Spontaneous Platelet Aggregation in Blood Is Mediated by Fc gamma RIIA Stimulation of Bruton's Tyrosine Kinase

Duan, Rundan; Goldmann, Luise; Li, Ya; Weber, Christian; Siess, Wolfgang und Hundelshausen, Philipp von (2022): Spontaneous Platelet Aggregation in Blood Is Mediated by Fc gamma RIIA Stimulation of Bruton's Tyrosine Kinase. In: International Journal of Molecular Sciences, Bd. 23, Nr. 1, 76

Abstract

High platelet reactivity leading to spontaneous platelet aggregation (SPA) is a hallmark of cardiovascular diseases;however, the mechanism underlying SPA remains obscure. Platelet aggregation in stirred hirudin-anticoagulated blood was measured by multiple electrode aggregometry (MEA) for 10 min. SPA started after a delay of 2-3 min. In our cohort of healthy blood donors (n = 118), nine donors (8%) with high SPA (> 250 AU*min) were detected. Pre-incubation of blood with two different antibodies against the platelet Fc-receptor (anti-Fc gamma RIIA, CD32a) significantly reduced high SPA by 86%. High but not normal SPA was dose-dependently and significantly reduced by blocking Fc of human IgG with a specific antibody. SPA was completely abrogated by blood pre-incubation with the reversible Btk-inhibitor (BTKi) fenebrutinib (50 nM), and 3 h after intake of the irreversible BTKi ibrutinib (280 mg) by healthy volunteers. Increased SPA was associated with higher platelet GPVI reactivity. Anti-platelet factor 4 (PF4)/polyanion IgG complexes were excluded as activators of the platelet Fc-receptor. Our results indicate that high SPA in blood is due to platelet Fc gamma RIIA stimulation by unidentified IgG complexes and mediated by Btk activation. The relevance of our findings for SPA as possible risk factor of cardiovascular diseases and pathogenic factor contributing to certain autoimmune diseases is discussed.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Sprache: Englisch