Inflammation promotes progression of thrombi in intracranial thrombotic aneurysms

  • Hime Suzuki
  • Takeshi MikamiEmail author
  • Tomoaki Tamada
  • Ryo Ukai
  • Yukinori Akiyama
  • Akinori Yamamura
  • Kiyohiro Houkin
  • Nobuhiro Mikuni
Original Article


Advances in the understanding of the pathogenesis of arteriosclerosis, abdominal aorta aneurysms and dissections, and carotid artery plaques have focused on chronic inflammation. In this study, we report that inflammatory changes of thrombi contribute to the enlargement and growth of giant intracranial thrombotic aneurysms. Surgical and postmortem samples were collected from 12 cases of large or giant intracranial thrombotic aneurysms diagnosed via pathological investigations. Degeneration of the aneurysmal wall and the infiltration of inflammatory cells in the thrombi were assessed. The number of blood cells and immunohistochemical stain-positive cells was enumerated, and the inflammation and neovascularization in the thrombi were assessed. In all cases, the appearance of inflammatory cells (CD68+ cells, CD206+ cells, lymphocytes, and neutrophils) was apparent in the thrombi. The number of CD34+ cells was moderately correlated with the number of CD68+ cells, and CD34+ cells significantly and strongly correlated with the number of CD206+ cells. Based on the number of neutrophils per CD68+ cells, we classified the cases into 2 groups: a macrophage inflammation-dominant group and a neutrophilic inflammation-dominant group. The neutrophilic inflammation-dominant group had significantly more cases with previous treatments and neurological symptoms due to mass effect than the macrophage inflammation-dominant group. Chronic inflammation due to macrophages in thrombi is a fundamental mechanism in the enlargement of an intracranial thrombotic aneurysm, and neutrophilic inflammation can accelerate this process. Microvascularization in thrombi is linked to inflammation and might promote thickening of the intima and repeated intimal microbleeds.


Thrombotic aneurysm Inflammation Cerebral aneurysm 


Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest..

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee (The ethics committee of Sapporo Medical University Hospital) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Patient consent was obtained with an opt-out policy using a website as this study was a retrospective case series. Therefore, formal consent was not required.


