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Mechanism of Platelet Activation and Hypercoagulability by Antithymocyte Globulins (ATG)
Author(s) -
Cumpelik A.,
Gerossier E.,
Jin J.,
Tsakiris D.,
Dickenmann M.,
Sadallah S.,
Schifferli J. A.,
Zecher D.
Publication year - 2015
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/ajt.13316
Subject(s) - complement system , platelet , platelet activation , phosphatidylserine , immunology , thrombin , medicine , microvesicle , microvesicles , chemistry , immune system , biochemistry , membrane , phospholipid , microrna , gene
T cell depletion with antithymocyte globulins (ATG) can be complicated by thrombopenia and hypercoagulability. The underlying mechanism is still unclear. We found that binding of ATG to platelets caused platelet aggregation, α‐granule release, membrane phosphatidylserine exposure and the rapid release of procoagulant platelet microvesicles (MV). Platelet activation and MV release were complement‐dependent and required membrane insertion of C5b‐8 but not stable lytic pore formation by C5b‐9. ATG also activated platelets via binding to the low‐affinity Fc gamma receptor FcγRII. However, only complement inhibition but not blockade of FcγRII prevented MV release and subsequent thrombin activation in plasma. In 19 hematopoietic stem cell and kidney transplant patients, ATG treatment resulted in thrombopenia and increased plasma levels of d‐dimer and thrombin‐antithrombin complexes. Flow cytometric analysis of complement fragments on platelet MV in patient plasma confirmed dose‐dependent complement activation by ATG. However, the rapid rise in MV numbers observed in vitro was not seen during ATG treatment. In vitro experiments suggested that this was due to adherence of C3b‐tagged MV to red blood cells via complement receptor CR1. These data suggest a clinically relevant link between complement activation and thrombin generation and offer a potential mechanism underlying ATG‐induced hypercoagulability.