Clonal hematopoiesis of indeterminate potential is a possible and not yet known cause of stroke

Authors: M. Haršány 1,2;  B. Kalousová 3,4;  R. Slavkovský 3,4;  V. Kunešová 1;  J. Drábek 3,4;  J. Stránská 3,4,5;  M. Hajdúch 3,4;  R. Mikulík 1,2
Authors‘ workplace: Meziná rodní centrum klinické ho, vý zkumu, FN u sv. Anny v Brně 1;  I. neurologická klinika, LF MU a FN u sv. Anny v Brně 2;  Ústav molekulární a translační medicíny, LF UP, Olomouc 3;  Laboratoř experimentální medicíny, FN Olomouc 4;  Neurologická klinika FN Olomouc 5
Published in: Cesk Slov Neurol N 2023; 86(4): 239-243
Category: Review Article


Clonal hematopoiesis of indeterminate potential (CHIP) occurs during human aging through the progressive accumulation of somatic and potentially preleukemic mutations in hematopoietic stem cells. These mutations occur in genes that, among other things, play an important role in the regulation of inflammation. The risk of hematological malignancy in carriers of CHIP mutations is relatively low. However, these patients have a 40% risk of all-cause mortality due to a higher incidence of myocardial infarction and stroke. Although there is recent evidence of a relationship between CHIP, inflammation and cardiovascular diseases, the relationship between CHIP and stroke has not yet been fully elucidated. The aim of this review is to highlight a timely and potentially clinically relevant issue that is undoubtedly a starting point for further research.


stroke – clonal hematopoiesis of indeterminate potential – CHIP


1. Haršány M, Kunešová V, Kalousová B et al. Klonální hematopoéza neurčitého potenciálu při ischemické cévní mozkové příhodě – studijní protokol. Cesk Slov Neurol N 2022; 85 (6): 496–500. doi: 10.48095/cccsnn2022496

2. Libby P, Sidlow R, Lin AE et al. Clonal hematopoiesis: crossroads of aging, cardiovascular disease, and cancer: JACC review topic of the week. J Am Coll Cardiol 2019; 74 (4): 567–577. doi: 10.1016/j.jacc.2019.06.007.

3. Khot UN, Khot MB, Bajzer CT et al. Prevalence of conventional risk factors in patients with coronary heart disease. JAMA 2003; 290 (7): 898–904. doi: 10.1001/ jama.290.7.898.

4. Kolominsky-Rabas PL, Weber M, Gefeller O et al. Epidemiology of ischemic stroke subtypes according to TOAST criteria: incidence, recurrence, and long-term survival in ischemic stroke subtypes: a population-based study. Stroke 2001; 32 (12): 2735–2740. doi: 10.1161/hs1201.100209.

5. Sacco RL, Adams R, Albers G et al. Guidelines for prevention of stroke in patients with ischemic stroke or transient ischemic attack: a statement for healthcare professionals from the American Heart Association/American Stroke Association Council on Stroke: co-sponsored by the Council on Cardiovascular Radiology and Intervention: the American Academy of Neurology affirms the value of this guideline. Stroke 2006; 37 (2): 577–617. doi: 10.1161/01.STR.0000199147.30016.74.

6. Howard DPJ, Gaziano L, Rothwell PM. Risk of stroke in relation to degree of asymptomatic carotid stenosis: a population-based cohort study, systematic review, and meta-analysis. Lancet Neurol 2021; 20 (3): 193–202. doi: 10.1016/S1474-4422 (20) 30484-1.

7. Jaiswal S, Libby P. Clonal haematopoiesis: connecting ageing and inflammation in cardiovascular disease. Nat Rev Cardiol 2020; 17 (3): 137–144. doi: 10.1038/s41569-019-0247-5.

8. Jaiswal S, Fontanillas P, Flannick J et al. Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med 2014; 371 (26): 2488–2498. doi: 10.1056/NEJMoa1408617.

9. Jaiswal S, Natarajan P, Silver AJ et al. Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease. N Engl J Med 2017; 377 (2): 111–121. doi: 10.1056/NEJMoa1701719.

10. Fuster JJ, MacLauchlan S, Zuriaga MA et al. Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice. Science 2017; 355 (6327): 842–847. doi: 10.1126/science.aag1381.

11. Ridker PM, Everett BM, Thuren T et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 2017; 377 (12): 1119–1131. doi: 10.1056/NEJMoa1707914.

12. Svensson EC, Madar A, Campbell CD et al. TET2-driven clonal hematopoiesis and response to canakinumab: an exploratory analysis of the CANTOS randomized clinical trial. JAMA Cardiol 2022; 7 (5): 521–528. doi: 10.1001/jamacardio.2022.0386.

13. Leoni C, Montagner S, Rinaldi A et al. Dnmt3a restrains mast cell inflammatory responses. Proc Natl Acad Sci U S A 2017; 114 (8): E1490–e1499. doi: 10.1073/pnas.1616420114.

14. Sano S, Oshima K, Wang Y et al. CRISPR-mediated gene editing to assess the roles of Tet2 and Dnmt3a in clonal hematopoiesis and cardiovascular disease. Circ Res 2018; 123 (3): 335–341. doi: 10.1161/CIRCRESAHA.118.313225.

15. Wang W, Liu W, Fidler T et al. Macrophage inflammation, erythrophagocytosis, and accelerated atherosclerosis in Jak2 (V617F) mice. Circ Res 2018; 123 (11): e35–e47. doi: 10.1161/CIRCRESAHA.118.313283.

16. Liu DJ, Peloso GM, Yu H et al. Exome-wide association study of plasma lipids in >300,000 individuals. Nat Genet 2017; 49 (12): 1758–1766. doi: 10.1038/ng.3977.

