A prospective study of G-CSF effects on hemostasis in allogeneic blood stem cell donors

Abstract

Summary:Granulocyte colony-stimulating factor (G-CSF) is used in healthy donors of peripheral blood stem cells (PBSC) for allogeneic transplantation. However, some data have recently suggested that G-CSF may induce a hypercoagulable state, prompting us to study prospectively 22 PBSC donors before and after G-CSF 5 g/kg twice daily. We sought evidence for changes in the following parameters: platelet count, von Willebrand factor antigen (vWF:Ag) and activity (vWF activity), ␤-thromboglobulin (␤-TG), platelet factor 4 (PF-4), platelet activation markers (GMP-140 and PAC-1), activated partial thromboplastin time (aPTT), prothrombin time (PT), coagulant factor VIII (FVIII:C), thrombin-antithrombin complex (TAT), prothrombin fragment 1+2 (F1+2), thrombomodulin (TM) and tissue plasminogen activator antigen (tPA:Ag) prior to G-CSF and immediately before leukapheresis. ADP-induced platelet aggregation studies were also performed. G-CSF administration produced only mild discomfort. We found a significant increase in vWF:Ag (from 0.99 ؎ 0.32 U/ml to 1.83 ؎ 0.69 U/ml; P Ͻ 0.001), in vWF activity (from 1.04 ؎ 0.34 U/ml to 1.78 ؎ 0.50 U/ml; P Ͻ 0.001) and in FVIII:C (from 1.12 ؎ 0.37 U/ml to 1.73 ؎ 0.57 U/ml; P Ͻ 0.001) after G-CSF. Of note, four donors with low baseline vWF had a two-to three-fold increase after receiving G-CSF. G-CSF had no impact on the platelet count, ␤-TG, PF-4, GMP-140 or PAC-1. The final% of platelet aggregation decreased from 73 ؎ 22% to 37 ؎ 26% after G-CSF (P Ͻ 0.001). We found a significant decrease in aPTT after G-CSF (29.9 ؎ 3.1 s to 28.3 ؎ 3.3 s; P = 0.004), but the PT was unaffected. In addition, we also observed a significant increase in TAT, F1+2 and TM, but not in tPA:Ag. Our data suggest that G-CSF may possibly induce a hypercoagulable state by increasing levels of FVIII:C and thrombin generation. In contrast to this information, we found reduced platelet aggregation after G-CSF administration. The clinical implications of these findings remain unclear and larger studies are definitely required.

Administration of granulocyte-colony-stimulating factor for allogeneic hematopoietic cell collection may induce the tissue factor-dependent pathway in healthy donors

“…The mechanism by which rhG-CSF exerts its effects on the endothelium has not been fully explained. Upon activation, neutrophils release reactive oxygen species and intracellular protease that perform several activities on endothelial cells and platelets and may modify the hemostatic balance toward a prothrombotic state, 11,17 to which a series of leukocyte-mediated events may have contributed, in addition to direct toxicity. As we did not investigate the relationship between levels of neutrophil-derived proteases and activation markers, we were not able to demonstrate the role of leukocytemediated endothelial toxicity.…”

Low risk of symptomatic venous thromboembolic events during growth factor administration for PBSC mobilization

“…They also showed a decrease in final percentage of ADP induced platelet aggregation whereas Kuroiwa et al showed an increase in platelet aggregation. 4,10 Prophylactic anticoagulation to prevent CAT is not routinely used. Recent studies suggest that thromboprophylaxis with either low-molecular-weight heparin (LMWH) or low-dose warfarin does not prevent symptomatic CAT in patients with cancer.…”

“…3 One showed a significant increase in thrombin/antithrombin complex, prothrombin fragment F 1 þ 2 (F1 þ 2), thrombomodulin, factor VIII, von Willebrand factor antigen and activity following G-CSF. 4 Platelet aggregation studies have shown hypercoagulability after G-CSF administration in stem cell donors. The high doses of growth factors used for PBSCM could potentially lead to a hypercoagulable state with increased risk for VTE.…”

Allogeneic peripheral blood stem cell transplantation (PBSCT) from HLA-identical sibling donors in children with hematological diseases: a single center pilot study

“…On the other hand, thrombotic events secondary to enhanced platelet aggregation with an increment in platelet count and development of a hypercoagulable state have been described in patients and donors treated with G-CSF. [53][54][55] Therefore, donors need to be followed carefully, monitoring platelet counts during and after PBSC mobilization and collection procedures. Ethical issues of this technology arise since there are no defined criteria for PBSC donation in children, and safety of the procedure for pediatric donors has not been totally addressed in the literature.…”