REDUCTION OF PLASMA FIBRINOLYTIC-ACTIVITY FOLLOWING HIGH-DOSE CYCLOPHOSPHAMIDE IS NEUTRALIZED INVIVO BY GM-CSF ADMINISTRATION

Background. GM-CSF has broad clinical applicability as a potent myelop oietic stimulator. However, its function is not restricted to the myel opoietic system and several observations suggest that GM-CSF may inter fere with the hemostatic balance. In order to assess whether GM-CSF ha s any influence on hemostasis, we evaluated some coagulative and fibri nolytic parameters in patients treated with GM-CSF following chemother apy. Methods. Fibrinolytic activity (FA), fibrinogen and D-dimer were evaluated before and after high-dose cyclophosphamide in 6 patients ad ditionally treated with GM-CSF and in 5 control patients; moreover, ti ssue plasminogen activator (tPA) was assayed in those treated with GM- CSF. Comparative in vitro analysis was performed on cultuered endothel ial cells before and after exposure to GM-CSF. Results. Control patien ts showed a significant decrease in plasma FA after chemotherapy compa red to basal values (FA/mm2: 15.6 +/- 2.1 at day + 2 and 20.8 +/- 19 a t day + 4 vs. 103.8 +/- 64.2 at day 0; p < 0.005); conversely, no FA r eduction was observed in GM-CSF-treated subjects. In this latter group a marked increase in tPA antigen was seen, consistent with enhanced F A. No significant changes in plasma D-dimer and fibrinogen values were detected in the two groups. tPA, urokinase-type plasminogen activator , PAI-1 and procoagulant activity were evaluated in vitro on cultured human endothelial cells and found to be unchanged following GM-CSF add ition. Conclusions. The results demonstrate that high-dose chemotherap y may negatively influence plasma FA. This adverse side effect is neut ralized by GM-CSF administration. The discrepancy found between in vit ro and in vivo GM-CSF activity on hemostatis may be explained by in vi vo GM-CSF stimulation of cell types other than endothelial cells.