Mechanism of Platelet Activation and Hypercoagulability by Antithymocyte Globulins (ATG).

Abstract

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.

• Authors: A Cumpelik, E Gerossier, J Jin, D Tsakiris, M Dickenmann, S Sadallah, J A Schifferli, D Zecher
• Journal: American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons (Am J Transplant) Vol. 15 Issue 10 Pg. 2588-601 (Oct 2015) ISSN: 1600-6143 [Electronic] United States
• PMID: 25966640 (Publication Type: Clinical Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.

Chemical References

• Antilymphocyte Serum
• Biomarkers
• Immunosuppressive Agents
• Thrombin

Topics

• Antilymphocyte Serum (adverse effects, therapeutic use)
• Biomarkers (blood)
• Cell-Derived Microparticles (drug effects)
• Complement Activation (drug effects)
• Graft Rejection (immunology, prevention & control)
• Graft vs Host Disease (immunology, prevention & control)
• Hematopoietic Stem Cell Transplantation
• Humans
• Immunosuppressive Agents (adverse effects, therapeutic use)
• Kidney Transplantation
• Platelet Activation (drug effects, immunology)
• Thrombin (metabolism)
• Thrombocytopenia (blood, chemically induced, diagnosis)
• Thrombophilia (blood, chemically induced, diagnosis)