Inflammation promotes progression of thrombi in intracranial thrombotic aneurysms


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.

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  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.

    CAS  Article  Google 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.

    Article  PubMed  PubMed Central  Google 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.

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Boyle JJ (2005) Macrophage activation in atherosclerosis: pathogenesis and pharmacology of plaque rupture. Curr Vasc Pharmacol 3:63–68

    CAS  Article  Google 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.

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Chyatte D, Bruno G, Desai S, Todor DR (1999) Inflammation and intracranial aneurysms. Neurosurgery 45:1137–1146 discussion 1146-1137

    CAS  Article  Google Scholar 

  7. 7.

    Crompton MR (1966) Mechanism of growth and rupture in cerebral berry aneurysms. Br Med J 1:1138–1142

    CAS  Article  Google 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.

    CAS  Article  PubMed  PubMed Central  Google 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.

    Article  PubMed  Google 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.

    Article  PubMed  Google 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.

    Article  PubMed  Google 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.

    Article  PubMed  Google 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.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Hashimoto T, Meng H, Young WL (2006) Intracranial aneurysms: links among inflammation, hemodynamics and vascular remodeling. Neurol Res 28:372–380.

    Article  PubMed  PubMed Central  Google 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.

    CAS  Article  PubMed  Google 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.

    CAS  Article  PubMed  Google 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.

    CAS  Article  PubMed  PubMed Central  Google 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.

    CAS  Article  PubMed  Google 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 30:1396–1401

    CAS  Article  Google 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 40:408–416

    CAS  PubMed  Google 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.

    Article  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Krings T, Piske RL, Lasjaunias PL (2005) Intracranial arterial aneurysm vasculopathies: targeting the outer vessel wall. Neuroradiology 47:931–937.

    Article  PubMed  Google 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 39:46–50

    CAS  Article  Google 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.

    Article  PubMed  Google 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.

    Article  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Mizutani T (1996) A fatal, chronically growing basilar artery: a new type of dissecting aneurysm. J Neurosurg 84:962–971.

    CAS  Article  PubMed  Google 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.

    CAS  Article  PubMed  Google 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.

    CAS  Article  PubMed  Google Scholar 

  29. 29.

    Moore KJ, Tabas I (2011) Macrophages in the pathogenesis of atherosclerosis. Cell 145:341–355.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Moreno PR, Purushothaman KR, Sirol M, Levy AP, Fuster V (2006) Neovascularization in human atherosclerosis. Circulation 113:2245–2252.

    Article  PubMed  Google Scholar 

  31. 31.

    Mosser DM (2003) The many faces of macrophage activation. J Leukoc Biol 73:209–212

    CAS  Article  Google 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 31:896–900

    CAS  Article  Google 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.

    Article  PubMed  Google 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.

    Article  PubMed  Google 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.

    Article  PubMed  Google 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.

    Article  PubMed  Google Scholar 

  37. 37.

    Soehnlein O (2012) Multiple roles for neutrophils in atherosclerosis. Circ Res 110:875–888.

    CAS  Article  PubMed  Google 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.

    Article  PubMed  Google Scholar 

  39. 39.

    Titlic M, Tonkic A, Jukic I, Kolic K, Dolic K (2008) Clinical manifestations of vertebrobasilar dolichoectasia. Bratisl Lek Listy 109:528–530

    CAS  PubMed  Google 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.

    Article  PubMed  Google 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.

    Article  PubMed  Google 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.

    CAS  Article  PubMed  Google 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) 38:860–864

    CAS  Article  Google 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.

    CAS  Article  PubMed  Google Scholar 

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Correspondence to Takeshi Mikami.

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Suzuki, H., Mikami, T., Tamada, T. et al. Inflammation promotes progression of thrombi in intracranial thrombotic aneurysms. Neurosurg Rev 43, 1565–1573 (2020).

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  • Thrombotic aneurysm
  • Inflammation
  • Cerebral aneurysm