Abstract

Cytotoxic drugs may potentiate the thrombotic complications in patients with malignancies and platelet function abnormalities have been reported after initiation of cisplatin therapy. This report describes a prolonged activation of platelets over 6-24 h co-culture with peripheral blood mononuclear cells (PBM) by pharmacological doses of cisplatin. Cisplatin had no direct effect on platelets and depended on PBM to produce aggregation which was apparently not mediated by products of the cyclooxygenase or lipoxygenase pathways, by platelet activation factor (PAF) or by thrombin. Although platelet aggregation normally involves the binding of fibrinogen to the beta3 integrin, GP IIb-IIIa, on activated platelets, the cisplatin-dependent platelet aggregation observed in the co-culture experiments was not inhibited by an anti-GP IIb-IIIa monoclonal antibody which blocks fibrinogen-dependent aggregation nor by an adhesive peptide containing the RGDS integrin recognition sequence. Rather, aggregation appeared to involve a novel 140 kD granule membrane protein (GMP-140) mediated mechanism since aggregation was almost completely blocked by Fab fragments of an antibody to GMP-140 and was inhibited by fluid-phase GMP-140. At concentrations of cisplatin, adriamycin, and LPS that induced equivalent levels of tissue factor. of blood monocytes, prothrombinase activity was significantly greater in cultures containing cisplatin. Prothrombinase activity was dependent on the presence of platelets and the rate of thrombin formation was enhanced by factor Xa generated by the tissue factor-factor VIIa complex. These studies suggest that the vascular and thrombotic complications associated with cisplatin therapy are mediated, at least in part, by platelet activation and aggregation and monocyte procoagulant activity.

Published in

British Journal of Haematology
1993, Volume: 83, number: 2, pages: 259-269
Publisher: BLACKWELL SCIENCE LTD

UKÄ Subject classification

Pharmaceutical Sciences


Publication identifier

DOI: https://doi.org/10.1111/j.1365-2141.1993.tb08281.x

Permanent link to this page (URI)

https://res.slu.se/id/publ/52780