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Loewenthal R.,Tissue Typing Laboratory | Loewenthal R.,Tel Aviv University | Loewenthal R.,National Blood Services Center | Rosenberg N.,Tissue Typing Laboratory | And 30 more authors.
Transfusion | Year: 2013

Background: Fetal neonatal alloimmune thrombocytopenia (FNAIT) is a life-threatening bleeding disorder in the fetus or neonate caused by maternal alloantibodies directed against fetal platelet (PLT) antigens inherited from the father. The immune-dominant antigen leading to severe FNAIT is the human PLT antigen (HPA)-1, whose polymorphism constitutes an epitope for human leukocyte antigens (HLAs), usually DRB30101 leading to an immune response. STUDY DESIGN AND METHODS: In this study our aims were to find whether other allele variants of the β subunit of the HLA-DR family specifically focused on the HLA residues that bind Position 33 of the HPA-1 integrin contribute to FNAIT development and affect response to treatment and whether coexistence of both anti-HPA-1a and anti-HLA Class I specific against the father's antigens leads to a more severe thrombocytopenia in the newborn. We examine the genotype of 23 mothers to newborns with FNAIT compared to a control group. Results: Our Results suggested that, when HPA-1 incompatibility with the husband is found, the presence of two HLA alleles (DRB301:01 and DRB401:01) in the mother increases the risk and severity of FNAIT and reduces the success of a preventive immunoglobulin G treatment. We provide a structural model for the molecular basis of the rational effects of the different HLA alleles. In addition, we found that the presence of both anti-HPA-1 and anti-HLAs did not aggravate FNAIT in comparison to mothers harboring only anti-HPA-1. CONCLUSION: Overall, we suggest that a specific genotyping of the mother in relation to HLA-DRB as well as HPA-1 can serve as an antenatal diagnostic tool, particularly in siblings of women who gave birth to neonates with FNAIT. © 2012 American Association of Blood Banks. Source


Salomon O.,The Amalia Biron Research Institute of Thrombosis and Hemostasis | Tohami T.,Institute of Hematology | Trakhtenbrot L.,Institute of Hematology | Meirov R.,Institute of Hematology | And 7 more authors.
Leukemia Research | Year: 2010

Background and objectives: The treatment of choice for the pregnant woman with CML has not been defined. Exposure to imatinib while pregnant may cause serious fetal malformations and interferon-α is sometimes associated with side effects. Furthermore, little is known of the possibility that BCR/ABL-positive cells might be passed to the fetus and the role of the treatment given to the pregnant mother. Design and methods: Detection of BCR-ABL transcripts in the peripheral blood of the mother, the newborn and the cord blood was performed by quantitative real time PCR and FISH. Results: A patient with CML diagnosed at the beginning of pregnancy was treated with leukapheresis at 31 weeks of gestation until delivery without any untoward effects. Since no tyrosine kinase inhibitor was administered BCR-ABL transcripts contamination of the cord blood and peripheral blood of the newborn was a reasonable concern. In practice no transcripts were detected in the cord blood or in the peripheral blood of the newborn at birth, at 1 month or 3 at months of age despite the fact that throughout her pregnancy and on the day of delivery the mother had 90% BCR/ABL positive cells in her blood. Interpretation and conclusions: Leukapheresis does not eliminate the malignant clone; however the absence of BCR-ABL transcripts in the peripheral blood of the neonate and in the cord blood supports the view that transmission of CML to a fetus is improbable even if the mother's treatment during pregnancy is suboptimal. © 2009 Elsevier Ltd. All rights reserved. Source


Zucker M.,The Amalia Biron Research Institute of Thrombosis and Hemostasis | Zucker M.,Tel Aviv University | Rosenberg N.,The Amalia Biron Research Institute of Thrombosis and Hemostasis | Rosenberg N.,Tel Aviv University | And 8 more authors.
Journal of Thrombosis and Haemostasis | Year: 2011

Background: Point mutations within exons are frequently defined as missense mutations. In the factor (F)XI gene, three point mutations, c.616C>T in exon 7, c.1060G>A in exon 10 and c.1693G>A in exon 14 were reported as missense mutations P188S, G336R and E547K, respectively, according to their exonic positions. Surprisingly, expression of the three mutations in cells yielded substantially higher FXI antigen levels than was expected from the plasma of patients bearing these mutations. Objectives: To test the possibility that the three mutations, albeit their positions within exons, cause splicing defects. Methods and results: Platelet mRNA analysis of a heterozygous patient revealed that the c.1693A mutation caused aberrant splicing. Platelet mRNA of a second compound heterozygote for c.616T and c.1060A mutations was undetectable suggesting its degradation. Cells transfected with a c.616T minigene favored production of an aberrantly spliced mRNA that skips exon 7. Cells transfected with a mutated minigene spanning exons 8-10 exhibited a significant decrease in the amount of normally spliced mRNA. In silico analysis revealed that the three mutations are located within sequences of exonic splicing enhancers (ESEs) that bind special proteins and are potentially important for correct splicing. Compensatory mutations created near the natural mutations corrected the putative function of ESEs thereby restoring normal splicing of exons 7 and 10. Conclusions: The present findings define a new mechanism of mutations in F11 and underscore the need to perform expression studies and mRNA analysis of point mutations before stating that they are missense mutations. © 2011 International Society on Thrombosis and Haemostasis. Source

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