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

Abstract

Genetically modified mice 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 2 hours and allowed dose-dependent adjustment of platelet count. The iDTR model caused complete thrombocytopenia within 4 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.

Authors+Show Affiliations

Institute of Vascular Biology and Thrombosis Research, Medical University of Vienna, Austria.Institute of Vascular Biology and Thrombosis Research, Medical University of Vienna, Austria.Institute of Vascular Biology and Thrombosis Research, Medical University of Vienna, Austria.Institute of Vascular Biology and Thrombosis Research, Medical University of Vienna, Austria.University Hospital and Rudolf Virchow Center, University of Würzburg, Germany.Institute of Vascular Biology and Thrombosis Research, Medical University of Vienna, Austria.Institute of Vascular Biology and Thrombosis Research, Medical University of Vienna, Austria.General Hospital, Medical University Vienna, Austria.Institute of Vascular Biology and Thrombosis Research, Medical University of Vienna, Austria.University Hospital and Rudolf Virchow Center, University of Würzburg, Germany.Institute of Vascular Biology and Thrombosis Research, Medical University of Vienna, Austria.Institute of Vascular Biology and Thrombosis Research, Medical University of Vienna, Austria; alice.assinger@meduniwien.ac.at.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31537686

Citation

Salzmann, Manuel, et al. "Genetic Platelet Depletion Is Superior in Platelet Transfusion Compared to Current Models." Haematologica, 2019.
Salzmann M, Schrottmaier WC, Kral-Pointner JB, et al. Genetic platelet depletion is superior in platelet transfusion compared to current models. Haematologica. 2019.
Salzmann, M., Schrottmaier, W. C., Kral-Pointner, J. B., Mussbacher, M., Volz, J., Hoesel, B., ... Assinger, A. (2019). Genetic platelet depletion is superior in platelet transfusion compared to current models. Haematologica, doi:10.3324/haematol.2019.222448.
Salzmann M, et al. Genetic Platelet Depletion Is Superior in Platelet Transfusion Compared to Current Models. Haematologica. 2019 Sep 19; PubMed PMID: 31537686.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Genetic platelet depletion is superior in platelet transfusion compared to current models. AU - Salzmann,Manuel, AU - Schrottmaier,Waltraud C, AU - Kral-Pointner,Julia B, AU - Mussbacher,Marion, AU - Volz,Julia, AU - Hoesel,Bastian, AU - Moser,Bernhard, AU - Bleichert,Sonja, AU - Morava,Susanne, AU - Nieswandt,Bernhard, AU - Schmid,Johannes A, AU - Assinger,Alice, Y1 - 2019/09/19/ PY - 2019/03/19/received PY - 2019/09/19/accepted PY - 2019/9/21/entrez KW - Cost Analysis KW - Disorders of Platelet Function KW - Platelets KW - Transfusion Medicine JF - Haematologica JO - Haematologica N2 - Genetically modified mice 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 2 hours and allowed dose-dependent adjustment of platelet count. The iDTR model caused complete thrombocytopenia within 4 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. SN - 1592-8721 UR - https://www.unboundmedicine.com/medline/citation/31537686/Genetic_platelet_depletion_is_superior_in_platelet_transfusion_compared_to_current_models L2 - http://www.haematologica.org/cgi/pmidlookup?view=long&pmid=31537686 DB - PRIME DP - Unbound Medicine ER -