Dataset Information

Genetic platelet depletion is superior in platelet transfusion compared to current models.

ABSTRACT: Genetically modified mice have advanced our knowledge on platelets in hemostasis and beyond tremendously. However, mouse models harbor certain limitations, including availability of platelet specific transgenic strains, and off-target effects on other cell types. Transfusion of genetically modified platelets into thrombocytopenic mice circumvents these problems. Additionally, ex vivo treatment of platelets prior to transfusion eliminates putative side effects on other cell types. Thrombocytopenia is commonly induced by administration of anti-platelet antibodies, which opsonize platelets to cause rapid clearance. However, antibodies do not differentiate between endogenous or exogenous platelets, impeding transfusion efficacy. In contrast, genetic depletion with the inducible diphtheria toxin receptor (iDTR) system induces thrombocytopenia via megakaryocyte ablation without direct effects on circulating platelets. We compared the iDTR system with antibody-based depletion methods regarding their utility in platelet transfusion experiments, outlining advantages and disadvantages of both approaches. Antibodies led to thrombocytopenia within two hours and allowed the dose-dependent adjustment of the platelet count. The iDTR model caused complete thrombocytopenia within four days, which could be sustained for up to 11 days. Neither platelet depletion approach caused platelet activation. Only the iDTR model allowed efficient platelet transfusion by keeping endogenous platelet levels low and maintaining exogenous platelet levels over longer time periods, thus providing clear advantages over antibody-based methods. Transfused platelets were fully functional in vivo, and our model allowed examination of transgenic platelets. Using donor platelets from already available genetically modified mice or ex vivo treated platelets, may decrease the necessity of platelet-specific mouse strains, diminishing off-target effects and thereby reducing animal numbers.

SUBMITTER: Salzmann M

PROVIDER: S-EPMC7271594 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Platelet transfusion refractoriness (PTR) is common in patients with hematology and oncology and is becoming an important barrier in the treatment of thrombocytopenia and hemorrhage. Bibliometrics is an effective method for identifying existing research achievements, important breakthroughs, current research hotspots, and future development trends in any given field. In recent years, research on PTR has received increasing attention, but a bibliometric analysis of this field has not yet been reported. In this study, we applied bibliometrics to analyze the existing literature on PTR research over the past 17 years. On November 1, 2021, we began a publications analysis of PTR research using the Science Citation Index Expanded of the Web of Science Core Collection with collection dates from 2004 to 2021. This research aimed to summarize the state of PTR research using Bibliometrix to identify connections between different elements (i.e., authors, institutions, countries, journals, references, and keywords) using VOS viewer analyses to visualize key topics and trends in PTR research using Cite Space and gCLUTO. The results of all 310 studies showed that the annual number of publications focused on PTR is steadily increasing, with the United States of America and Japan making significant contributions. We noted that the research group led by Dr. Sherrill J. Slichter was prominent in this field, while Estcourt Lise may become the most influential newcomer. Transfusion was the most popular journal, and Blood was the most cited journal. Using various analyses, including co-cited analysis, historiography analysis, citation burst analysis, and factorial analysis, we pointed out and discussed contributing publications. According to occurrence analysis, co-word biclustering analysis, landform map, thematic evolution, and thematic map, we believe that "activation," "p-selection," "CD36 deficiency," "gene-frequencies," "CD109," "HPA-1," and "beta (3) integrin" may become new trends in PTR research. The outcome of our bibliometric analyses has, for the first time, revealed profound insights into the current state and trends in PTR research. The systematic analysis provided by our study clearly demonstrates the field's significant advancements to all researchers who are interested in a quick and comprehensive introduction to the field.

Project description:Inherited platelet disorders (IPDs), which manifest as primary hemostasis defects, often underlie abnormal bleeding and a family history of thrombocytopenia, bone marrow failure, hematologic malignancies, undefined mucocutaneous bleeding disorder, or congenital bony defects. Wide heterogeneity in IPD types with regard to the presence or absence of thrombocytopenia, platelet dysfunction, bone marrow failure, and dysmegakaryopoiesis is observed in patients. The individual processes involved in platelet production and hemostasis are genetically controlled; to date, mutations of more than 50 genes involved in various platelet biogenesis steps have been implicated in IPDs. Representative IPDs resulting from defects in specific pathways, such as thrombopoietin/MPL signaling; transcriptional regulation; granule formation, trafficking, and secretion; proplatelet formation; cytoskeleton regulation; and transmembrane glycoprotein signaling are reviewed, and the underlying gene mutations are discussed based on the National Center for Biotechnology Information database and Online Mendelian Inheritance in Man accession number. Further, the status and prevalence of genetically confirmed IPDs in Korea are explored based on searches of the PubMed and KoreaMed databases. IPDs are congenital bleeding disorders that can be dangerous due to unexpected bleeding and require genetic counseling for family members and descendants. Therefore, the pediatrician should be suspicious and aware of IPDs and perform the appropriate tests if the patient has unexpected bleeding. However, all IPDs are extremely rare; thus, the domestic incidences of IPDs are unclear and their diagnosis is difficult. Diagnostic confirmation or differential diagnoses of IPDs are challenging, time-consuming, and expensive, and patients are frequently misdiagnosed. Comprehensive molecular characterization and classification of these disorders should enable accurate and precise diagnosis and facilitate improved patient management.

Project description:Platelet transfusion can elicit alloimmune responses leading to alloantibody formation against donor-specific polymorphic residues, ultimately resulting in platelet transfusion refractoriness. Universal leukoreduction significantly reduced the frequency of alloimmunization after platelet transfusion, thereby showing the importance of white blood cells (WBCs) in inducing this alloresponse. It is, however, unknown if the residual risk for alloimmunization is caused by WBCs remaining after leukoreduction or if alloimmunization can be induced by platelets themselves. This study investigated the capacity of platelets to induce alloimmunization and identified potential product-related risk factors for alloimmunization. First, internalization of allogeneic platelets by dendritic cells (DCs) was demonstrated by confocal microscopy. Second, after internalization, presentation of platelet-derived peptides was shown by mass spectrometry analysis of human leukocytes antigen (HLA)-DR eluted peptides. Third, platelet-loaded DCs induced platelet-specific CD4 T cell responses. Altogether, this indicates a platelet-specific ability to induce alloimmunization. Therefore, factors enhancing platelet internalization may be identified as risk factor for alloimmunization by platelet concentrates. To investigate if storage of platelets is such a risk factor, internalization of stored platelets was compared with fresh platelets and showed enhanced internalization of stored platelets. Storage-induced apoptosis and accompanied phosphatidylserine exposure seemed to be instrumental for this. Indeed, DCs pre-incubated with apoptotic platelets induced the strongest IFN-γ production by CD4 T cells compared with pre-incubation with untreated or activated platelets. In conclusion, this study shows the capacity of platelets to induce platelet-specific alloimmune responses. Furthermore, storage-induced apoptosis of platelets is identified as potential risk factor for alloimmunization after platelet transfusions.

Dataset Information

Genetic platelet depletion is superior in platelet transfusion compared to current models.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets