Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Case report study of thalidomide therapy in 18 patients with severe arteriovenous malformations

Nature Cardiovascular Research volume 1, pages 562–567 (2022)Cite this article

Subjects

Abstract

Arteriovenous malformations (AVMs) are fast-flow lesions that may be destructive and are the most difficult-to-treat vascular anomalies. Embolization followed by surgical resection is commonly used; however, complete resection is rarely possible and partial resection often leads to dramatic worsening. Accumulating data implicate abnormal angiogenic activity in the development of AVMs. Thalidomide has been reported as an inhibitor of vascular proliferation. Here, we report a prospective experimental observational study testing the effects of the angiogenesis inhibitor thalidomide on 18 patients with a severely symptomatic AVM that is refractory to conventional therapies. All patients experienced a rapid reduction in pain, cessation of bleeding, and ulcer healing. Cardiac failure resolved in all three affected patients. Reduced vascularity on arteriography was observed in two patients. One AVM appeared to be cured after 19 months of thalidomide and an 8-year follow-up. Eight AVMs were stable after a mean thalidomide cessation of 58 months, and four lesions recurred after 11.5 months. Combined treatment with embolization permitted dose reduction in five patients with clinical improvement. Grade 3 side effects were dose dependent, including asthenia (n = 2) and erythroderma (n = 2). The results suggest that thalidomide is efficacious in the management of chronic pain, bleeding and ulceration of extensive AVMs that are refractory to conventional therapy. Further clinical study is needed to confirm the safety and efficacy of thalidomide treatment in AVM.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Clinical aspects of AVMs.
Fig. 2: Patient 5 with AVM of the right upper eyelid.
Fig. 3: Patient 12 with AVM of the hand.

Similar content being viewed by others

Data availability

All data generated and analyzed during this study are included in this published article.

References

  1. Liu, A. S., Mulliken, J. B., Zurakowski, D., Fishman, S. J. & Greene, A. K. Extracranial arteriovenous malformations: natural progression and recurrence after treatment. Plast. Reconstr. Surg. 125, 1185–1194 (2010).

    Article  CAS  Google Scholar 

  2. Boon, L. M. & Vikkula, M. in Harper’s Textbook of Pediatric Dermatology 4th edn (eds Irvine, A. D., Hoeger, P. H. & Yan, A. C.) Ch. 118 (Wiley-Blackwell, 2019).

  3. Young, E. J. & Fishman S. J. in Mulliken and Young’s Vascular Anomalies: Hemangiomas and Malformations 2nd edn (eds Mulliken, J. B., Burrows, P. E. & Fishman, S. J.) Ch. 15 (Oxford University Press, 2013).

  4. Boon, L. M. & Vikkula M. in Mulliken and Young’s Vascular Anomalies: Hemangiomas and Malformations 2nd edn (eds Mulliken, J. B., Burrows, P. E. & Fishman, S. J.) Ch. 9 (Oxford University Press, 2013).

  5. Revencu, N. et al. RASA1 mosaic mutations in patients with capillary malformation-arteriovenous malformation. J. Med. Genet. 57, 48–52 (2020).

    Article  CAS  Google Scholar 

  6. Amyere, M. et al. Germline loss-of-function mutations in EPHB4 cause a second form of capillary malformation-arteriovenous malformation (CM-AVM2) deregulating RAS-MAPK signaling. Circulation 136, 1037–1048 (2017).

    Article  CAS  Google Scholar 

  7. Shovlin, C. L., Hughes, J. M. B., Scott, J., Seidman, C. E. & Seidman, J. G. Characterization of endoglin and identification of novel mutations in hereditary hemorrhagic telangiectasia. Am. J. Hum. Genet. 61, 68–79 (1997).

    Article  CAS  Google Scholar 

  8. Shovlin, C. L. Hereditary haemorrhagic telangiectasia: pathophysiology, diagnosis and treatment. Blood Rev. 24, 203–219 (2010).

