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Correspondence:
jwm.heemskerk@maastrichtuniversity.nl
Received: July 26, 2017.
Accepted: December 7, 2017. Pre-published: December 14, 2017.
doi:10.3324/haematol.2017.176974
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Platelet Biology & Its Disorders
Variable impairment of platelet functions in patients with severe, genetically linked immune deficiencies
Magdolna Nagy,1 Tom G. Mastenbroek,1* Nadine J.A. Mattheij,1*
Susanne de Witt,1 Kenneth J. Clemetson,2 Janbernd Kirschner,3
Ansgar S. Schulz,4 Thomas Vraetz,5 Carsten Speckmann,6 Attila Braun,7 Judith M.E.M. Cosemans,1 Barbara Zieger6* and Johan W.M. Heemskerk1*
1Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands; 2Department of Haematology, Inselspital, University of Bern, Switzerland; 3Department of Neuropediatrics and Muscle Disorders, Medical Center, University of Freiburg, Germany; 4Department of Pediatrics and Adolescent Medicine, University Medical Centre Ulm, Germany; 5Department of Pediatrics and Adolescent Medicine, Medical Center-University of Freiburg, Faculty of Medicine, Germany; 6Center for Chronic Immunodeficiency and Department of Pediatrics and Adolescent Medicine, Medical Centre, University of Freiburg, Germany and 7Institute of Experimental Biomedicine, University Hospital and Rudolf Virchow Centre, University of Würzburg, Germany
*TGM, NJAM, BZ and JWMH contributed equally to this work.
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 con- firmed 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 aggre- gation 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 SOCE 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 strong- ly reduced regardless of the microspot. Bone marrow transplantation, required by 2 patients, resulted in overall improvement of platelet func- tion. 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) aber- rant 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.
Introduction
Severe, genetically linked immunodeficiency can be accompanied by platelet function defects, especially in cases of rare mutations in the ORAI1, STIM1 and FERMT3 genes on platelet properties, in spite of solid evidence for a role of the mouse orthologs in arterial thrombosis.
In platelets and other blood cells, stromal interaction molecule 1 (STIM1) acts as a major Ca2+ sensor located in the endoplasmic reticulum. When the reticular Ca2+
Haematologica 2018 Volume 103(3):540-549
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haematologica | 2018; 103(3)
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