Platelet proteome analysis reveals integrin-dependent aggregation defects in patients with myelodysplastic syndromes

Julia Fröbel, Ron Patrick Cadeddu, Sonja Hartwig, Ingmar Bruns, Christian M. Wilk, Andrea Kun̈dgen, Johannes C. Fischer, Thomas Schroeder, Ulrich G. Steidl, Ulrich Germing, Stefan Lehr, Rainer Haas, Akos Czibere

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26 Scopus citations

Abstract

Bleeding complications are a significant clinical problem in patients with myelodysplastic syndromes even at sufficient platelet counts (>50,000/μl). However, the underlying pathology of this hemorrhagic diathesis is still unknown. Here, we analyzed the platelet proteome of patients with myelodysplastic syndromes by quantitative two-dimensional difference gel electrophoresis followed by mass spectrometric protein identification. Proteins identified with lower concentrations, such as Talin-1, Vinculin, Myosin-9, Filmain-A, and Actin play critical roles in integrin αIIbβ 3 signaling and thus platelet aggregation. Despite normal agonist receptor expression, calcium flux, and granule release upon activation, the activation capacity of integrin αIIbβ3 was diminished in myelodysplastic syndrome platelets. Förster resonance energy transfer analysis showed a reduced co-localization of Talin-1 to the integrin's β3-subunit, which is required for receptor activation and fibrinogen binding. In addition, platelet spreading on immobilized fibrinogen was incomplete, and platelet aggregation assays confirmed a general defect in integrin-dependent platelet aggregation in patients with myelodysplastic syndromes. Our data provide novel aspects on the molecular pathology of impaired platelet function in myelodysplastic syndromes and suggest a mechanism of defective integrin αIIbβ3 signaling that may contribute to the hemorrhagic diathesis observed in these patients.

Original languageEnglish (US)
Pages (from-to)1272-1280
Number of pages9
JournalMolecular and Cellular Proteomics
Volume12
Issue number5
DOIs
Publication statusPublished - May 1 2013

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ASJC Scopus subject areas

  • Analytical Chemistry
  • Biochemistry
  • Molecular Biology

Cite this

Fröbel, J., Cadeddu, R. P., Hartwig, S., Bruns, I., Wilk, C. M., Kun̈dgen, A., ... Czibere, A. (2013). Platelet proteome analysis reveals integrin-dependent aggregation defects in patients with myelodysplastic syndromes. Molecular and Cellular Proteomics, 12(5), 1272-1280. https://doi.org/10.1074/mcp.M112.023168