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, alpha-granule release, membrane phosphatidylserine exposure

and the rapid release of 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. Full platelet aggregation and activation by ATG also required the low affinity

Fc gamma receptor FcγRII. MV release, however, was FcγRII-independent. Platelet MV

expressed high prothrombinase activity. Moreover, blocking C5 inhibited ATG-induced thrombin

generation in platelet rich plasma. In 19 hematopoietic stem cell and kidney transplant patients,

ATG treatment resulted in thrombopenia and increased plasma levels of d-dimer and thrombin-anti-

thrombin-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.

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