Reduction of plasma fibrinolytic activity following high-dose cyclophosphamide is neutralized in vivo by GM-CSF administration.
BACKGROUND
GM-CSF has broad clinical applicability as a potent myelopoietic stimulator. However, its function is not restricted to the myelopoietic system and several observations suggest that GM-CSF may interfere with the hemostatic balance. In order to assess whether GM-CSF has any influence on hemostasis, we evaluated some coagulative and fibrinolytic parameters in patients treated with GM-CSF following chemotherapy.


METHODS
Fibrinolytic activity (FA), fibrinogen and D-dimer were evaluated before and after high-dose cyclophosphamide in 6 patients additionally treated with GM-CSF and in 5 control patients; moreover, tissue plasminogen activator (tPA) was assayed in those treated with GM-CSF. Comparative in vitro analysis was performed on cultured endothelial cells before and after exposure to GM-CSF.


RESULTS
Control patients showed a significant decrease in plasma FA after chemotherapy compared to basal values (FA/mm2: 15.6 +/- 2.1 at day + 2 and 20.8 +/- 19 at day + 4 vs. 103.8 +/- 64.2 at day 0; p < 0.005); conversely, no FA reduction was observed in GM-CSF-treated subjects. In this latter group a marked increase in tPA antigen was seen, consistent with enhanced FA. 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 addition.


CONCLUSIONS
The results demonstrate that high-dose chemotherapy may negatively influence plasma FA. This adverse side effect is neutralized by GM-CSF administration. The discrepancy found between in vitro and in vivo GM-CSF activity on hemostatic may be explained by in vivo GM-CSF stimulation of cell types other than endothelial cells.
Bazzan
M
M
Dipartimento di Medicina ed Oncologia Sperimentale, Ospedale Molinette, Torino, Italy.
Pannocchia
A
A
Tarella
C
C
Stella
S
S
Garbarino
G
G
Pileri
A
A
Tamponi
G
G
D000328:Adult; D002478:Cells, Cultured; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000009:adverse effects / Q000037:antagonists & inhibitors*; D004198:Disease Susceptibility / Q000139:chemically induced; D004730:Endothelium, Vascular / Q000187:drug effects; D005260:Female; D005342:Fibrinolysis / Q000187:drug effects*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use; D008228:Lymphoma, Non-Hodgkin / Q000097:blood / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000097:blood / Q000188:drug therapy; D017395:Plasminogen Activator Inhibitor 1 / Q000032:analysis; D013927:Thrombosis / Q000139:chemically induced; D010959:Tissue Plasminogen Activator / Q000032:analysis
D007155:Immunologic Factors; D017395:Plasminogen Activator Inhibitor 1; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D003520:Cyclophosphamide; D010959:Tissue Plasminogen Activator