Biological Approaches to the Aggressive CVM Lesion (Antiangiogenic Therapy)

  • Patricia E. Burrows


While drug treatment has been used to treat infantile hemangiomas for decades, targeted treatment for vascular malformations is relatively new, based largely on better understanding of the molecular regulatory pathways that control angiogenesis (Blatt et al., Pharmacol Ther 139(3):327–333, 2013; Margolin et al., Semin Plast Surg 28(2):79–86, 2014). In a small number of cases, drugs that inhibit various aspects of angiogenesis have been used for arteriovenous malformation (AVM). Mammalian target of rapamycin (MTOR) inhibitors are used in patients with severely symptomatic venous and lymphatic malformations as well as patients with symptomatic hamartomas in phosphatase and tensin homolog (PTEN) tumor hamartoma syndrome (Iacobas et al., Pediatr Blood Cancer 57(2):321–323, 2011).


  1. 1.
    Blatt J, McLean TW, Castellino SM, Burkhart CN. A review of contemporary options for medical management of hemangiomas, other vascular tumors, and vascular malformations. Pharmacol Ther. 2013;139(3):327–33.CrossRefPubMedGoogle Scholar
  2. 2.
    Margolin JF, Soni HM, Pimpalwar S. Medical therapy for pediatric vascular anomalies. Semin Plast Surg. 2014;28(2):79–86.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Iacobas I, Burrows PE, Adams DM, Sutton VR, Hollier LH, Chintagumpala MM. Oral rapamycin in the treatment of patients with hamartoma syndromes and PTEN mutation. Pediatr Blood Cancer. 2011;57(2):321–3.CrossRefPubMedGoogle Scholar
  4. 4.
    Murphy PA, Kim TN, Lu G, Bollen AW, Schaffer CB, Wang RA. Notch4 normalization reduces blood vessel size in arteriovenous malformations. Sci Transl Med. 2012;4(117):117ra8.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Tual-Chalot S, Oh SP, Arthur HM. Mouse models of hereditary hemorrhagic telangiectasia: recent advances and future challenges. Front Genet. 2015;6:25.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Walcott BP. BMP signaling modulation attenuates cerebral arteriovenous malformation formation in a vertebrate model. J Cereb Blood Flow Metab. 2014;34(10):1688–94.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Mouchtouris N, Jabbour PM, Starke RM, Hasan DM, Zanaty M, Theofanis T, et al. Biology of cerebral arteriovenous malformations with a focus on inflammation. J Cereb Blood Flow Metab. 2015;35(2):167–75.CrossRefPubMedGoogle Scholar
  8. 8.
    Rangel-Castilla L, Russin JJ, Martinez-Del-Campo E, Soriano-Baron H, Spetzler RF, Nakaji P. Molecular and cellular biology of cerebral arteriovenous malformations: a review of current concepts and future trends in treatment. Neurosurg Focus. 2014;37(3):E1.CrossRefPubMedGoogle Scholar
  9. 9.
    Kulungowski AM, Hassanein AH, Nose V, Fishman SJ, Mulliken JB, Upton J, et al. Expression of androgen, estrogen, progesterone, and growth hormone receptors in vascular malformations. Plast Reconstr Surg. 2012;129(6):919e–24e.CrossRefGoogle Scholar
  10. 10.
    Maclellan RA, Vivero MP, Purcell P, Kozakewich HP, DiVasta AD, Mulliken JB, et al. Expression of follicle-stimulating hormone receptor in vascular anomalies. Plast Reconstr Surg. 2014;133(3):344e–51e.CrossRefGoogle Scholar
  11. 11.
    Lu L, Bischoff J, Mulliken JB, Bielenberg DR, Fishman SJ, Greene AK. Increased endothelial progenitor cells and vasculogenic factors in higher-staged arteriovenous malformations. Plast Reconstr Surg. 2011;128(4):260e–9e.CrossRefGoogle Scholar
