Abstract
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 μg/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.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
Abbreviations
- KMS:
-
Kasabach-Merritt syndrome
- Tpo:
-
thrombopoietin
- c-Mpl:
-
c-mpl proto-oncogene
- Peg-rHu-MGDF:
-
pegylated recombinant human megakaryocyte growth and development factor
- H&E:
-
hematoxylin and eosin
- BCE:
-
bovine capillary endothelial cells
- bFGF:
-
basic fibroblast growth factor
References
Kasabach HH, Merritt KK 1940 Capillary hemangioma with extensive purpura: report of a case. Am J Dis Child 59: 1063–1070
El-Dessouky M, Azmy AF, Raine PAM, Young DG 1988 Kasabach-Merritt syndrome. J Pediatr Surg 23: 109–111
Sarkar M, Mulliken JB, Kozakewich HPW, Robertson RL, Burrows PE 1997 Thrombocytopenic coagulopathy (Kasabach Merritt Phenomenon) is associated with Kaposiform hemangioendothelioma and not with common infantile hemangioma. Plast Reconstr Surg 100: 1377–1386
Konras SB, Green OC, King L, Duran RJ 1963 Giant hemangioma with thrombocytopenia. Am J Dis Child 105: 188–195
Warrell RP Jr, Kempin SJ, Benua RS, Reiman RE, Young CW 1983 Intratumoral consumption of indium-111 labeled platelets in a patient with hemangiomatosis and intravascular coagulation (Kasabach-Merritt syndrome). Cancer 52: 2256–2260
Enjolras O, Wassef M, Mazoyer E, Frieden IJ, Rieu PN, Drouet L, Taieb A, Stalder JF, Escande JP 1997 Infants with Kasabach-Merritt syndrome do not have “true” hemangiomas. J Pediatr 130: 631–640
Phillips WG, Marsden JR 1993 Kasabach-Merritt syndrome exacerbated by platelet transfusion. J R Soc Med 86: 231–232
Kaushansky K, Lok S, Holly RD, Broudy VC, Lin N, Bailey MC, Forstrom JW, Buddle MM, Oort PJ, Hagen FS, Roth GJ, Papayannopoulou T, Foster DC 1994 Promotion of megakaryocyte progenitor expansion and differentiation by the c-Mpl ligand thrombopoietin. Nature 369: 568–574
Sauvage FJ, Hass PE, Spencer SD, Malloy BE, Gurey AL, Spencer SA, Darbonne WC, Henzel WJ, Wong SC, Kuang WJ, Oles KJ, Hultgren B, Solberg LA, Goeddel DV, Eaton DL 1994 Stimulation of megakaryocytopoiesis and thrombopoiesis by the c-Mpl ligand. Nature 369: 533–538
Bartley TD, Bogenberger J, Hunt P, Li YS, Lu HS, Martin F, Chang MS, Samal B, Nichol JL, Swift S, Johnson MJ, Su RY, Parker VP, Suggs S, Skrine JD, Merewether LA, Clogston C, Hsu E, Hokom MM, Hornkohl A, Choi E, Pangelinan M, Sun Y, Mar V, McNinch J, Simonet L, Jacobsen F, Xie C, Schutter JE, Basu R, Selander L, Trollinger D, Sieu L, Padilla D, Trail G, Elliott G, Izumi R, Covey T, Crouse J, Garcia A, Xu W, Del Castillo J, Biron J, Cole S, Hu MCT, Pacifici R, Ponting I, Saris C, Wen D, Yung YP, Lin H, Bosselman RA 1994 Identification and cloning of a megakaryocyte growth and development factor that is a ligand for the cytokine receptor Mpl. Cell 77: 1117–1124
Basser RL, Rasko JE, Clarke K, Cebon J, Green MD, Hussein S, Alt C, Menchaca D, Tomita D, Marty J, Fox RM, Begley CG 1996 Thrombopoietic effects of pegylated recombinant human megakaryocyte growth and development factor in patients with advanced cancer. Lancet 348: 1279–1281
Nimer SD 1997 Platelet stimulating agents: off the launching pad. Nature Med 3: 154–155
