The Role of Platelet Factor 4 in Radiation-Induced Thrombocytopenia
- Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA (United States)
Purpose: Factors affecting the severity of radiation-induced thrombocytopenia (RIT) are not well described. We address whether platelet factor 4 (PF4; a negative paracrine for megakaryopoiesis) affects platelet recovery postradiation. Methods and Materials: Using conditioned media from irradiated bone marrow (BM) cells from transgenic mice overexpressing human (h) PF4 (hPF4+), megakaryocyte colony formation was assessed in the presence of this conditioned media and PF4 blocking agents. In a model of radiation-induced thrombocytopenia, irradiated mice with varying PF4 expression levels were treated with anti-hPF4 and/or thrombopoietin (TPO), and platelet count recovery and survival were examined. Results: Conditioned media from irradiated BM from hPF4+ mice inhibited megakaryocyte colony formation, suggesting that PF4 is a negative paracrine released in RIT. Blocking with an anti-hPF4 antibody restored colony formation of BM grown in the presence of hPF4+ irradiated media, as did antibodies that block the megakaryocyte receptor for PF4, low-density lipoprotein receptor-related protein 1 (LRP1). Irradiated PF4 knockout mice had higher nadir platelet counts than irradiated hPF4+/knockout litter mates (651 vs. 328 x 106/mcL, p = 0.02) and recovered earlier (15 days vs. 22 days, respectively, p <0.02). When irradiated hPF4+ mice were treated with anti-hPF4 antibody and/or TPO, they showed less severe thrombocytopenia than untreated mice, with improved survival and time to platelet recovery, but no additive effect was seen. Conclusions: Our studies show that in RIT, damaged megakaryocytes release PF4 locally, inhibiting platelet recovery. Blocking PF4 enhances recovery while released PF4 from megakaryocytes limits TPO efficacy, potentially because of increased release of PF4 stimulated by TPO. The clinical value of blocking this negative paracrine pathway post-RIT remains to be determined.
- OSTI ID:
- 21587655
- Journal Information:
- International Journal of Radiation Oncology, Biology and Physics, Journal Name: International Journal of Radiation Oncology, Biology and Physics Journal Issue: 5 Vol. 80; ISSN IOBPD3; ISSN 0360-3016
- Country of Publication:
- United States
- Language:
- English
Similar Records
Postirradiation thrombocytopoiesis: suppression, recovery, compensatory states, and macromegakaryocytosis
Atomic description of the immune complex involved in heparin-induced thrombocytopenia
Related Subjects
ANIMAL CELLS
ANIMAL TISSUES
ANIMALS
ANTIBODIES
BIOLOGICAL MATERIALS
BLOOD
BLOOD CELLS
BLOOD PLATELETS
BODY
BODY FLUIDS
BONE MARROW
BONE MARROW CELLS
COLONY FORMATION
CONNECTIVE TISSUE CELLS
GROWTH FACTORS
HEMATOPOIETIC SYSTEM
LIPIDS
LIPOPROTEINS
LYMPHOKINES
MAMMALS
MATERIALS
MEDICINE
MEMBRANE PROTEINS
MICE
MITOGENS
ORGANIC COMPOUNDS
ORGANS
POST-IRRADIATION THERAPY
PROTEINS
RECEPTORS
RODENTS
SOMATIC CELLS
THERAPY
TRANSGENIC ANIMALS
TRANSGENIC MICE
VERTEBRATES