Spontaneous Platelet Aggregation in Blood Is Mediated by FcRIIA Stimulation of Bruton's Tyrosine Kinase
Research article published in International journal of molecular sciences (2021)
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-FcγRIIA, 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 FcγRIIA 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.
Abstract sourced from PubMed (NCBI) for the cited record. See the original publication for the authoritative version.
Zusammenfassung
High platelet reactivity leading to spontaneous platelet aggregation (SPA) is a hallmark of cardiovascular diseases; however, the mechanism underlying SPA remains obscure.
Warum dies für die Hirudotherapie relevant ist
Diese Studie untersuchte den Mechanismus der spontanen Thrombozytenaggregation (SPA) in Hirudin-antikoaguliertem Blut von 118 gesunden Spendern, gemessen mittels Multi-Elektroden-Aggregometrie. Die Autoren fanden, dass eine hohe SPA (>250 AU*min), vorhanden bei 8 % der Spender, durch Antikörper, die den thrombozytären FcγRIIA-Rezeptor blockieren, signifikant reduziert und durch Bruton-Tyrosinkinase-Inhibitoren (Fenebrutinib in vitro; Ibrutinib in vivo) vollständig aufgehoben wurde. Hirudin diente in diesem Assay als Antikoagulans für die Blutentnahme, was es für ASH als Laboranwendung eines aus Blutegeln stammenden Antikoagulans in der Thrombozytenfunktionsforschung relevant macht. Der Schwerpunkt der Studie liegt jedoch auf der Signalbiologie der Thrombozyten, nicht auf der Hirudotherapie oder dem therapeutischen Einsatz des Blutegel-Sekretoms; Hirudin wird lediglich als Reagenz verwendet, und es sind weder Blutegel noch therapeutische Anwendungen involviert.
Zitation
Spontaneous Platelet Aggregation in Blood Is Mediated by FcRIIA Stimulation of Bruton's Tyrosine Kinase
Duan R et al. · International journal of molecular sciences, 2021
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