  1. 1.
    Ammirati E, Moroni F, Norata GD, Magnoni M, Camici PG (2015) Markers of inflammation associated with plaque progression and instability in patients with carotid atherosclerosis. Mediat Inflamm 2015:718329–718315. CrossRefGoogle Scholar
  2. 2.
    Back M, Yurdagul A Jr, Tabas I, Oorni K, Kovanen PT (2019) Inflammation and its resolution in atherosclerosis: mediators and therapeutic opportunities. Nat Rev Cardiol 16:389–406. CrossRefPubMedGoogle Scholar
  3. 3.
    Batra R, Suh MK, Carson JS, Dale MA, Meisinger TM, Fitzgerald M, Opperman PJ, Luo J, Pipinos II, Xiong W, Baxter BT (2018) IL-1beta (Interleukin-1beta) and TNF-alpha (tumor necrosis factor-alpha) impact abdominal aortic aneurysm formation by differential effects on macrophage polarization. Arterioscler Thromb Vasc Biol 38:457–463. CrossRefPubMedGoogle Scholar
  4. 4.
    Boyle JJ (2005) Macrophage activation in atherosclerosis: pathogenesis and pharmacology of plaque rupture. Curr Vasc Pharmacol 3:63–68CrossRefGoogle Scholar
  5. 5.
    Chan WL, Pejnovic N, Liew TV, Hamilton H (2005) Predominance of Th2 response in human abdominal aortic aneurysm: mistaken identity for IL-4-producing NK and NKT cells? Cell Immunol 233:109–114. CrossRefPubMedGoogle Scholar
  6. 6.
    Chyatte D, Bruno G, Desai S, Todor DR (1999) Inflammation and intracranial aneurysms. Neurosurgery 45:1137–1146 discussion 1146-1137CrossRefGoogle Scholar
  7. 7.
    Crompton MR (1966) Mechanism of growth and rupture in cerebral berry aneurysms. Br Med J 1:1138–1142CrossRefGoogle Scholar
  8. 8.
    Dale MA, Xiong W, Carson JS, Suh MK, Karpisek AD, Meisinger TM, Casale GP, Baxter BT (2016) Elastin-derived peptides promote abdominal aortic aneurysm formation by modulating M1/M2 macrophage polarization. J Immunol 196:4536–4543. CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    dos Santos ML, Spotti AR, dos Santos RM, Borges MA, Ferrari AF, Colli BO, Tognola WA (2013) Giant intracranial aneurysms: morphology and clinical presentation. Neurosurg Rev 36:117–122; discussion 122. CrossRefPubMedGoogle Scholar
  10. 10.
    Frosen J, Piippo A, Paetau A, Kangasniemi M, Niemela M, Hernesniemi J, Jaaskelainen J (2004) Remodeling of saccular cerebral artery aneurysm wall is associated with rupture: histological analysis of 24 unruptured and 42 ruptured cases. Stroke 35:2287–2293. CrossRefPubMedGoogle Scholar
  11. 11.
    Frosen J, Piippo A, Paetau A, Kangasniemi M, Niemela M, Hernesniemi J, Jaaskelainen J (2006) Growth factor receptor expression and remodeling of saccular cerebral artery aneurysm walls: implications for biological therapy preventing rupture. Neurosurgery 58:534–541; discussion 534-541. CrossRefPubMedGoogle Scholar
  12. 12.
    Frosen J, Tulamo R, Paetau A, Laaksamo E, Korja M, Laakso A, Niemela M, Hernesniemi J (2012) Saccular intracranial aneurysm: pathology and mechanisms. Acta Neuropathol 123:773–786. CrossRefPubMedGoogle Scholar
  13. 13.
    Golledge AL, Walker P, Norman PE, Golledge J (2009) A systematic review of studies examining inflammation associated cytokines in human abdominal aortic aneurysm samples. Dis Markers 26:181–188. CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Hashimoto T, Meng H, Young WL (2006) Intracranial aneurysms: links among inflammation, hemodynamics and vascular remodeling. Neurol Res 28:372–380. CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Houard X, Ollivier V, Louedec L, Michel JB, Back M (2009) Differential inflammatory activity across human abdominal aortic aneurysms reveals neutrophil-derived leukotriene B4 as a major chemotactic factor released from the intraluminal thrombus. FASEB J 23:1376–1383. CrossRefPubMedGoogle Scholar
  16. 16.
