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      Blood platelet research in autism spectrum disorders: In search of biomarkers

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          Abstract

          Autism spectrum disorder ( ASD) is a clinically heterogeneous neurodevelopmental disorder that is caused by gene‐environment interactions. To improve its diagnosis and treatment, numerous efforts have been undertaken to identify reliable biomarkers for autism. None of them have delivered the holy grail that represents a reproducible, quantifiable, and sensitive biomarker. Though blood platelets are mainly known to prevent bleeding, they also play pivotal roles in cancer, inflammation, and neurological disorders. Platelets could serve as a peripheral biomarker or cellular model for autism as they share common biological and molecular characteristics with neurons. In particular, platelet‐dense granules contain neurotransmitters such as serotonin and gamma‐aminobutyric acid. Molecular players controlling granule formation and secretion are similarly regulated in platelets and neurons. The major platelet integrin receptor α IIbβ3 has recently been linked to ASD as a regulator of serotonin transport. Though many studies revealed associations between platelet markers and ASD, there is an important knowledge gap in linking these markers with autism and explaining the altered platelet phenotypes detected in autism patients. The present review enumerates studies of different biomarkers detected in ASD using platelets and highlights the future needs to bring this research to the next level and advance our understanding of this complex disorder.

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          Normal platelet function.

          Platelets play an important role in the vessel. Following their formation from megakaryocytes, platelets exist in circulation for 5-7 days and primarily function as regulators of hemostasis and thrombosis. Following vascular insult or injury, platelets become activated in the blood resulting in adhesion to the exposed extracellular matrix underlying the endothelium, formation of a platelet plug, and finally formation and consolidation of a thrombus consisting of both a core and shell. In pathological conditions, platelets are essential for formation of occlusive thrombus formation and as a result are the primary target for prevention of arterial thrombus formation. In addition to regulation of hemostasis in the vessel, platelets have also been shown to play an important role in innate immunity as well as regulation of tumor growth and extravasations in the vessel. These primary functions of the platelet represent its normal function and versatility in circulation.
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            Pathological priming causes developmental gene network heterochronicity in autism patient-derived neurons

            Autism spectrum disorder (ASD) is thought to emerge during early cortical development. However, the exact developmental stages and associated molecular networks that prime disease propensity are elusive. To profile early neurodevelopmental alterations in ASD with macrocephaly, we monitored patient-derived induced pluripotent stem cells (iPSCs) throughout the recapitulation of cortical development. Our analysis revealed ASD-associated changes in the maturational sequence of early neuron development, involving temporal dysregulation of specific gene networks and morphological growth acceleration. The observed changes tracked back to a pathologically primed stage in neural stem cells (NSCs), reflected by altered chromatin accessibility. Concerted overrepresentation of network factors in control NSCs was sufficient to trigger ASD-like features, and circumventing the NSC stage by direct conversion of ASD iPSCs into induced neurons (iPSC-iNs) abolished ASD-associated phenotypes. Our findings identify heterochronic dynamics of a gene network that, while established earlier in development, contributes to subsequent neurodevelopmental aberrations in ASD.
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              Blood serotonin levels in autism spectrum disorder: a systematic review and meta-analysis.

              Elevated blood serotonin (5-HT) levels were the first biomarker identified in autism research. Many studies have contrasted blood 5-HT levels in autistic patients and controls, but different measurement protocols, technologies, and biomaterials have been used through the years. We performed a systematic review and meta-analysis to provide an overall estimate of effect size and between-study heterogeneity, while verifying whether and to what extent different methodological approaches influence the strength of this association. Our literature search strategy identified 551 papers, from which 22 studies providing patient and control blood 5-HT values were selected for meta-analysis. Significantly higher 5-HT levels in autistic patients compared to controls were recorded both in whole blood (WB) [O.R.=4.6; (3.1-5.2); P=1.0×10(-12]), and in platelet-rich plasma (PRP) [O.R.=2.6 (1.8-3.9); P=2.7×10(-7)]. Predictably, studies measuring 5-HT levels in platelet-poor plasma (PPP) yielded no significant group difference [O.R.=0.54 (0.2-2-0); P=0.36]. Altogether, elevated 5-HT blood levels were recorded in 28.3% in WB and 22.5% in PRP samples of autistic individuals, as reported in 15 and 4 studies, respectively. Studies employing HPLC vs fluorometric assays yield similar cumulative effect sizes, but the former display much lower variability. In summary, despite some limitations mainly due to small study sample sizes, our results significantly reinforce the reliability of elevated 5-HT blood levels as a biomarker in ASD, providing practical indications potentially useful for its inclusion in multi-marker diagnostic panels for clinical use.
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                Author and article information

                Contributors
                @ManishaPadmaku1
                kathleen.freson@med.kuleuven.be , @kathleenfreson
                Journal
                Res Pract Thromb Haemost
                Res Pract Thromb Haemost
                10.1002/(ISSN)2475-0379
                RTH2
                Research and Practice in Thrombosis and Haemostasis
                John Wiley and Sons Inc. (Hoboken )
                2475-0379
                16 July 2019
                October 2019
                : 3
                : 4 ( doiID: 10.1002/rth2.v3.4 )
                : 566-577
                Affiliations
                [ 1 ] Department of Cardiovascular Sciences Center for Molecular and Vascular Biology KU Leuven Leuven Belgium
                Author notes
                [*] [* ] Correspondence

                Kathleen Freson, Center for Molecular and Vascular Biology, Leuven, Belgium

                Email: kathleen.freson@ 123456med.kuleuven.be

                Author information
                https://orcid.org/0000-0002-1138-0999
                https://orcid.org/0000-0002-4381-2442
                Article
                RTH212239
                10.1002/rth2.12239
                6781926
                31624776
                83fce4df-a633-4d9b-9a7a-4a3a62bd847e
                © 2019 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals, Inc on behalf of International Society on Thrombosis and Haemostasis.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                History
                : 02 April 2019
                : 03 June 2019
                Page count
                Figures: 2, Tables: 2, Pages: 12, Words: 8883
                Categories
                Review Article
                Review Articles
                Custom metadata
                2.0
                rth212239
                October 2019
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.7.0 mode:remove_FC converted:08.10.2019

                autism spectrum disorders,blood platelets,gamma‐aminobutyric acid,integrin αiibβ3,melatonin,neurotransmitter agents,platelet dense granules,serotonin

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