Metcalfe P, Williamson LM, Reutelingsperger CP, Swann I, Ouwehand WH, Goodall AH 1997 Activation during preparation of therapeutic platelets affects deterioration during storage: a comparative flow cytometric study of different production methods. Br J Haematol 98: 86–95
Hoak JC, Warner ED, Cheng HF, Fry GL, Hankenson RR 1971 Hemangioma with thrombocytopenia and microangiopathic anemia (Kasabach-Merritt syndrome): an animal model. J Lab Clin Med 77: 941–950
Goldman R, Bar-Shavitz Z 1979 Dual effect of normal and stimulated macrophages and their conditioned media on target cell proliferation. J Natl Cancer Inst 63: 1009–1016
Kenyon BM, Voest EE, Chen C, Flynn E, Folkman J, D'Amato RJ 1996 A model of angiogenesis in the mouse cornea. Invest Opthalmol Vis Sci 37: 1625–1632
Moliterno AR, Hankins WD, Spivak JL 1998 Impaired expression of the thrombopoietin receptor by platelets from patients with polycythemia vera. N Engl J Med 338: 572–580
Porcelijn L, Folman CC, Bossers B, Huiskes E, Overbeeke MAM, van der Schoot CE, de Haas M, von dem Borne AE 1998 The diagnostic value of thrombopoietin level measurement in thrombocytopenia. Thromb Haemost 79: 1101–1115
Verheul HMW, Hoekman K, Luykx-de Bakker S, Eekman J, Broxterman HJ, Pinedo HM 1997 Platelet: transporter of vascular endothelial growth factor. Clin Cancer Res 3: 2187–2190
Pinedo HM, Verheul HMW, D'Amato RJ, Folkman J 1998 Involvement of platelets in angiogenesis?. Lancet 352: 1775–1777
Huang X, Molema G, King S, Watkins L, Edington TS, Thorpe PE 1997 Tumor infarction in mice by antibody directed targeting of tissue factor to tumor vasculature. Science 275: 547–550
Warrel RP Jr, Kempin SJ 1985 Treatment of severe coagulopathy in the Kasabach-Merritt syndrome with aminocaproic acid and cryoprecipitate. N Engl J Med 313: 309–312
Lanutti BJ, Gately ST, Quevedo ME, Soff GA, Paller S 1997 Human angiostatin inhibits murine hemangioendothelioma tumor growth in vivo. Cancer Res 57: 5277–5280
O'Reilly MS, Brem H, Folkman J 1995 Treatment of murine hemangioendotheliomas with the angiogenesis inhibitor AGM-1470. J Pediatr Surg 30: 325–330
Murray NA, Waits TL, Roberts IA 1998 Endogenous thrombopoietin levels and effect of recombinant human thrombopoietin on megakaryocyte precursors in term and preterm babies. Pediatr Res 43: 148–151
Acknowledgements
The authors thank Dr. Antonio Perez-Atayde, pathologist at Children's Hospital, for his interpretation of the immunohistochemical stainings.
Author information
Authors and Affiliations
Additional information
This study was supported by a grant to the Children's Hospital from Entremed (Rockville, MD). H.M.W.V. is the recipient of the Margot Mattheijssen-van der Voort fellowship and a grant from the Nijbakker Morra Society.
Rights and permissions
About this article
Cite this article
Verheul, H., Panigrahy, D., Flynn, E. et al. 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. Pediatr Res 46, 562 (1999). https://doi.org/10.1203/00006450-199911000-00012
Received:
Accepted:
Issue date:
DOI: https://doi.org/10.1203/00006450-199911000-00012
This article is cited by
-
Integrin β3/Akt signaling contributes to platelet-induced hemangioendothelioma growth
Scientific Reports (2017)
