Platelet-mediated proteolytic down regulation of the anticoagulant activity of protein S in individuals with haematological malignancies

Ilze Dienava-Verdoold; Marina R. Marchetti; Liane C. J. te Boome; Laura Russo; Anna Falanga; Harry R Koene; Koen Mertens; Herm Jan M. Brinkman

doi:10.1160/TH11-07-0457

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2012; 107(03): 468-476
DOI: 10.1160/TH11-07-0457

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

Platelet-mediated proteolytic down regulation of the anticoagulant activity of protein S in individuals with haematological malignancies

Ilze Dienava-Verdoold

¹Department of Plasma Proteins, Sanquin Research, Amsterdam, The Netherlands

,

Marina R. Marchetti

²Immunohematology and Transfusion Medicine Department, Ospedali Riuniti di Bergamo, Bergamo, Italy

,

Liane C. J. te Boome

³Department of Hematology, Academical Medical Center, University of Amsterdam, Amsterdam, The Netherlands

⁴Present address: Department of Hematology, Academic Medical Center, University of Utrecht, Utrecht, The Netherlands

,

Laura Russo

²Immunohematology and Transfusion Medicine Department, Ospedali Riuniti di Bergamo, Bergamo, Italy

,

Anna Falanga

²Immunohematology and Transfusion Medicine Department, Ospedali Riuniti di Bergamo, Bergamo, Italy

,

Harry R Koene

³Department of Hematology, Academical Medical Center, University of Amsterdam, Amsterdam, The Netherlands

⁵Pressent address: Department of Internal Medicine, St. Antonius Hospital, Nieuwegein, The Netherlands

,

Koen Mertens

¹Department of Plasma Proteins, Sanquin Research, Amsterdam, The Netherlands

⁶Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands

,

Herm Jan M. Brinkman

¹Department of Plasma Proteins, Sanquin Research, Amsterdam, The Netherlands

› Author Affiliations

Abstract

Summary

The natural anticoagulant protein S contains a so-called thrombin-sensitive region (TSR), which is susceptible to proteolytic cleavage. We have previously shown that a platelet-associated protease is able to cleave protein S under physiological plasma conditions in vitro. The aim of the present study was to investigate the relation between platelet-associated protein S cleaving activity and in vivo protein S cleavage, and to evaluate the impact of in vivo protein S cleavage on its anticoagulant activity. Protein S cleavage in healthy subjects and in thrombocytopenic and thrombocythaemic patients was evaluated by immunological techniques. Concentration of cleaved and intact protein S was correlated to levels of activated protein C (APC)-dependent and APC-independent protein S anticoagulant activity. In plasma from healthy volunteers 25% of protein S is cleaved in the TSR. While in plasma there was a clear positive correlation between levels of intact protein S and both APC-dependent and APC-independent protein S anticoagulant activities, these correlations were absent for cleaved protein S. Protein S cleavage was significantly increased in patients with essential thrombocythaemia (ET) and significantly reduced in patients with chemotherapy-induced thrombocytopenia. In ET patients on cytoreductive therapy, both platelet count and protein S cleavage returned to normal values. Accordingly, platelet transfusion restored cleavage of protein S to normal values in patients with chemotherapy-induced thrombocytopenia. In conclusion, proteases from platelets seem to contribute to the presence of cleaved protein S in the circulation and may enhance the coagulation response in vivo by down regulating the anticoagulant activity of protein S.

Keywords

Coagulation - thrombin generation - protein S - cellular proteases - platelets

Full Text

References

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