title: The role of platelet factor 4 in radiation-induced thrombocytopenia.
abstract: OBJECTIVE
  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
  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 × 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.
authors: Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. lambertm@email.chop.edu
authors: Michele P
authors: MP
authors: Lambert
authors: Liqing
authors: L
authors: Xiao
authors: Yvonne
authors: Y
authors: Nguyen
authors: M Anna
authors: MA
authors: Kowalska
authors: Mortimer
authors: M
authors: Poncz
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000166:cytology / Q000528:radiation effects*; D001853:Bone Marrow / Q000528:radiation effects; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D003114:Colony-Forming Units Assay / Q000379:methods; D017077:Culture Media, Conditioned / Q000528:radiation effects; D006801:Humans; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008533:Megakaryocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010976:Platelet Count; D010978:Platelet Factor 4 / Q000037:antagonists & inhibitors / Q000502:physiology*; D011973:Receptors, LDL / Q000037:antagonists & inhibitors; D013921:Thrombocytopenia / Q000097:blood / Q000188:drug therapy / Q000209:etiology*; D034061:Thrombopoiesis / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D013926:Thrombopoietin / Q000494:pharmacology; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors
chemical_list: D017077:Culture Media, Conditioned; D026503:Low Density Lipoprotein Receptor-Related Protein-1; C486645:Lrp1 protein, mouse; D011973:Receptors, LDL; D025521:Tumor Suppressor Proteins; D010978:Platelet Factor 4; D013926:Thrombopoietin