Clonal Hematopoiesis in Venous Thromboembolism: An Emerging Risk Factor

Alessandro Pozzi¹, Giorgio Rosati¹, Isabella Russo¹, Cristina Barale¹, Marco De Gobbi¹, Alessandro Morotti^1*

¹Dept of Clinical and Biological Sciences, University of Turin, Orbassano, Italy

Abstract

Clonal hematopoiesis of indeterminate potential (CHIP) is defined by the presence of somatic mutations in genes associated with myeloid neoplasms at a variant allele fraction ≥2% in the absence of overt hematologic disease. While CHIP has been extensively linked to atherosclerotic cardiovascular disease, its role in venous thromboembolism (VTE) has only recently begun to emerge. Several observational studies suggest that CHIP may represent a novel risk factor for VTE, although the strength and consistency of this association remain less robust than for arterial disease. In particular, mutations in genes such as JAK2 and TET2 appear to confer a higher thrombotic risk, whereas the contribution of other CHIP-associated mutations remains less clear. Limited evidence also suggests a potential role of CHIP in the development of chronic thromboembolic complications, including chronic thromboembolic pulmonary hypertension. Data regarding VTE at unusual sites are scarce but may carry important clinical implications. Notably, a high prevalence of CHIP—particularly JAK2 and DNMT3A mutations—has been observed in patients with idiopathic splanchnic vein thrombosis, suggesting that specific CHIP-associated mutations may contribute to distinct thrombotic phenotypes. Mechanistically, CHIP-related thrombosis is thought to arise from chronic low-grade inflammation, immune dysregulation, endothelial injury, and enhanced platelet and neutrophil activation. However, the relative contribution of different mutations and clonal characteristics remains incompletely understood. In this commentary, we review current evidence regarding the epidemiology and pathogenesis of CHIP-associated VTE and discuss potential implications for risk stratification, monitoring, and future therapeutic strategies.

Introduction

Clonal Hematopoiesis of Indeterminate Potential (CHIP) is defined as the presence of an acquired somatic mutation of a gene associated with a myeloid neoplasm at a variant allele fraction (VAF) of ≥2%, in the absence of a hematological disorder defined by the World Health Organization (WHO)^1–4. CHIP is more frequently observed in elderly individuals, although its prevalence varies depending on the specific mutations involved⁵. Beyond its potential to progress to an overt myeloid neoplasm, this condition has been associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD), particularly in older individuals⁶. In this context, the mutations most strongly linked to ASCVD include JAK2, TET2, and ASXL1. Moreover, the presence of CHIP has demonstrated prognostic significance in patients with established coronary artery disease, ischemic stroke, or peripheral arterial disease⁷. More recently, CHIP has been associated with an increased risk of several other chronic diseases (like solid malignancies⁸, chronic obstructive pulmonary disease⁹, chronic kidney disease¹⁰, type 2 diabetes mellitus¹¹, liver disease¹², and obesity¹³) as well as of venous thromboembolism (VTE)¹⁴. However, evidence linking CHIP and VTE is weaker if compared to ASCVD and even less is known about its prognostic role in developing chronic complications. Among thrombotic manifestations, we recently observed a high prevalence of DNMT3A-mutated CHIP in patients with idiopathic splanchnic vein thrombosis (SVT)¹⁵. Notably, DNMT3A mutations are not typically associated with an increased risk of VTE. These findings may suggest that different CHIP-associated mutations could contribute to distinct clinical phenotypes. In this commentary, we review the current evidence on the epidemiology and potential pathogenetic mechanisms linking CHIP to VTE. We also discuss how further research in this field may influence the diagnostic and therapeutic management of patients with VTE, as well as strategies for primary thrombosis prevention.

