Effect of thrombopoietin receptor agonists on leukocyte and haematopoietic stem and progenitor cells in the peripheral blood of patients with immune thrombocytopenic purpura

Abstract

The thrombopoietin receptor agonists (TPO-RAs), romiplostim and eltrombopag, stimulate megakaryopoiesis and thereby increase platelet counts. Both drugs are increasingly used in the treatment of immune thrombocytopenic purpura (ITP). To assess the effect of TPO-RAs on trilineage haematopoiesis, colony-forming cell (CFC) assays were performed on peripheral blood mononuclear cells of 8 healthy donors and 52 ITP patients. Additionally, we revaluated the regular and complete blood counts (CBCs) performed during romiplostim therapy in 45 patients and the CBCs performed in 9 patients during eltrombopag therapy. The clonogenic capacity of PBMCs was significantly increased in patients treated with TPO-RAs compared with healthy donors and untreated patients [BFU-E, 69 ± 47; CFU-GM, 61 ± 48; CFU-GEMM, 16 ± 11; CFU-total, 145 ± 94; P values < 0.05)]. Relative leukocytosis was observed in routine blood counts in 12 of 45 (26%) patients treated with romiplostim. The regular CBCs, performed time dependent within the first 5 days, revealed a maximum increase of leukocytes on days 2 and 3 following romiplostim administration. There were no significant changes in red blood cell parameters. None of the affected patients did recognise any significant symptom, which may be related to leukocytosis. Similarly, we observed a statistically significant increase of leukocyte count in a small cohort of ITP patients (n = 9) in whom CBCs were controlled following treatment initiation (P = 0.044). Our results indicate that TPO-RAs may also mobilize haematopoietic stem and progenitor cells (HSPCs) in peripheral blood and the occurrence of such relative leukocytosis may signalize an early symptom of myelofibrosis due to treatment with TPO-RAs.

Eltrombopag for myelodysplastic syndromes or chronic myelomonocytic leukaemia with no excess blasts and thrombocytopenia: a French multicentre retrospective real‐life study

“…This observation was also made in aplastic anaemia 22,25 . Such responses could potentially be explained by ‘off‐target’ effects of ELT (including iron chelation and immunomodulation) that could restore and/or stimulate normal haematopoiesis 26,27 …”

“…22,25 Such responses could potentially be explained by 'off-target' effects of ELT (including iron chelation and immunomodulation) that could restore and/or stimulate normal haematopoiesis. 26,27 Switching between the two available TPO-RAs had not been explored in MDS. This switch had been evaluated in ITP, 28 with a response rate of 60% to the second TPO-RA when the switch was made for lack of response to the first, regardless of the direction of the switch.…”

Pathophysiology of Autoimmune Thrombocytopenia: Current Insight with a Focus on Thrombopoiesis

“…94,95 Recently, Bal et al reported an additional therapeutic effect of TPO-R agonists showing increased proliferation, mobilization and differentiation of HSCs and early cell progenitors of all three haematopoietic lineages. 96 Consequently, HSCs seem to be a promising tool for novel cell-based therapies in ITP.…”

Ferulic Acid, A Potential Antithrombotic Drug

“…Ma et al found that FA significantly increased the recovery of platelets and leukocytosis because it increased the formation of clones of hematopoietic progenitor cells 6 . These hematopoietic cells can differentiate into platelet and leukocyte under the induction by the corresponding cytokines [20][21][22] . Moreover, in the concentration range of 0-500 nM, FA had no cytotoxic effect on IEC-6 but exhibited a protective effect against heat stress-induced intestinal epithelial barrier dysfunction 23 .…”