Proteomic landscapes of inherited platelet disorders with different etiologies

Iris C. Kreft, Elise J. Huisman, Marjon H. Cnossen, Floris P.J. van Alphen, Carmen van der Zwaan, Karin van Leeuwen, Rosalina van Spaendonk, Leendert Porcelijn, Caroline S.B. Veen, Maartje van den Biggelaar, Masja de Haas, Alexander B. Meijer, Arie J. Hoogendijk*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

3 Citations (Scopus)


Background: Inherited platelet disorders (IPDs) are a heterogeneous group of rare diseases that are caused by the defects in early megakaryopoiesis, proplatelet formation, and/or mature platelet function. Although genomic sequencing is increasingly used to identify genetic variants underlying IPD, this technique does not disclose resulting molecular changes that impact platelet function. Proteins are the functional units that shape platelet function; however, insights into how variants that cause IPDs impact platelet proteomes are limited. Objectives: The objective of this study was to profile the platelet proteomics signatures of IPDs. Methods: We performed unbiased label-free quantitative mass spectrometry (MS)–based proteome profiling on platelets of 34 patients with IPDs with variants in 13 ISTH TIER1 genes that affect different stages of platelet development. Results: In line with the phenotypical heterogeneity between IPDs, proteomes were diverse between IPDs. We observed extensive proteomic alterations in patients with a GFI1B variant and for genetic variants in genes encoding proteins that impact cytoskeletal processes (MYH9, TUBB1, and WAS). Using the diversity between IPDs, we clustered protein dynamics, revealing disrupted protein-protein complexes. This analysis furthermore grouped proteins with similar cellular function and location, classifying mitochondrial protein constituents and identifying both known and putative novel alpha granule associated proteins. Conclusions: With this study, we demonstrate a MS–based proteomics perspective to IPDs. By integrating the effects of IPDs that impact different aspects of platelet function, we dissected the biological contexts of protein alterations to gain further insights into the biology of platelet (dys)function.

Original languageEnglish
Pages (from-to)359-372.e3
JournalJournal of Thrombosis and Haemostasis
Issue number2
Publication statusPublished - Feb 2023

Bibliographical note

Funding Information:
The work presented here was supported by the Landsteiner Foundation for Blood Transfusion Research [LSBR-1517 to M.v.d.B., LSBR-1923 to M.v.d.B. and A.J.H]. We acknowledge all the patients and family members who contributed to this research. The authors would like to thank the people from the research facility of Sanquin for helping with isolation of platelets.

Publisher Copyright:
© 2022 International Society on Thrombosis and Haemostasis


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