Treatment of the Kasabach-Merritt syndrome with pegylated recombinant human megakaryocyte growth and development factor in mice: elevated platelet counts, prolonged survival, and tumor growth inhibition.
Kasabach-Merritt Syndrome (KMS) is seen in children with large vascular tumors. KMS is characterized by very low platelet counts and a consumption of coagulation factors causing life-threatening complications. It has been proposed that thrombopenia in these patients is caused by intratumoral trapping of platelets. The truncated form of the cMpl-receptor ligand thrombopoietin, pegylated human megakaryocyte growth and development factor (Peg-rHuMGDF), is an agent that stimulates platelet production. We hypothesized that stimulation of the platelet production would prevent the life-threatening complications of patients with KMS owing to low platelet counts. In a mouse model of KMS, with tumors derived from a hemangioendothelioma cell line, we studied the effect of Peg-rHuMGDF. Treatment with Peg-rHuMGDF (10 microg/kg/day intraperitoneally) increased platelet counts by 7-8-fold compared with control tumor-bearing mice after 11 d of treatment (p < 0.001, n = 8). Survival was significantly increased, with 50% of treated animals alive at 1 mo versus 0% in untreated controls. Interestingly, we also observed an inhibition of tumor growth by 75% (p < 0.001, n = 8). Hematoxylin and eosin staining showed fresh fibrin clots in the treated tumors, suggesting that higher platelet counts caused intravascular thrombosis of tumor vessels. We conclude that increased platelet production in this model of KMS resulted in an antivascular tumor effect via platelet trapping. Further, we propose that thrombopoietin may be of critical value in preventing life-threatening complications from KMS.
Verheul
H M
HM
The Department of Medical Oncology, Academic Hospital Vrije Universiteit, Amsterdam, The Netherlands.
Panigrahy
D
D
Flynn
E
E
Pinedo
H M
HM
D'Amato
R J
RJ
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002417:Cattle; D002460:Cell Line; D006391:Hemangioma / Q000097:blood / Q000188:drug therapy* / Q000401:mortality; D006801:Humans; D007150:Immunohistochemistry; D007274:Injections, Intraperitoneal; D051379:Mice; D010976:Platelet Count / Q000187:drug effects; D011092:Polyethylene Glycols / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000627:therapeutic use; D013268:Stimulation, Chemical; D015996:Survival Rate; D013577:Syndrome; D013921:Thrombocytopenia / Q000097:blood / Q000188:drug therapy* / Q000401:mortality; D013926:Thrombopoietin / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D011994:Recombinant Proteins; C103117:polyethylene glycol-recombinant human megakaryocyte growth and development factor; D011092:Polyethylene Glycols; D013926:Thrombopoietin