Epidemiology of CHIP and VTE

CHIP is increasingly being recognized as a novel risk factor for VTE. However, data are less consistent compared to its role in ASCVD even though more and more evidence is adding up to the existing literature. In a single-center study from Guillotin et al. on 94 VTE patients CHIP was present in only 7 individuals showing no significant differences with the control group. The most commonly mutated genes were TET2 and DNMT3A. There was no difference between groups regarding the number of genes mutated or the type of mutation¹⁶. On the contrary, a larger study from Saadatagah on 3980 VTE patients showed a prevalence of CHIP of 24.7% over a median of a 7-year follow-up. In this cohort VTE was significantly more frequent among CHIP carriers (4.5 vs 3.2%) and TET2 was significantly associated with VTE risk (HR: 2.25; p: 0.006)¹⁷. Similarly, a community base cohort-study on more than 14,000 CHIP carriers demonstrated an increased risk of pulmonary embolism (PE) (HR: 1.17) among individuals with CHIP mainly noted for CHIP with TET2 (HR: 1.42) or JAK2 (HR: 4.17) mutation¹⁸. It is worth noting that CHIP has also been associated with an increased risk of developing chronic thromboembolic pulmonary hypertension (CTEPH), potentially highlighting its prognostic significance¹⁹. JAK-2 mutated CHIP emerged as a risk factor for both incident and prevalent VTE (OR: 6.58; HR: 4.2) also in a study on data from a UK Biobank including exome sequencing of more than 400,000 individuals. In this study CHIP was modestly associated with incident VTE with a hazard ratio (HR) of 1.17 and TET2-mutant CHIP was associated with incident VTE with a HR of 1.33²⁰. Lastly, a recent meta-analysis from Nasrollahizadeh et al. which included 4 studies revealed a borderline statistically significant association between CHIP and increased VTE risk [HR: 1.52 (95% CI: 1.00–2.30); p = 0.05]. Statistical significance was not reached between various CHIP mutations regarding risk of VTE and between the presence of CHIP and the risk of PE alone. However, TET2 mutations showed the highest risk of VTE²¹. It should be noted that these association studies were not designed to evaluate specific subsets of thrombotic manifestations, such as provoked versus unprovoked events or age-related differences. Moreover, information on thrombus extension, severity of PE, and recurrence of thrombotic events is largely absent from these analyses. More detailed and stratified investigations will therefore be necessary to better clarify the contribution of CHIP to the pathogenesis and clinical course of classical VTE. The association between CHIP and VTE has been evaluated in oncological patients as well. No significant difference was noted between CHIP carriers and controls in terms of VTE prevalence and prognosis, but even in this case no stratifications on tumor histology, stage and therapies are reported²². Interestingly, when cohorts of patients with similar clinical characteristics are analyzed, the presence of CHIP is associated with an increased risk of VTE. This association was observed in a cohort of 557 survivors of autologous transplantation for lymphoma, particularly in patients harboring PPM1D (HR 4.12) or TP53 (HR 5.31) mutations²³. This observation again highlights the need for well-defined and homogeneous patient cohorts to accurately assess the contribution of CHIP to VTE.

With respect to VTE occurring at unusual sites, only a limited number of studies have been published, although their findings may carry important clinical implications. In particular, we previously demonstrated a high prevalence (46%) of CHIP in patients with idiopathic SVTs. The majority of the mutations involved JAK-2 and DNMT3A¹⁵. Interestingly, while the JAK2-V617F mutation is known to drive a prothrombotic phenotype, DNMT3A mutations may further increase the risk of thrombosis in patients with MPN. These data suggest that JAK2-V617F– and DNMT3A-driven CHIP may define a phenotype similar to that observed in thrombotic MPN, even in the absence of an overt MPN disease.

Pathogenesis of CHIP-related thrombosis

CHIP arises from stochastic acquisition of somatic mutations in hematopoietic stem cells followed by clonal expansion because of selective pressure within the hematopoietic niches²⁴. CHIP is more common in older age as a result of lifelong accumulation of spontaneous mutations; in addition, this process is further enhanced by exposure to acquired stressors like radiations, smoke, chemotherapy and chronic inflammation which is, on the other hand, promoted by CHIP itself. The most commonly mutated genes involve epigenetic regulators (DNMT3A, TET2, and ASXL1), DNA damage repair mechanisms (PPM1D and TP53), tyrosine kinases (JAK2) and mRNA spliceosome components (SF3B1, SRSF2, U2AF1)¹⁴.