  12. 12.
    Dupuis-Girod S, Ginon I, Saurin JC, Marion D, Guillot E, Decullier E, et al. Bevacizumab in patients with hereditary hemorrhagic telangiectasia and severe hepatic vascular malformations and high cardiac output. Jama. 2012;307(9):948–55.CrossRefPubMedGoogle Scholar
  13. 13.
    Kanellopoulou T, Alexopoulou A. Bevacizumab in the treatment of hereditary hemorrhagic telangiectasia. Expert Opin Biol Ther. 2013;13(9):1315–23.CrossRefPubMedGoogle Scholar
  14. 14.
    Lupu A, Stefanescu C, Treton X, Attar A, Corcos O, Bouhnik Y. Bevacizumab as rescue treatment for severe recurrent gastrointestinal bleeding in hereditary hemorrhagic telangiectasia. J Clin Gastroenterol. 2013;47(3):256–7.CrossRefPubMedGoogle Scholar
  15. 15.
    Young LH, Henderson KJ, White RI, Garcia-Tsao G. Bevacizumab: finding its niche in the treatment of heart failure secondary to liver vascular malformations in hereditary hemorrhagic telangiectasia. Hepatology. 2013;58(1):442–5.CrossRefPubMedGoogle Scholar
  16. 16.
    Azzopardi N, Dupuis-Girod S, Ternant D, Fargeton AE, Ginon I, Faure F, et al. Dose – response relationship of bevacizumab in hereditary hemorrhagic telangiectasia. MAbs. 2015;7(3):630–7.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Lebrin F, Srun S, Raymond K, Martin S, van den Brink S, Freitas C, et al. Thalidomide stimulates vessel maturation and reduces epistaxis in individuals with hereditary hemorrhagic telangiectasia. Nat Med. 2010;16(4):420–8.CrossRefPubMedGoogle Scholar
  18. 18.
    Frenzel T, Lee CZ, Kim H, Quinnine NJ, Hashimoto T, Lawton MT, et al. Feasibility of minocycline and doxycycline use as potential vasculostatic therapy for brain vascular malformations: pilot study of adverse events and tolerance. Cerebrovasc Dis. 2008;25(1-2):157–63.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Burrows PE, Mulliken JB, Fishman SJ, Klement GL, Folkman J. Pharmacological treatment of a diffuse arteriovenous malformation of the upper extremity in a child. J Craniofac Surg. 2009;20(Suppl 1):597–602.CrossRefPubMedGoogle Scholar
  20. 20.
    Hammill AM, Wentzel M, Gupta A, Nelson S, Lucky A, Elluru R, et al. Sirolimus for the treatment of complicated vascular anomalies in children. Pediatr Blood Cancer. 2011;57(6):1018–24.CrossRefPubMedGoogle Scholar
  21. 21.
    Lackner H, Karastaneva A, Schwinger W, Benesch M, Sovinz P, Seidel M, et al. Sirolimus for the treatment of children with various complicated vascular anomalies. Eur J Pediatr. 2015;174(12):1579–84.CrossRefPubMedGoogle Scholar
  22. 22.
    Trenor 3rd CC. Sirolimus for refractory vascular anomalies. Pediatr Blood Cancer. 2011;57(6):904–5.CrossRefPubMedGoogle Scholar
  23. 23.
    Boscolo E, Limaye N, Huang L, Kang KT, Soblet J, Uebelhoer M, et al. Rapamycin improves TIE2-mutated venous malformation in murine model and human subjects. J Clin Invest. 2015;125(9):3491–504.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Brown C, Subramanian V, Wilcox CM, Peter S. Somatostatin analogues in the treatment of recurrent bleeding from gastrointestinal vascular malformations: an overview and systematic review of prospective observational studies. Dig Dis Sci. 2010;55(8):2129–34.CrossRefPubMedGoogle Scholar

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© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  1. 1.Medical College of Wisconsin, Children’s Hospital of WisconsinMilwaukeeUSA

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