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

Nagy, Magdolna; Mastenbroek, Tom G; Mattheij, Nadine J A; de Witt, Susanne; Clemetson, Kenneth John; Kirschner, Janbernd; Schulz, Ansgar S; Vraetz, Thomas; Speckmann, Carsten; Braun, Attila; Cosemans, Judith M E M; Zieger, Barbara; Heemskerk, Johan W M (2018). Variable impairment of platelet functions in patients with severe, genetically linked immune deficiencies. Haematologica - the hematology journal, 103(3), pp. 540-549. Ferrata-Storti Foundation 10.3324/haematol.2017.176974

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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 in nine rare patients, including relatives, with confirmed genetic mutations of ORAI1, STIM1 or FERMT3, platelet responsiveness by multi-parameter assessment of whole blood thrombus formation under high-shear flow conditions. In platelets isolated from 5 out of 6 patients with ORAI1 or STIM1 mutations, store-operated Ca2+ entry (SOCE) was (in)completely defective compared to control platelets. Parameters of platelet adhesion and aggregation on collagen microspots were impaired for 4/6 patients, in part related to a low platelet count. For 4 patients, platelet adhesion/aggregation and procoagulant activity on VWF/rhodocytin and VWF/fibrinogen microspots were impaired, independently of platelet count and partly correlated with SOCE deficiency. Measurement of thrombus formation at low shear rate confirmed a larger 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 two 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.

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