Platelet-mediated proteolytic down regulation of the anticoagulant activity of protein S in individuals with haematological malignancies.
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.
Department of Plasma Proteins, Sanquin Research, Amsterdam, The Netherlands.
Ilze
I
Dienava-Verdoold
Marina R
MR
Marchetti
Liane C J
LC
te Boome
Laura
L
Russo
Anna
A
Falanga
Harry R
HR
Koene
Koen
K
Mertens
Herm Jan M
HJ
Brinkman
D058833:Antithrombin Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001777:Blood Coagulation / Q000187:drug effects; D001780:Blood Coagulation Tests; D001792:Blood Platelets / Q000378:metabolism* / Q000473:pathology; D020134:Catalytic Domain / Q000235:genetics; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D019337:Hematologic Neoplasms / Q000097:blood* / Q000150:complications / Q000188:drug therapy; D006801:Humans; D008297:Male; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017713:Platelet Transfusion; D011486:Protein C / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000235:genetics; D017293:Protein S / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis / Q000187:drug effects; D013920:Thrombocythemia, Essential / Q000097:blood* / Q000517:prevention & control; D013921:Thrombocytopenia / Q000097:blood* / Q000209:etiology / Q000517:prevention & control
D058833:Antithrombin Proteins; D010446:Peptide Fragments; D011486:Protein C; D017293:Protein S