Variable impairment of platelet functions in patients with severe, genetically linked immune deficiencies

Magdolna Nagy, Tom G. Mastenbroek, Nadine J. A. Mattheij, Susanne de Witt, Kenneth J. Clemetson, Janbernd Kirschner, Ansgar S. Schulz, Thomas Vraetz, Carsten Speckmann, Attila Braun, Judith M. E. M. Cosemans, Barbara Zieger, Johan W. M. Heemskerk*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

32 Citations (Web of Science)

Abstract

In patients with dysfunctions of the Ca2+ channel ORAI1, stromal interaction molecule 1 (STIM1) or integrin-regulating kindlin-3 (FERMT3), severe immunodeficiency is frequently linked to abnormal platelet activity. In this paper, we studied platelet responsiveness by multi-parameter assessment of whole blood thrombus formation under high-shear flow conditions in 9 patients, including relatives, with confirmed rare genetic mutations of ORAI1, STIM1 or FERMT3. In platelets isolated from 5 out of 6 patients with ORAI1 or STIM1 mutations, store operated Ca2+ entry (SOCE) was either completely or partially defective compared to control platelets. Parameters of platelet adhesion and aggregation on collagen microspots were impaired for 4 out of 6 patients, in part related to a low platelet count. For 4 patients, platelet adhesion/aggregation and procoagulant activity on von Willebrand Factor (VWF)/rhodocytin and VWF/fibrinogen microspots were impaired independently of platelet count, and were partly correlated with SOLE deficiency. Measurement of thrombus formation at low shear rate confirmed a greater impairment of platelet functionality in the ORAI1 patients than in the STIM1 patient. For 3 patients/relatives with. a FERMT3 mutation, all parameters of thrombus formation were strongly reduced regardless of the microspot. Bone marrow transplantation, required by 2 patients, resulted in overall improvement of platelet function. We concluded that multiparameter assessment of whole blood thrombus formation in a surface-dependent way can detect: i) additive effects of low platelet count and impaired platelet functionality; ii) aberrant ORAI1-mediated Ca2+ entry; iii) differences in platelet activation between patients carrying the same ORAI1 mutation; iv) severe platelet function impairment linked to a FERMT3 mutation and bleeding history.
Original languageEnglish
Pages (from-to)540-549
Number of pages10
JournalHaematologica-the Hematology Journal
Volume103
Issue number3
DOIs
Publication statusPublished - 28 Feb 2018

Keywords

  • INTERACTION MOLECULE-1 DEFICIENCY
  • TUBULAR AGGREGATE MYOPATHY
  • STEM-CELL TRANSPLANTATION
  • THROMBUS FORMATION
  • STIM PROTEINS
  • ORAI1
  • CHANNEL
  • ACTIVATION
  • MUTATION
  • ADHESION

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