The precise mechanisms leading to thromboembolism are not well defined yet but are likely and vastly linked to low-grade chronic inflammation and inflammation leading to augmented expression of pro-inflammatory mediators, activation of platelets and complement cascade, release of neutrophil extracellular traps (NETs) and endothelial injury^25,26. Moreover, differences in allele burden, clonal architecture, type of mutation and gene involved, may contribute in specific ways to the pathogenesis of atherothrombosis^14,27. In this regard, DNMT3A mutant monocytes have been shown to promote an inflammatory state through the expression of pro-inflammatory cytokines (IL-1B, IL-6, and NLRP3 inflammasome) and the induction of T cell via CD58 while TET2 function deficiency in macrophages enhances secretion of IL-1B. In an elegant model based on single-cell analysis, DNMT3A-mutant monocytes were shown to acquire a procoagulant phenotype, providing a mechanistic link between the presence of small aberrant hematopoietic clones and the activation of pathogenic thrombotic pathways²⁸. As for JAK-2, it is linked to enhanced intravascular thrombosis via augmented formation of NETs¹⁴. JAK-2, DNMT3A, ASXL1 and TET2 mutated CHIP are also responsible for platelet hyperactivity and hyperproduction²⁷. As for SVTs, if we exclude cirrhosis, their etiopathology is more strongly associated with an inflammatory trigger (solid cancers, myeloproliferative neoplasms, paroxysmal nocturnal hemoglobinuria, inflammatory bowel diseases, abdominal surgery and infections) if compared with DVT, in which blood flow stasis and thrombophilia are major players²⁹. Therefore, it could be speculated that this is one of the reasons why SVTs are strongly associated with MPNs and, as observed in our study, with CHIP; partially explaining the differences in etiologies and risk factors among different sites of VTE. Although the core pathogenesis of CHIP-related thrombosis seems to lie in chronic inflammation (which on one hand is promoted by CHIP and on the other hand contributes to the expansion of the mutant clone) the relevance of each mechanism in different clinical contexts (e.g. DVT, PE, Unusual sites thrombosis, ASCVD) is not fully elucidated; therefore, a deeper understanding of its pathophysiology is needed to specifically address the diagnostic and prognostic significance of each CHIP marker in several clinical scenarios.

Discussion

Given its relatively recent recognition in the context of VTE, the clinical relevance of CHIP remains to be fully defined, and specific recommendations in current clinical guidelines are lacking. A deeper understanding of the underlying pathogenic mechanisms and the inclusion of wide cohort of patients, together with the clinical significance of individual CHIP-associated mutations across different clinical settings, may help to more accurately stratify the risk of first and recurrent thrombotic events.

Owing to the limited size of available patient cohorts, it remains difficult to delineate the pathogenic contribution of CHIP mutations to VTE, including thrombosis at unusual sites, or to determine whether specific mutations preferentially associate with SVT rather than classical VTE.

Nevertheless, two complementary considerations may be proposed. First, at the mechanistic level, although DNMT3A- and TET2-mutated cells share the ability to promote a pro-inflammatory state—particularly through IL-1β signaling—emerging evidence suggests that their downstream effects may not be entirely overlapping. DNMT3A-mutant monocytes appear to exhibit a broader pro-inflammatory and procoagulant phenotype, including increased expression of IL-6, activation of the NLRP3 inflammasome, and enhanced interactions with T cells. In contrast, TET2 deficiency has been more specifically linked to augmented IL-1β production in macrophages. These observations support the notion that CHIP-associated mutations operate within a shared inflammatory framework while retaining partially distinct functional profiles that could differentially contribute to thrombus formation across vascular territories.

Second, from a clonal evolution perspective, CHIP may exert differential effects depending on the temporal hierarchy of mutation acquisition, as suggested in the context of myeloproliferative neoplasms³⁰. In this regard, in our cohort of patients with SVT, DNMT3A mutations were identified in 3 out of 15 cases, including one patient harboring a concomitant JAK2-V617F mutation. Although limited, this observation highlights the need to explore whether clonal architecture and mutation order may influence the emergence of prothrombotic phenotypes, potentially modulating the clinical presentation of CHIP-associated thrombosis.

Beyond mechanistic investigations, the study of CHIP in patients with thrombosis may have important clinical implications, particularly in clarifying its potential contribution to the development of chronic complications such as CTEPH, clinically significant portal hypertension, and post-thrombotic syndrome. Ultimately, these insights could influence clinical practice, including decisions regarding the duration of anticoagulant therapy and the potential role of long-term or primary antithrombotic prophylaxis. To this end, prospective studies in larger and well-characterized patient cohorts—including individuals with thrombosis at unusual sites, such as SVT—are warranted.

