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.
Summary
High platelet reactivity leading to spontaneous platelet aggregation (SPA) is a hallmark of cardiovascular diseases; however, the mechanism underlying SPA remains obscure.
Why This Matters for Hirudotherapy
This study investigated the mechanism of spontaneous platelet aggregation (SPA) in hirudin-anticoagulated blood from 118 healthy donors, measured by multiple electrode aggregometry. The authors found that high SPA (>250 AU*min), present in 8% of donors, was significantly reduced by antibodies blocking the platelet FcγRIIA receptor and was completely abrogated by Bruton's tyrosine kinase inhibitors (fenebrutinib in vitro; ibrutinib in vivo). Hirudin served as the anticoagulant for blood collection in this assay, making it relevant to ASH as a laboratory application of a leech-derived anticoagulant in platelet function research. However, the study's focus is platelet signaling biology, not hirudotherapy or therapeutic use of the leech secretome; hirudin is used only as a reagent, and no leeches or therapeutic applications are involved.
Citation
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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