2-O, 3-O desulfated heparin mitigates murine chemotherapy- and radiation-induced thrombocytopenia

Abstract

Key Points• ODSH counters the inhibitory effect of PF4 on megakaryopoiesis in murine and human cell cultures.• ODSH improves platelet count recovery in murine models of both CIT and RIT.Thrombocytopenia is a significant complication of chemotherapy and radiation therapy.Platelet factor 4 (PF4; CXCL4) is a negative paracrine of megakaryopoiesis. We have shown that PF4 levels are inversely related to steady-state platelet counts, and to the duration and severity of chemotherapy-and radiation-induced thrombocytopenia (CIT and RIT, respectively). Murine studies suggest that blocking the effect of PF4 improves megakaryopoiesis, raising nadir platelet counts and shortening the time to platelet count recovery. We examined the ability of 2-O, 3-O desulfated heparin (ODSH), a heparin variant with little anticoagulant effects, to neutralize PF4's effects on megakaryopoiesis.Using megakaryocyte colony assays and liquid cultures, we show that ODSH restored megakaryocyte proliferation in PF4-treated Cxcl4 2/2 murine and human CD34 1 -derived megakaryocyte cultures (17.4% megakaryocyte colonies, P , .01 compared with PF4). In murine CIT and RIT models, ODSH, started 24 hours after injury, was examined for the effect on hematopoietic recovery demonstrating higher platelet count nadirs (9% 6 5% treated vs 4% 6 4% control) and significantly improved survival in treated animals (73% treated vs 36% control survival). Treatment with ODSH was able to reduce intramedullary free PF4concentrations by immunohistochemical analysis. In summary, ODSH mitigated CIT and RIT in mice by neutralizing the intramedullary negative paracrine PF4. ODSH, already in clinical trials in humans as an adjuvant to chemotherapy, may be an important, clinically relevant therapeutic for CIT and RIT.

Activating SRC/MAPK signaling via 5-HT1A receptor contributes to the effect of vilazodone on improving thrombocytopenia

“…Thrombocytopenia caused by long-term radiotherapy and chemotherapy exists in cancer treatment ( Tkaczynski et al, 2018 ; Kiang et al, 2014 ). This complication seriously affects the prognosis and endangers the life of patients ( Mouthon et al, 1999 ).…”

“…Among them, radiotherapy and chemotherapy for tumor treatment are the key factors leading to thrombocytopenia complications. Radiation-induced thrombocytopenia (RIT) is a significant cause of morbidity and mortality and is particularly important in the hematopoietic form of acute radiation syndrome ( Tkaczynski et al, 2018 ). According to several studies, platelet count correlates more strongly with survival following total body irradiation than any other hematologic parameter ( Mouthon et al, 1999 ; Kiang et al, 2014 ; Lebois et al, 2016 ).…”

UHPLC/MS-Based Serum Metabolomics Reveals the Mechanism of Radiation-Induced Thrombocytopenia in Mice

“…Thrombocytopenia is a primary complication of radiotherapy that can be life threatening. Platelet count was reported to be an important indicator of surviving radiation exposure [ 36 , 37 ]. However, the clinical treatment of thrombocytopenia is usually insufficient.…”

Heparan Sulfate Mimetics in Cancer Therapy: The Challenge to Define Structural Determinants and the Relevance of Targets for Optimal Activity

“…The derivative was well tolerated and the combination was associated with a high rate (92%) of morphologic complete remissions. The rapid hematological recovery was also encouraging, an effect that could be related to the binding and neutralization of platelet factor 4, a negative regulator of megakariopoiesis [ 195 ]. Interestingly, parallel in vitro studies suggested that CX-01 may interfere with the CXCL12/C–X–C chemokine receptor 4 (CXCR4) axis implicated in the homing of leukemic stem cells in marrow stromal niches via competitive inhibition for the binding of CXCL12 to the marrow HS [ 186 ].…”