    Hu JH, Du L, Chu T, Otsuka G, Dronadula N, Jaffe M, Gill SE, Parks WC, Dichek DA (2010) Overexpression of urokinase by plaque macrophages causes histological features of plaque rupture and increases vascular matrix metalloproteinase activity in aged apolipoprotein e-null mice. Circulation 121:1637–1644. CrossRefPubMedGoogle Scholar
  17. 17.
    Jetten N, Verbruggen S, Gijbels MJ, Post MJ, De Winther MP, Donners MM (2014) Anti-inflammatory M2, but not pro-inflammatory M1 macrophages promote angiogenesis in vivo. Angiogenesis 17:109–118. CrossRefPubMedGoogle Scholar
  18. 18.
    Kaneko H, Anzai T, Takahashi T, Kohno T, Shimoda M, Sasaki A, Shimizu H, Nagai T, Maekawa Y, Yoshimura K, Aoki H, Yoshikawa T, Okada Y, Yozu R, Ogawa S, Fukuda K (2011) Role of vascular endothelial growth factor-A in development of abdominal aortic aneurysm. Cardiovasc Res 91:358–367. CrossRefPubMedGoogle Scholar
  19. 19.
    Kataoka K, Taneda M, Asai T, Kinoshita A, Ito M, Kuroda R (1999) Structural fragility and inflammatory response of ruptured cerebral aneurysms. A comparative study between ruptured and unruptured cerebral aneurysms. Stroke 30:1396–1401CrossRefGoogle Scholar
  20. 20.
    Kita Y, Nakamura K, Itoh H (1990) Histologic and histometric study of the aortic media in dissecting aneurysm. Comparison with true aneurysm and age-matched controls. Acta Pathol Jpn 40:408–416PubMedGoogle Scholar
  21. 21.
    Krings T, Lasjaunias PL, Geibprasert S, Pereira V, Hans FJ (2008) The aneurysmal wall. The key to a subclassification of intracranial arterial aneurysm vasculopathies. Interv Neuroradiol 14(Suppl 1):39–47. CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Krings T, Piske RL, Lasjaunias PL (2005) Intracranial arterial aneurysm vasculopathies: targeting the outer vessel wall. Neuroradiology 47:931–937. CrossRefPubMedGoogle Scholar
  23. 23.
    Kuwahara F, Kai H, Tokuda K, Shibata R, Kusaba K, Tahara N, Niiyama H, Nagata T, Imaizumi T (2002) Hypoxia-inducible factor-1alpha/vascular endothelial growth factor pathway for adventitial vasa vasorum formation in hypertensive rat aorta. Hypertension 39:46–50CrossRefGoogle Scholar
  24. 24.
    Lukasiewicz A, Reszec J, Kowalewski R, Chyczewski L, Lebkowska U (2012) Assessment of inflammatory infiltration and angiogenesis in the thrombus and the wall of abdominal aortic aneurysms on the basis of histological parameters and computed tomography angiography study. Folia Histochem Cytobiol 50:547–553. CrossRefPubMedGoogle Scholar
  25. 25.
    Miyamoto M, Nakayama N, Hokari M, Kuroda S, Takikawa S, Houkin K (2014) Pathological considerations for unruptured dissecting aneurysm in the posterior inferior cerebellar artery: case report. NMC Case Rep J 1:9–11. CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Mizutani T (1996) A fatal, chronically growing basilar artery: a new type of dissecting aneurysm. J Neurosurg 84:962–971. CrossRefPubMedGoogle Scholar
  27. 27.
    Mizutani T, Goldberg HI, Parr J, Harper C, Thompson CJ (1982) Cerebral dissecting aneurysm and intimal fibroelastic thickening of cerebral arteries. Case report. J Neurosurg 56:571–576. CrossRefPubMedGoogle Scholar
  28. 28.
    Mizutani T, Miki Y, Kojima H, Suzuki H (1999) Proposed classification of nonatherosclerotic cerebral fusiform and dissecting aneurysms. Neurosurgery 45:253–259. CrossRefPubMedGoogle Scholar
  29. 29.
    Moore KJ, Tabas I (2011) Macrophages in the pathogenesis of atherosclerosis. Cell 145:341–355. CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Moreno PR, Purushothaman KR, Sirol M, Levy AP, Fuster V (2006) Neovascularization in human atherosclerosis. Circulation 113:2245–2252. CrossRefPubMedGoogle Scholar
  31. 31.
