Andreas Margraf1, Claudia Nussbaum1, Ina Rohwedder1, Sarah Klapproth1, Angela R M Kurz1, Annamaria Florian1, Volker Wiebking1, Joachim Pircher1, Monika Pruenster1, Roland Immler1, Steffen Dietzel1, Ludmila Kremer1, Friedemann Kiefer1, Markus Moser1, Andreas W Flemmer1, Elizabeth Quackenbush1, Ulrich H von Andrian1, Markus Sperandio2. 1. From the Walter Brendel Centre of Experimental Medicine, Munich, Germany (A.M., C.N., I.R., S.K., A.R.M.K., A.F., J.P., M.P., R.I., S.D., M.S.); Division of Neonatology, Hauner Children's University Hospital and Perinatal Centre, Ludwig Maximilians University, Munich, Germany (C.N., A.F., V.W., A.W.F.); Medizinische Klinik und Poliklinik I, Klinikum der Ludwig Maximilians Universität, Munich, Germany (J.P.); Max Planck Institute for Molecular Biomedicine, Münster, Germany (L.K., F.K.); Max PIanck Institute of Biochemistry, Department of Molecular Medicine, Martinsried, Germany (M.M.); Roche Inc, New York, NY (E.Q.); and Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA (U.H.v.A.). 2. From the Walter Brendel Centre of Experimental Medicine, Munich, Germany (A.M., C.N., I.R., S.K., A.R.M.K., A.F., J.P., M.P., R.I., S.D., M.S.); Division of Neonatology, Hauner Children's University Hospital and Perinatal Centre, Ludwig Maximilians University, Munich, Germany (C.N., A.F., V.W., A.W.F.); Medizinische Klinik und Poliklinik I, Klinikum der Ludwig Maximilians Universität, Munich, Germany (J.P.); Max Planck Institute for Molecular Biomedicine, Münster, Germany (L.K., F.K.); Max PIanck Institute of Biochemistry, Department of Molecular Medicine, Martinsried, Germany (M.M.); Roche Inc, New York, NY (E.Q.); and Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA (U.H.v.A.). markus.sperandio@lmu.de.
Abstract
OBJECTIVE: Platelet function has been intensively studied in the adult organism. However, little is known about the function and hemostatic capacity of platelets in the developing fetus as suitable in vivo models are lacking. APPROACH AND RESULTS: To examine fetal platelet function in vivo, we generated a fetal thrombosis model and investigated light/dye-induced thrombus formation by intravital microscopy throughout gestation. We observed that significantly less and unstable thrombi were formed at embryonic day (E) 13.5 compared with E17.5. Flow cytometry revealed significantly lower platelet counts in E13.5 versus E17.5 fetuses versus adult controls. In addition, fetal platelets demonstrated changed activation responses of surface adhesion molecules and reduced P-selectin content and mobilization. Interestingly, we also measured reduced levels of the integrin-activating proteins Kindlin-3, Talin-1, and Rap1 during fetal development. Consistently, fetal platelets demonstrated diminished spreading capacity compared with adults. Transfusion of adult platelets into the fetal circulation led to rapid platelet aggregate formation even in young fetuses. Yet, retrospective data analysis of a neonatal cohort demonstrated no correlation of platelet transfusion with closure of a persistent ductus arteriosus, a process reported to be platelet dependent. CONCLUSIONS: Taken together, we demonstrate an ontogenetic regulation of platelet function in vivo with physiologically low platelet numbers and hyporeactivity early during fetal development shedding new light on hemostatic function during fetal life.
OBJECTIVE: Platelet function has been intensively studied in the adult organism. However, little is known about the function and hemostatic capacity of platelets in the developing fetus as suitable in vivo models are lacking. APPROACH AND RESULTS: To examine fetal platelet function in vivo, we generated a fetal thrombosis model and investigated light/dye-induced thrombus formation by intravital microscopy throughout gestation. We observed that significantly less and unstable thrombi were formed at embryonic day (E) 13.5 compared with E17.5. Flow cytometry revealed significantly lower platelet counts in E13.5 versus E17.5 fetuses versus adult controls. In addition, fetal platelets demonstrated changed activation responses of surface adhesion molecules and reduced P-selectin content and mobilization. Interestingly, we also measured reduced levels of the integrin-activating proteins Kindlin-3, Talin-1, and Rap1 during fetal development. Consistently, fetal platelets demonstrated diminished spreading capacity compared with adults. Transfusion of adult platelets into the fetal circulation led to rapid platelet aggregate formation even in young fetuses. Yet, retrospective data analysis of a neonatal cohort demonstrated no correlation of platelet transfusion with closure of a persistent ductus arteriosus, a process reported to be platelet dependent. CONCLUSIONS: Taken together, we demonstrate an ontogenetic regulation of platelet function in vivo with physiologically low platelet numbers and hyporeactivity early during fetal development shedding new light on hemostatic function during fetal life.
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