impairment seemed to be a consequence of depression, almost independently of number and severity of TTP episodes.

PMID: 28337761 [PubMed - as supplied by publisher]




Efficacy and safety of the drugs used to reverse direct oral anticoagulants: a systematic review and meta-analysis.
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Efficacy and safety of the drugs used to reverse direct oral anticoagulants: a systematic review and meta-analysis.

Transfusion. 2017 Mar 24;:

Authors: da Luz LT, Marchand M, Nascimento B, Tien H, Nathens A, Shah P

Abstract
BACKGROUND: Direct oral anticoagulants (DOACs) are effective and safe for prophylaxis and treatment of thromboembolic phenomena. However, managing DOACs during bleeding emergencies is challenging. A systematic review and meta-analysis was conducted on studies addressing efficacy and safety of the drugs used for reversal of DOACs.
STUDY DESIGN AND METHODS: Medline, Embase, Cochrane Library, and ClinicalTrials.gov were searched up to September 2016. Studies that examined clinical and laboratory effects of drugs used to reverse DOACs were included. Risk of bias was assessed using Newcastle-Ottawa scale and Cochrane Collaboration tool. Primary and secondary outcomes assessed were reversal of clinical bleeding, clotting assays, and safety, respectively. Overall effect estimates were pooled, and clinical and statistical heterogeneity were assessed. Meta-analysis was conducted using random-effects model.
RESULTS: Four cohort studies in bleeding patients (n = 230) and eight randomized controlled trials in healthy volunteers (n = 381) were included, both with moderate risk of bias. Reversal of clotting assays in healthy volunteers was frequently reported, demonstrating that prothrombin complex concentrate (PCC) reversed prothrombin time (PT) and endogenous thrombin potential (ETP) substantially. For PT, pooled mean difference was 1.68 seconds (95% confidence interval [CI], -0.33 to 3.70 sec; p < 0.01; I(2)  = 97%). For ETP, pooled mean difference was 2.16 seconds (95% CI, 0.57 to 3.75 sec; p < 0.01; I(2)  =( ) 98%). Andexanet alfa and idarucizumab both reverse clotting assays. No important safety concerns were identified.
CONCLUSIONS: Clotting assays are partially reversed by PCC in healthy volunteers. Idarucizumab and andexanet alfa have solid laboratory reversal effect and potential to be clinically efficacious and safe. However, clinical evidence is still lacking for all agents.

PMID: 28337750 [PubMed - as supplied by publisher]




Branched I antigens on leukemia cells enhanced sensitivity against natural killer-cell cytotoxicity through affecting the target-effector interaction.
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Branched I antigens on leukemia cells enhanced sensitivity against natural killer-cell cytotoxicity through affecting the target-effector interaction.

Transfusion. 2017 Mar 24;:

Authors: Lee YH, Liao YJ, Huang CH, Chang FL, Fan TH, Twu YC

Abstract
BACKGROUND: The aberrant glycosylation on proteins and lipids has been implicated in malignant transformations for promoting the tumorigenesis, metastasis, and evasion from the host immunity. The I-branching β-1,6-N-acetylglucosaminyltransferase, converting the straight i to branched I histo-blood group antigens, reportedly could influence the migration, invasion, and metastasis of solid tumors.
STUDY DESIGN AND METHODS: We first chose the highly cytotoxic natural killer (NK)-92MI cells as effector against leukemia for this cell line has been used in several clinical trials. Fluorescence-activated cell sorting and nonradioactive cytotoxicity assay were performed to reexamine the role of NK-activating receptors, their corresponding ligands, and the tumor-associated carbohydrate antigens in this NK-92MI-leukemia in vitro system. The I role on cytotoxic mechanism was further studied especially on the effector-target interactions by cytotoxic analysis and conjugate formation assay.
RESULTS: We showed that expression levels of leukemia surface ligands for NK-activating receptors did not positively reflect susceptibility to NK-92MI. Instead, the expression of I antigen on the leukemia cells was found important in mediating the susceptibility to NK targeting by affecting the interaction with effector cells. Furthermore, susceptibility was shown to dramatically increase while overexpressing branched I antigens on the I- cells. By both conjugate and cytotoxicity assay, we revealed that the presence of I antigen on leukemia cells enhanced the interaction with NK-92MI cells, increasing susceptibility to cell-mediated lysis.
CONCLUSION: In our system, branched I antigens on the leukemia were involved in the immunosurveillance mediated by NK cells specifically through affecting the effector-target interaction.

PMID: 28337749 [PubMed - as supplied by publisher]