    Mosser DM (2003) The many faces of macrophage activation. J Leukoc Biol 73:209–212CrossRefGoogle Scholar
  32. 32.
    Nakatomi H, Segawa H, Kurata A, Shiokawa Y, Nagata K, Kamiyama H, Ueki K, Kirino T (2000) Clinicopathological study of intracranial fusiform and dolichoectatic aneurysms: insight on the mechanism of growth. Stroke 31:896–900CrossRefGoogle Scholar
  33. 33.
    Nurminen V, Lehecka M, Chakrabarty A, Kivisaari R, Lehto H, Niemela M, Hernesniemi J (2014) Anatomy and morphology of giant aneurysms--angiographic study of 125 consecutive cases. Acta Neurochir 156:1–10. CrossRefPubMedGoogle Scholar
  34. 34.
    Roccatagliata L, Guedin P, Condette-Auliac S, Gaillard S, Colas F, Boulin A, Wang A, Guieu S, Rodesch G (2010) Partially thrombosed intracranial aneurysms: symptoms, evolution, and therapeutic management. Acta Neurochir 152:2133–2142. CrossRefPubMedGoogle Scholar
  35. 35.
    Signorelli F, Pailler-Mattei C, Gory B, Larquet P, Robinson P, Vargiolu R, Zahouani H, Labeyrie PE, Guyotat J, Pelissou-Guyotat I, Berthiller J, Turjman F (2018) Biomechanical characterization of intracranial aneurysm wall: a multiscale study. World Neurosurg 119:e882–e889. CrossRefPubMedGoogle Scholar
  36. 36.
    Signorelli F, Sela S, Gesualdo L, Chevrel S, Tollet F, Pailler-Mattei C, Tacconi L, Turjman F, Vacca A, Schul DB (2018) Hemodynamic stress, inflammation, and intracranial aneurysm development and rupture: a systematic review. World Neurosurg 115:234–244. CrossRefPubMedGoogle Scholar
  37. 37.
    Soehnlein O (2012) Multiple roles for neutrophils in atherosclerosis. Circ Res 110:875–888. CrossRefPubMedGoogle Scholar
  38. 38.
    Suzuki H, Mikami T, Komatsu K, Noshiro S, Miyata K, Hirano T, Wanibuchi M, Mikuni N (2017) Assessment of the cortical artery using computed tomography angiography for bypass surgery in moyamoya disease. Neurosurg Rev 40:299–307. CrossRefPubMedGoogle Scholar
  39. 39.
    Titlic M, Tonkic A, Jukic I, Kolic K, Dolic K (2008) Clinical manifestations of vertebrobasilar dolichoectasia. Bratisl Lek Listy 109:528–530PubMedGoogle Scholar
  40. 40.
    Tulamo R, Frosen J, Hernesniemi J, Niemela M (2010) Inflammatory changes in the aneurysm wall: a review. J Neurointerv Surg 2:120–130. CrossRefPubMedGoogle Scholar
  41. 41.
    Tulamo R, Frosen J, Junnikkala S, Paetau A, Pitkaniemi J, Kangasniemi M, Niemela M, Jaaskelainen J, Jokitalo E, Karatas A, Hernesniemi J, Meri S (2006) Complement activation associates with saccular cerebral artery aneurysm wall degeneration and rupture. Neurosurgery 59:1069–1076; discussion 1076-1067. CrossRefPubMedGoogle Scholar
  42. 42.
    Virmani R, Kolodgie FD, Burke AP, Finn AV, Gold HK, Tulenko TN, Wrenn SP, Narula J (2005) Atherosclerotic plaque progression and vulnerability to rupture: angiogenesis as a source of intraplaque hemorrhage. Arterioscler Thromb Vasc Biol 25:2054–2061. CrossRefPubMedGoogle Scholar
  43. 43.
    Yasui T, Sakamoto H, Kishi H, Komiyama M, Iwai Y, Yamanaka K, Nishikawa M, Nakajima H, Kobayashi Y, Inoue T (1998) Rupture mechanism of a thrombosed slow-growing giant aneurysm of the vertebral artery--case report. Neurol Med Chir (Tokyo) 38:860–864CrossRefGoogle Scholar
  44. 44.
    Zhao L, Moos MP, Grabner R, Pedrono F, Fan J, Kaiser B, John N, Schmidt S, Spanbroek R, Lotzer K, Huang L, Cui J, Rader DJ, Evans JF, Habenicht AJ, Funk CD (2004) The 5-lipoxygenase pathway promotes pathogenesis of hyperlipidemia-dependent aortic aneurysm. Nat Med 10:966–973. CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of NeurosurgerySapporo Medical UniversitySapporoJapan
  2. 2.Department of Neurosurgery, Graduate School of MedicineHokkaido UniversitySapporoJapan

Personalised recommendations