    Article  CAS  Google Scholar 

  9. Marsh, D. J. et al. Germline PTEN mutations in Cowden syndrome-like families. J. Med. Genet. 35, 881–885 (1998).

    Article  CAS  Google Scholar 

  10. Marsh, D. J. et al. PTEN mutation spectrum and genotype-phenotype correlations in Bannayan-Riley-Ruvalcaba syndrome suggest a single entity with Cowden syndrome. Hum. Mol. Genet. 8, 1461–1472 (1999).

    Article  CAS  Google Scholar 

  11. Kohout, M. P., Hansen, M., Pribaz, J. J. & Mulliken, J. B. Arteriovenous malformations of the head and neck: natural history and management. Plast. Reconstr. Surg. 102, 643–654 (1998).

    Article  CAS  Google Scholar 

  12. Soulez, G., Gilbert, P., Giroux, M.-F., Racicot, J.-N. & Dubois, J. Interventional management of arteriovenous malformations. Tech. Vasc. Interv. Radiol. 22, 100633 (2019).

    Article  Google Scholar 

  13. Koshima, I. et al. Free perforator flap for the treatment of defects after resection of huge arteriovenous malformations in the head and neck regions. Ann. Plast. Surg. 51, 194–199 (2003).

    Article  Google Scholar 

  14. Wong, M. et al. Soft tissue reconstruction and facial reanimation with bilateral latissimus dorsi flaps after extensive resection of head and neck arteriovenous malformation: a case report. Ann. Plast. Surg. 83, 73–77 (2019).

    Article  CAS  Google Scholar 

  15. Lee, B. B. et al. Consensus Document of the International Union of Angiology (IUA)-2013. Current concept on the management of arterio-venous management. Int. Angiol. 32, 9–36 (2013).

    CAS  PubMed  Google Scholar 

  16. Hammer, F. D., Boon, L. M., Mathurin, P. & Vanwijck, R. R. Ethanol sclerotherapy of venous malformations: evaluation of systemic ethanol contamination. J. Vasc. Interv. Radiol. 12, 595–600 (2001).

    Article  CAS  Google Scholar 

  17. Burrows, P. E., Mulliken, J. B., Fishman, S. J., Klement, G. L. & Folkman, J. Pharmacological treatment of a diffuse arteriovenous malformation of the upper extremity in a child. J. Craniofac. Surg. 20, 597–602 (2009).

    Article  Google Scholar 

  18. McBride, W. G. Thalidomide embryopathy. Teratology 16, 79–82 (1977).

    Article  CAS  Google Scholar 

  19. D’Amato, R. J., Loughnan, M. S., Flynn, E. & Folkman, J. Thalidomide is an inhibitor of angiogenesis. Proc. Natl Acad. Sci. USA 91, 4082–4085 (1994).

    Article  Google Scholar 

  20. Lebrin, F. et al. Thalidomide stimulates vessel maturation and reduces epistaxis in individuals with hereditary hemorrhagic telangiectasia. Nat. Med. 16, 420–428 (2010).

    Article  CAS  Google Scholar 

  21. Buscarini, E. et al. Safety of thalidomide and bevacizumab in patients with hereditary hemorrhagic telangiectasia. Orphanet J. Rare Dis. 14, 28 (2019).

    Article  Google Scholar 

  22. Zhu, W. et al. Thalidomide reduces hemorrhage of brain arteriovenous malformations in a mouse model. Stroke 49, 1232–1240 (2018).

    Article  CAS  Google Scholar 

  23. Fink, E. C. & Ebert, B. L. The novel mechanism of lenalidomide activity. Blood 126, 2366–2369 (2015).

    Article  CAS  Google Scholar 

  24. Burrows, P. E. Endovascular treatment of slow-flow vascular malformations. Tech. Vasc. Interv. Radiol. 16, 12–21 (2013).

    Article  Google Scholar 

  25. Mulliken J. B. in Mulliken and Young’s Vascular Anomalies: Hemangiomas and Malformations 2nd edn (eds Mulliken, J. B., Burrows, P. E. & Fishman, S. J.) Ch. 23 (Oxford University Press, 2013).