Furthermore, due to the centrality of inflammation in the genesis of CHIP, several therapeutic approaches have been attempted in order to reduce CHIP-related thrombotic manifestations. Anti-inflammatory drugs like Canakinumab (IL-1B antagonist), colchicine and Tocilizumab (IL-6 antagonist) have shown to reduce the incidence of cardiovascular events and the activation of the inflammatory cascade in the presence of CHIP in both mouse models (as for Tocilizumab, Canakinumab and colchicine) and clinical trials (Canakinumab)^14,27,31. These medications could in future have a role for selected patients; however, they are not recommended in the management of CHIP in actual clinical practice. On the other hand, lifestyle seems to have a significant impact on the consequences of CHIP; probably due to its effect in reducing chronic low-grade inflammation^32,33. It is worth noting that this data is mainly referred to ASCVD and quality data on VTE are still lacking.

Lastly, it is important to emphasize that the identification of CHIP in patients with SVT and in general VTE may warrant careful longitudinal monitoring as well. Indeed, certain CHIP-associated mutations—particularly those involving genes implicated in myeloproliferative neoplasms—may represent an early clonal event with the potential to evolve into overt hematologic malignancies over time (Figure 2). In this context, the detection of CHIP, and in particular JAK2 mutated ones, in patients presenting with SVT could identify a subgroup at increased risk of progression toward myeloproliferative neoplasms (MPN). Therefore, periodic clinical and hematologic surveillance may be advisable in these patients to enable early recognition of clonal expansion or the emergence of overt MPN. In conclusion, CHIP is a promising field of research in order to better understand and treat the different manifestations of VTE. Larger prospective studies are needed to evaluate the role of different markers and their impact on the different sites of thrombosis in MPN. The role of CHIP in developing chronic complications of VTE could also be an area of clinical interest. We believe that, in the future, a greater understanding of CHIP could lead to significant changes in clinical practice for patients with thrombosis.

Figure 1: Normal versus CHIP-driven hematopoiesis.(A) A schematic representation of normal hematopoiesis is shown, with the hematopoietic stem cell (HSC) at the center, giving rise to terminally differentiated blood cells. (B) Acquisition of mutations in an HSC leads to the expansion of a clonal population. (C) The mutated HSC generates terminally differentiated cells that carry mutated proteins derived from the altered genes.

Figure 2: Consequences of CHIP This figure illustrates the potential consequences of CHIP. On one hand, CHIP may progress to hematologic malignancies (A). On the other hand, CHIP can be associated with systemic manifestations, including thrombosis (B).

Acknowledgment

We thank all the members of internal medicine – hematology of the San Luigi Hospital for help and support. Figures were created with BioRender.com.

Author Contribution

A.P. and A.M. conceptualized and wrote the manuscript. G.R, I.R, C.B and M.DG reviewed the manuscript.

Declaration of Competing Interest

Authors have no conflict of interest.