17. Arends CM, Galan-Sousa J, Hoyer K et al. Hematopoietic lineage distribution and evolutionary dynamics of clonal hematopoiesis. Leukemia 2018; 32 (9): 1908–1919. doi: 10.1038/s41375-018-0047-7.

18. Genovese G, Kähler AK, Handsaker RE et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N Engl J Med 2014; 371 (26): 2477–2487. doi: 10.1056/NEJMoa1409405.

19. Zink F, Stacey SN, Norddahl GL et al. Clonal hematopoiesis, with and without candidate driver mutations, is common in the elderly. Blood 2017; 130 (6): 742–752. doi: 10.1182/blood-2017-02-769869.

20. van Vlijmen BJ, Gerritsen G, Franken AL et al. Macrophage p53 deficiency leads to enhanced atherosclerosis in APOE*3-Leiden transgenic mice. Circ Res 2001; 88 (8): 780–786. doi: 10.1161/hh0801.089261.

21. Merched AJ, Williams E, Chan L. Macrophage-specific p53 expression plays a crucial role in atherosclerosis development and plaque remodeling. Arterioscler Thromb Vasc Biol 2003; 23 (9): 1608–1614. doi: 10.1161/01.ATV.0000084825.88022.53.

22. Bhattacharya R, Zekavat SM, Haessler J et al. Clonal hematopoiesis is associated with higher risk of stroke. Stroke 2022; 53 (3): 788–797. doi: 10.1161/STROKEAHA.121.037388.

23. Mayerhofer E, Strecker C, Becker H et al. Prevalence and therapeutic implications of clonal hematopoiesis of indeterminate potential in young patients with stroke. Stroke 2023; 54 (4): 938–946. doi: 10.1161/STROKEAHA.122.041416.

24. Shuaib A, Hachinski VC. Mechanisms and management of stroke in the elderly. CMAJ 1991; 145 (5): 433–443.

25. Sierra C, Coca A, Schiffrin EL. Vascular mechanisms in the pathogenesis of stroke. Curr Hypertens Rep 2011; 13 (3): 200–207. doi: 10.1007/s11906-011-0195-x.

26. Charidimou A, Pantoni L, Love S. The concept of sporadic cerebral small vessel disease: a road map on key definitions and current concepts. Int J Stroke 2016; 11 (1): 6–18. doi: 10.1177/1747493015607485.

27. Yang SJ, Shao GF, Chen JL et al. The NLRP3 inflammasome: an important driver of neuroinflammation in hemorrhagic stroke. Cell Mol Neurobio­l 2018; 38 (3): 595–603. doi: 10.1007/s10571-017-0526-9.

28. Mehndiratta P, Manjila S, Ostergard T et al. Cerebral amyloid angiopathy-associated intracerebral hemorrhage: pathology and management. Neurosurg Focus 2012; 32 (4): E7. doi: 10.3171/2012.1.FOCUS11370.

29. Frösen J, Piippo A, Paetau A et al. Remodeling of saccular cerebral artery aneurysm wall is associated with rupture: histological analysis of 24 unruptured and 42 ruptured cases. Stroke 2004; 35 (10): 2287–2293. doi: 10.1161/01.STR.0000140636.30204.da.

30. Ishibashi R, Aoki T, Nishimura M et al. Contribution of mast cells to cerebral aneurysm formation. Curr Neurovasc Res 2010; 7 (2): 113–124. doi: 10.2174/156720210791184 916.

31. Jayaraman T, Berenstein V, Li X et al. Tumor necrosis factor alpha is a key modulator of inflammation in cerebral aneurysms. Neurosurgery 2005; 57 (3): 558–564. doi: 10.1227/01.neu.0000170439.89041.d6.

32. Starke RM, Raper DMS, Ding D et al. Tumor necrosis factor-a modulates cerebral aneurysm formation and rupture. Transl Stroke Res 2014; 5 (2): 269–277. doi: 10.1007/s12975-013-0287-9.

33. Wang J, Wei L, Lu H et al. Roles of inflammation in the natural history of intracranial saccular aneurysms. J Neurol Sci 2021; 424: 117294. doi: 10.1016/j.jns.2020.117294.

34. Young AM, Karri SK, You W et al. Specific TNF-alpha inhibition in cerebral aneurysm formation and subarachnoid hemorrhage. Curr Drug Saf 2012; 7 (3): 190–196. doi: 10.2174/157488612803251315.

35. Carrillo-Jimenez A, Deniz Ö, Niklison-Chirou MV et al. TET2 regulates the neuroinflammatory response in microglia. Cell Rep 2019; 29 (3): 697–713.e8. doi: 10.1016/j.celrep.2019.09.013.

36. Natarajan P, Jaiswal S, Kathiresan S. Clonal hematopoiesis: somatic mutations in blood cells and atherosclerosis. Circ Genom Precis Med 2018; 11 (7): e001926. doi: 10.1161/CIRCGEN.118.001926.

37. Bick AG, Pirruccello JP, Griffin GK et al. Genetic interleukin 6 signaling deficiency attenuates cardiovascular risk in clonal hematopoiesis. Circulation 2020; 141 (2): 124–131. doi: 10.1161/CIRCULATIONAHA.119.044362.

38. Khetarpal SA, Qamar A, Bick AG et al. Clonal hematopoiesis of indeterminate potential reshapes age-related CVD: JACC review topic of the week. J Am Coll Cardiol 2019; 74 (4): 578–586. doi: 10.1016/j.jacc.2019.05.045.

Paediatric neurology Neurosurgery Neurology
Forgotten password

Enter the email address that you registered with. We will send you instructions on how to set a new password.


Don‘t have an account?  Create new account