  26. Park, K. B. et al. Predictive factors for response of peripheral arteriovenous malformations to embolization therapy: analysis of clinical data and imaging findings. J. Vasc. Interv. Radiol. 23, 1478–1486 (2012).

    Article  Google Scholar 

  27. Pugh, C. W. & Ratcliffe, P. J. Regulation of angiogenesis by hypoxia: role of the HIF system. Nat. Med. 9, 677–684 (2003).

    Article  CAS  Google Scholar 

  28. Carmeliet, P. & Jain, R. K. Angiogenesis in cancer and other diseases. Nature 407, 249–257 (2000).

    Article  CAS  Google Scholar 

  29. Lu, L. et al. Increased endothelial progenitor cells and vasculogenic factors in higher-staged arteriovenous malformations. Plast. Reconstr. Surg. 128, 260e–269e (2011).

    Article  CAS  Google Scholar 

  30. Komorowski, J. et al. Effect of thalidomide affecting VEGF secretion, cell migration, adhesion and capillary tube formation of human endothelial EA.hy 926 cells. Life Sci. 78, 2558–2563 (2006).

    Article  CAS  Google Scholar 

  31. Grinspan, D. Significant response of oral aphthosis to thalidomide treatment. J. Am. Acad. Dermatol. 12, 85–90 (1985).

    Article  CAS  Google Scholar 

  32. Ghobrial, I. M. & Rajkumar, S. V. Management of thalidomide toxicity. J. Support. Oncol. 1, 194–205 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Couto, J. A. et al. Somatic MAP2K1 mutations are associated with extracranial arteriovenous malformation. Am. J. Hum. Genet. 100, 546–554 (2017).

    Article  CAS  Google Scholar 

  34. Nikolaev, S. I., Fish, J. E. & Radovanovic, I. Somatic activating KRAS mutations in arteriovenous malformations of the brain. N. Engl. J. Med. 378, 1561–1562 (2018).

    Article  Google Scholar 

  35. Van Damme, A., Seront, E., Dekeuleneer, V., Boon, L. M. & Vikkula, M. New and emerging targeted therapies for vascular malformations. Am. J. Clin. Dermatol. 21, 657–668 (2020).

    Article  Google Scholar 

  36. Seront, E., Van Damme, A., Boon, L. M. & Vikkula, M. Rapamycin and treatment of venous malformations. Curr. Opin. Hematol. 26, 185–192 (2019).

    Article  CAS  Google Scholar 

  37. Gabeff, R. et al. Efficacy and tolerance of sirolimus (rapamycin) for extracranial arteriovenous malformations in children and adults. Acta Derm. Venereol. 99, 1105–1109 (2019).

    CAS  PubMed  Google Scholar 

  38. Lekwuttikarn, R., Lim, Y. H., Admani, S., Choate, K. A. & Teng, J. M. C. Genotype-guided medical treatment of an arteriovenous malformation in a child. JAMA Dermatol. 155, 256–257 (2019).

    Article  Google Scholar 

  39. Edwards, E. A. Monitoring arteriovenous malformation response to genotype-targeted therapy. Pediatrics 146, e20193206 (2020).

    Article  Google Scholar 

  40. Wu, J. J., Huang, D. B., Pang, K. R., Hsu, S. & Tyring, S. K. Thalidomide: dermatological indications, mechanisms of action and side-effects. Br. J. Dermatol. 153, 254–273 (2005).

    Article  CAS  Google Scholar 

  41. Lokhorst, M. M. et al. Development of a condition-specific patient-reported outcome measure for measuring symptoms and appearance in vascular malformations: the OVAMA questionnaire. Br. J. Dermatol. 185, 797–803 (2021).

    Article  CAS  Google Scholar 

  42. Gagne, J. J., Thompson, L., O’Keefe, K. & Kesselheim, A. S. Innovative research methods for studying treatments for rare diseases: methodological review. BMJ 349, g6802 (2014).

