Complement activation: the missing link between ADAMTS-13 deficiency and microvascular thrombosis of thrombotic microangiopathies

Maria Piedad Ruiz-Torres; Federica Casiraghi; Miriam Galbusera; Daniela Macconi; Sara Gastoldi; Marta Todeschini; Francesca Porrati; Daniela Belotti; Enrico Maria Pogliani; Marina Noris; Giuseppe Remuzzi

doi:10.1160/TH04-07-0450

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2005; 93(03): 443-452
DOI: 10.1160/TH04-07-0450

Blood Coagulation, Fibrinolysis and Cellular Haemostais

Schattauer GmbH

Complement activation: the missing link between ADAMTS-13 deficiency and microvascular thrombosis of thrombotic microangiopathies

Authors

Maria Piedad Ruiz-Torres

¹Mario Negri Institute for Pharmacological Research, Center for Research on Organ Transplantation “Chiara Cucchi de Alessandri e Gilberto Crespi”, Villa Camozzi–Ranica, Italy

²Department of Physiology, Alcala University, Alcala de Henares, Madrid, Spain
Federica Casiraghi

¹Mario Negri Institute for Pharmacological Research, Center for Research on Organ Transplantation “Chiara Cucchi de Alessandri e Gilberto Crespi”, Villa Camozzi–Ranica, Italy
Miriam Galbusera

¹Mario Negri Institute for Pharmacological Research, Center for Research on Organ Transplantation “Chiara Cucchi de Alessandri e Gilberto Crespi”, Villa Camozzi–Ranica, Italy
Daniela Macconi

¹Mario Negri Institute for Pharmacological Research, Center for Research on Organ Transplantation “Chiara Cucchi de Alessandri e Gilberto Crespi”, Villa Camozzi–Ranica, Italy
Sara Gastoldi

¹Mario Negri Institute for Pharmacological Research, Center for Research on Organ Transplantation “Chiara Cucchi de Alessandri e Gilberto Crespi”, Villa Camozzi–Ranica, Italy
Marta Todeschini

¹Mario Negri Institute for Pharmacological Research, Center for Research on Organ Transplantation “Chiara Cucchi de Alessandri e Gilberto Crespi”, Villa Camozzi–Ranica, Italy
Francesca Porrati

¹Mario Negri Institute for Pharmacological Research, Center for Research on Organ Transplantation “Chiara Cucchi de Alessandri e Gilberto Crespi”, Villa Camozzi–Ranica, Italy
Daniela Belotti

³Division of Haematology, “San Gerardo” Hospital, Monza, Italy
Enrico Maria Pogliani

³Division of Haematology, “San Gerardo” Hospital, Monza, Italy
Marina Noris

¹Mario Negri Institute for Pharmacological Research, Center for Research on Organ Transplantation “Chiara Cucchi de Alessandri e Gilberto Crespi”, Villa Camozzi–Ranica, Italy
Giuseppe Remuzzi

¹Mario Negri Institute for Pharmacological Research, Center for Research on Organ Transplantation “Chiara Cucchi de Alessandri e Gilberto Crespi”, Villa Camozzi–Ranica, Italy

⁴Unit of Nephrology and Dialysis, Azienda Ospedaliera, Ospedali Riuniti di Bergamo, Italy

Abstract

Summary

Endothelial injury is the central factor in the events leading to thrombotic microangiopathy (TMA); however, the mechanisms involved are not fully understood. Here we investigate the role of neutrophils (PMNs) and of complement activation in inducing microvascular damage and loss of thromboresistance in TMA associated with ADAMTS-13 deficiency. PMNs isolated during the acute phase of the disease released excessive amounts of reactive-oxygen species (ROS), N-derived oxidants and proteinases and induced damage and thromboresistance loss in human microvascular endothelial cell line (HMEC-1) ex vivo. Endothelial cytotoxicity and thromboresistance loss was also induced by TMA serum. Complement-derived products were responsible for the above effects: in fact, TMA serum caused C3 and Membrane Attack Complex (MAC) deposition on HMEC-1 and its cytotoxic effect was abolished by complement inhibition. TMA serum caused surface expression of P-selectin on HMEC-1 which may promote PMN adhesion and resulted in increased PMN cytotoxicity, indicating that complement may have a role in PMN activation. In addition, TMA serum stimulated control PMNs to release ROS and proteinases, and to cause endothelial cell cytotoxicity. All of the above effects were abrogated by complement inactivation. These data document for the first time that complement-initiated PMN activation and endothelial injury may have a crucial role in microvascular thrombosis of TMA associated with ADAMTS-13 deficiency.

Keywords

Thrombotic microangiopathy - ADAMTS-13 - reactive oxygen species - neutrophils - complement

Full Text

References

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