References

1. 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.
2. 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.
3. Khoury JD, Solary E, Abla O, et al. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms. Leukemia. 2022;36(7):1703–1719.
4. Weeks LD, Ebert BL. Causes and consequences of clonal hematopoiesis. Blood. 2023;142(26):2235–2246.
5. Dhuri K, Alachkar H. Differences in the mutational landscape of clonal hematopoiesis of indeterminate potential among races and between male and female patients with cancer. Exp Hematol. 2024;138:104271.
6. 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.
7. Todorovski A, Wang T-F, Carrier M, Xu Y. CHIP away at the marrow-clot connection: inflammation, clonal hematopoiesis, and thromboembolic disease. Blood Adv. 2025;9(2):343–353.
8. Pich O, Bernard E, Zagorulya M, et al. Tumor-Infiltrating Clonal Hematopoiesis. N Engl J Med. 2025;392(16):1594–1608.
9. Miller PG, Qiao D, Rojas-Quintero J, et al. Association of clonal hematopoiesis with chronic obstructive pulmonary disease. Blood. 2022;139(3):357–368.
10. Larsen MK, Skov V, Kjaer L, et al. Clonal haematopoiesis of indeterminate potential and impaired kidney function—A Danish general population study with 11 years follow-up. Eur J Haematol. 2022;109(5):576–585.
11. Tobias DK, Manning AK, Wessel J, et al. Clonal Hematopoiesis of Indeterminate Potential (CHIP) and Incident Type 2 Diabetes Risk. Diabetes Care. 2023;46(11):1978–1985.
12. Wong WJ, Emdin C, Bick AG, et al. Clonal haematopoiesis and risk of chronic liver disease. Nature. 2023;616(7958):747–754.
13. Komic L, Kumric M, Urlic H, et al. Obesity and Clonal Hematopoiesis of Indeterminate Potential: Allies in Cardiovascular Diseases and Malignancies. Life (Basel). 2023;13(6):1365.
14. Singh I, Singh A. Clonal Hematopoiesis of Indeterminate Potential: Current Understanding and Future Directions. Curr Oncol Rep. 2023;25(6):539–547.
15. Carrà G, Giugliano E, Camerlo S, et al. Clonal hematopoiesis by DNMT3A mutations as a common finding in idiopathic splanchnic vein thrombosis. Haematologica. 2023;108(5):1447–1449.
16. Guillotin F, Mercier É, Fortier M, et al. Clonal haematopoiesis of indeterminate potential in patients with venous thromboembolism. J Thromb Thrombolysis. 2023;56(2):351–354.
17. Saadatagah S, Kim RB, Sukumar S, et al. Clonal hematopoiesis of indeterminate potential and incidence of venous thromboembolism in older adults. J Thromb Haemost. 2025;23(7):2235–2241.
18. Liu Q, Smedby KE, Xue H, et al. Clonal hematopoiesis of indeterminate potential and the risk of pulmonary embolism: an observational study. EClinicalMedicine. 2024;74:102753.
19. Momoi M, Katsumata Y, Kunimoto H, et al. Clonal Hematopoiesis in Chronic Thromboembolic Pulmonary Hypertension. J Am Heart Assoc. 2024;13(23):e035498.
20. Zon RL, Sekar A, Clapham K, et al. JAK2-mutant clonal hematopoiesis is associated with venous thromboembolism. Blood. 2024;144(20):2149–2154.
21. Nasrollahizadeh A, Moradi M, Javankiani S, et al. Association Between Clonal Hematopoiesis of Indeterminate Potential and Risk of Venous Thromboembolism: A Systematic Review and Meta-Analysis. Eur J Haematol. 2025;115(5):436–442.
22. Englisch C, Jäger R, Gassner J, et al. Clonal hematopoiesis in patients with cancer and its association with risk of thrombosis and prognosis of disease. Res Pract Thromb Haemost. 2025;9(4):102882.
23. Gangaraju R, Chen Y, Hageman L, et al. Clonal hematopoiesis and subsequent venous thromboembolism among survivors of autologous transplantation for lymphoma. J Natl Cancer Inst. 2025;117(11):2394–2398.
24. Arends CM, Galan-Sousa J, Hoyer K, et al. Hematopoietic lineage distribution and evolutionary dynamics of clonal hematopoiesis. Leukemia. 2018;32(9):1908–1919.
25. Liu W, Pircher J, Schuermans A, et al. Jak2 V617F clonal hematopoiesis promotes arterial thrombosis via platelet activation and cross talk. Blood. 2024;143(15):1539–1550.
26. Mooney L, Goodyear CS, Chandra T, et al. Clonal haematopoiesis of indeterminate potential: intersections between inflammation, vascular disease and heart failure. Clin Sci (Lond). 2021;135(7):991–1007.
27. Byun JH, Jung J, Woo J. Clonal hematopoiesis and thromboembolic diseases: a review. J Thromb Haemost. 2025;23(9):2697–2709.
28. Abplanalp WT, Schuhmacher B, Cremer S, et al. Cell-intrinsic effects of clonal hematopoiesis in heart failure. Nat Cardiovasc Res. 2023;2(9):819–834.
29. Camerlo S, Ligato J, Rosati G, et al. Shedding Light on the Pathogenesis of Splanchnic Vein Thrombosis. Int J Mol Sci. 2023;24(3):2262.
30. Ortmann CA, Kent DG, Nangalia J, et al. Effect of Mutation Order on Myeloproliferative Neoplasms. N Engl J Med. 2015;372(7):601–612.
31. 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.
32. Bhattacharya R, Zekavat SM, Uddin MM, et al. Association of Diet Quality With Prevalence of Clonal Hematopoiesis and Adverse Cardiovascular Events. JAMA Cardiol. 2021;6(9):1069–1077.
33. Haring B, Reiner AP, Liu J, et al. Healthy Lifestyle and Clonal Hematopoiesis of Indeterminate Potential: Results From the Women’s Health Initiative. J Am Heart Assoc. 2021;10(5):e018789.