    Article  Google Scholar 

Download references

Acknowledgements

All authors but one (A.D.) are members of the VASCA Working Group of VASCERN, project no. 769036. We are grateful to all of the patients for their invaluable participation. This work is part of the thesis project of J.C., who was supported by a Fond de la Recherche Clinique (FRC) des Cliniques universitaires Saint-Luc. These studies were financially supported by Fonds de la Recherche Scientifique (FNRS) grants T.0247.19 (to M.V.) and P.C013.20 (to L.M.B.), and the Fund Generet managed by the King Baudouin Foundation (grant 2018-J1810250-211305) (to M.V.). The authors are grateful to J.B. Mulliken, P.E. Burrows and J. Dubois for their expert review of and suggestions for the manuscript; the nurse coordinator, O. Debue, for his excellent assistance in patient follow-up; and L. Niculescu and L. Huybrechts for their skilled secretarial help.

Author information

Author notes

  1. Deceased: Anne Jeanjean.

Authors and Affiliations

  1. Division of Plastic Surgery, Center for Vascular Anomalies, Cliniques universitaires Saint-Luc, UCLouvain, VASCERN VASCA European Reference Centre, Brussels, Belgium

    Laurence M. Boon, Valérie Dekeuleneer, Julien Coulie, Anne-Christine Bataille & Miikka Vikkula

  2. Human Molecular Genetics, de Duve Institute, UCLouvain, Brussels, Belgium

    Laurence M. Boon & Miikka Vikkula

  3. Division of Dermatology, Center for Vascular Anomalies, Cliniques universitaires Saint-Luc, UCLouvain, VASCERN VASCA European Reference Centre, Brussels, Belgium

    Liliane Marot & Anne-Christine Bataille

  4. Division of Vascular and Interventional Radiology, Center for Vascular Anomalies, Cliniques universitaires Saint-Luc, UCLouvain, VASCERN VASCA European Reference Centre, Brussels, Belgium

    Frank Hammer

  5. Division of Pediatric Radiology, Center for Vascular Anomalies, Cliniques universitaires Saint-Luc, UCLouvain, VASCERN VASCA European Reference Centre, Brussels, Belgium

    Philippe Clapuyt

  6. Department of Neurology, Center for Vascular Anomalies, Cliniques universitaires Saint-Luc, UCLouvain, VASCERN VASCA European Reference Centre, Brussels, Belgium

    Anne Jeanjean

  7. Department of Dermatology, Université de Caen Basse Normandie, CHU Caen, Caen, France

    Anne Dompmartin

Authors
  1. Laurence M. Boon
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Valérie Dekeuleneer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Julien Coulie
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Liliane Marot
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Anne-Christine Bataille
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Frank Hammer
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Philippe Clapuyt
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Anne Jeanjean
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Anne Dompmartin
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Miikka Vikkula
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

L.M.B. and M.V. conceived and designed the study; L.M.B., J.C., V.D., L.M., A.-C.B. and A.J. followed the patients; F.H. and P.C. analyzed the radiological data; and A.D. L.M.B., J.C., V.D., L.M. and A.-C.B. analyzed the data. All authors contributed to writing the paper and reviewed the final manuscript.

Corresponding author

Correspondence to Laurence M. Boon.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Cardiovascular Research thanks Joyce M. C. Teng and the other, anonymous, reviewers for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Extended Data Table 1 Characteristics of patients before and after high-dose thalidomide medication
Full size table
Extended Data Table 2 Characteristics of patients before and after low-dose thalidomide medication
Full size table

Extended Data Fig. 1

Patient #1 with dramatic progressive aggravation of her AVM due to several partial surgical resection and embolization. (a) stage I AVM involving her upper lip at the age of 20. (b) stage IV AVM at the age of 50 now involving her entire central face and causing labial and palatal ulceration. (c) arteriography showing the extensiveness of her AVM. (D) 1 month after thalidomide initiation (d,e) showing cessation of mucosal bleeding of the lip, cessation of drooling and complete healing of her palate.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Boon, L.M., Dekeuleneer, V., Coulie, J. et al. Case report study of thalidomide therapy in 18 patients with severe arteriovenous malformations. Nat Cardiovasc Res 1, 562–567 (2022). https://doi.org/10.1038/s44161-022-00080-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s44161-022-00080-2

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research