Cisplatin-induced platelet activation requires mononuclear cells: role of GMP-140 and modulation of procoagulant activity.
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 beta 3 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.
Yen
T
T
Heart Research Institute, Camperdown, N.S.W., Australia.
Walsh
J D
JD
Pejler
G
G
Berndt
M C
MC
Geczy
C L
CL
D001779:Blood Coagulation Factors / Q000096:biosynthesis; D001792:Blood Platelets / Q000201:enzymology; D015815:Cell Adhesion Molecules / Q000502:physiology; D002450:Cell Communication; D002945:Cisplatin / Q000494:pharmacology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005165:Factor V / Q000378:metabolism; D005170:Factor X / Q000378:metabolism; D015951:Factor Xa; D006801:Humans; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D009000:Monocytes / Q000502:physiology*; D019007:P-Selectin; D015539:Platelet Activation / Q000187:drug effects*; D010974:Platelet Aggregation / Q000187:drug effects; D010980:Platelet Membrane Glycoproteins / Q000502:physiology
D001779:Blood Coagulation Factors; D015815:Cell Adhesion Molecules; D016861:Cyclooxygenase Inhibitors; D016859:Lipoxygenase Inhibitors; D019007:P-Selectin; D010980:Platelet Membrane Glycoproteins; C045071:leukocyte procoagulant activity; C022475:prothrombinase complex; D005165:Factor V; D005170:Factor X; D015951:Factor Xa; D002945:Cisplatin