Increased platelet aggregation and in vivo platelet activation after granulocyte colony-stimulating factor administration

Abstract

Granulocyte colony-stimulating factor (G-CSF) stimulates the bone marrow to produce granulocytes and stem cells and is widely used to accelerate neutrophil recovery after chemotherapy. Interestingly, specific G-CSF receptors have been demonstrated not only on myeloid cells, but also on platelets. Data on the effects of G-CSF on platelet function are limited and partly conflicting. The objective of this study was to determine the effect of G-CSF on platelet aggregation and in vivo platelet activation. Seventy-eight, healthy volunteers were enrolled into this randomised, placebo-controlled trial. Subjects received 5 μg/kg methionyl human granulocyte colony-stimulating factor (r-metHuG-CSF, filgrastim) or placebo subcutaneously for four days. We determined platelet aggregation with a whole blood impedance aggregometer with various, clinically relevant platelet agonists (adenosine diphosphate [ADP], collagen, arachidonic acid [AA], ristocetin and thrombin receptor activating peptide 6 [TRAP]). Filgrastim injection significantly enhanced ADP (+40%), collagen (+60%) and AA (+75%)-induced platelet aggregation (all p<0.01 as compared to placebo and p<0.001 as compared to baseline). In addition, G-CSF enhanced ristocetin-induced platelet aggregation (+18%) whereas TRAP-induced platelet aggregation decreased slightly (-14%) in response to filgrastim. While baseline aggregation with all agonists was only slightly but insignificantly higher in women than in men, this sex difference was enhanced by G-CSF treatment, and became most pronounced for ADP after five days (p<0.001). Enhanced platelet aggregation translated into a 75% increase in platelet activation as measured by circulating soluble P-selectin. G-CSF enhances platelet aggregation and activation in humans. This may put patients suffering from cardiovascular disease and cancer at risk for thrombotic events.

Tbo-Filgrastim versus Filgrastim during Mobilization and Neutrophil Engraftment for Autologous Stem Cell Transplantation

“…However, this difference demonstrated no clinical significance on efficacy or cost outcomes, evidenced by the equivalent median number of transfusions given in both groups. Although there is evidence that G-CSF may promote platelet aggregation related to a G-CSF receptor identified on platelets [36], this has no correlation to the statistical difference we report related to number of platelet transfusions before platelet engraftment.…”

No evidence for cell activation or brain vaso-occlusion with plerixafor mobilization in sickle cell mice

“…It is possible that, with plerixafor, cell activation does not occur coincident with HPC mobilization and thus detection of cell activation was missed. However, with G-CSF, platelet/endothelial [12] and neutrophil activation [13] occur coincident with HPC mobilization, and in the one paper of which we are aware that reported on cell activation with plerixafor (in multiple myeloma patients also given G-CSF), 4 h after plerixafor administration no increased adhesion marker expression on CD34+ cells was observed [14]. …”

Granulocyte colony-stimulating factor (G-CSF) increases histone-complexed DNA plasma levels in healthy volunteers

“…Moreover, repeated doses of G-CSF increased C-reactive protein levels approximately twofold (0.23–0.51 mg/dl). However, this increase is still within the limits of the normal range [12]. Considering these findings, the increase in hc-DNA may be more likely to be a consequence of an increase in circulating DNA rather than an increase in histones.…”

“…As NETs also seem to play a pathogenic role in deep venous thrombosis, they may constitute an important link between inflammation and thrombosis [9, 10]. G-CSF injection markedly enhances platelet aggregation and shear-dependent platelet function [11, 12]. …”